NDA No /' “(41
`Reviewer: BeLinda A. Ha es Ph.D.
`
`
`
`2.6.5 PHARMACOKINETICS TABULATED SUMMARY
`
`Absorption:
`
`Pharmacokinetics parameters of lacosamide following oral administration to mice.
`
`AUCMmulvgmll]
`Farrah
`
`0.5“
`
`‘ 015“
`0.5“
`0.5"
`
`.
`
`140
`i3
`229
`
`U!
`(D
`‘13.-
`"U
`0m
`93..
`g.
`(p
`o
`'8
`<
`
`,
`
`‘
`
`31(4)
`
`15.0
`40.7
`hdinidmldmormedimsfi'an 2prrcfilesm m.
`n--f1'rst mpljrgtine
`Dm sauces: Tabla;£65 313. -— 1344?.04; T1hl*"'"- 53C, 7 BTTZI05;Ta1:J.e 2.6.33'
`42..32] ”131212.420 Agrpam.)14232.2 '- 13123.00.Appa:\.d3{10-5.
`4.23.411." B124I03.£;>puflix 11-5.
`'
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`109
`
`0.5"
`0.5”
`
`10
`
`.5“
`
`16 .0
`17 .7
`16 .8
`20 .0
`32.6
`26 .9
`41 .6
`2'9 .0
`29.9
`33 .9
`29 .3
`
`13.3
`16.9
`14.0
`20.4
`16.6
`24.”?
`29.5
`2'16
`290
`3‘10
`30.4
`39.9
`30.1
`46.3
`36.6
`
`

`

`
`
`Reviewer: BeLinda A. Ha es PhD. NDA No.
`
`Pharmacokinetics parameters of lacosamide following oral administration to rats.
`
`
`27.5
`05"
`3.5“
`169
`22.2
`3.5"
`3.5"
`139
`13.9
`3.5“
`0.5“
`130
`34.4
`35“
`1
`299
`46.6
`1
`1
`333
`29.3
`0.5“
`n.5“
`323
`1
`25.3
`262
`26.4
`235
`33.7
`296
`22.0
`142
`36.n
`172
`5?.3
`514
`-
`512
`-
`635
`30.7
`33.9
`62.4
`59.6
`
`1?.6
`
`15.2
`
`213
`21.3
`
`57.9
`495
`32 I?
`38.2
`4'." .0
`
`1 year
`-as
`6116111115
`1 year
`2 years
`1 day
`31:16:31.5
`691mm
`111a]
`311mm
`MW
`1year
`2 -ars
`
`180
`
`-
`
`300
`
`
`
` _2
`
`
`
`
`
`216
`218
`l
`40.3
`342
`111337
`1
`403
`340
`1
`5'11
`33.6
`3 months
`
`17611125 mmed'nns trmems m= 2m 3 pofflesyorphmuckmticpmemswu‘e calmhtgdwirhmem
`phmncmemnfimu.
`n -fiIV;t9mplirgtine
`Dan smrces: 423.25. 148—231 Himacfihefiz wahmicnmpurt; 4232.6. _- 32217903. 2‘1)qu 10-5;
`4.23.4.1} -— 3295403. @1391de 11-5.
`
`
`
`
`
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`w
`(D
`'59--
`'8
`U,
`2_
`0'
`6
`
`o0 a
`
`b i
`(4)
`
`193
`232
`429
`3:1
`342
`311
`313
`339
`152
`229
`659
`-
`
`'
`
`1
`
`1 1l
`
`3.5“
`
`.5“
`
`3
`l
`1
`
`1 2
`
`.
`
`5
`
`35'
`4
`2
`2
`2
`1
`1
`2
`U 5"
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`110
`
`

`

`
`
` Reviewer: BeLinda A. Ha es Ph.D. NDA N0. M 5(4)
`
`Pharmacokinetics parameters of lacosamide following oral administration to adult
`dogs.
`
`Cm“ [plg'mL]
`blah
`Fen‘mh
`
`]
`
`In
`
`5
`
`
`
` Dose Dm-adion
`
`
`Tmm [ll]
`fiUChn DrudmL]
`Farrah
`blah
`Farrah
`luah
`
`1.5 '
`1
`1
`1
`1.3
`1.5
`
`1.3
`0.5
`
`0.5 [D.25"-1)
`1 (0.5-1)
`0.80151)
`0.3 (0.51)
`
`1(051)
`03(05-1)
`
`
`31.6
`
`
`
`
`
`
`
`
`1E]
`
`12
`
`12
`- 1'11
`16
`(1)111)
`24
`
`25
`
`
`
`Sda
`
`13.5116
`
`Eda
`
`15.7118
`
`
`
`—
`61.81143
`-
`11-1
`
`79.5
`33.1
`0.8 (0.2552)
`1 (0.52)
`59.4
`55 2
`1 (0.52)
`1 (0.25-1)
`
`
`
`3 (1-4)
`1 (0.5-2)
`10?
`32.7
`
`
`
`85.2
`
`
`68.6
`95.6
`
`
`129
`134
`
`133
`166
`
`
`124
`142
`Values are means it SDJtn=2. 4 cr 5) magic: T,.u|;1nedim1}1mgen.AU'C,_.v1-as mma amt one dose
`immal.
`n - firs. samplingtime
`held:twine(11111‘1yl:1211101111511p"ml
`Dmsomces: Tabla 25.5.31. — 5654.02; 4.2.3.110. 98825 "mmcoltib‘sti: mhaximrepurt;
`42 32.1]. 9%61 Tmicdximfia: enhmimrepm; 4.2.3.1111 .— 1.96.00. 21912-131111}: 10-5.
`
`
`
`
`
`A303amassed1,539
`
`0.5 (0.25“- 1)
`1 (0.52)
`0.5 (0.50 5)
`
`
`
`0.6 (025'- 1)
`1 (0.51)
`1.5 (0.52)
`
`
`
`
`461
`
`43.4
`49 .0
`
`105"—
`
`-
`
`43.51101
`
`-
`
`-
`
`—
`
`,
`“‘43
`
`111
`
`

