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アレサガテープ に関する資料...アレサガテープ 4mg アレサガテープ 8mg...
Transcript of アレサガテープ に関する資料...アレサガテープ 4mg アレサガテープ 8mg...
アレサガテープ 4mg アレサガテープ 8mg
に関する資料
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帰属するものであり、当該情報を本薬剤の適正使用以外の営利目的に利用す
ることはできません。
久光製薬株式会社
4mg8mg
1.5 ................................................................................................ 5 1.5.1 ..................................................................................................................... 5 1.5.2 ..................................................................................................................................... 5
1.5.2.1 .................................................................................................................................. 8 1.5.2.2 .................................................................................................................. 8 1.5.2.3 .................................................................................................................. 8 1.5.2.4 .................................................................................................................... 10
1.5.3 ........................................................................................................................... 14 1.5.3.1 ............................................................................................................................ 14 1.5.3.2 .................................................................... 14
1.5.4 ....................................................................................................................................... 15
- 2 -
HP-3060
1cm2 0.5mg 0.5mg/cm2
1 8cm2 4mg
1 16cm2 8mg
[14C]HP-306014C 1cm2 0.5mg
0.5mg/cm2
AUC0-24 0 24 -
AUC0-t 0 t -
AUC0- 0 -
CHO chinese hamster ovary
Cmax
CYP cytochrome P450 P450
FAS full analysis set
HepG2 human hepatocellular carcinoma cells
hERGhuman ether-a-go-go related gene
IC50 50% inhibitory concentration 50%
JRQLQJapan Rhinoconjunctivitis Quality of Life Questionnaire
QOL
LOCF last observation carried forward
QOL quality of life
t1/2 log - z
TK toxicokinetics
tmax
- 3 -
01HP-3060-JP-01
02HP-3060-JP-02
03HP-3060-JP-03
04
HP-3060-JP-04
05HP-3060-JP-05
- 4 -
benzimidazole
1) 1981
1993 1996
1997 2, 3)
2
2
24)
(1) (2)
(3) 1 1 24)
2 65%
66% 14%5) 2
1 1
24
1 1
HP-3060
1.5-1
- 5 -
-6-
1.5-1
20
-7-
1.5-1
HP-3060
1 1 1
15 6 3
0603001 9
5 28 422
36
H1 H2 H3
HP-3060
HP-3060
24
HP-3060
hERG CHO hERG IC50
0.24μmol/L HP-3060
144mg/body 15.93mg/kg
in vitro
HP-3060
HP-3060 Cmax
AUC0-24
- 8 -
[14C]HP-3060
7
CYP CYP
HepG2 in vitro CYP1A2 2E1
3A4 CYP
in vitro
[14C]HP-3060
In vitro
HP-3060 4
13 39
20xx x 20xx x
20xx x
20xx x
- 9 -
4
TK
TK
4
HP-3060
HP-3060 03
8mg 14 Cmax 8.4 12
AUC0-24 7.1 10
4
13 39
12 HP-3060 1.5 3
6 12 24mg 24
2mg HP-3060
HP-3060 1.5 24mg Cmax AUC0-t AUC0-
HP-3060 tmax 16 26hr t1/2 11.7 13.8hr
tmax 4hr t1/2 7.62hr
HP-3060
HP-3060 1.5 24mg 24
20 HP-3060 8mg 5 5
24
- 10 -
HP-3060 8mg Cmax AUC0-t AUC0-
HP-3060 8mg tmax
16 28hr t1/2 12.0 15.8hr HP-3060
HP-3060 8mg
24
96 24 × 4 HP-3060
4 8 12mg 1 1 14 2
HP-3060 Cmax AUC0-24 4 12mg
2 LOCF HP-3060 8mg
HP-3060 4mg 12mg
2 LOCF
1 HP-3060
HP-3060
1 1 14 2
2
HP-3060 8mg
20xx x
- 11 -
04 05
1276 04 HP-3060 4 8mg
2
HP-3060
HP-3060 5mg
FAS 1273 383 HP-3060 4mg 384 8mg 380
126 FAS
2 LOCF HP-3060 4mg 8mg
HP-3060
HP-3060
FAS 2 LOCF
HP-3060
1
HP-3060
HP-3060
- 12 -
HP-3060 4mg
8mg 1
HP-3060
1275 384 HP-3060 4mg 384 8mg 381
126 15.4%
59/384 HP-3060 4mg 13.8% 53/384 8mg 18.1% 69/381
13.5% 17/126
10.9% 42/384 HP-3060 4mg 11.2% 43/384 8mg 14.2% 54/381
11.9% 15/126
0.5% 2/384 HP-3060 4mg 3.4% 13/384 8mg 4.7% 18/381
1.6% 2/126 0
0.5%
7.0% 27/384
HP-3060 4mg 5.2% 20/384 8mg 6.3% 24/381 4.8% 6/126
HP-3060
HP-3060 4mg 75.0% 8mg
83.3% 2
247 HP-3060 4 8mg 12 52
HP-3060
247 HP-3060 4mg 124 8mg 123
HP-3060 4mg 60.5% 75/124 8mg 61.0% 75/123
HP-3060 4mg 26.6% 33/124 8mg 23.6%
29/123
HP-3060
4mg 6.5% 8/124 8mg 10.6% 13/123 HP-3060 8mg
2%
HP-3060 4mg 20.2% 25/124
8mg 17.9% 22/123
HP-3060 4mg 72.0% 8mg 81.7% 1
- 13 -
HP-3060 52
FAS 247 HP-3060 4mg 124 8mg 123
1
52 52 HP-3060 4mg -2.65 8mg -2.39
52 / HP-3060 4mg -2.59 8mg -2.47
6 QOL JRQLQ
2 4 12
1 16, 7)
PTP
(1)
QOL
04
HP-3060 4mg 8mg
5mg
HP-3060
05
HP-3060 4mg 8mg
04 05
05 QOL JRQLQ
- 14 -
HP-3060 QOL
(2)
24
01 02
03 24
05
04
HP-3060 4mg 8mg
HP-3060 8mg 2 LOCF
1
1
HP-3060 HP-3060
HP-3060 4mg 8mg
1
24
4mg
8mg
1 4mg
24 1 8mg
1) . ® ®
.
