Reviewer: David B. Hawver, Ph.D.
`
`NDA No. 21-926
`
`2.6.6.6 Reproductive and developmental toxicology
`
`_
`Reviewer ’5 Note:
`The Sponsor was informed during the Pre-IND Meeting of 28 FEB 2002 for IND 68,436
`that a Segment II study in rabbits would suffice to evaluate the potential for additive or
`synergistic effects of the combination of SS and NAP on reproduction and development,
`since the components are currently marketed1n the U. S. for chronic or
`chron1c/1nterm1ttent use. Hence, the only studies submitted and reviewed below are a
`definitive embryo-fetal development study1n pregnant rabbits, and dose-r—anging embryo-
`fetal development studiesIn rabbit and rat.
`
`Eméiyofetd/development
`
`Oral (Stomach Tube) Developmental Toxicity Study of Sumatriptan Succinate
`Combined with Naproxen Sodium1n Rabbits
`
`-
`Key study findings:
`o The maternal and developmental NOAELs were less than 9/5 mg/kg/day NAP/SS,
`due to significant reductions1n maternal and fetal weights observed at 9/5 mg/kg/day
`NAP/SS and all other treated groups.
`0 Groups 90/50 and 90/0 showed roughly equivalent significant reductions in litter size,
`and increases in total resorptions per litter, early resorptions per litter, percent of dead
`or resorbed conceptuses per litter, and in the number of does with any resorptions.
`0 Groups 9/5, 45/25, and 0/50 showed non--significant1ncreases in numbers of early or
`late resorptions, average number oftotal resorptions, and percent dead or resorbed
`conceptuses per litter.
`0 The highest percentage of fetal alterations was observed1n groups 90/50 and 90/0,
`with1ncreases in the incidences of specific malformations (interventricular septal
`defect1n group 90/50, and msed caudal vertebrae1n both 90/50 and 90/0 groups) and
`variations (absent intermediate lobe of the lung, irregular ossification of the skull, and
`incompletely ossified stemal centra in both groups).
`0 Except for the finding of isolated interventricular septal defects described above in
`group 90/50, the toxicities reported for groups 90/50 and 90/0 are quite similar in this
`study, suggesting that the combination of SS and NAP is not likely to induce greater
`reproductive and developmental toxicity than NAP alone.
`0 The safety margin between the NOEL for teratogenicity1n rabbits given the
`combination of NAP and SS and the expected plasma exposures in humans given one
`oral tablet of Trex1ma® are 20-28—fold for SS, and 1 -2-fold for NAP. However,
`teratogenicity was only observed at doses well above those that were maternally
`toxic.
`
`Study no.: POZEN Study #MT400-T12, - Study # 2216-010
`Volume #, and page #: eNDA 21 —,926 Module 4, Section 4.2, Page 6948
`Conducting laboratory and location:
`’ —
`Date of study initiation. 18 MAY 2002
`GLP compliance: Yes, statement signed 25 SEP 2003 by the Study Director
`
`139
`
`