`

`
`
` Reviewer: BeLinda A. Ha es Ph.D. NDA N0.
`
`—————
`
`bM}
`
`Comparative pharmacokinetic data and systemic exposure to lacosamide following
`intravenous administration of lacosamide to dogs and human volunteers.
`
`Paramehr [unit]
`
`
`
`
`
`A0103elqgssodI398
`
`Male
`
`Dog
`intavemus
`
`(b 0115)
`
`Cram [llgfmIJ
`
`Tau-z [h]
`
`AUCO-hl’ lh'lla’le
`
`[Why]
`
`4
`8 (NOEL)
`
`Female
`
`16
`4
`
`
`
`8 (NOEL)'-
`
`.
`
`Male
`
`Dan 11er are after repeated mucus bobs injectim althe mi cf a Nahydog mun em d: SD.n=-I per
`sexlorr afiu' single 10-minute imam-anon; Mimmhgflhywmgma}: volunteers memiSDm=5to 6).
`11- human abodgmighofmhgnas assumedISLL mm 133, 330mgpar suitjectjl.
`Dun sauces: 4.2.3.2.14‘ 93793. Eiarmucobhmj: mhmmmpm; 53 3.15.5Pfi34‘Tnhle 14.2.1.
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`112
`
`

`

`
`
`NDA No. 'Reviewer: BeLinda A. Ha es Ph.D. hm)
`
`
`
`
`
`Comparative pharmacokinetic data following repeated oral administration of
`lacosamide to mice, rats, dogs and human VOIunteers.
`Parameter of lacosamifle [unit]
`
`Cray-ax [llg’nll‘]
`
`T Max M AIt‘ltrhn mltfl’mL]
`
`
`
`10 (HOAEL) 25
`
`Female
`
`5
`
`
`
`
`
`Adooelqgssod4333
`
`b‘fl)
`'1
`,
`
`133
`133
`so
`
`a] (NOAEL)
`133
`180
`
`33
`90 (NOAEL)
`12:0
`
`Male,
`
`Few 33
`90 (NOAEL)
`1m
`5
`
`Male
`
`Male
`
`ID25(NOAEL)
`119 :t 18.3
`3 (1 -6)
`12.6 :I: 2.2
`3.625Day 15 (High)
`126:1: 1'14
`1(1- 2)
`145i1.7
`Day16[day)
`Chilflcapsule)
`Dnmnegmmdm afmrrepemdcnlndnifistmfimatme enrich 3-mocrthmmlfi'ndjmflnldfin16-mmflimt
`(medians IFZJ. 13mmuhrbg¢ned1mn=21 and 115-duyhmm1rhlSP588 means i: SD n=12. Tmmedim
`flange 3). hmmnbodymigmod'm kgwxs again edtflx mflmgpu' subject/thy”),
`AUG”, ninth mome.mmddog.mdAUCp.mhmmm giant“
`mummy-1.23.2.2. ~13123m.2Ҥpmdix105.4.2.3.2.fi h .mmll Appendix 1115;41:3211
`. BIQSIOJJEtpmdm w-S;5.3.3.1.4.SP583.Sectim9.4.
`
`APPEARS THIS WAY
`
`0N ORIGINAL
`
`113
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`A603elQlSSOd1999
`
`
`
`
`
`
`NDA No.Reviewer: BeLinda A. Ha es Ph.D. ‘5‘
`
`
`
`n14):
`
`Metabolism:
`
`Metabolism: Interspecies comparison of maximum observed concentration of
`
`plasma metabolites.
`’
`R.
`
`(ml
`
`an].
`
`oral
`
`u‘al
`
`(mil
`
`»
`
`oral
`
`hiravawus hummus
`
`2-85mm—
`m-“————_—
`
`m
`
`-m-—————_—
`
`mmm -———— -—_
`EE--__———mlfi-lfil
`—-——————_—
`
`———_—m————
`——_—m—————
`E_--_——_——_
`Ina-m
`me
`.mq —— .m «m
`
`
`
`
`
`
`
`—--—————— 1462
`
`Major metabolites in plasma following single oral administration of [14C]-
`lacosamide to mice, rats and dogs.
`Reimfiml
`
`hhzchnum % ofradinactirityinchmm‘bgrmn
`
`Dog
`Rat
`Mom
`Male
`Female Male Farah Male
`Female
`13.?
`2'10
`2.45
`2.40
`-
`-
`
`
`
`Mediumpolar fi'action
`S PM 1281 '1 (13-1012)
`S PM 8912 (M5)
`Unknown
`
`18 - 24
`26
`2‘15
`29
`
`-
`BLQ
`6.85
`4.98
`
`-
`2.2?
`8.98
`8.41
`
`-
`4.34
`
`—
`
`13.9
`5.40
`BLQ
`-
`
`15.2
`1‘33
`BLQ
`—
`
`.
`
`-
`
`36.2
`33.4
`17 .1
`15.4
`22.0
`1'? .2
`3D
`S PM 12839 (Ml)
`88.3
`88.6
`118.1
`62.2
`75.?
`7'00
`35‘
`Lacosamide
`Dampemdm afiershgh mlmifistmtim [ 'Cl-hzosnmifie mill] tlniceHD mislead 10mgkg£dngst
`Phannsmplesm cbtaimdatfimfolwmgtinespost dose: lmdfilwu's mussel-1» mail-$110.11: (1111.3. dog:
`Mminms. 0.5. 1.2. 4. 8.12. 34 and-18 (dog).
`BLQ =belmrthe mtocrqlmmajMMdanmm. - = magma
`
`114
`
`

