Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`ELECTROCARDIOGRAMS SUMMARY
`WEEK 1
`MALES
`
`
`
`GROUP 1
`GROUP 2
`o DIG/RC
`10 Maine
`
`
`GROUP 3
`35 HG/KG
`
`SRO”? 4
`120, an HG/KG
`
`
`usanr RAT:
`
`(bpm)
`
`Before
`dosing
`
`MEAN
`57.nzv.
`N
`1h titer W
`dosing
`ST.DEV.
`R
`P AMPLITka luv)
`
`Bofare
`dosing
`
`1h after
`dozing
`
`HEAR
`ST.DEV.
`N
`
`MEAN
`5121)“.
`N
`
`r» DURATION (nun
`
`Before.
`fiesing
`
`143M
`81.937.
`N
`Mill
`ST.D8V.
`N
`P-u INTKKvaL (ma)
`
`1b a£ter
`dosing
`
`Beloxe
`fleeing
`'
`
`um
`ST.QBV,
`N
`
`1!: after
`dosing
`
`MEAN
`ST-DKV.
`H
`0R5 INTERVAL (nu)
`
`Ettore
`dosing
`
`MEAN
`ST.DRV.
`N
`
`1h after
`don ing
`
`as»:
`5? .DEV.
`'N
`0-1 INTERVAL (ma)
`
`Estate
`dosing
`
`1!: aite:
`doaing
`
`HzAN
`ST.DXV.
`N
`
`pm»:
`5T.DBV.
`N
`
`’
`
`118
`20
`6
`105
`22
`6
`
`0.23
`0.05
`6
`
`0.19
`0-06
`6
`
`‘0
`0
`6
`‘0
`0
`6
`
`82
`7
`6
`
`Z7
`8
`6
`
`40
`o
`S
`
`40
`O
`6
`
`190
`9
`6
`
`us
`12
`5
`
`98
`_ 10
`I
`103
`13
`i
`
`0 13
`0.93
`i
`
`0.26
`0 08
`i
`
`4,0
`D
`4
`49
`D
`4
`
`84
`14
`4
`
`89 ,
`13
`4
`
`10
`o
`i
`
`40
`0
`4
`
`'
`
`193
`10
`l
`
`195
`10
`4
`
`118
`17
`4
`£18
`26
`4
`
`'
`
`0.21
`0.11
`1
`
`0.28
`0.12
`4
`
`40
`o
`4
`to
`0
`4
`
`83
`15
`4
`
`88
`15
`4
`
`Q0
`0
`i
`
`40
`0
`4
`
`198
`5
`4
`
`199
`6
`l
`
`122
`28
`5
`312
`33
`6
`
`0.27
`o 06
`5
`
`5.13
`0.55
`6
`
`~10
`0
`6
`an
`0
`6'
`
`85
`ii
`6
`
`9'3
`22
`6
`
`40
`c
`6
`
`40
`0
`6
`
`155
`6
`
`215
`31
`5
`
`~2-
`
`'J"= Darnetz-test hasnd on pooled variancc gig. at 5* or ii Invel.
`= L:
`(«255: 51;n;f;:a:t at 59 n:
`ié Leveé: befcxe 23. after dggxng.
`
`136
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22—304
`
`ELECTROCARDIOGRAMS SUMMARY
`WEEK 1
`FEMALES
`
`ww‘mmm
`
`GROUP 1
`GROUP 2
`0 Hana;
`10 Home
`
`~-- .1..—.M.~uuw.~._.-
`
`GROUP 3
`35 name
`
`GROUP 4
`120, an MG/
`
`
`
`HEART RATE (hm)
`
`Before
`dosing
`
`HEAR
`SLDEV.
`h‘
`
`1!: after W
`dosing
`ELDEV.
`N
`P MP1.11092 (mVl
`
`Baton
`dosing
`
`W
`SLDKV‘.
`n
`
`1!: after W
`dosing
`SLBXV.
`N
`P DURATION (m)
`
`Bezoze
`jnning
`
`W
`SIZE“.
`N
`MEAN
`SLDXV.
`N
`P—Q INTERVAL (ms)
`
`12: after
`dozing
`
`Before
`dosing
`
`MAN
`51.0w.
`N
`MEAN
`5121330].
`N
`Gas INTERVAL (as)
`
`12) alter
`cloning
`
`Before
`dosing
`
`MEAN
`anew.
`N
`
`1h- ulcer M
`dosiny
`51mm].
`N
`INTERVAL (u)
`
`0-1‘
`
`Betote
`dosing
`
`1h after
`65::ng
`
`MEAN
`SLDBV.
`N
`
`IBM
`ST.DB\'.
`N
`
`138
`u
`6
`
`123
`33
`6
`
`0.29
`0.09
`6
`
`0.23
`0.11
`S
`
`13
`5
`6
`42
`I
`6
`
`86
`3
`6
`89
`9
`6
`
`40
`O
`6
`
`‘0
`0
`6
`
`157
`16
`6
`
`185
`18
`6
`
`.
`
`130
`18
`l
`
`123
`13
`d
`
`0.25
`0.66
`4
`
`0.21
`0.03
`C
`
`40
`0
`4
`40
`D
`*1
`
`85
`6
`4
`86
`5
`d
`
`40
`D
`I
`
`40
`D
`II
`
`I.“
`5
`4
`
`195
`10
`I
`
`105
`25
`4
`
`108
`30
`4
`
`0.11
`0.06
`4
`
`0.21
`0.05
`4
`
`40
`0
`4
`40
`0
`4
`
`88
`10
`4
`89
`11
`4
`
`4D
`0
`4
`
`40
`O
`I
`
`203
`5
`4
`
`.210
`18
`I
`
`,
`
`117
`25
`6
`
`108
`13
`5
`
`0.23
`3.07
`5
`
`5.29
`0.09
`5
`
`42
`«I
`5
`43
`3
`6
`
`94
`12
`6
`104
`13
`6
`
`40 »
`D
`6
`
`90
`i
`G
`
`192
`15
`6
`
`237 N
`15
`5
`
`'f“: Bunnezt-tes: based onpooled variance uig. at. 51s or 1'! level.
`(1"
`
`' Sign
`-_-a:‘.
`:2:
`{:1 o: 1':
`level: 13:21:; "5.. 5.515" ussinz.
`
`137
`
`n
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`ELECTROCARDIOGRAMS SUMMARY
`WEEK 13‘
`MALES
`
`GROUP 1
`0 HG/XG
`
`GROUP 2
`10 HG/RQ
`
`
`
`
`GROUP 3
`15 MGIKO
`
`GROUP 4
`120. 30 HGIK
`
`HEART RATS {bpm}
`
`Beinra
`dosing
`
`NEAR
`5T.DEV.
`N
`
`1:: arts:
`dosing
`
`‘
`mm:
`‘ ST.DBV.
`N
`P AX?LITUD3 lmV)
`
`Beloxe
`dosing
`
`MEAN
`ST.DBV.
`H
`
`1h atcer
`dosing
`
`MEAN
`51.9w.
`N
`P DURATION (um)
`
`Before
`dnsing
`
`MXAN
`ST.DRV.
`N
`“BAN
`3T.DEV.
`N
`P-Q INTERVAL (ma)
`
`1h after
`dosing
`
`Eefcre
`dosing
`
`MEAN
`ST.DBV.
`N
`
`'
`
`1h utter
`dosing
`
`M38”
`ST.DBV.