`

`
`
`Reviewer: David B. Hawver Ph.D. NDA No. 21-926
`
`QA reports: yes (X) no ( ), statement signed 25 SEP 2003 by the QA Principle Auditor
`Drug, lot #, and % purity: Sumatriptan Succinate (SS) Lot # QTO 1004, Purity 99.5%
`Naproxen Sodium (NAP) Lot #NPXNAM-127, Purity 99.3%
`
`Methods
`Doses:
`
`' 7'
`
`'
`
`Dosage‘
`(make/day)
`
`'
`
`'
`'
`Concentration'
`(mg/ml.)
`
`'
`Volume
`(mL/kg)
`
`
`
`Number of
`Rabbits
`
`Assigned RabbitNumbets
`
`Main Study
`
`Satellite Study
`
`. Group
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`0/0
`
`9/5
`
`45/25
`
`90/50
`
`0/50
`
`IV
`
`v
`
`v1
`
`010
`
`0.9/0.5 -
`
`4.5/2.5
`
`90/50.
`
`9.0/0
`
`0/50
`
`20+2
`
`b
`
`20 + 4
`
`b
`
`20+4"
`
`20+4°
`
`20+4
`
`20+4
`
`b
`
`b
`
`201 -220
`
`321- 322
`
`221 -240
`
`241 -260
`
`323 -326
`
`327 -330
`
`261 -280
`
`331 - 334
`
`.
`
`281 - 300
`
`335 — 338
`
`Expressed as naproxen sodium/sumauiptan base (NAP/SB).
`a.
`Rabbits assigned to toxicokinetic study.
`b.
`The test article was considered 100% pure for the purpose of dosage calculations.
`
`339 - 342
`301 - 320
`
`7
`
`(reproduced directly from eNDA 21-926, Module 4, Section 4.2, Page 6965)
`
`Species/strain: New Zealand White [Hra:(NZW)SPF] pregnant female rabbits, 5-
`6 month old, 2.8-4.3 kg, from
`——-
`Number/sex/group: 20 F/group Main Study
`Route, formulation, volume, and infusion rate: oral (stomach tube) solution in
`reverse osmosis membrane processed deionized water; dosage volume was
`adjusted daily on the basis of individual body weight
`Satellite groups used for toxicokinetics:_ 4 F/group treated, 2 F control
`Study design: dosing occurred once daily from DGs 6-18 in main study, and DGs
`6-20 in the TK satellite study; main study rabbits were sacrificed by IV
`Beuthanasia®-D on DG 29, and fetuses were removed by C-section.
`' Parameters and endpoints evaluated: observations (0-60 min postdose, daily);
`body weight (BW, daily); food consumption (FC, daily); TK (DG 6 & 19; 0.5,
`l, 2, 4, 8, 12, 16, and 24 hrs postdose; DG 20 ~1 hr postdose maternal & fetal);
`gross lesions were examined upon sacrifice and C-section for main study
`rabbits DG 29; number and distribution of corpora lutea; pregnancy status;
`number and distribution of implantation sites; number of early and late
`resorptions; number of live and dead fetuses; size, color, and shape of placenta;
`fetus weights; gross external alterations on fetus; fetus sex; fetal brain
`examination in situ after cross-section between parietal and frontal bones;
`examination for skeletal alterations after staining with alizarin red S;
`examination of rabbits found dead or sacrificed moribund or aborted; gross
`lesions were recorded and retained in fixative.
`‘
`
`140
`
`

`

`
`
` Reviewer: David B. Hawver Ph.D. NDA No. 21-926
`
`Results
`
`Mortality ( dams ):
`45/25 NAP/SS: 1/20 found dead (FD) DG 24; 1/20 aborted DG 26
`
`90/50 NAP/SS: 1/20 aborted DG 21
`
`90/0 NAP/SS: 1/20 FD DG19; 1/20 aborted DG 21
`
`0/50 NAP/SS: 2/20 FD DG 12 & 18; 2/20 sacrificed moribund (SM) D18 & 28; 1/20
`aborted DG 26; (1/20 FD DG 14 due to gavage error)
`
`Clinical signs (dams):
`Treatment-related increases were observed in the following signs:
`0
`scant/sofi/liquid feces (9/5, 45/25/ 90/50, 90/0, and 0/50 groups)
`0
`dehydration, emaciation, 1motor activity, clear perinasal substance, lateral
`recumbency (0/50 group only in does that were FD, SM, or aborted)
`
`Body weight (dams):
`Significant decreases in BW were observed in the following groups: 45/25 (18-11% DG
`1329), 90/50 (19-14% DG 1129), 90/0 (18-10% DG 16-28), and 0/50 (8-9% DG 15-
`17).
`,
`
`Significant decrease in body weight gain (BWG) was observed in group 9/5 (DG 16-19),
`and significant BW losses were observed in the following groups: 45/25 (DG 9-12),
`90/50 (DG 6-12), 90/0 (DG 8-12, 15-19), and 0/50 (DG 9-12).
`
`Mean BWG (DG 0-29) was reduced significantly in a dosage-related manner in 9/5
`(124%), 45/25 (169%), 90/50 (156%), and 90/0 (153%) groups compared to the 0/0
`control group.
`
`Mean changes in BW from DG 6 to DG 19 (the dosing period) were:
`0/0 (16.8%), 9/5 (13.7%), 45/25 (10.3%), 90/50 (14.8%), 90/0 (12.2%), 0/50 (T4.0%).
`
`Examination of the graph of maternal body weight changes below suggests that BW
`reductions induced during the dosing period by HD NAP (90 mg/kg/day) and by HD SS
`(50 mg/kg/day) were additive. Mean maternal BW in the combined HD NAP/SS group
`(90/50) was clearly below those of both HD NAP and HD SS groups during the entire
`dosing period.
`
`141
`
`