`

`Reviewer: BeLinda A. Ha es Ph.D. NDA NO. ,—
`
`mm
`
`Major metabolites in urine following single oral administration of [14C]-lacosamide
`to mice, rats and dogs.
`
`% ofadminktm'ed 11.0512
`
`10183210173312
`
`2 .76
`
`3.23
`3.20
`0.835
`
`111151.12 Femah MahD Female
`
`0.449
`2.84
`1.15
`10.5
`3.41
`5.97
`5.36
`
`BLQ
`2 .40
`1 .75
`826
`457
`5.44
`
`77.9
`
`Urdrruwn
`Unkruwn
`Unkrnwn “
`
`M4 [GkUA arm)
`3 PM 12814 (p—MB)
`Sulfate of‘M2
`
`3 PM 12817 (13-1112)
`S PM 6912 (M5)
`M6
`
`S PM 12339 (Ml)
`Lacosamjde
`Tubal
`
`BLQ
`BLQ
`31.8
`8.0
`79.4
`
`Dampesmmdare after shgle a'alafln'njsuafion [ 'C]-1ax:osamidz a120 (1111:2140 1:111st 10mghgtdog5).
`ndinI-IF'L C-MSIMS
`Pooledurhe samples [U-241mrsjmre imastigamdby
`a — Irmsfigafimwifil ["C] lacosamiie labelzdeiharatfltm cubmyli: cr anhe hmzylix carbmamm sugestflae
`fazm atim cf a deshem'yhmim clarinet-12.14.61. 347 J.
`b - When employmgthe HPL C m emodxmidmms madfocrlnmmm fi'cm u-hl SP6 Dine 6- and Baum
`peaks co-ehxedas cmpeak ataretmimttne of 1.6111111111501211. 1003)
`BLD =be1m/thelimim'm1mtificmml'fllfi- 0.63%0cf1he don't-=mdmmd
`
`32.5
`6.13
`
`
`
`
`
`Adooe\qissod1,839
`
`Excretion:
`
`Mice: Excretion of radioactivity following single administration of
`[14
`C]- lacosamide.
`
`
` Route of
`$2628
`
`Pmmge 01'an dose
`[11311;] alnnn'nirat'xm
`
`Urine
`Feces
`Carcass
`T otal
`
`
`M0115 a
`
`
`
`1.81:0.2
`83.1 d: 7.1 4.5: 2.0
`90114.8
`
`
`
`
`17t0.2
`80.9 :1: 2.5 5.3:1: 23
`88.7 :1: 3.0
`oral [s irgle)
`
`
`Era-Mm dmmdwu' lmhou's. Vines aremeams iSD 1:11: 31. Um includes cagewash [34.3%:
`113%11111 ales 111111239345: 13D%i'1f€ma1esj. Tctalinchdes ndjoacLiriiyincage debris.
`Data sauce: Tabb 21551325.. 6997-16
`
`Female
`
`oral (s irgle)
`
`115
`
`

`

`
`
`Reviewer: BeLinda A. Ha es PhD. NDA N0,
`
`_——.
`
`' ”
`
`M43
`
`Rat: Excretion of radioactivity following single administration of
`[14C]—lacosamide.
`
`Species
`
`Rat
`
`Puma-dag: ofadnfilfistemfl dose
`Rnuteof
`[11%] almm'nirafion Urine
`Feces
`Camass
`T otal
`
`oralfisingle)
`iv (single)
`
`81.8 1 2.9 16.3 1 3.1
`78.1 1 7.2 17.6 1 6.7
`
`1.6 1 0.2
`1.8 1 0.5
`
`ora1(single)
`
`81.11 1.5 8.01 0.5
`
`39 1 0.3
`
`99.7 11.1
`98.0 1 5.0
`
`929 11.2
`
`
`
`Rat
`
`91510.7
`3.7109
`798110 8014.7
`oralfiepeat)
`90.7112
`3310.5
`82812.8 4.5120
`0131(5th
`94512.0
`3510.6
`83011.5 8010.9
`oral(single)
`40
`Male
`94010.9
`3910.6
`86012.6 4.1112
`oral(single)
`40
`Female
`Ekcmbnwas detem'mdwer ’32 cr lfihmrs. Values are means 15D 61:3). Tl'ne mlnies cage mshifljm.
`T0131 'ncludgs miioncmriy in cage debris («D .17.) and ”n Eiqximd air (<0 57.).
`Dan sauces: Table 2.65.1313.le2; Table 2.65.13C. 699747; Table 2155.131). 0699.023
`
`Dogs: Excretion of radioactivity following single administration of
`[14C]-lacosamide.
`
`
`
`
`
`Adogeaqissod1963
`
`Route of
`
`Percentage ofallmfin'mtelul dose
`
`Wm'mmm‘im Urine
`
`Feces
`
`Tohl
`
`oral(si1gle)
`
`85417.4
`
`7.2167
`
`92.6135
`
`iv(singlej
`
`75.91116
`
`7.1166
`
`83.01113 ora1(si.ng1e)
`
`10
`10
`
`ora1(sirng1e)
`ivfsingle)
`
`.
`ivfisingh]
`10
`Emmfimw dammdorm 72 cr lfihmrs. ‘ihlms are mums *SD tn= BJOImedians $1152). 11m imhdes
`cng'mm (< 11%).
`a - Total imhdesndjmmm cage debris (<0 3%;
`Dan sauces: Table 2.65.1351. F232;Tab12 2.65.1317. 699748
`
`Human: Excretion of radioactivity following single administration of
`[14C]—lacosamide.
`
`
`
`backs
`
`
`may: ofaflmin'xtetul dose
`Route of
`Dose
`5m:
`[mg]
`admin'xtm'lian
`Urine
`Feces
`To131
`oral (single)
`94.19 1 3.09
`0.38 1 0.17
`94.57 1 3.12
`iv (1-hour, single)
`96.82 1 2.62
`0.30 1 0.07
`97.13 1 2.65
`Eccmjmm mmdmr 168110115 hlmlfliymalehmmmbjem folhwiig s'ngla onladm'nisumonou:
`mar lhourirmnmms izfiJsiomoflmmg["C]-1acomfia.lfah25 aremenns 1 SD tn: 5 per gulp}.
`Dan QUIIce: 53.1.1.1. 39519. Tabh 13.0. Tame 13.10
`
`
`
`
`
`2.6.6 TOXICOLOGY
`
`2.6.6.1 Overall toxicology summary
`
`General toxicology:
`
`116
`
`