`N
`033 INTERVAL (ms)
`
`chnrc
`dnaing
`
`lb alter
`dosing
`
`KERN
`ST.DBV.
`N
`
`MEAN
`81.33‘4.
`N
`
`0-? INTERVAL (u)
`
`Baicre
`inning
`
`1h alter
`dosing
`
`MBA)!
`3T.DBV.
`N
`MEAN
`ST.DEV.
`N
`
`95
`1|
`6
`
`95
`£0
`6
`
`0.18
`0.05
`6
`
`0.18
`0.05
`.6
`
`40
`0
`6
`40
`0
`6
`
`87
`10
`6
`
`85
`9
`6
`
`40
`G
`6
`
`4U
`0
`6
`
`‘
`
`26?
`11
`6
`205
`10
`6
`
`38
`1?
`fl
`
`mo
`11
`4
`
`0.}?
`0.05
`1
`
`0.19
`0.06
`4
`
`-'
`
`110,
`26
`4
`
`105
`24
`4
`
`0.23
`0.15
`i
`
`0.25
`0.3.5
`i
`
`do
`D
`4
`40
`D
`4
`
`84
`13
`4
`
`53
`12
`4
`
`40
`D
`4
`
`40
`D
`1
`
`>
`
`209
`15
`4
`205
`ED
`q
`
`43
`5
`a
`43
`.5
`4
`
`90
`15
`i
`
`51
`15
`O
`
`40
`0
`4
`
`40
`0
`4
`
`203
`13
`4
`213
`15
`4
`
`133
`*6
`Q
`
`no
`18
`4
`
`0.31
`0.09
`4
`
`3.25
`0.97
`I
`
`Q3
`S
`4
`4E
`5
`4
`
`7a
`5
`4
`
`83
`13
`4
`
`4c
`fi
`4
`
`40
`G
`4
`
`195 '
`16
`4
`213
`12
`4
`
`i
`
`
`
`Dunnett-tegt based on pooled vaxiincu 919. at 5% or 13 level.
`,_.g,.. =.-,....
`___. _-.u...:ax: a: S: 2: Es -ev.2; hkfbtt 2x. site:
`ixexng.
`
`1%
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`ELECTROCARD IOGRAMS SUMMARY
`WEEK 13
`FEMALES ,
`
`GROUP 1
`GROUP- 2
`GROUP 3
`GROUP 4
`0 MIG/KG‘
`20 HG/KG
`35 MGIKG
`126.. 30 NGI'KU
`
`
`HEART RAT:
`
`(bpm)
`
`Baler:
`dosing
`
`M35“
`ST.DBV.
`fl
`
`1h aftoz‘
`dosing
`
`IRAN
`ST.DBV.
`N
`P MPLI'I‘UDB lmV)
`
`Before
`dosing
`
`1}) nine:
`dosing
`
`“tan
`81.931).
`H
`
`MEAN
`51.nzv.
`N
`
`1’ DURATION (ma)
`
`Befara
`6:03an
`
`1h after
`dosing
`
`-
`
`MEAN
`ST.DEV.
`K
`NEAR
`ST.DRV.
`N
`
`9-0 IRTBRVAL Km!) ‘
`
`scion-1 , W
`dostng
`sr.DxV.
`N
`
`1h ulcer
`dosing
`
`Mshn
`STJJEV.
`K
`
`Dis KRTBRVAL {ma}
`
`Belote
`doting
`
`' mm
`ST.D3V.
`N
`mm;
`57.3“.
`N
`Q-T INTERVAL {my}
`
`1h atcex
`dosing
`
`Before
`do: ing
`
`XEAE
`ST. DEV .
`N
`111 after W
`do: Lng
`3?. DEV .
`N
`
`130
`38
`6
`
`123
`27
`6
`
`0.21
`0.08
`6
`
`0.25
`0.07
`6
`
`‘
`
`'
`
`43
`5
`6
`43
`5
`6
`
`BB
`9
`6
`
`88
`9
`6
`
`40
`0
`6
`40
`0
`6
`
`133
`15
`6
`158
`11
`6
`
`135
`26
`4
`
`133
`22
`4
`
`0.29
`0.13
`4
`
`0.28
`0.09
`1
`-
`
`‘
`
`40
`o
`i
`40
`0
`#-
`
`90
`a
`‘
`
`95
`6
`4
`
`4.0
`0
`4
`4O
`O
`4
`
`186
`s
`4
`193
`26
`4
`
`105
`39
`4
`
`93
`21
`4
`
`0.25
`0.0!
`a
`
`0.23
`0-03
`4
`
`£3
`5
`i
`43
`5
`i
`
`94
`11
`4
`
`98
`13
`ll
`
`m
`0
`4
`10
`0 ‘
`4
`
`195
`6
`l
`120 v -‘.'z
`14
`4
`
`-
`
`‘
`
`103
`29
`6
`
`105
`19
`6
`
`0.22
`0.04
`6
`
`(1.23
`0.0;
`E
`
`43
`5
`6
`43
`5
`6
`
`95
`12
`5
`
`94
`13
`6
`
`40
`a
`6
`90
`0
`6
`
`200
`13
`6
`212
`38
`6
`
` .
`
`:53:
`
`s 1.;fzzanz a: 5- 0:
`
`1E levei: befzre rs. 51:2: 305;:c
`
`139
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22—304
`
`ELECTROCARDIOGRAMS (Q-T CORRECTED)
`PRETEST
`.
`MALES
`
`SUMMARY
`
`GROUP 1
`0 RIO/KO
`
`GROUP 2
`10 FIG/KG
`
`
`
`GROUP 3
`35 RIG/XS
`
`
`
`GROUP ‘1
`120. BB HG/XG
`
`van de water's correction
`
`Precast
`
`MEAN
`ST.DEV.
`N
`
`Yfidafieia'a correction
`
`Preteat
`
`MEAN
`show.
`x
`
`22?
`15
`s
`
`231
`17
`6
`
`223
`7
`4
`
`213
`B
`4
`
`230
`B
`4
`
`233
`11
`4
`
`323
`B
`6
`
`225
`9
`u
`
`ELECTROCARDIOGRAMS (Q ~ 'I' CORRECTED)
`PRETEST
`FEMALES
`
`SUMMARY
`
`
`
`GROUP 2
`1-D HGIEG
`
`GROUP 3
`35 NG/XG
`
`GROUP 4
`120. BO MGIKG
`
`Van de Water ' a correction
`
`Pretes I
`
`MEAN
`ST . DEV .
`)2
`Pridexxcia ' a correction
`
`Pretea :
`
`. MEAN
`31' . DEV .
`N
`
`1 2 5
`1E
`6
`
`2 3 1
`20
`6
`
`23G
`1
`4,
`
`232
`5
`4
`
`22')
`4
`6
`
`131
`7
`6-
`
`226
`9
`Q
`
`235
`14
`4
`
`1%
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`ELECTROCARDIOGRkMS (Q-T CORRECTED)
`WEEK 1
`MALES
`
`SUMMARY
`
`GROUP 1
`0 Hence
`
`GROUP 2
`10 216/116
`
`GROUP 3
`35 HG/KG
`
`63011? 4
`120.
`8’.) HG/KG
`
`
`
`Van de water's carnation
`
`Soto”
`dozing
`
`W
`ST . DEV.
`I!
`
`1!) nine: m
`dosing
`STJIWV.
`N
`i'ridszicia‘s con’ection
`
`Before
`dosing
`
`1h alter
`doting
`
`MEAN
`ELI)“.