- 15 -
1997; 40: 231-45.
2) MSD : 1mg, 2mg .
8 , 2013.
3) : 1mg, 2mg .
5 , 2013.
4) . 5 .
2016 8 . : ; 2015. p. 36-82.
5) , . 2
. Progress in Medicine 2008; 28:
2285-96.
6) : 1mg, 2mg . 5 , 2013.
7) : 10mg, 10mg . 15 ,
2015.
- 16 -
4mg8mg
2017 9
- 2 -
4mg8mg
-2-
1.7-1
4mg 8mg 1mg 2mg
1993 4 2
2003 3 26
1 8cm2 16 cm2 4mg8mg
1 1mg 2mg
1 4mg24
1 8mg
1 1 2mg 1 2
-3-
1.7-1
1.
2.(1)
(2) 4mg 8mg
(3)
(4)
(5)
3.
1.
2.(1)
(2) 4mg/ 2mg/
(3)
(4)
3.
-4-
1.7-1
4.1,060 201 19.0%
116 10.9%48 4.5% 21 2.0% 52
4.9%
5% 0.1% 5%
ALT GPT ASTGOT
LDH -GTP
4.14,168 1,040 7.34%
6.30% 0.61%0.23% 0.14% 0.13% 0.11%
0.10% ALT GPT0.21% AST GOT 0.16% LDH 0.13% -GTP0.10%
5% 10% 0.1% 5% 0.1%
-5-
1.7-1
5.
6.(1)
5% 10% 0.1% 5% 0.1%
AST GOTALT GPT
LDH-GTP
Al-P
5.1 1mg
6.(1)
-6-
1.7-1
(2)
7.
8.
9.
(1)(2)
(3)
(1)
(2)(3) 1
(2)
7.
8.
9.(1)(2) PTP PTP
PTP
-7-
1.7-1
2013 8 5
-8-
1.7-2
5mg0.05%
10mg10mg
1%
5mg 2010 10 270.05% 2014 1 17
10mg 2002 7 510mg 2004 2 27
1% 2007 10 19
2018 10 26 2014 3 242015 9 17
1 5mg1mL 0.5mg
1 10mg1g 10mg
-9-
1.7-2
1 5mg 1 11
10mg
7 15 1 2.5mg1 2
1 10mL 5mg 1 1
1 20mL 10mg
6 1 1 2.5mL1.25mg 1 1
1 7 1 2.5mL1.25mg 1 2
7 15 1 5mL2.5mg 1 2
1 10mg 1 1
7 1 10mg 1 1
1 10mg 1g 11
3 7 1 5mg0.5g 7 1
10mg 1g 1 1
-10-
1.7-2
10mL/min
mL/min80 50 79 30 49 10 29
5mg1 1
2.5mg1 1
2.5mg2 1
2.5mg 23 4 1
® 10mg
(1)
(2) 10mL/min
1.(1)
(2)(3)
(4)
1.(1)
(2) descarboethoxyloratadineDCL
(3)
-11-
1.7-2
2.(1)
(2)
(3)
3.
1)
1)
1)
16%
1)
1)
40%
-11%
1)
2.(1)
(2)
3.DCL CYP3A4 CYP2D6
DCLCYP3A4
CYP2D6
DCL
DCL
-12-
1.7-2
1)
1) R-
4.
R-
95mg 1292 207
16.0% 67 5.2%42 3.3% 39 3.0%
4.
® 10mg 1,653 17310.5% 105 6.4% 231.4% 15 0.9% 15 0.9% 9 0.5%
1,482 72 4.9%ALT GPT 13 0.9% AST GOT 10 0.7%
7,049 110 1.6%52 0.7% 7 0.1%
6 0.1% 5 0.1%104 5 4.8%
2 1.9%
-13-
1.7-2
1396 18913.5%
1396 140 10.0% 84 6.0%12 0.9% 9 0.6% 7 0.5%
AST GOT 1.4% 17/1182 ALTGPT 1.5% 18/1181 0.8% 9/1114
0.5% 6/11335759 163
207 3.6%149 2.6% 9 0.2% 9 0.2%
8 0.1% 6 0.1%
602 25 4.2%ALT GPT 8 1.3% 6 1.0%
R-
197 105.1% 7 3.6% 2 1.0%
197 6 3.0%ALT GPT 2 1.0% AST GOT 2 1.0%
774 6 0.8%2 0.3%
157 6 3.8%2 1.3%
-14-
1.7-2
95mg 1292 207
16.0% 67 5.2%42 3.3% 39 3.0%
6 260
1396 18913.5%
1396 140 10.0% 84 6.0%12 0.9% 9 0.6% 7 0.5%
AST GOT 1.4% 17/1182 ALTGPT 1.5% 18/1181 0.8% 9/1114
0.5% 6/11335759 163
207 3.6%149 2.6% 9 0.2% 9 0.2%
8 0.1% 6 0.1%
-15-
1.7-2
602 25 4.2%ALT GPT 8 1.3% 6 1.0%
(1)1) 2)
2) 2)
3) 0.6% 2) AST GOT ALT GPT -GTPLDH Al-P
4) 2)
2)
(1)1)
2)
3)
4) AST GOT ALT GPT -GTP Al-PLDH
-16-
1.7-2
(2)
0.1 5% 0.1%
3) 3)
3)
3)
3)
3)
3)
3) 3)
3)
(2)
1% 0.1 1% 0.1%
AST GOTALT GPT
Al-P -GTP
BUN
-17-
1.7-2
0.1 5% 0.1%
3)
ALT GPTAST GOT
Al-P
3) BUN3)
3)
3)
3)
3)
5.
2.5mg
1% 0.1 1% 0.1%
5.
-18-
1.7-2
6.(1)
(2) 1)
1) R-
7.
7
6
8.
3 5
6.(1)
(2)
7.