`

`Reviewer: BeLinda A. Hayes, Ph.D.
`
`NDA No. ‘6‘“
`
`Wei
`
`In support of the chronic indication, the systemic toxicity of lacosamide was studied in
`mice, rats, dogs and rabbits. The key repeat—dose toxicology studies to support the
`chronic indication were conducted in mice up to 13 weeks, in rats up to 6 months and up
`to 12 months in dogs.
`
`In a 13-week repeat dose mouse study, CD—1 mice were administered lacosamide by oral
`gavage at doses of 30, 60, 120 and 180 mg/kg/day. Dose levels were based on the
`findings of the 2-week dose~range finding study _ “=- l3122/00)L Clinical signs of
`toxicity included ataxia, abdominal position and reduced motility at 120 and 180
`mg/kg/day. Ataxia was observed in all animals on the first day of dosing and was
`observed on most days of the study. Reduced motility was not observed until day 16 of
`the study and was observed in all animals until termination of the study. Two deaths
`occurred in the high dose group (180 mg/kg). There were no microscopic findings in this
`study. The NOAEL was 60 mg/kg/day based on clinical signs not considered to be
`significant safety issues. This NOAEL was associated with a mean AUC(0_24) of 97.0
`ng.h/mL in males and Cmax of 29.04 ug/mL (males) and 27.62 ug/mL (females).
`
`NA)
`
`In the 13-week repeat dose rat study, Sprague-Dawley rat were administered lacosamide
`by oral gavage at doses of 30, 100 and 300 mg/kg/day. Dose levels were based on the
`findings of the l—month dose-range finding study ; \1108-005). In the dose—range
`finding study, female rats were orally administered lacosamide at dosages of 0, 100, 200
`and 300 mg/kg to determine the MTD. At the highest dose (300 mg/kg/day), two
`treatment-related deaths occurred in week 1. At 200 mg/kg/day and higher, clinical signs
`of toxicity included muscle flaccidity, decreased motor activity, impaired righting reflex,
`splayed limbs, ataxia and head bobbing. In addition to these clinical signs, loss of
`righting reflex, bradypnea and excessive salivation were observed at 300 mg/kg/day.
`Based on these clinical signs, the NOAEL was 100 mg/kg and the MTD was established
`at S 200 mg/kg/day. In the 13—week study, treatment-related clinical signs included
`ataxia, hypoactivity, prostration and convulsions (female only). Five deaths, which were
`attributed to lacosamide, occurred in the female high dose group. Treatment—related
`increases in mean liver-to-body weight were noted in both males and females at all dose
`levels. The increase in liver weight in the high dose female group was attributed to the
`observed increase in alanine aminotransferase and alkaline phosphatase. Changes in
`urine chemistry indicate that lacosamide has a diuretic-like effect. Significant increases
`in urine volume were observed in both male and females starting at the lowest dose (30
`mg/kg/day). Based on clinical signs, not considered to be safety issues, 100 mg/kg/day
`(mean Cmax of 906 ng/mL and mean AUC 'of 14,252 ng.h/mL) was established as the
`NOAEL in this study.
`
`A 6-month oral toxicity study was conducted in rats that closed the animals once daily
`with 0 (vehicle), 30, 90 and 180 mg/kg/day. The top dose was selected based on a dose-
`range finding study (StudyReport N2 1108—005) that was conducted in rats that observed
`minimal toxicity at 100 mg/kg/day. In the 6-month study, clinical signs of toxicity
`included excessive salivation, reduced motility, increased muscle tone, abdominal or
`lateral position and apathy in the high-dose group (180 mg/kg/day). These clinical signs
`
`117
`
`M4)
`
`