`N
`
`my
`5T.DB'V.
`3
`
`232
`s
`<6
`
`234
`10
`6
`
`237
`12
`6
`
`235
`13
`6
`
`225
`-B
`4
`
`231.
`5
`4
`
`226
`9
`4
`
`233
`5
`4
`
`210
`4
`4
`
`240
`9
`9
`
`24?
`’f
`4
`
`24'}
`15
`4
`
`22?
`12
`6
`
`3‘
`
`254 '
`19
`6
`
`'
`
`233
`:B
`5
`
`264 -
`22
`6
`
`figggTEOCARDIOGRAMS (Q-T CORRECTED)
`FEMALES
`
`SUMMARY
`
`GROUP 1
`D KG/RG
`
`
`GROUP 2
`X0 MG/KG
`
`'
`
`GROWS; 3
`35 MG/XG
`
`GROUP ')
`120, 50 313/116
`
`Van cle Water‘s correction
`
`Befcre
`dosing
`
`MEAN
`STJJBV.
`N
`
`3h attet
`dosing
`
`MEAN
`ST.D3V.
`N
`Pridericia ' a corteation
`
`Betore
`dosing
`
`1h after
`dosing
`
`MEAN
`5125811.
`N
`
`mm
`STJJBV.
`N
`
`233
`13
`6
`
`225
`ll
`6
`
`243
`20
`6
`
`230
`13
`6
`
`238
`B
`4
`
`246 '
`.13
`i
`
`143
`15
`4
`
`253
`16
`4
`
`.
`
`232
`11
`5
`
`275 0 r
`9
`6
`
`23"
`16
`6
`
`28‘: ".2
`9
`6
`
`23‘!
`a
`-t
`
`240
`13
`4
`
`238
`15
`I
`
`297
`19
`1
`
`MI
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`ELECTROCARDIOGRAMS (Q~T CORRECTED)
`WEEK 13
`MALES
`
`SUMMARY
`
`
`GROUP 1
`GROUP 2
`GROUP 3
`D NOIKG
`10 MGIXG
`35 HG/KG
`
`
`GROUP 4
`125. 80 HG/KG
`
`Van an Water's correction
`
`Before
`dosing
`
`1h after
`dosing
`
`MEAN
`ST.DSV.
`N
`KERN
`sr.nsv.
`N
`
`Pridegicinis correction
`
`heIora
`dosing
`
`1h after
`flexing
`
`NSAH
`313.1)“.
`N
`
`253M!
`5:.DBV.
`N
`
`.
`
`238
`10
`6
`231
`a
`6
`
`240
`12
`5
`
`339
`10
`6
`
`233
`6
`4
`233
`3
`l
`
`234
`5
`4
`
`2-12
`4
`4
`
`240
`4
`4
`243
`12
`9
`
`246
`8
`d
`
`154
`16
`4
`
`'
`
`230
`15
`4
`243
`5
`4'
`
`239
`26
`4
`
`256 '
`5
`4
`
`'lo': Dunnebt-test based on pooled variance gig. at 5% or 1% levei.
`a.::
`r—zes: a:;nit;2&nt a: E9 :1 2% level; hetoze vs. size: dzsinq.
`
`ELECTROCARDIOGRAMS (Q-T CORRECTED)
`WEEK 13
`'
`FEMALES
`
`SUMMARY
`
`
`
`GROUP 1
`O HG/KG
`
`GROUP 2
`10 XII/x1:
`
`GROUP 3
`35 ‘MG/KG
`
`GRCL’)‘ i
`120, 86 Mai)“:
`
`Van de Hacur’u co:re:tian
`
`Buforn
`dosing
`
`W
`ST.DBV.
`N
`M33!!!
`ST.DEV.
`N
`Pridari:ia'n cotrlctinn
`
`211 after
`dosing
`
`Before
`dosing
`
`1h after
`canny
`
`W
`ST.DEV.
`N
`
`MEAN
`51' . DEV.
`n
`
`227
`8
`6
`23).
`10
`6
`
`-
`
`23‘
`H
`6
`
`238
`14
`5
`
`234
`3
`4
`239
`151
`4
`
`243
`B
`i
`
`249
`2 L
`d
`
`_
`
`213
`13
`4
`149
`14
`Q
`
`232
`22
`I!
`
`253
`19
`i
`
`236
`11
`5
`242
`13
`E
`
`24)
`H
`B
`
`154
`19
`5
`
`HH: Eunnctt-tns: bnscd an pooled variancn wig. at 5% or 1% level.
`:a 5* a: 2' Laval: bofnzv vs‘ after
`
`
`
`I42
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`Enncmoczxnnxocmns (Q—T CORRECTED) summzy
`AFTER RECOVERY
`MALES
`
`GROUP 1
`D HG/‘RG
`
`2‘29
`0
`1
`
`229
`0
`2
`
`
`
`BRO!!!“ d
`120. 80 MG/KG
`
`2‘14
`-..
`J.
`
`252
`---
`J.
`
`Van de flater'a correction
`
`Recovery
`
`MEAN
`STJDEV.
`.‘l
`Prideticia‘n curtactinn
`
`-
`
`Recmmty
`
`mm
`5'12!)th
`N
`
`ELECTROCARDIOGRAMS (Q~T CORRECTED)
`AFTER RECOVERY
`FEMALES
`
`SUMMARY
`
`' amour 1
`O HG/KG
`
`axon? 4
`3.20. 80 DIG/KG
`
`Van de Water's correccion
`
`Recovery
`
`mm
`BLDBV.
`N
`
`Fridericia's confection
`
`Recovery
`
`mm
`$T.DKV.
`N
`
`2“
`12
`2
`
`254
`24
`2
`
`24].
`13,
`2
`
`‘255
`1.5
`2
`
`Hematology: Slight Tred blood cell count, hematocrit and hemoglobin in HD M (120/80
`mg/kg/day) compared to controls (not significant, as the pre-test values in the HD
`animals were higher than in control pre-test values) in Weeks 6 and 13, higher in Week
`13; no treatment-related findings after 4-week recovery.
`
`'
`
`Clinical chemistfl: Slight Tsodium compared to baseline in HDM and HDF in Weeks 6
`and 13, with minimal increases at the MD in Week 13; no associated changes in
`electrolytes, no treatment-related findings after the 4-week recovery period.
`
`Urinalysis: No treatment-related effects.
`
`Gross pathology: No treatment—related effects. 2 HD M that died or were sacrificed
`during the study (No.5 18 and 20) showed dark red thymus and jejunum discoloration,
`associated with acute congestion/hemorrhages commonly found in animals found dead or
`incompletely exsanguinated.
`'
`
`1%
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`Organ weights: No treatment-related effects, as all differences from controls were
`within range of normal biologic variation.