(1) 3 7 1%
(2) 3
3
8.
3 5
-19-
1.7-2
9.
10.
PTP PTPPTP
9.40mg 180mg
10.(1) 10mg
PTP PTPPTP
(2) ® 10mg1)
a. PTP
b.c.
®
2)
-20-
1.7-2
5mg 2017 2 60.05% 2017 2 3
10mg 10mg 2017 1 161% 2017 1 9
-21-
1.7-3
2.5 5OD 2.5 OD 5
0.5%
30mg 60mgOD 60mg
5%
2.5 5 2000 12 22OD 2.5 OD 5 2010 5 10
0.5% 2011 7 1
30mg 2006 10 2060mg 2000 9 22
OD 60mg 2010 12 145% 2014 1 17
2.5 5 2009 12 212.5 5 OD 2.5 OD 5 0.5% 7
2015 9 170.5% 2 7 2017 3 30
30mg 60mg 2011 9 292013 4 4 7
5% 6 72018 1 16
1 2.5mg 5mg1g 5mg
1 30mg 60mgOD 1 60mg
1g 50mg
-22-
1.7-3
1 5mg1 2
7 1 5mg1 2
1 5mg 1g1 2
7 1 5mg1g 1 2
2 7 12.5mg 0.5g 1 2
1 60mg 1 2
7 12 130mg 1 2 12 1
60mg 1 2
1 60mg1.2g 1 2
12 1 60mg1.2g 7 12
1 30mg 0.6g 1 2
2 7 1 30mg0.6g 6 2
1 15mg 0.3g 1 2
-23-
1.7-3
OD ODOD
9.
1.1)
2)3)
2.1)
2)
3)
4)
1.(1)
(2)
-24-
1.7-3
3.
9,620 1,05611.0% 1,402
674 7.0% ALT GPT 68 0.7%53 0.6% AST GOT 46 0.5% 36 0.4%
2.
P
3.
6,809 1,060 5,7491,093 16.1%
310 4.6% 158 2.3% 83 1.2%
3,876 61 1.6%19
0.5% 8 0.2% 5 0.1%
-25-
1.7-3
OD4,413 210
4.8% 231149 3.4% ALT GPT 20 0.5% AST
GOT 9 0.2% 7 0.2% 4 0.1%
158 13 8.2%5 3.2% ALT GPT
3 1.9% -GTP 2 1.3% 2 1.3%
3,313 23 0.69%6 0.18%
2 0.06% 2 0.06%4 174
304 10 3.3%AST GOT 5
1.6% ALT GPT 2 0.7%
212 2 0.9%1 0.5%
1 0.5%158 13 8.2%
5 3.2%ALT GPT 3 1.9% -GTP 2 1.3% 2 1.3%
-26-
1.7-3
1)AST GOT ALT
GPT -GTP LDH Al-P
3,313 23 0.69%6 0.18%
2 0.06% 2 0.06% 4174
304 10 3.3%AST GOT 5 1.6% ALT
GPT 2 0.7%
6,809 1,0605,749 1,093 16.1%
310 4.6% 158 2.3%83 1.2%
3,876 611.6%
19 0.5% 8 0.2% 5 0.1%
(1)1) 1)
2) 1) AST GOT ALT GPT -GTPAl-P LDH
-27-
1.7-3
2)
5% 0.1 5% 0.1%
ALT GPTAST GOTLDH -GTPAl-P
3) 1) 0.2% 2) 0.1%2)
1)2)
(2)3) 0.1 5% 4) 0.1% 4)
1)
2) AST GOTALT GPT
1)2)
-28-
1.7-3
5% 0.1 5% 0.1%
BUN
4.
5.1)
2)
3)4)
4.
5.(1)
(2)
-29-
1.7-3
6.
2
7.
6.
6
7.
3 5
8.
2 1800 3600mg
-30-
1.7-3
8.
1)PTP PTP
PTP
2)
OD1)
PTP PTPPTP
2)
9.
9.(1) 30mg 60mg
PTP PTPPTP
(2) OD 60mg1)
a. PTP
b.OD
c.d.
2)a.
b.
-31-
1.7-3
2.5 5 2017 4 19OD 2.5 OD 5 2017 4 8
0.5% 2017 4 5
30mg 60mg OD 60mg 2013 5 165% 2015 10 2
-32-
1.7-4
5mg 10mgOD 5mg OD 10mg
5 101.25%
5mg 10mg 2000 7 3OD 5mg OD 10mg 2007 3 14
5 10 1998 6 301.25% 2005 10 21
2010 6 292019 5 25
2008 10 32016 6 24
1 5mg 10mgOD 1 5mg 10mg
1 5mg 10mg1g 12.5mg
1 10mg 1 2 10mg1 10mg 1 1
1 20mg
-33-
1.7-4
7 1 10mg 1 2
OD
5mg
1 10mg 1 1
1 20mg
7 15 1 5mg 12
1 0.8g 10mg 1 1
1 1.6g20mg
2 7 1 0.2g 2.5mg1 2
7 15 1 0.4g 5mg1 2
10mL/min
-34-
1.7-4
mL/min80 50 79 30 49 10 29
10mg1 1
10mg1 1
5mg1 1
5mg2 1
1.
1 5mg
2.1)
2
(1)
(2) 10mL/min
1.(1)
(2)
(3)
(4)
2.(1)
-35-
1.7-4
2)
3)
4)
(2)
(3)
3.
16%
40%-11%
-36-
1.7-4
3.
1,446137 9.5% 83 5.7% 16
1.1% 12 0.8% 7 0.5% 7 0.5%6 0.4% 4 0.3% 4 0.3%
1,225 64 5.2% ALT GPT 1,209 252.1% 1,020 11 1.1% -GTP 1,130 10
0.9% AST GOT 1,210 8 0.7%4,453
89 2.0% 591.3%
1) 5 15 1,31614 1.1%
5 0.4% 2 0.2% 2 0.2%7 15
615 14 2.3%5 0.8% 2 0.3% AST GOT
2 0.3%
4.