`

`Reviewer: BeLinda A. Hayes, Ph.D.
`
`1
`
`' NDA No. F‘“
`
`11(4)
`
`had a rapid onset, starting 15 to 20 minutes after dosing, and lasting for a few hours
`(reduced motility) or up to 24 hours (salivation). The observed reduced motility and
`apathy peaked within the range of Tmax for lacosamide. Three deaths occurred in the
`study; one female in the control group, one female in the low dose group and one male in
`the high dose group. The Sponsor concluded that the death of the male was treatment-
`related. However, no macroscopic changes 'were identified. A marginal but dose-related
`(90 to 180 mg/kg/day) reduction in body weight was observed in the male rats. At the
`end of the dosing period (day 182), relative to control, a 7% reduction in body weight
`was noted1n the males1n the high dose group Serum cholesterol levels were
`significantly increased by 41% and 25%1n females at 180 mg/kg/day1n weeks 13 and 26,
`respectively. Although not statistically significant, compared to the control, serum
`cholesterol levels were increased by 29% and 20% at weeks 13 and 26, respectively, in
`males at 180 mg/kg/day. Increased ALT levels were noted in the rats at 180 mg/kg/day.
`At week 13, ALT levels in females were significantly increased by 43%. ALT levels
`Were increased by 30% (not statistically significant) at week 13 in females in the high
`dose group. Also at 180 mg/kg/day, the relative liver weight and liver-to-brain weight
`was significantly increased by 13.3% and 14.8%, respectively, compared to the control.
`No macroscopic or histopathological changes in the liver of females in the high dose
`group were observed. The increased ALT activities and increased liver weights were
`reversible; within the 4-week recovery period, the ALT levels and liver weights were
`within normal range. Urinalysis results suggest that lacosamide can produce a diuretic-
`like effect. At 180 mg/kg/day, the urine volume was increased by 12% and 84% in males
`and females, respectively. Also the high dosed female, drinking water consumption was
`transiently increased up to 21% compared controls in week 6. Specific gravity was
`minimally, but statistically significantly, decreased in females at .90 and 180 mg/kg/day.
`The NOAEL was 90 mg/kg/day based on clinical signs not considered to be significant
`safety issues. This NOAEL was associated with a mean AUC(0_24) of 325.8 h.ug/mL and
`Cmax of 27.45 ug/mL.
`
`A 12-month oral toxicity study was conducted in dogs that dosed animals once daily with
`0, 5, 10, 20 (first 5 weeks) and 25 mg/kg. The high dose was adjusted from 20 to 25
`mg/kg/day in week 6 because 20 mg/kg/day only produced mild systemic toxicity. No
`deaths occurred during the study. Consistent with the observed clinical signs in rodents,
`lacosamide produced evidence of CNS and gastrointestinal toxicity in dogs. At 20
`mg/kg/day, vomiting, tonic-clonic convulsions, sedation, ataxia, abdominal and/or lateral
`position, were observed among a few dogs on some isolated days. At 25 mg/kg/day,
`these clinical signs were observed in more dogs and were more pronounced and occurred
`more frequently. Also new clinical signs, i.e. reduced motility, tremor, salivation,
`increased defecation and vocalization, emerged. Onset of the clinical signs was generally
`at Cmax between 5 and 60 minutes after dosing and lasted for up to 2 hours; increased
`salivation was noted for 24 hours. EKG data were obtained on test days 1 and 3, and at
`the end of weeks 13, 26, 39 and 52. Blood pressure data was obtained before and 2.5
`hours after dosing at the end of weeks 13, 26, 39 and 52. Cardiac effects were minimal
`following oral administration of lacosamide. In females, a dose-dependent decrease in
`peripheral arterial systolic blood pressure was noted on test day 1. Statistically
`significant decrease in peripheral arterial blood pressure was observed at 10 mg/kg/day
`
`118
`
`

`

`Reviewer: BeLinda A. Hayes, Ph.D.
`
`NDA No
`
`‘—‘
`
`to
`
`(30% decrease) and 20 mg/kg/day (35% decrease). During week 13, a 37% decrease in
`peripheral arterial blood pressure was observed compared to control. No further
`lacosamide-related effects was observed after week 13. In males, there was no
`lacosamide-related effect on blood pressure up to 25 mg/kg. Single statistically
`significant changes appeared to be inconsistent in direction (increase / decrease), not
`dose-related and/or were observed prior to dosing. Lacosamide did not induce significant
`ECG changes. No treatment-related changes were observed in QRS interval, PQ interval,
`P-segment and QT electrocardiographic complexes in either male or females. A
`statistically significant increase of the QTc (as calculated by Fridericia) value for high
`dose females was caused by relatively low QTc values of the controls and considered to
`be within the normal range. The NOAEL was 10 mg/kg/day based on the lack of
`toxicological findings and on the increased heart rate not being statistically significant
`and is monitorable. This corresponds to AUC values of 71.0 and 54.6 hug/mL in males
`and females respectively, after repeated daily dosing for 12 months. Cmax values at this
`dose were 15.52 and 13.15 ug/mL in males and females, respectively.
`
`Genetic toxicology:
`
`The Sponsor conducted five genetic toxicology studies to evaluate the genotoxicity
`and/or mutagenicity of lacosamide. Three of the five studies were in vitro studies and the
`remaining 2 studies were in vivo Dr. Edward Fisher reviewed these studies, specific
`details can be found in the NDA (NDA N9 22-253) review prepared by Dr. Fisher.
`
`Carcinogenicity:
`
`To evaluate the carcinogenic potential of lacosamide, the Sponsor conducted a 2-year
`carcinogenicity bioassays were in mice and rats. Drs. Edward Fisher and Terry Peters
`reviewed these studies. Specific details of these studies can be found in NDA 22-253
`review from Drs. Fisher and Peters.
`
`Reproductive toxicology:
`
`The Sponsor conducted a standard battery of reproductive toxicology studies. Dr.
`Edward Fisher reviewed these studies. Specific details of these studies can be found in
`NDA 22-253 review from Dr. Fishers
`
`2.6.6.2 Single—dose toxicity
`Single-dose toxicology studies were conducted in mice and rats.
`
`Study title: Acute Toxicity Study of SPM 927 by Oral Administration to CD-l Mice.
`
`Key study findings: A single dose of SPM 927 (31.6, 100, 316, and 464 mg/kg) was
`administered via gavage to mice. The mice were observed for 14 days following dosing.
`The following key findings were obtained:
`
`119
`
`