`
`Histopathology:
`
`_
`0 TIncidence and severity of-thymic atrophy
`0 Several M given 35 (2/4) and 120/80 (3/4) mg/kg/day, vs. 2/4 in the
`controls and 1/4 in the LD male dogs
`0 Mean severity 1.0, 1.0, 3.0, and 2.3 in the control, LD, MD, and HD dogs,
`respectively (scale of 0-4 with increasing severity)
`0 Possibly associated to treatment-induced stress response
`0 Tlncidence of chronic inflammation of the prostate ’
`0 Several M given 35 (4/4) and 120/80 (4/4) mg/kg/day, compared to
`finding1n 2/4 controls and 1/4 LD M
`o No treatment-related effects on severity: mean severity 2.5, 1.0, 2.0, and
`2.3 in the control, LD, MD, and HD dogs, respectively (scale 0-4)
`0 Probably not a direct treatment effect, but due to poor general health
`condition, also common in sexually mature M dogs
`0 TIneidence and severity of adrenal corticocellular hypertrophy
`o M given 35 (2/4) and 120/80 (4/4) mg/kg/day, vs. 1/4 in the controls
`0 No treatment-related effects in the MD and HD F
`
`0 within normal range of biological variation
`0 without correlation to adrenal weight in the affected animals
`0 No histopathology findings in the 4-week recovery animals
`
`The notable histopathology findings are presented in the following table:
`
`Daily Dose (mg/kg)
`Number oi'Animals
`Thymus - :tixophy
`Prostate gland— chronic inflammation
`n.d. = not determined.
`
`0 (Conxrgn
`52
`l
`mi.
`
`AM
`2
`2
`
`1Q
`5E
`O
`n.6,
`
`3M
`i
`1
`
`51
`3E
`7
`n.d.
`
`m
`2
`4
`
`.LlQiQ
`31’,
`0
`mi.
`
`m
`3
`=1
`
`Toxicokinetics: Test article exposure was demonstrated in all treated dogs, with high
`intra-individual variability in plasma concentrations, particularly at the HD. There was a
`greater than dose-proportional increase in plasma concentrations. Peak plasma
`tapentadol concentrations observed at approximately 0.5-1 h after dosing. The results of
`the toxicokinetic evaluation are presented in the following table (provided from the
`original NDA submission):
`
`5 nus WM
`cit ORlGlNM
`
`144
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`Table A:
`
`Mean Cmax and AUCM values of CGS503 base
`
`[mg/kg]
`
`.
`
`day 1
`
`4.19: 1.19
`
`4.42: 1.34
`
`26.9: 13.6
`
`43.4:110
`
`86.0: 7.25
`
`day 91
`
`37.1: 19.1
`
`40.5: 11.1
`
`101 : 14.2
`
`110: 42.3
`
`day 91
`
`310: 382
`
`338:534
`
`491: 447
`
`511 : 469
`
`1) The dose had to be reduced from 120 mglkg to 80 mglkg starting with day 22
`
`
`
`
`
`
`Dose
`
`
`ce5503
`[h]
`
`
`
` 17.5 i 3.85
`
`
`13.7: 12.6
`10.1: 3.22
`30.9: 16.7
`
`
`
`18.9: 3.31
`17.1: 2.98
`
`
`Other: Evaluation of hepatic microsomal enzymes showed significant induction of
`aminopyrine N-demethylase activity in M and F. Also, glucuronyltransferase activity
`was inhibited in the M. There were no treatment-related effects on O-deethylase activity.
`The results of the enzyme activity analyses are presented in the following tables
`(provided from the original NDA submission):
`
`-
`
`The mean (2‘. SD.) P450 contents and enzyme activities in male dogs were:
`
`
`
`
`[mglkg]
`Control
`120
`
`
`
`[pmollmg]
`
`[pkattmg]
`
`475 t 87
`
`25.0 i 3.3
`
`not significant not significant
`ANOVA p—values
`
`Induction is expressed as 120 mglkg vs. control ratio
`
`[pkat/mg]
`31.1 : 1.5
`40.2 i 1.4
`
`
`
`
`0.001
`
`[pkat/mg]
`17.5 : 0.4
`13.2 i 1.?
`
`0.012
`
`
`
`
`The mean P450 contents and enzyme activities in female dogs were:
`
`[mg/kg]
`
`120
`
`
`[pmol/mg}
`
`586 :r 81
`
`[pk’attmg]
`
`
`
`51.8 i 14.1
`
`
`
`[pkat/mg]
`
`{pkab’mgfl
`
`55.7 i 10.9
`
`14.9 i 3.3
`
`
`
`
`
`
`165
`
`
`
`95
`
`not significant
`
`
`
`induction [%]
`
`
`ANOVA p—values
`Induction is expressed as 120 mglkg vs. control ratio
`
`128
`
`158
`
`145
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22—304
`
`Study title: CG5503: 52-Week Oral (Gavage) Toxicity Study in the Dog
`
`Key study findings:
`The target organs were the CNS and cardiovascular system
`Convulsions at the HD in 2 F (80 mg/kg/d, exposure slightly less than that at the
`clinical MRHD on an AUC basis, and approximately 2 times the exposure on a
`Cmax basis)
`0 Resulted in sacrifice in extremis in one of the dogs
`0 Known effect of opioid receptor agonists
`
`o Reversal by naloxone supports relationship to opioid pharmacological
`
`effect
`
`0 Not observed after the recovery period
`, T includin
`Tc
`ridericia’s and Van de Water’s corrections
`prolongation at the HD
`0 Observed throughout the study1n nearly all of the HD M and F
`o Reversible; not observed after the 4—week recovery period
`Slight, minimal decrease in partial thromboplastin time in the HD M and-F
`throughout the treatment period, not reversible (observed at end of recovery)
`Slight increase in plasma sodium at the HD, compared to controls but not to
`baseline measurements, and with no associated changes in other electrolytes
`Minimal to slight focal gliosis with perivascular mononuclear cell infiltration
`in the medulla oblongata and/or pons in 1 HD F and in 2 MD F and 1 MD M,
`without relationship to convulsions and considered to be spontaneous, in
`agreement with the pathologist
`No treatment-related effects on P450 content; however, dose-related increases in
`O-deethylase activity were observed in F and dose-related increases in N-
`demethylase activity were observed in M and F.. 2—amin0phenol
`glucuronyltransferase activity was decreased in M and F.
`The NOAEL was 10 mg/kg/day
`'
`The systemic exposure to the parent drug at the NOAEL (AUC = 23.3 mcg.h/ml
`in the males and 16.6 mcg.h/m1 in the females) represented approximately 0.05
`times the clinical exposure (=500 ng.h/ml) at the MRHD of 600 mg/day.
`The peak plasma tapentadol concentrations (Cmax) at the NOAEL (6.8 meg/L in
`M and 6.3 mcg/L in F) represented approximately 0.06 times the Cmax (z 118
`ng/ml) at the MRHD of 600 mg/day.
`Exposure to the O-glucuronide metabolite at the NOAEL represented
`approximately 1.5 times the clinical exposure at the MRHD, AUC basis
`0 Demonstrates lower metabolic transformation to the glucuronide in dog,
`when compared to rat which showed considerably higher glucuronide
`exposures
`
`Study no.: TP2441
`
`I46
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`a
`
`Conducting laboratory and location: C
`
`,,
`
`,
`
`j _
`
`Date of study initiation: June 10, 2002
`GLP compliance: Yes
`QA report: yes (x) no ( )
`Drug tapentadol (here also referred to as BN200 and/or CG5503), lot # (Batch
`CEWSl 12, and % purity: 98.3%
`
`Methods
`Doses: 0, 10, 30, and 80 mg/kg/day; the doses were selected based on the results
`of the 13-week study in Beagle dogs (See Study TP2415). The animal allocations are
`presented in the following table (provided from the original NDA submission):
`
`Dose Levei
`.