1,396 18913.5%
1,396 140 10.0% 84 6.0%12 0.9% 9 0.6% 7 0.5%
AST GOT 1.4% 17/1,182 ALTGPT 1.5% 18/1,181 0.8% 9/1,114
0.5% 6/1,1335,759
163 207 3.6%149 2.6% 9 0.2% 9
0.2% 8 0.1% 6 0.1%
602 25 4.2%ALT GPT 8 1.3% 6 1.0%
3,157 42 1.3%22 0.7%
5 1.25%
(1)1)
-37-
1.7-4
0.1 5% 0.1%
AST GOT ALTGPT -GTP
LDH
2) 0.1%
3)AST GOT ALT GPT -GTP LDH Al-P
4)
(2)
0.1% 5% 0.1%
-38-
1.7-4
0.1 5% 0.1% 0.1% 5% 0.1%
ALT GPTAST GOT
Al-P
BUN
-39-
1.7-4
4.
5.1)
2)
6. 1)
5.
5mg
6.(1)
(2)
7.
(1) 2 71.25%
(2) 2
2
-40-
1.7-4
7.
PTP PTPPTP
OD(1)
PTP PTPPTP
(2)1)
2)
8.
3 5
9.
10.
PTP PTPPTP
-41-
1.7-4
5mg 10mg 2017 10 16OD 5mg OD 10mg 2017 10 8
5 10 2016 10 251.25% 2016 10 25
-42-
1.7-5
10 20
10 20 1994 4 1
2003 1 17
1 10mg 20mg
1.
1 20mg 1 1
2.1 10 20mg 1 1
-43-
1.7-5
1.
2.(1)
(2)
(3)
(4)
(5)
3.8,443
263 3.12%102 1.21% 28 0.33% 27 0.32%
17 0.20% 15 0.18%
-44-
1.7-5
(1)1) AST GOT ALT GPT -GTP Al-P
LDH
2)
(2)
0.1 5% 0.1%1)
2)
-45-
1.7-5
0.1 5% 0.1%
2)
1)2)
4.
10mg/
5.(1)
(2)
-46-
1.7-5
6.
7.
PTP PTPPTP
8.
10 20 2011 9 8
4mg8mg
1.8 .................................................................................................................................... 4 1.8.1 ......................................................................................... 4
1.8.1.1 .................................................................................................................. 4 1.8.1.2 .............................................................................................. 4
1.8.2 ......................................................................................... 4 1.8.2.1 .................................................................................................................. 4 1.8.2.2 .............................................................................................. 4
1.8.3 ............................................. 7 1.8.4 ............................................. 7 1.8.5 ..................................................................................... 7
1.8.5.1 .......................................................................................................................................... 7 1.8.5.2 .......................................................................................................................................... 7 1.8.5.3 .................................................................................................................................. 7 1.8.5.4 .................................................................................................................................. 7 1.8.5.5 .................................................................................................................. 8 1.8.5.6 .................................................................................................................................. 8 1.8.5.7 ...................................................................................................................................... 9 1.8.5.8 ...................................................................................................................... 9 1.8.5.9 ........................................................................................ 10 1.8.5.10 .................................................................................................................... 10 1.8.5.11 ................................................................................................ 10 1.8.5.12 ................................................................................................................................ 10 1.8.5.13 ........................................................................................................................ 11 1.8.5.14 ........................................................................................................................ 11
1.8.6 ....................................................................................................................................... 12 1.8.7 ........................................................................................................................... 12
- 2 -
HP-3060
1cm2 0.5mg 0.5mg/cm2
1 8cm2 4mg
1 16cm2 8mg
FAS full analysis set
JRQLQJapan Rhinoconjunctivitis Quality of Life Questionnaire
QOL
LOCF last observation carried forward
QOL quality of life
tmax
01HP-3060-JP-01
02HP-3060-JP-02
03HP-3060-JP-03
04
HP-3060-JP-04
05HP-3060-JP-05
- 3 -
1276 04 HP-3060 4 8mg
2
FAS 2 LOCF -0.45 HP-3060 4mg -1.22
8mg -1.50 HP-3060 4mg 8mg
HP-3060
p < 0.0001 Dunnett
HP-3060
4mg 8mg 2.5.4.3.2
247 05 HP-3060 4 8mg 12
52
52 /
HP-3060 4mg 8mg -2.59 -2.47
1 52
QOL JRQLQ
2.5.4.3.3
04
05
1 4mg
24 1 8mg
- 4 -
(1)
12 HP-3060 1.5 3
6 12 24mg 24 01
tmax 16 26hr 2.5.3.3.1.1 16 26
1 24
96 HP-3060
4 8 12mg 14 2 03
24 7 14
2.5.3.3.2.1
HP-3060 1
1
20 5 5 HP-3060 8mg
24 02
HP-3060 8mg 24
2.5.3.3.1.2
(2)
96 03 2 LOCF
HP-3060 8mg
p = 0.0185 HP-3060
4mg 2.5.4.3.1
HP-3060 4mg 8mg
2.7.6.3.4.11 1 1 14 2
2.5.5.2
03 HP-3060 4 8mg
1276 04 HP-3060 4 8mg 2
FAS 2 LOCF
- 5 -
95% HP-3060 4mg -0.77 -1.02 0.51 8mg -1.05 -1.30 0.80
HP-3060 4mg 8mg HP-3060 4mg p < 0.0001
8mg p < 0.0001 Dunnett 2.5.4.3.2 HP-3060
4mg 8mg 2.5.5.2
247 05 HP-3060 4 8mg 12
52 1
52
52 HP-3060 4mg -2.65 8mg -2.39 HP-3060 4mg
-2.59 8mg -2.47 2.5.4.3.3 HP-3060 4mg 8mg
HP-3060 8mg 2.5.5.2 05
HP-3060 8mg HP-3060 4mg 2
2 4 12 HP-3060
2.5.3.3.2.2
4 8mg
4 8mg
4mg 03 04 4mg
8mg 03 HP-3060 8mg
4mg 8mg
4mg 8mg
1 4mg
24
1 8mg
- 6 -
- 7 -
(1)
(2) 4mg 8mg
(3)
(4)
(5)
(1)
(2) 8mg
4mg
8mg
8mg
(3)
1)
(4)1)
(5)
- 8 -
1,060 201 19.0%
116
10.9% 48 4.5% 21 2.0%
52 4.9%
5% 0.1% 5%
ALT GPTAST GOT
LDH -GTP
- 9 -
(1)
(2)
2)
- 10 -
(1)
(2)
(3)
(1)
(2)
(3) 1
(1)
2.6.4.3.1.4
(2)
(3)
(1)
(2)
(3) 1 24
- 11 -
1) . 5 . . .