`

`Reviewer: BeLinda A. Hayes, Ph.D.
`
`NDA No.
`
`~=-‘
`
`M4?
`
`1. All animals in the high-dose group (464 mg/kg) died within 20 minutes to 2
`hours after oral administration of lacosamide.
`
`U.)
`
`2. Reduced motility, mortality, ataxia, tremor, mydriasis, dysponea, increased
`muscle tone and abdominal position were the primary treatment-related
`clinical signs.
`. No treatment-related macroscopic changes were noted.
`4. No treatment-related histological changes were observed in the liver or
`kidney.
`'
`5. Based on clinical signs, NOEL is 31.6 mg/kg.
`
`12(4)
`
`Study N2:
`
`Report No. ‘ {3121/00
`
`M4)
`
`4.23.1.1
`
`~ N
`
`—
`
`Volume #, and page #:
`Conducting laboratory and location:
`
`Date of study initiation:
`GLP compliance:
`QA report:
`Drug, lot #, and % purity:
`
`April 18, 2000
`Yes
`yes ( x ) no ( )
`SPM 927, Batch N2 KK 02457, 99.67%
`
`Methods
`Doses: 31.6, 100, 316, and 464 mg/kgbmy
`Species/strain: Mice;
`-— CD®
`Number/seX/group or time point (main study): 3/sex/group
`Route, formulation, volume, and infusion rate: Oral gavage, Solution, 20 mL/kg
`Satellite groups used for toxicokinetics or recovery: None
`Age: Males: 24 days; Females: 25 days
`Weight: Males: 25-26 g; females: 20—25 g
`Sampling times: N/A
`Unique study design or methodology (if any): None
`
`Observations and times:
`
`Mortality: Mortality was examined once daily.
`Clinical signs: Clinical signs were observed before and immediately, 5, 15, 30, and 60
`minutes and 3, 6, and 24 hours after dosing. All surviving animals were observed for 14
`days. During this 2-week period, the animals were observed once daily for changes in
`skin and fur, eyes and mucus membranes, respiratory and circulatory function, autonomic
`and central nervous system and somatomotor activity and behavioral pattern.
`Body weights: Body weight was recorded pre—dosing, and than weekly until end of
`study.
`Food consumption: Not monitored
`Ophthalmoscopy: Not performed
`&: Not performed
`Hematology: Not performed
`Clinical chemistry: Not performed
`
`120
`
`

`

`Reviewer: BeLinda A. Hayes, Ph.D.
`
`NDA No. 7.6.;
`
`MA}
`
`Urinalysis: Not performed
`Gross pathology: Surviving animals were euthanized under ether anesthesia.
`Macroscopic evaluation was performed.
`Organ weights: Relative organ weight of liver and kidney was calculated.
`Histopathology: Liver and kidney were fixed in 7% buffered formalin and stained with
`haematoxylin—eosin stain prior to being examined microscopically.
`
`Results
`
`Mortality: Treatment-related deaths were observed. All subjects in the high-dose group
`(464 mg/kg) died within 20 minutes and 2 hours after dosing. The Sponsor reported that '
`prior to their death; the animals were comatose and displayed an abdominal position (not
`described). LD50 for lacosamide at 24 hours and 14 days posting dosing was 383 mg/kg
`for both males and females.
`
`Clinical signs: Treatment-related clinical signs were dose—dependent. No treatment-
`related clinical signs were observed in the low-dose group (31.6 mg/kg). As indicated in
`the table 1 below, reduced motility, ataxia, tremor, tonic convulsions, abdominal position,
`mydriasis, dysponea, and increased muscle tone were the primary treatment-related
`clinical signs. These primary treatment-related clinical signs had a rapid onset of action;
`occurring within 5 to 15 minutes after dosing. These clinical signs were observed for up
`to 6 hours.
`
`Table 1
`
`
`
`Dose (mg/kg) ‘
`>
`'
`n E 3/sex/_rou .
`)—|O. O
`
`_'131.6— .
`316
`.
`
`
`
`
`5 Wm —_-———-_
`mum-mu“
`—-_-_-—_—n-_
`_mnn
`”Emma-_—
`”nunn——
`_nm-m
`_nnm
`—-—_———n-_
`human-nu“
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Body weights: No treatment-related effects on body weight were noted.
`
`Gross pathology: At necropsy, all animals were observed for identifying macroscopic
`lesions. No treatment-related macroscopic changes were identified.
`
`Organ weights: No treatment-related effects on relative liver and kidney weight were
`observed in any groups.
`'
`
`121
`
`