`Male Numbers
`
`Group 1
`
`Group 2
`
`Group 3
`
`Group 4
`
`. 0 mglkglday
`1-6
`
`10 mglkglday
`7-10
`
`30 mglkglday
`11—14
`
`80 mgI-kglday
`15-20
`
`
`
`Female Numbers 35-40 21—26 27-30 31-34
`
`
`
`
`
`
`
`Dose levels are expressed in terms of the material as supplied
`
`Animal Nos. 5, 6, 19, 20, 25, 26, 38 and 39 In Groups 1 and 4 were allocated to a 4-weeK
`recovery period following the treatment period.
`
`jvaccinated
`Species/strain: Pure—bred Beagle dogs (C
`against distemper, leptospirosis, parainfluenza, contagious hepatitis, bordetella, canine
`papilloma virus, rabies and parvovirus)
`Number/sex/group or time point (main study): 4/sex/dose
`Route, formulation, volume, and infusion rate: The test article was dissolved
`in tap water, and administered by oral gavage at 2 ml/kg, once daily. Dose formulations
`were analyzed using triplicate samples (2 ml/sample) on Day 1 and during Weeks 6, 26,
`32, 45, and 52.
`Satellite groups used for’toxicokinetics or recovery: 2 additional dogs/sex/dose
`controls and HD for 4-week evaluation of reversibility
`v
`Age: 6-8 months
`Weight: 7.7-11.7 kg
`Unique study design or methodology: The dogs were housed in group pens,
`although separated during feeding and observations, and were fed 350 g/day pelleted
`standardp: '
`:ldog maintenance diet at 1h after dosing. The feed was removed
`from access after 3 hours. Tap drinking water was provided ad libitum. Microsomes
`were prepared from the livers of 3 males and females in the groups administered 0, 30,
`and 80 mg/kg/day CG5503, for analysis of P450 content, and N-dealkylation, O-
`dealkylation, and glucuronyltransferase activities.
`
`13(4)
`
`h(4)
`
`M7
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`Observation times:
`
`Mortalifl: Twice daily.
`
`Clinical signs: Twice daily.
`
`Body weights: Baseline and once weekly.
`
`Food consumption: Baseline and once daily.
`
`Ophthalmoscopy: Baseline, during Dosing Weeks 13, 25, 39, and 52, Recovery Week 5.
`
`EKG: Before dosing and at 1 hour post dose at baseline and during Dosing Weeks 1, 13,
`25, 39, and 51, and Recovery Week 5.
`
`Hematology: Blood samples collected from the jugular vein at baseline and during
`Weeks 6, 13, 25, 39, 52 and recovery Week 5, from all fasted-overnight animals;
`standard parameters were evaluated.
`
`Clinical chemistry: Blood samples collected from the jugular vein at baseline and
`during Weeks 6, 13, 25, 39, 52 and recovery Week 5, from all fasted-ovemight animals;
`standard parameters were evaluated.
`
`Urinalysis: Urine was collected using a catheter from all dogs during Weeks 6, 13, 25,
`39, 52 and recovery Week 5; standard parameters were evaluated.
`.
`
`Gross pathology: All animals were examined, including decedents. The surviving dogs
`were examined after 52 weeks treatment and 4 weeks recovery.
`
`Organ weights: The following organs were weighed, from all dogs at necropsy: adrenal
`glands, brain (including brainstem), heart, kidneys, liver, ovaries, pituitary gland, prostate
`gland, spleen, testes with epididymides, thymus, thyroid gland with parathyroid and
`uterus.
`
`Histogathology: Adequate Battery: yes ( x ), no( )
`Peer review: yes ( ),
`rig ( x)
`Principal Investigator: L
`
`_
`
`b“)
`
`The following organs and tissues were examined microscopically: adrenal glands, aorta,
`bone (femur with articular surface), bone marrow (sternum), brain (including
`medulla/pons, cerebral and cerebellar cortex), epididymides (fixed in Bouin’s solution),
`esophagus, eyes (with optic nerve, Heidenhains’s Susa solution), female mammary gland
`area, male mammary gland area, gallbladder, heart, kidneys with ureters, large intestine
`(cecum, colon, rectum), larynx, liver, lungs (with bronchi and bronchioles, infused with
`formalin), lymph nodes (retropharyngeal, mesenteric), ovaries, pancreas, Peyer’s patches,
`pituitary gland, prostate gland, salivary glands (mandibular, parotid, sublingual), sciatic
`
`148
`
`

`

`Reviewer: Kathleen Young, PhD.
`
`NDA No. 22-304
`
`nerve, skeletal muscle, skin, small intestine (duodenum, jejunum, ileum), spinal cord
`(cervical, mid-thoracic, lumbar), spleen, stomach, testes (fixed in Bouin’s solution),
`thymus, thyroid gland including parathyroid gland, tongue, trachea, urinary bladder,
`uterus with cervix and oviducts, vagina and all'gross lesions.
`
`Toxicokinetics: Blood samples (4 ml from the jugular vein) were collected on Day 1 and
`in Weeks 26, 39, and 52, at 0.5, 1, 3, 6, 8, 12, and 24 hours afier dosing
`
`
`Other: Liver samples collected from all dogs at necropsy, for enzyme activity analysis.
`
`Results:
`
`Mortality: There was one death in. a HD F (#40), which was sacrificed in extremis on
`Study Day 12 following observations of convulsions on 2 days (Days 4 and 12).
`
`Clinical signs:
`0 Convulsions were observed in 2 HD (80 mg/kg/day) F
`. 0 Days 4 and 12, 30 minutes after dosing in dog #40
`I
`resultingin sacrifice in extremis
`I
`dosing stopped from Days 5-7, resumed on Day 8
`I
`no abnormal necropsy findings1n this dog
`0 Days 178, 308, 316, 344, 345, and 358, starting 20-30 minutes after
`dosing, and lasting 5 hours in dog #37
`o Convulsions accompanied by paddling movements, muscle twitching,
`tremor, recumbency and decreased activity with deep respiration.
`o Reversed by naloxone administration
`- Decreased activity and salivation daily throughout study "at 30 and 80 mg/kg/day
`0
`Frequent recumbency, vomiting, and tremor, and occasional whimpering at 30
`and 80 mg/kg/day
`Fearfiilness, occasionally at 80 mg/kg/day
`o
`0 Clinical signs started at 15-30 minutes after dosing and lasted up to 5 hours.
`
`The treatment-related clinical signs during the study are summarizedin the following
`table (provided from the original NDA submission):
`
`Dally dnse (mg/kg)
`Xumber or Animals
`('liniml Obsen-nlious
`Ccnwlsions
`Decreased acriviry
`Sammie-1
`Tram-:1
`Fearful
`Recumbeucy
`V'umixing
`F.ces ccummg mucus
`
`0 (Control
`91
`
`.
`.
`—
`.
`-
`-
`Yes
`‘1'es
`
`m
`
`.
`.
`-
`.
`-
`-
`-
`Y:5
`
`'
`
`fl
`
`52
`
`.
`_
`-
`_
`-
`-
`Yes
`Yes
`
`m
`
`.
`.
`—
`.
`-
`-
`Yes
`Yes
`
`_3_0_
`
`=15,
`
`3Q
`m 1;:
`
`.
`+
`+.+—+
`.;.
`-
`Yes
`Yes
`Yes
`
`_
`+
`—:.+—1-
`_
`-
`Yes
`Yes
`Yes
`
`—
`_
`—:.—1—'r
`_
`-
`Yes
`Yes
`Yes
`
`m
`
`.
`s
`23+
`.;.