2016 8 . :
; 2015. p. 66-70.
2) Sakai T, Takahashi H, Hamada T, Awata N, Watanabe J. The biological fate of 1-(2-ethoxyethyl)
-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate (KB-2413) III Transfer to fetus and milk
in rats. 1987; 2: 147-54.
- 12 -
201 1 87449
36
ALLESAGA®TAPE
4mg 8mg
1
4mg
1
8mg
1
22.3mm × 36.1mm 31.5mm × 51.0mm
8cm2 16cm2
HP3204T HP3208T
1 4mg
24
1 8mg
(1)
(2) 4mg 8mg
(3)
(4)
(5)
- 13 -
1,060 201 19.0%
116 10.9% 48
4.5% 21 2.0% 52 4.9%
ALT GPT
AST GOT
LDH -GTP
(1)
(2)
(1)
(2)
(3)
(1)
(2)
(3) 1
1)
12
1.5 3 6 12 24mg 24
Cmax AUC0-t AUC0- 1.5 24mg
1 4 8mg
- 14 -
Cmax
(ng/mL)AUC0-t
(ng hr/mL)AUC0-
(ng hr/mL)tmax
a)
(hr)t1/2
(hr)1.5mg(12)
0.320± 0.112
8.48± 3.03
9.15± 2.97
2611.7
± 3.193mg(12)
0.642± 0.235
18.4± 5.44
19.3± 5.41
16, 2613.2
± 2.006mg(12)
1.59± 0.567
43.8± 13.2
46.2± 13.1
2613.8
± 2.2912mg(12)
3.09± 1.01
86.4± 25.3
90.5± 24.9
1613.0
± 2.4724mg(12)
5.43± 1.89
156± 53.3
164± 52.7
2613.0
± 2.84
a) 2)
20
8mg 24
AUC0-t
0.930 1.000 0.923 0.740
AUC0-t
3)
4 8 12mg 1 1 14
Cmax AUC0-24 4 12mg
7
1 4 8mg
Cmax
(ng/mL)AUC0-24
(ng hr/mL)tmax
a)
(hr)t1/2
(hr)
1
4mg(23)
1.16± 0.419
16.3± 7.54
20 -
8mg(24)
2.32± 0.832
31.7± 14.9
20 -
12mg(24)
2.94± 1.49
38.8± 24.1
20 -
7
4mg(22)
1.80± 0.579
36.0± 10.9
16 -
8mg(24)
3.98± 1.18
79.5± 23.8
12 -
12mg(24)
5.49± 2.62
112± 57.1
16 -
14
4mg(21)
2.03± 0.641
40.6± 12.3
12, 1615.5
± 2.368mg(24)
4.42± 1.40
88.8± 30.3
12, 1615.5
± 1.5912mg(24)
6.28± 2.86
128± 62.1
1216.2
± 2.83
a)
4, 5)
[14C]
8
7
6)
[14C]
in vitro 7, 8)
CYP1A2 2E1
3A41)
12
1.5 3 6 12 24mg 24
0 96
6- 5-
2.9 4.4% 12.4
15.9%
9)
4 8mg 1 1 2
a)
95%CI
3836.45
± 1.636.16
± 2.03-0.29± 1.86
4mg384
6.56± 1.65
5.46± 1.98
-1.10± 1.89
-0.77-1.02 -0.51
p < 0.0001b)
8mg380
6.47± 1.61
5.12± 2.13
-1.35± 1.98
-1.05-1.30 -0.80
p < 0.0001b)
a)
b) Dunnett p 5%
- 15 -
10)
4 8mg 1 1 52
1 52
4mg124
6.45 ± 1.81 3.86 ± 1.99 -2.59 ± 1.93
8mg123
6.35 ± 1.58 3.88 ± 1.84 -2.47 ± 1.99
2411)
in vitro 12)
in vitro 13)
H1
H2 H3
in vitro 14, 15)
C4
P
in vitro 16)
B4
Emedastine Fumarate JAN
1-(2-Ethoxyethyl)-2-(4-methyl-1,4-diazepan-1-yl)-
1H-benzimidazole difumarate
C17H26N4O 2C4H4O4
534.56
99.5 100
149 152
4mg 70 1 / 1 × 70
8mg 70 1 / 1 × 70
1) I
2) I
3) I/II
4)
5)
6) Sakai, T., et al.: 1987; 2: 147-154.
7) in vitro
8) : 1997; 31: 3089-3093.
9) III
10) III
11)
12) Fukuda, T., et al.: Arzneimittelforschung 1984; 34: 801-805.
13) Sharif, NA., et al.: J. Ocul. Pharmacol. 1994; 10: 653-664.
14) Nishimura, N., et al.: Immunopharmacol. Immunotoxicol.
1987; 9: 511-521.
15) Saito, T., et al.: Jpn. J. Pharmacol. 1993; 62: 137-143.
16) : 1993; 55: 1081-1085.