`

`Reviewer: BeLinda A. Hayes, Ph.D.
`
`NDA No.
`
`__._,_
`
`33(4)
`
`Histopathology: Histological examination of the liver and kidney did not reveal any
`treatment-related changes
`
`Study title: Acute Toxicity Study of SPM 927 by Single Oral Administration to CD
`Rats.
`
`Key study findings: A single dose of lacosamide (31.6, 100, 316, and 464 mg/kg) was
`administered via gavage to rats. The rats were observed for 14 days following dosing.
`The following key findings were obtained:
`
`1. All animals in the high-dose group (464 mg/kg) died within 3 hours after oral
`administration of lacosamide.
`
`2. Reduced motility, mortality, ataxia, dyspnea, reduced muscle tone and lateral
`position were the primary treatment-related clinical signs.
`3. No treatment-related macroscopic changes were noted.
`4. Based on clinical signs, NOEL is 31.6 mg/kg.
`
`Study N2:
`
`Report No.
`
`-—=~ ‘ 17964/04
`
`31(4)
`
`Volume #, and page #2
`
`I
`
`4.2.3.1.3
`
`Conducting laboratory and location:
`
`/
`
`/
`
`/
`
`Date of study initiation:
`GLP compliance:
`QA report:
`Drug, lot #, and % purity:
`
`Methods
`
`June 18, 2004
`Yes
`yes ( x ) no ( )
`SPM 927, Batch N9 WE 11837 (537.1008,
`2»:
`99.6%
`
`Doses: 31.6, 100, 316, and 464 mg/kg
`Species/strain: Rat/CD®
`Number/sex/group or time point (main study): 3/sex/group
`Route, formulation, volume, and infusion rate: Oral gavage, Solution, 20 mL/kg
`Satellite groups used for toxicokinetics or recovery: None
`Age: Males: 48 days; Females: 55 days
`Weight: Males: 207-230 g; Females: 177—202 g
`Sampling times: N/A
`Unique study design or methodology (if any): None
`
`Observations and times:
`
`Mortaligg: Mortality was examined once daily.
`Clinical signs: Clinical signs were observed before and immediately, 5, 15, 30, and 60
`minutes and 3, 6, and 24 hours after dosing. All surviving animals were observed for 14
`
`122
`
`N4)
`
`‘
`
`M4)
`
`

`

`31(4)
`
`Reviewer: BeLinda A. Hayes, Ph.D.
`
`NDA No.
`
`‘4:
`
`days. During this 2-week period, the animals were observed once daily for changes in
`skin and fur, eyes and mucus membranes, respiratory and circulatory function, autonomic
`and central nervous system and somatomotor activity and behavioral pattern.
`Body weights: Body weight was recorded pre—dosing, and then weekly until end of
`study.
`_
`Food consumption: Not monitored '
`Ophthalmoscopy: Not performed
`
`EKG: Not performed
`Hematology: Not performed
`Clinical chemistry: Not performed
`Urinalysis: Not performed
`Gross pathology: Surviving animals were euthanized under ether anesthesia.
`Macroscopic evaluation was performed.
`Organ weights: Not performed
`Histopathology: Not performed
`
`Results
`
`Mortalifl: No treatment-related deaths were observed in the 31.6 and 100 mg/kg groups.
`Treatment—related deaths were observed in the 316 and 464 mg/kg groups. One male and
`one female died in the 316 mg/kg group. All subjects in the high-dose group (464
`mg/kg) died within 3 hours after dosing. The Sponsor reported that prior to their death;
`the animals were comatose and displayed an abdominal position (not described). LD50
`for lacosamide at 24 hours and 14 days posting dosing was 383 mg/kg for both males and
`females.
`
`Clinical signs: Treatment-related clinical signs were dose-dependent. No treatment-
`related clinical signs were observed in the low-dose group (31.6 mg/kg). As indicated in
`the table 2 below, reduced motility, ataxia, reduced muscle tone, clonic convulsions,
`lateral position, and dyspnea were the primary treatment-related clinical signs. These
`primary treatment-related clinical signs had a rapid onset of action; occurring within 5 to
`15 minutes after dosing. These clinical signs were observed for up to 6 hours.
`
`The Sponsor noted that reduced motility, ataxia, and dyspnea as slight to moderate.
`Reduced muscle tone ranged form slight to severe.
`
`Body weights: No treatment-related effects on body weight were noted.
`
`Gross pathology: At necropsy, all animals were observed for identifying macroscopic
`lesions. No treatment-related macroscopic changes were identified.
`
`Table 2.
`
`
`
`123
`
`

`

`
`
` Reviewer: BeLinda A. Ha es PhD. NDA No.
`
`”7"
`
`3(4)
`
`
`
`Reduced Motili
`
`Ataxia
`
`Clonic convulsion
`Lateral Position
`
`Mortality
`
`Reduced Muscle Tone
`
`Study title: Acute Toxicity Study of SPM 927 by Single Intravenous Administration to
`CD—l Mice.
`
`Key study findings: A single dose of lacosamide (10, 31.6, 100, and 316 mg/kg) was
`administered intravenous to mice. The mice were observed for 14 days following dosing.
`The following key findings were obtained:
`
`1. All animals in the high—dose group (316 mg/kg) died within 15 hours after
`oral administration of lacosamide.
`
`2. Reduced motility, death, ataxia, dyspnea, reduced muscle tone, tremor, clonic
`convulsions, abdominal position and lateral position were the primary
`treatment-related clinical signs.
`3. No treatment-related macroscopic changes were noted.
`4. Based on clinical signs, NOEL is 10 mg/kg.
`
`Study N2:
`
`Report No. Q 17963/04
`
`M4)
`
`Volume #, and page #:
`
`Conducting laboratory and location:
`
`4.23.1.2
`
`/! / /
`
`/
`
`b“)
`
`'
`
`Date of study initiation:
`‘ GLP compliance:
`QA report:
`Drug, lot #, and % purity:
`
`June 18, 2004
`Yes
`yes ( x ) no ( )
`SPM 927, Batch N9 WE 11837 (537.1008,
`/— , 99.6%
`
`Methods
`
`b“)
`
`Doses: 10, 31.6, 100, and 316 mg/kg
`Species/strain: CD—l Mice Rat ’“ .CD1®
`Number/sex/group or time point (main study): 3/sex/group
`Route, formulation, volume, and infusion rate: Intravenous, Solution, 20 mL/kg, 15 sec infusion ratr
`Satellite groups used for toxicokinetics or recovery: None
`Age: Males: 32 days; Females: 33 days
`Weight. Males. 20-23 g, Females. 17—20 g
`Sampling times: N/A
`Unique study design or methodology (if any): None
`
`‘
`
`APPEfigQS 7mg Willi
`0“ OMGWM‘
`
`124
`
`