`

`
`
`Reviewer: David B. Hawver Ph.D. NDA No. 21-926
`
`mama: om. Mm mummasmmmm mmmm snow
`mmémsmouaan’ssmnvm: "HO-TI?)
`E
`N
`
`MATERNAL BODY WEIGHTS
`Figure 1
`
`WEIGHT
`
`(KG)
`
`oo10a10111213141513111310202122324252321252:
`DAYOFGESTATION
`mmmmmam
`
`(reproduced directly from eNDA 21-926, Module 4, Section 4.2, Page 6995)
`
`.
`Food consumption (dams):
`Mean daily FC was significantly reduced DG 6-19 compared to group 0/0 in groups:
`9/5 (l14%), 45/25 (¢31%), 90/50 “62%), 90/0 ($3M)
`
`Appears This Way
`On Original
`
`142
`
`

`

`Reviewer: David B. Hawvera Ph.D.
`
`NDA No. 21-926
`
`Toxicokinetics:
`
`Tibial.
`
`'
`
`M‘fll’dMGfl-fi-Mfluwm
`
`m m Don
`ID‘
`
`Day
`
`
`
`My”
`hu- MIC». M MIC“:
`hr
`ll'
`I!
`II'
`-
`0.5
`1.0
`
`127
`
`187
`
`Efsgfififif§§§§fiffifififirffifififi
`
`2I
`
`
`
`S
`
`(reproduced directly from eNDA 21-926, Module 4, Section 4.2, Page 7285)
`
`143
`
`

`

`Reviewer: David B. Hawvera Ph.D.
`
`NDA No. 21-926
`
`Terminal and necroscopic evaluations: C-section data (implantation sites, pre- and post-
`implantation lossa etc):
`Treatment—related findings included the following:
`0 Groups 90/50 and 90/0 showed ~Llitter size, Tresorptions/litter, Tearly
`resorptions/litter, Tresorbed conceptuses/litter, and T# does with resorptions. These
`effects were slightly greater for the 90/0 group than the 90/50 group.
`0 Groups 9/5, 45/25, and 0/50 showed Tearly or late resorptions/litter, Ttotal resorption,
`and T % dead or resorbed conceptuses/litter; however, none of these increases were
`statistically significant compared to the 0/0 group.
`. Fetal BW/litter was reduced at 9/5 (t14%), 45/25 ($1104), and 0/50 012%) (lack of
`significant reductions in 90/50 and 90/0 groups was thought to be due to the smaller
`litter sizes in these two groups).
`
`No treatment-related changes were observed in fetal sex ratios, # of dead fetuses, or
`placentae.
`
`mm 2216-010: om (m m) ml. mam STUDY 0! mm succnmn mm um mm 5mm
`1' mm (sun's m man.
`”400-112)
`mm 0 (PM! 1): m—smaflmmm- sum
`
`scam m
`mam: (us/mm“).
`I
`mm m
`11(5)
`m
`I")
`mun) mo
`I")
`mm men
`m m sacrum I")
`mm AID ”1'1ch X")
`mun-3mm
`cam-33mm
`17
`17
`10
`10
`1!
`(I DAY 2! 0, m“ H
`10.1 3
`5.5 g
`10.3 g
`10.9 g
`10.5 g
`00am mm.
`mam.
`9.4 g
`0.2 g
`9.2 g
`10.3 2
`9.0 g
`mm Md).
`5.1 t
`5.2 *
`7.0 g
`I.‘ z
`0.3 x
`um 5:22.:
`IIAIQBJ).
`90
`00
`127
`14.
`155
`LIV! m I
`5.3 g
`5.2 g
`7.0 g
`0.2 g
`0.2 g
`“98.0.
`0
`1
`0
`7
`2
`I
`0.0 2
`0.0 t
`0.0 g
`0.4 2
`0.1 g
`“5.0.
`4.1 g
`2., g
`2.2 g
`1.7 g
`0.0 g
`mgS.D.
`40
`37
`32
`G
`0
`H
`2.0 t
`2.2 g
`1.0 g
`0.3 1
`0.4 g
`”33.1).
`22
`13
`1
`24
`7
`I
`1.3 t
`0.2 g
`0.4 g
`1.3 g
`0.4 g
`“23.0.
`15‘ 00.2)
`15( 00.2)
`121 55.1)
`5! 50.0)
`7( 30.0)
`nous mm Al! WW I")
`a. noun mod on by. 6 cm 1- of gestation. my. in expand a W loam/mtupun bi...
`' significantly auteur In. the which contxol group all): (950.05) .
`N 51.311111“an alum: Iron ch- vuhiclc control group value (930.01) .
`
`DIM must:
`
`mamas
`M‘! Immune
`
`an hummus
`
`2.1
`2.5
`2.5
`
`2.5
`
`0.4
`1.1
`
`0.0
`
`1.0
`
`1.7
`1.5
`2.2
`
`2.7
`
`0.0
`2.4
`
`0.7
`
`2.2
`
`I
`0/0
`20
`20(100.0)
`o( 0.0)
`0( 0.0)
`0( 0.0)
`1( 5.0)
`
`11
`5/5
`20
`15( 55.0)
`0( 0.0)
`0( 0.0)
`l( 5.3)
`0( 0.0)
`
`11!
`45/25
`20
`20l100.0)
`1!
`5.0)
`0‘
`0.0)
`1( 5.0)
`0! 0.0)
`
`IV
`90/50
`20
`1H 90.0)
`0( 0.0)
`0‘ 0.0)
`1( 5.5)
`0( 0.0)
`
`.
`
`V
`90/0
`20
`1I( 50.0)
`0( 0.0)
`0‘ 0.0)
`I 1‘ 5.5)
`0( 0.0)
`
`VI
`0’50
`2| - "-
`15( 55.0)
`3( 15.2)
`2( 10.5)
`1( 5.3)
`0( 0.0)
`
`1)
`11.7 3
`10.5 :
`0.0 :
`11'.
`0.5 :
`1
`0.2 3
`1.7 :
`12
`0.9 :
`14
`0.0 g
`5( 46.2)
`
`3.4
`2.2
`0.0
`
`3.4
`
`0.0
`2.5
`
`1.9
`
`2.0
`
`1.4
`1.6
`3.4.
`
`3.4
`
`0.0
`3.2“
`
`2.0"
`
`2.1
`
`1.7
`2.5
`2.5
`
`2.‘
`
`0.0
`2.5
`
`2.4
`
`0.0
`
`2.2
`2.2
`2.0“
`
`2.4"
`
`0.2
`2.2"
`
`2.0"
`
`0.5
`
`(reproduced directly from eNDA 21-926, Module 4, Section 4.2, Page 7010)
`
`144
`
`