100-6330 4 1
0120-381332
FAX. (03)5293-1723
9:00 17:50
841-0017 408
- 16 -
4mg8mg
62 6 25 1 16 19 8 6
0806001
Emedastine Fumarate
- 2 -
4mg8mg
1 1 2mg 1 2
1 1.14mg*
1mg 1 1mg
2mg 1 2mg
LD50 mg/kg
2547 712 101
2206 609 93
2151 666 72
1854 643 77
193
mg/kg/ mg/kg/
3 10, 50, 250,
1250
10 ChE GPT AlP
A/G LDH BUN Ca2+
P K+
3 3, 15, 75 15
AlP
TG
2mg
- 2 -
mg/kg/ mg/kg/
1 1, 3, 10, 50 10 ChE
1 1, 3, 15, 45
15
AlP
1 +
3
0.3, 1, 3, 45
192 / 1229 = 15.6%
155
19
9
6
4
- 3 -
1 4mg
24 1 8mg
4mg 1 8cm2 4mg
8mg 1 16cm2 8mg
mg/kg/day mg/kg/day
4
+ 4
0, 4.5, 9, 18 18
4 0, 1, 3, 9 9
181 / 1060 = 17.1% 21 / 1060 = 2.0%
116 7
52
48 4
21
3
3
- 4 -
4mg8mg
/
3.2.S
3.2.P.1
3.2.P.2 2020
3.2.P.3 2020
3.2.P.4 2020
3.2.P.5 2020
3.2.P.6
3.2.P.7
3.2.P.820
20
3.2.A 2020
アレサガテープ
1.12 添付資料一覧
Page 2
3.3-1 26 12 5 34 .
3.3-2 28 1 22 170 .
3.3-3 Iemura R, Hori M, Ohtaka H. Syntheses of the metabolites of 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H -1,4-diazepin-1-yl)-1H -benzimidazole difumarate(KG-2413) and related compounds. Chem Pharm Bull 1989; 37: 962-6.
3.3-4 2 in silico 947-15-K-0196 . 2016.
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4.2.1.1-1 HP-3060 2020
4.2.1.3-1 Effects of emedastine difumarate on hERG currents 2020
4.2.1.3-2 HP-3060 2020
4.2.2.1-1 Bioanalytical method validation and stability study for determination of emedastine inmouse (ICR) plasma by LC/MS/MS
2020
4.2.2.1-2 Bioanalytical method partial validation for determination of emedastine in mouse (B6C3F1)plasma by LC/MS/MS
2020
4.2.2.1-3 Bioanalytical method validation and stability study for the determination of emedastine inrat plasma by LC/MS/MS
2020
4.2.2.1-4 Partial validation for the determination of emedastine in F344 rat plasma by LC/MS/MS 2020
4.2.2.1-5 Bioanalytical method validation and stability study for the determination of emedastine inrabbit plasma by LC/MS/MS
2020
4.2.2.1-6 Bioanalytical method validation and stability study for the determination of emedastine indog plasma by LC/MS/MS
2020
4.2.2.2-1 Pharmacokinetic study of oral administration of emedastine difumarate and percutaneousadministration of HP-3060 patch to rats
2020
4.2.2.2-2 Pharmacokinetic study of emedastine difumarate in rats after single subcutaneous orintravenous administration
2020
4.2.1.4
4.2.2.1
4.2.2.2
4.2.1.3
4.2.1.1
4.2.1.2
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1.12 添付資料一覧
Page 4
/
4.2.2.2-3 Pharmacokinetics study of single percutaneous administration of [14C]-HP-3060 patch torats
2020
4.2.2.2-4 Pharmacokinetic study of single intravenous administration of emedastine difumarate andpercutaneous administration of HP-3060 patch to dogs
2020
4.2.2.3-1 Pharmacokinetics study of repeated percutaneous administration of [14C]-HP-3060 patch torats
2020
4.2.2.4-1 In vitro metabolism study of [14C]emedastine difumarate20
20
4.2.2.4-2 Identification of enzymes involved in glucuronidation of 5-hydroxyemedastine and 6-hydroxyemedastine
2020
4.2.2.6-1 Inhibitory effects of emedastine difumarate on drug metabolizing enzyme activities inhuman liver microsomes
2020
4.2.2.6-2 In vitro studies on emedastine difumarate transport of MDR1, BCRP, OATP1B1,OATP1B3 and OCT1
2020
4.2.2.6-3 In vitro inhibitory effects of emedastine difumarate on the transport activity 2020
4.2.3.2-1 A 4-week repeated dose percutaneous toxicity study of HP-3060 patch in rats followed by a4-week recovery period
2020
4.2.3.2-2 A four-week repeated dose percutaneous toxicity study of HP-3060 patch in dogs 2020
4.2.3.2
4.2.2.3
4.2.2.4
4.2.2.5
4.2.2.6
4.2.2.7
4.2.3.1
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Page 5
/
4.2.3.4.2-1 A 4-week repeated dose range finding study for a medium-term skin carcinogenesisbioassay of emedastine fumarate in mice
2020
4.2.3.4.2-2 A medium-term skin carcinogenesis bioassay of emedastine fumarate in mice 2020
4.2.3.5.2-1 A 7-day repeated dose subcutaneous study of emedastine fumarate in non-pregnant rabbits 2020
4.2.3.5.2-2 A preliminary study for effects of emedastine fumarate on embryo-fetal development bysubcutaneous administration in pregnant rabbits
2020
4.2.3.5.2-3 Reproductive and developmental toxicity study of emedastine fumarate in rabbits bysubcutaneous administration - Study for effects on embryo-fetal development -
2020
4.2.3.6-1 A primary skin irritation study of HP-3060 patch in rabbits 2020
4.2.3.6-2 A 13-week cumulative skin irritation study of HP-3060 patch in minipigs 2020
4.2.3.6-3 A 39-week cumulative skin irritation and 4-week recovery study of HP-3060 patch inminipigs
2020
4.2.3.3
4.2.3.44.2.3.4.1
4.2.3.4.2
4.2.3.4.3
4.2.3.54.2.3.5.1
4.2.3.5.2
4.2.3.5.3
4.2.3.5.4
4.2.3.6
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Page 6
/
4.2.3.6-4 A skin sensitization study of HP-3060 patch in guinea pigs 2020
4.2.3.7.7-1 A skin phototoxicity study of emedastine fumarate in guinea pigs 2020
4.2.3.7.7-2 A skin photosensitization study of HP-3060 patch in guinea pigs 2020
4.2.3.7.7-3 Toxicokinetic study of emedastine fumarate in mice after single oral dose 2020
4.2.3.7.7-4 Toxicokinetics study of a single oral administration of emedastine difumarate to F344 rats 2020
4.2.3.7.7-5 Toxicokinetics study of a single oral administration of emedastine difumarate to SDpregnant rats
2020
4.2.3.7.7-6 Toxicokinetics study of a single oral administration of emedastine difumarate to dogs 2020
4.2.3.7.7-7 Toxicokinetics study of a repeat oral administration of emedastine difumarate to SD rats 2020
4.2.3.7.1
4.2.3.7.3
4.2.3.7.7
4.2.3.7.6
4.2.3.7.5
4.2.3.7.4
4.2.3.7.2
4.2.3.7
アレサガテープ
1.12 添付資料一覧
Page 7
4.3-1 . ® , ®
. 1997; 40: 231-45.