`

`Reviewer: BeLinda A. Hayes, Ph.D.
`
`NDA No
`
`4—“
`
`M4)
`
`Observations and times:
`
`Mortalifl: Mortality was examined once daily.
`Clinical signs: Clinical signs were observed before and immediately, 5, 15, 30, and 60
`minutes and 3, 6, and 24 hours after dosing. All surviving animals were observed for 14
`days. During this 2-week period, the animals were observed once daily for changes in
`skin and fur, eyes and mucus membranes, respiratory and circulatory function, autonomic
`and central nervous system and somatomotor activity and behavioral pattern.
`Body weights: Body weight was recorded pre—dosing, and then weekly until end of
`study.
`Food consumption: Not monitored
`Ophthalmoscopy: Not performed
`Egg: Not performed
`Hematology: Not performed
`Clinical chemistry: Not performed
`Urinalysis: Not performed
`Gross pathology: Surviving animals were euthanized under ether anesthesia.
`Macroscopic evaluation was performed.
`Organ weights: Not performed
`Histopathology: Not performed
`
`Results
`
`Mortality: Treatment-related deaths were observed. All subjects in the high-dose group
`(316 mg/kg) died within 15 minutes after dosing. LD50 for lacosamide at 24 hours and 14
`days posting dosing was 178 mg/kg for both males and females.
`
`Clinical signs: Treatment-related clinical signs were dose-dependent. No treatment-
`related clinical signs were observed in the low-dose group (10 mg/kg). As indicated in
`the table 3 below, reduced motility, ataxia, reduced muscle tone, clonic convulsions,
`lateral position, abdominal position and dyspnea were the primary treatment-related
`clinical signs. These primary treatment-related clinical signs had a rapid onset of action;
`occurring within 0 to 5 minutes after dosing. These clinical signs were observed for up to
`6 hours.
`
`Body weights: N0 treatment-related effects on body weight were noted.
`
`Gross pathology: At necropsy, all animals were observed for identifying macroscopic
`lesions. No treatment-related macroscopic changes were identified.
`
`
`
`
`Reduced Motili:ty_
`
`Dose (mg/kg)
`n = 3/sex/_rou 0
`
`125
`
`

`

`
`
`NDA N0.Reviewer: BeLinda A. Ha es Ph.D. “=“'
`
`
`
`
`
`31(4)
`
`0
`
`0
`
`3
`
`3
`
`
`
`Ataxia
`Tremor
`Clonic cOnvulsion
`Lateral Position
`Abdominal Position
`D snea
`Reduced Muscle Tone
`
`Mortality
`
`
`
`Study title: Acute IV Study of ADD 234037 in Rats.
`
`Key study findings: A single dose of lacosamide (25, 50, and 100 mg/kg) was
`administered intravenously to rats. The rats were observed for 14 days following dosing.
`The following key findings were obtained:
`
`1. No mortality occurred following the intravenous administration of
`lacosamide.
`
`2. Treatment-related clinical signs included labored breathing, reduced righting
`ability, limb weakness, ataxia, limb splay and flattened posture.
`3. Macroscopic changes were noted in the kidney and stomach of some animals
`in the 50 mg/kg and 100 mg/kg treatment groups.
`4. Based on clinical signs, NOEL is 25 mg/kg.
`
`Study N2:
`
`Report No. 18566-0-800
`
`Volume #, and page #:
`Conducting laboratory and location:
`
`42.3.15
`-——-———~
`
`”(4)
`
`Date of study initiation:
`GLP compliance:
`QA report:
`Drug, lot #, and % purity:
`
`May 6, 1997
`' Yes
`yes ( x ) no ( )
`ADD 234037, Lot N2 PEH-A-170, % purity
`not stated
`
`.
`
`Methods
`
`Doses: 25, 50, and 100 mg/kg
`Species/strain: Rat/Sprague Dawley®SD®
`Number/sex/group or time point (main study): 5/males/group (l & 2);
`'2/sex/group (3)
`Route, formulation, volume, and infusion rate: Intravenous, Solution, 1.7, 3.3,
`and 6.7 mL/kg to achieve the desired dose of 25, 50, and 100 mg/kg, respectively,
`2 mL/minute
`
`Satellite groups used for toxicokinetics or recovery: None
`Age: approximately 8—weeks
`Weight: 225 to 264 g
`Sampling times: N/A
`
`126
`
`

`

`Reviewer: BeLinda A. Hayes, Ph.D.
`
`‘ NDA No /
`
`M4)
`
`Unique study design or methodology (if any): None
`
`Observations and t