`-
`Yes
`Yes
`Yes
`
`— = No note.V.‘;.-'o:th findings += Mild .—‘ = Modem“: —-L-Z- =Marked
`
`I49
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`’
`
`NDA No. 22-304
`
`Body weights: Slight reduction in BW (-0.2 to -0.8 kg) at 80 mg/kg/day during first 2
`study weeks. Body weights reduced in F at 10 (-1.0%), 30 (-4.0%), and 80 (-4.0%)
`mg/kg/day compared to controls, at end of study. The body weight evaluation results are
`presented in the following table (provided from the original NDA submission):
`
`m
`in
`91mm]:
`Daily dose (mg/kg)
`m g
`3):.
`fl
`g
`4._\-I
`fig
`_6__M.
`Number of animals
`+0.9
`4.0
`i—‘l.0
`0
`-L0
`+5.6
`9.9
`10.7
`Bully weight (kg’)
`a) at the end ofdosing period. For controls= means are shown. For treated groups, percentage differences from controls are $110wa 1
`
`111
`
`»
`
`Food consumption:~ Slight reduction in food consumption at the highest dose during the
`first 2 weeks of the study (-11% to -23% in M and -9% to‘ -11% in F). At the end of the
`study, food consumption was reduced in the HD M and HD F, compared to controls. The
`results of the food consumption measurements are presented in the following table
`(provided from the original NDA submission):
`
`‘ Daily dose (111ka
`NW“? 01 Min-“‘5
`Food consumption (animal/day“)
`
`W
`5}.
`295
`
`m
`350
`
`1‘21
`0
`
`1-9
`
`E
`+2.4
`
`1‘21
`0
`
`3-9-
`LE
`+4.1
`
`-
`
`.89.
`M 9.5
`4.6
`-5.4
`
`a) at the end of dosing period. For controls: means are shown. For treated groups, percentage differences fi'om controls are shown.
`
`Ophthalmoscopy: There were no treatment-related effects.
`
`EKG: Dose-related prolonged QT
`0
`beginning at 1 hour after closing in almost all HD animals
`0
`observed throughout the study
`0
`increased corrected QTc interval values at the HD (80 mg/kg/day), suggesting QT
`prolongation effect not related to heart rate fluctuations
`reversible, no treatment-related effects during and after the recovery period.
`no other treatment-related effects in the ECG evaluation
`
`-
`0
`
`The results of the EKG observations for QT interval (in ms., iS.D.) are presented in the
`following tables (provided from the original NDA submission):
`
`QT Interval Observation Summary: Males
`GROUP 1
`GROUP 3
`6101!? 3
`6303? 4
`
` 0 Fifi/KG 10 file/KG 30 £6le ' 80 ”6/16
`
`
`
`G—I‘
`
`IXTZRVAL (m3)
`
`Pretest
`
`Protest
`
`“BAN
`ST-DEV.
`N
`
`192
`15
`6
`
`208
`10
`4
`
`201
`9
`4
`
`190
`13
`6
`
`150
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`11m (in Nauru: correction
`
`Erato-t W .
`Sikh“.
`w
`rfldexlcil‘ I corn: um:
`
`Prom“: W
`arm".
`l!
`
`,
`
`234
`11
`s
`
`239
`n
`6
`
`2“
`7
`4
`
`253
`12
`O
`
`Week 1
`
`'
`
`our xmuvu (m)
`
`sue:- m
`doling
`51' . DEV .
`n
`
`in at“: W
`dosing
`smmw.
`n
`
`Van do Nacot'l cognuuon
`
`3010!! M
`(losing
`31' .3)“.
`x
`1h litcx W
`dating
`31.9w.
`fl
`iridoxtch‘ a cots-action
`
`Bulozn m
`dosing
`3?.DW._
`)l
`1!: 51:1: W
`doling
`smm.
`N
`
`234
`3.4
`6
`239
`1‘
`6
`
`212
`18
`6
`all
`1.9
`6
`
`A
`
`133
`16
`s
`
`195
`2a
`s
`
`203
`13
`4
`
`210
`14
`4
`
`‘
`
`2‘0
`7
`4
`23!
`1.0
`i
`
`215
`11
`4
`242
`11
`4
`
`137 ‘
`10
`6
`
`219
`24
`a
`
`215
`G
`4
`
`253
`6
`l
`
`343
`10
`4
`243
`4
`4
`
`250
`14
`4
`2"
`5
`O
`
`no
`3
`4
`
`208
`:5
`4
`
`‘
`
`23 S
`a
`6
`
`215
`11
`6
`
`237
`8
`6
`35‘
`17
`6
`
`2“
`13
`6
`259
`2.5
`6
`
`0-1 INTERVAL (m)
`
`Week 13
`
`Before
`dating
`
`um ‘
`81.13211.
`N
`
`19?
`14
`6
`
`195
`25
`l
`
`-
`
`‘
`
`201
`10
`G
`
`102
`19
`6
`
`1h aftor
`dosing
`
`an»:
`57.0”.
`R
`
`203
`a
`6
`
`305
`31
`4
`
`'
`
`6
`
`I
`
`210
`12
`II
`
`220
`2|)
`
`APPEARS nus my
`on! ORIGINAL
`
`151
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`Vim d. uncaz's con-action
`
`3.1an m
`“Bing
`SLIDE.
`R
`
`11; um:
`doting
`
`mm:
`STJDW.
`N
`l'ridezicia'a ”traction
`-.-..-....--.--...--...
`
`fi._
`
`actors W
`dosing
`snmzv.
`N
`
`ID “to:
`dating
`
`new
`31.1mm
`n
`
`232
`5
`6
`
`:32
`10
`6
`
`235
`6
`6
`
`234
`15
`s
`
`232
`M
`4
`
`234
`15
`0
`
`236
`12
`I
`
`331
`13
`A
`
`336
`10
`I
`
`2:1
`7
`d
`
`240
`17
`I
`
`239
`10
`4
`
`241
`15
`6
`
`254 .
`1‘
`6
`
`247
`14
`5
`
`259 0
`15
`5
`
`
`
`9-1 Imnvm.
`
`(mi)
`
`Week 25
`
`Saint.
`dosing
`
`mm!
`SLIDE},
`n
`
`195
`8
`6
`
`200
`14
`4
`
`205
`25
`4
`
`194
`13
`6
`
`1!: liter
`dosing
`
`213
`200
`20'
`303
`HEM!
`20
`16
`22
`8
`ELDEV.
`N
`.
`6
`4
`4
`6
`
`
`Va: is “new: con-action
`
`actors W
`dosing
`SLDBV.
`H
`
`1h fiftix
`doling
`
`HE”!
`smuw.
`N
`Iridexicia ' a cotton tlon
`...-.-_-.--...-----....
`
`Buforo
`dosing
`
`“RAN
`$2.13“.
`N
`
`\r
`
`231
`7
`6
`
`237
`5
`6
`
`233
`9
`6
`
`238
`6
`4
`
`215
`12
`i
`
`245
`13
`Q
`
`234
`9
`l
`
`238
`9
`4
`
`237
`12
`4
`
`237
`4
`5
`
`2‘7
`13
`G
`
`I46
`6
`6
`
`11" liter
`“ling
`
`253
`243
`151
`2-10
`MEAN
`16
`10
`12
`B
`SILDBV.
`N
`6
`4
`4
`6
`
`
`9-1 IM'K'RVAL (nu)
`
`Batons
`dosing
`
`1]: liter
`dosing
`
`m
`snnxv.