4.3-2 . 1 . 2016 8 .: ; 2015. p. 2-5.
4.3-3 . 3 . 20168 . : ; 2015. p. 16-8.
4.3-4 Fukuda T, Morimoto Y, Iemura R, Kawashima T, Tsukamoto G, Ito K. Effect of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)-benzimidazole difumarate(KB-2413), a new antiallergic, on chemical mediators. Arzneimittelforschung 1984; 34: 801-5.
4.3-5 Nishimura N, Ito K, Tomioka H, Yoshida S. Inhibition of chemical mediator release from human leukocytes and lung in vitro by a novel antiallergic agent, KB-2413. Immunopharmacol Immunotoxicol 1987; 9: 511-21.
4.3-6 Saito T, Hagihara A, Igarashi N, Matsuda N, Yamashita A, Ito K, et al. Inhibitory effects of emedastine difumarate on histamine release. Jpn J Pharmacol 1993;62: 137-43.
4.3-7 Spangler DL, Brunton S. Efficacy and central nervous system impairment of newer-generation prescription antihistamines in seasonal allergic rhinitis. SouthMed J 2006; 99: 593-9.
4.3-8Sharif NA, Su SX, Yanni JM. Emedastine: a potent, high affinity histamine H1-receptor-selective antagonist for ocular use: receptor binding and secondmessenger studies. J Ocul Pharmacol 1994; 10: 653-64.
4.3-9 , , , , . Emedastine Difumarate . 1993;55: 1081-5.
4.3-10 Saito T, Fukuda T, Sukamoto T, Yoshidomi M, Morimoto Y, Shimohara K, et al. General pharmacology of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate. 1st communication: Effects on the central nervous system. Arzneimittelforschung 1988; 38: 66-9.
4.3-11Tasaka K, Kamei C, Katayama S, Kitazumi K, Akahori H, Hokonohara T. Comparative study of various H1-blockers on neuropharmacological and behavioraleffects including 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate (KB-2413), a new antiallergic agent. Arch Int Pharmacodyn Ther1986; 280: 275-91.
4.3-12 Saito T, Fukuda T, Tajima S, Sukamoto T, Yamashita A, Kanazawa T, et al. General pharmacology of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate. 2nd communication: Effects on the circulation and the other systems. Arzneimittelforschung 1988; 38: 267-72.
4.3-13 , , . KG-2413 . 1989; 23: 3145-7.
4.3-14 EMADINE® Review documents, Clinical pharmacology and biopharmaceutics review(s) (NDA 20-706).
4.3-15 Sakai T, Takahashi H, Hamada T, Awata N, Watanabe J. The biological fate of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate(KB-2413) I Absorption and excretion after oral administration to rats and guinea pigs. 1987; 2: 123-31.
4.3-16 Sakai T, Hamada T, Awata N, Watanabe J. Interspecies differences in pharmacokinetics of an antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1,4-diazepin-1-yl)benzimidazole difumarate (KG-2413) after intravenous administration to rats, guinea pigs and dogs. Chem Pharm Bull 1989; 37: 753-6.
4.3-17 Sakai T, Takahashi H, Hamada T, Awata N, Watanabe J. The biological fate of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate(KB-2413) III Transfer to fetus and milk in rats. 1987; 2: 147-54.
アレサガテープ
1.12 添付資料一覧
Page 8
4.3-18 , , , , , . 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H -1,4-diazepin-1-yl)-1H -benzimidazole difumarate KG-2413 . 1989; 4: 459-70.
4.3-19 , , , , . 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H -1,4-diazepin-1-yl)-1H -benzimidazoledifumarate KG-2413 , . 1989; 4: 471-80.
4.3-20 , , , , . 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H -1,4-diazepin-1-yl)-1H -benzimidazoledifumarate KG-2413 . 1989; 109: 318-28.
4.3-21 Hamada T, Awata N. Metabolism of a new antiallergic agent, emedastine difumarate, in human. 1990; 5: 871-81.
4.3-22 , , , . in vitro . . 1990;110: 40-8.
4.3-23 , , , . P450 . 1997; 31: 3089-92.
4.3-24 Sakai T, Hamada T, Awata N, Watanabe J. Pharmacokinetics of an antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H -1,4-diazepin-1-yl)-1H -benzimidazole difumarate (KG-2413) after oral administration: interspecies differences in rats, guinea pigs and dogs. J Pharmacobio-Dyn 1989; 12: 530-6.
4.3-25 Sakai T, Hamada T, Awata N, Watanabe J. Binding of 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1,4-diazepin-1-yl)benzimidazole difumarate (KG-2413) toserum or plasma proteins in man, guinea pig and rat. J Pharmacobio-Dyn 1988; 11: 262-7.
4.3-26 , , . / ,KG-2413 , . 1989; 109: 749-54.
4.3-27 EMADINE® Review documents, Pharmacology Review(s) (NDA 20-706).
4.3-28 Sakai T, Takahashi H, Hamada T, Awata N, Watanabe J. The biological fate of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate(KB-2413) II Distribution after single and multiple oral administration to rats. 1987; 2: 133-45.