`N
`
`Hz»:
`SLDIV.
`N
`
`W
`
`198
`26
`i
`
`195
`30
`I
`
`183
`15
`6
`
`183
`9
`6
`
`203
`13
`4
`
`213
`21
`«I
`
`186
`23
`6
`
`207
`31
`6
`
`
`
`152
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No; 22-304
`
`V“ dc Water's “traction
`.----~uy—----.—----v-..s-
`
`Solon m
`donut;
`SLDSV.
`u
`
`in In" W
`doling
`3111)“ .
`.
`N
`
`iridoricia' ; cot-nation
`lunl-w‘t-iw-w--~vwr-—-—
`
`“for.
`doting
`
`ms
`52.9w.
`a
`
`1]: nits: m
`doling
`smnxv.
`N
`
`225
`B
`s
`
`230
`I
`6
`
`227
`8
`s
`
`235
`a
`a
`
`2.3.1
`11
`4
`
`230
`15
`4
`
`234
`7
`i
`
`23:
`12
`1
`
`.
`
`235
`10
`4
`
`249 .
`9
`I!
`
`233
`12
`4
`
`155 ' i
`1
`4
`
`2:5
`16
`5
`
`241
`n
`6
`
`237
`11
`i
`
`2157
`15
`6
`
`
`
`9—! IMSRVRL (an)
`
`Mil
`
`anion m
`dosing
`snbzv.
`n
`
`193
`8
`s
`
`.
`
`190
`O
`4
`
`.
`
`1.85
`.1!
`4
`
`187
`16
`5
`
`203 .
`19:
`us
`137
`an»:
`11: nice:
`'
`9
`15
`1o
`3
`snow.
`dos—lug
`
`
`
`
`, 5 4 4n s
`
`
`
`vnn at Water's cox-nation
`~--..-_--.----..--..---vv
`
`3.10?! W
`doting
`51mm.
`2:
`~
`
`1h if“: m
`doling
`SL9“.
`N
`mastieia' a correction
`
`Belar-
`doling
`I
`
`mm
`Sikh” .
`I!
`
`230
`10
`‘
`
`232
`I
`s
`
`132
`14.
`5
`
`233
`12
`4
`
`225
`11
`4
`
`239
`11
`C
`
`337
`10
`4
`
`231
`9
`4
`
`231
`10
`0
`
`‘
`
`229
`8
`6
`
`233
`C
`6
`
`234
`9
`6
`
`11: liter
`donut:
`
`ram
`$1.9“ .
`H
`
`237
`10
`6
`
`226
`14
`4
`
`23.1
`9
`4
`
`235
`6
`
`6 F
`
`ollowing 4-Week Recovery
`GROUP 1
`anon? ‘
`D HBIIG
`80 KG/Xa
`
`
`9-1 xmxmm. {an
`
`'
`
`Rucwory
`
`mm
`STJJBV.
`n
`
`195
`7
`2
`
`no
`14
`
`2
`
`153
`
`

`

`Reviewer: Kathleen Young, ‘Ph.D.
`
`NDA No. 22-304
`
`Van do "not": cart-cum:
`
`Racovory m
`51‘ .0“.
`fl
`
`"id-dun: correction
`
`22!
`2
`2
`
`245
`6
`:
`
`2‘9
`223
`mm
`R-covory
`S
`4
`ST .9”.
`
`
`2N I
`v": Dmitt~to|t bnaa on paona mama‘s ulc- inst o: H mm.
`
`
`QT Interval Observation Summary: Females
`
`no» 1
`' may 2
`snow 3
`new a
`ll DEG/KG
`1.0 Mlle
`30 nan/m
`ID FIG/KG
`
`
`9-! zmnvm. (nfl
`
`Pretest
`
`Prutqat
`
`199
`205
`19B
`200
`mm
`87-bit
`14
`1‘)
`10
`22
`N
`6
`4
`I
`6
`
`
`_
`
`van do “not": «traction.
`
`nun:
`
`nun
`Slab“.
`n
`thaorictn'l emulation
`
`2“
`11
`s
`
`:35
`11
`4
`
`'
`
`241
`9
`i
`
`239
`14
`6
`
`
`
`245
`11
`4
`
`246
`16
`6
`
`255
`14
`6
`
`240
`11
`4
`
`.
`
`0-! INTERVAL (In!)
`
`Week 1
`
`aurora
`dosing
`
`193
`198
`193
`192
`W
`19
`13
`5
`10
`SLDIV.
`6
`a
`.
`i
`6
`N
`227 ' l
`210
`198
`20!
`1!: after m
`doling
`S'LDW.
`.
`‘ 14
`5
`12
`16
`R
`5
`i
`4
`6
`
`
`.
`
`Van do Haror'c correction
`
`Baler.
`dosing
`
`W
`ELDBV.
`n
`
`1h alter
`dosing
`
`Ham
`51.1751.
`N
`Priduricln'l carnation
`
`Baler.
`dosing
`
`ms
`SILDBV.
`N
`
`u; an“ m '
`doling
`52.1731].
`N
`
`234
`11
`6
`
`1“
`13
`6
`
`no
`17
`6
`
`:51
`19
`s
`
`.
`
`239
`10
`a
`
`an
`11
`i
`
`m
`u
`4
`
`an
`14
`4
`
`239
`11
`6
`
`269 .. I
`13
`G
`
`2‘8
`10
`6
`
`232 n .
`14
`6
`
`235
`7
`4
`
`240
`11
`4
`
`241
`10
`4
`
`247
`17
`A
`
`154
`
`‘
`
`

`

`Reviewer: Kathleen Young, PhD.
`
`NDA No. 22-3 04
`
`0—1!
`
`IN'IJZRVAL (ma)
`
`Week 13
`
`Rotor:
`dosing
`
`HEAR
`srmxv.
`N
`
`202
`O
`5
`
`.
`
`189
`13
`I
`
`130
`12
`‘
`
`190
`1‘
`5
`
`22‘:
`no
`205
`no
`1h nu: W
`don 1:19
`3': . mzv .
`9
`1.0
`12
`25
`
`‘
`ll
`6
`_
`4
`6
`5
`
`'
`
`Van dc "aux”. carnation
`
`3.20:-
`dosing
`
`W
`ST . DIV .
`x
`
`1h Altar
`closing
`
`ms
`81mm.
`N
`Priduricia ' a correction
`
`auox'.
`don my
`
`ms
`31'. DIV.
`N
`1!: like: W
`doting
`51.1)“.
`N
`‘
`
`333
`8
`6
`
`233
`16
`5
`
`:36
`11
`6
`335
`16
`5
`
`223
`'J
`A
`
`237
`10
`I
`
`231
`a
`4
`240
`14
`I
`
`233
`10
`t
`
`2‘3
`4
`-I
`
`:31
`11
`C
`216
`C
`I
`
`232
`14
`5
`
`262 ‘1.
`16
`5
`
`202
`20
`5
`.212 D. .
`17
`5
`
`0-7 INTXRVAL (ma)
`
`Week 25
`
`136
`18!
`190
`197
`Eclorc m
`15
`10
`12
`8
`dosing
`51.12“.
`5
`«I
`i
`6
`N
`203
`195
`138
`203
`m}!
`1h utter
`dosing
`$1 . D317 .
`4
`10
`10
`20
`H
`6
`4
`4
`5
`
`Van do interim corructlon
`
`Eoforb m
`doping
`snmzv.
`-
`N
`1h at“: W
`dosing
`STJIV.
`R
`Pridortcia'l correction
`
`
`Batons
`dosing
`
`MEAN
`81.0!V.
`H
`
`239
`7
`6
`239
`B
`6
`
`245
`S
`6
`
`241
`1.2
`4
`235
`10
`4
`
`255
`16
`4
`
`23‘
`12
`i
`228
`J
`l
`
`241
`17
`4
`
`‘
`
`236
`15
`5
`2“
`H
`5
`
`249
`20
`5
`
`259
`229
`243
`253
`111 after W
`doting
`Ear-DIV.
`13
`13
`1
`16
`ll
`6
`4
`I
`5
`
`
`0-1 INTERVAL (m)
`
`3020:.
`doling
`
`MAN
`51.13817.
`N
`
`1h utter W
`dosing
`SLDKV.
`N
`
`Week 39
`
`'
`
`'
`
`194
`9
`4
`
`139
`10
`4
`
`19']
`3
`‘ S
`
`197
`u
`S
`
`180 '
`0
`4
`
`193 "
`10
`4
`
`190
`12
`5
`
`195
`11
`5
`
`155
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22—304
`
`Van do Water's correction
`
`Bifon W
`“fling
`S‘LDW.
`N
`
`1h lit-r W
`(lasing
`STA)”.
`.
`N
`Rid-data ‘ I cart-etion
`
`Before m
`doting
`51.939.
`R
`1h altar W
`do-ing
`51‘ . va .
`N
`
`our zmznwu.
`
`(as)
`
`392mm
`dfililg
`
`in am:-
`dosing
`
`NBA"
`3‘: . DEV .
`H
`ms
`57.1387.
`N
`‘
`
`Van do HIEBE'S corraction
`
`Eaters
`dating
`
`‘
`
`m an“
`cloning
`
`IBM
`81.5“.
`n
`
`mm
`ST-DBV-
`N
`
`tridericia': correction
`
`Before
`douing
`
`REM
`57-9w.
`N
`
`235
`B
`6
`
`233
`10
`6
`
`245
`12
`6
`247
`11
`S
`
`193
`B
`6
`155
`16
`6
`
`233
`7
`6
`
`230 "
`5
`a
`
`'
`
`247
`9
`6
`
`230
`l
`4
`
`230
`11
`i
`
`232
`10
`e
`235
`1‘!
`l
`
`_
`
`-
`
`’
`
`3196.191
`
`'
`
`188
`10
`II
`no
`I
`4
`
`'
`
`-
`
`‘
`
`230
`5
`4
`
`225
`3
`I
`
`‘
`
`235
`7
`4
`
`22'!
`2
`4
`
`235
`10
`l
`
`233
`5
`4
`241
`1.!
`4
`
`1:33
`10
`4
`u»
`14
`1
`
`227
`9
`4
`
`230
`12
`4
`
`231
`u
`4
`
`232
`19
`5
`
`238
`11
`5
`
`“3
`25
`5
`218
`1'!
`5
`
`231
`a
`5
`
`am
`u
`s
`
`2‘1
`1.1
`5
`
`188 4
`11
`5
`203
`an
`5
`
`11: “cu-
`dissing
`
`um
`smmzv.
`n
`
`23: '
`5
`6
`
`no
`10
`4
`
`2:“
`.u
`1
`
`2n
`20
`
`5 F
`
`ollowing 4-Week Recovery Period
`GROW I.
`‘
`GROUP 4
`a mine
`so Helm
`
`
`0-? INTERVAL (n5,
`
`Rocovory.
`
`130
`200
`xx»!
`O
`0
`52.0“;
`N
`2
`2
`
`Van do Water'l correction
`
`Rocovury
`
`MEAN
`ST.DIV.
`N
`Iridancin'n corroction
`
`Recovery
`
`xx»!
`STJIEV.
`N
`
`212
`3
`3
`
`2!!
`5
`2
`
`231
`1
`2
`
`242
`4
`2
`
`156
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`"9-: manager-test based on pooled variance 319. at 5! or 1% 1W6].—
`a!!.:: bias: significant at 53 or 1! level.- bear-‘4 v5. after dosing.
`
`Hematology: Partial thromboplastin time (PTT) was decreased in the HD M and F
`throughout the study, compared to controls. The PTT values are presented in the
`following tables (provided from the original NDA submission):
`
`M
`
`PTT
`
`H .1
`
`1531
`
`6
`
`1831 13
`
`£131 25
`
`111511 S
`
`sax &
`
`m was
`
`.
`
`m
`amp 11am;
`1m m1
`
`sac
`
`Rap 1
`11am
`1 m
`
`amp 2
`Lu Dose
`111 nuns;
`
`cm; :1
`11111 case
`31 1191119
`
`amp 4
`1119*» nose
`an m
`
`If!"
`5.0.
`11
`
`1-911
`3.0.
`14
`
`EM
`8.0.
`11
`
`1611
`8.11.
`11
`
`FEW
`SD.
`H
`
`11341
`3.0.
`11
`
`rim
`3.0.
`11
`
`19.2533
`1.41
`‘6
`
`18.45ad
`(LE
`s
`
`211.7%
`hfi
`s
`
`21.6311
`11.54
`e
`
`19.2%
`0.55
`-6
`
`211.139 11
`133
`s
`
`mesa
`2.76
`2
`
`2LE
`1.47
`4
`
`17.15
`1.29
`4
`
`211.33
`1.07
`4
`
`211.41
`11.3
`4
`
`211.13
`1.49
`4
`
`_
`
`.
`
`21.42
`2.83 _
`4
`
`-
`
`1* = 1741.11
`
`w
`
`.
`
`18.77
`11.49
`4
`
`15.84
`1.32
`4
`
`1931
`0.814
`4
`
`111.711
`1.91
`4
`
`£332
`1.15
`4
`
`18.83
`2M .
`4
`
`17m
`212
`s
`
`15.82“
`0.63
`15
`
`13.1191
`0.91
`a
`
`17.112"
`1.51
`s
`
`15.12“
`0.75
`6
`
`18.42
`1.52
`a
`
`2445
`0.92
`2
`
`6111;: 4
`m 3
`mm 2
`(mm 1
`(‘mm
`111m Dose
`11111 nose
`L114 nose
`001mm
`(m: We
`80 119119
`:51 1191119
`10 WM
`11 1191119
`Dose 151131
`....................................................................................................................................
`
`157
`
`

`

`Reviewer: Kathleen Young, PhD.
`
`NDA No. 22-304
`
`PIT
`
`sec
`
`fl -1
`
`m 6
`
`“391 13
`
`PB 25
`
`IE! 39
`
`sex 52
`
`P8204911 “£1 5
`
`'
`
`If!”
`8.0.
`H
`
`m
`3.0.
`11
`
`EM _
`3.0.
`N
`
`M
`SD.
`N
`
`m
`SD.
`N
`
`19111
`8.0.
`N
`
`m
`SD.
`11
`
`17.35 a
`0.5
`6
`
`16.3? a
`1.02
`6
`
`18331
`0.91
`5
`
`”ma
`1.48
`6‘
`
`15.08 3
`1.35
`5
`
`18.fi3 a
`2.07
`6
`
`$.70 a
`#24
`2
`
`17.45
`OR
`
`15.75
`[LE
`
`18.2?
`0.45
`
`17.17
`0.5
`
`15.40
`0.2
`
`18.2
`{1.87
`