4.3-29 , , , , , . Emedastine Difumarate KG-2413 3. 1990; 39: 231-68.
4.3-30 , , , , , . Emedastine Difumarate KG-2413 1. 1990; 39: 285-317.
4.3-31 , , , , , . Emedastine Difumarate KG-2413. 1990; 39: 209-14.
4.3-32 , , , , , . Emedastine Difumarate KG-2413 3. 1990; 39: 215-29.
4.3-33 , , , , , . Emedastine Difumarate KG-2413 1. 1990; 39: 269-83.
4.3-34 , , , , , . Emedastine Difumarate KG-2413. 1990; 39: 319-28.
4.3-35 , , , , , . Emedastine Difumarate KG-2413 . 1990; 39: 329-42.
アレサガテープ
1.12 添付資料一覧
Page 9
4.3-36 , , , , , . Emedastine Difumarate KG-2413. 1990; 39: 343-54.
4.3-37 Remmer H. Induction of drug metabolizing enzyme system in the liver. Euro J clin Pharmacol 1972; 5: 116-36.
4.3-38 , , , , , . . 2015;56: 42-8.
アレサガテープ
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5.3.1.4-1 Bioanalytical method validation and stability study for the determination ofemedastine in human plasma by LC/MS/MS
2020
5.3.1.4-2 Bioanalytical method validation and stability study for the determination ofemedastine and its metabolites in human urine by LC/MS/MS
2020
5.3.2.2-1 In vitro metabolism study of [14C]emedastine difumarate20
20
5.3.2.2-2 Identification of enzymes involved in glucuronidation of 5-hydroxyemedastineand 6-hydroxyemedastine
2020
5.3.2.2-3 Inhibitory effects of emedastine difumarate on drug metabolizing enzymeactivities in human liver microsomes
2020
5.3.2.2-4 In vitro studies on emedastine difumarate transport of MDR1, BCRP,OATP1B1, OATP1B3 and OCT1
2020
5.3.2.2-5 In vitro inhibitory effects of emedastine difumarate on the transport activity 2020
5.3.3.1-1 HP-3060 2020
5.3.3.1-2 HP-3060 2020
5.3.3.1 PK
5.3.1.3 In Vitro -In Vivo
5.3.1.4
5.3.2.1
5.3.2.2
5.3.2.3
5.3.1.1 BA
5.3.1.2 BA BE
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5.3.5.1-1 HP-3060 2020
5.3.5.1-2 HP-3060
21
2020
5.3.5.2-1 HP-306011
2020
5.3.7.15.3.7.25.3.7.35.3.7.45.3.7.5
5.3.5.1
5.3.5.2
5.3.5.3
5.3.5.4
5.3.3.2 PK
5.3.3.3 PK
5.3.3.4 PK
5.3.3.5 PK
アレサガテープ
1.12 添付資料一覧
Page 12
5.4-1 . 1 . 2016 8 .: ; 2015. p. 2-5.
5.4-2 . 1 . . . : ; 2005. p. 16-21.
5.4-3 . : QOL . 2015; 4734: 20-1.
5.4-4 . 2 . 2016 8 . :; 2015. p. 8-13.
5.4-5 . 3 . 20168 . : ; 2015. p. 16-8.
5.4-6 . 5 . 2016 8 . :; 2015. p. 36-82.
5.4-7 , . 2. Progress in Medicine 2008; 28: 2285-96.
5.4-8 . ® ®
. 1997; 40: 231-45.
5.4-9 MSD : 1mg, 2mg . 8 , 2013.
5.4-10 : 1mg, 2mg . 5 , 2013.
5.4-11 EMADINE® Review documents, Clinical pharmacology and biopharmaceutics review(s) (NDA 20-706).
5.4-12 , , , , , . Emedastine Difumarate KG-2413 3. 1990; 39: 231-68.
5.4-13 , , , , , . Emedastine Difumarate KG-2413 1. 1990; 39: 285-317.
5.4-14 Herranz U, Rusca A, Assandri A. Emedastine-ketoconazole: pharmacokinetic and pharmacodynamic interactions in healthy volunteers. Int J Clin PharmacolTher 2001, 39: 102-9.
5.4-15 Sakai T, Hamada T, Awata N, Watanabe J. Binding of 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1,4-diazepin-1-yl)benzimidazole difumarate (KG-2413) toserum or plasma proteins in man, guinea pig and rat. J Pharmacobio-Dyn 1988; 11: 262-7.
5.4-16 , , , , . 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H -1,4-diazepin-1-yl)-1H -benzimidazoledifumarate KG-2413 . 1989; 109: 318-28.
5.4-17 Hamada T, Awata N. Metabolism of a new antiallergic agent, emedastine difumarate, in human. 1990; 5: 871-81.
アレサガテープ
1.12 添付資料一覧
Page 13
5.4-18 , , , . P450 . 1997; 31: 3089-92.
5.4-19 MSD : 1mg, 2mg . 7 , 2013.
5.4-20 , . 1 CKD . CKD 2012. 1 . : ; 2012. p. 1-4.
5.4-21 Malmstrom K, Schwartz J, Reiss TF, Sullivan TJ, Reese JH, Jauregui L, et al. Effect of montelukast on single-dose theophylline pharmacokinetics. Am J Ther1998; 5: 189-95.
5.4-22 . 5 . . 20137 . : ; 2013. p. 60-3.
5.4-23 Guidance for Industry. Allergic rhinitis: Clinical development programs for drug products. Draft guidance. FDA. April 2000.
5.4-24 . 1 . . 20137 . : ; 2013. p. 2.
5.4-25 . 4 . . 5. QOL . 2013 7 . : ; 2013. p. 27-9.
5.4-26 , , , , , . OHIO ChamberOD . 2011; 60: 2216-29.
5.4-27 : 30mg, 60mg, OD 60mg . 20 , 2014. p. 20.
5.4-28 : 10mg . p. 526-60.
5.4-29 : 1mg, 2mg . 5 , 2013.
5.4-30 : 10mg, 10mg . 15 , 2015.
アレサガテープ
1.12 添付資料一覧
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