`

`Reviewer: David B. Hawver, Ph.D.
`
`NDA No. 21-926
`
`moon 2216-010: on». (m 1'08!) 0mm TOXICITY arm Of Mmm 0mm "11'! mm scum
`II “1.15 (M's 511:)! m1 "GOO-HZ)
`man I (I’m 2); m-zmmmmmm-M
`
`1
`0/0
`20
`2011004))
`0( 0.0)
`0( 0.0)
`0( 0.0)
`u 5.0)
`
`u
`9/9
`20
`19¢ 95.0)
`at 0.0)
`0( 0.0)
`11 9.3)
`at 0.0)
`
`n:
`45/25
`20
`anuoom)
`u 5.0)
`or
`0.0)
`u 5.0)
`0( 0.0)
`
`xv
`90/50
`20
`m 90.0)
`01 0.0)
`or 0.0)
`u 5.5)
`0( 0.0)
`
`v
`90/0
`:0
`lat 90.0)
`at 0.0)
`at 0.0)
`n 5.6)
`or 0.0)
`
`00m amp
`003m (balm/m).
`a
`mm m
`nu)
`mm-
`um
`mun mo
`1m)
`um men:
`m m mum mu
`pm no men )m)
`lam-rs mm- m
`cum-mum
`on m 29 or ans-mum
`nous m an. mm
`N 11.0)
`1( 5.9)
`0( 0.0)
`0( 0.0)
`0( 0.0)
`am
`mm onnsoaun
`15( 00.2)
`ut 90.1)
`1|(100.0)
`101100.”
`191100.»
`0035 wrm mm me am
`“(100.0)
`17(100.0)
`“(100.”
`10(100.0)
`19(100.0)
`PM mm mum. 10 um
`a. Dongs occun‘d on day- 6 through 1! at gunner). Doug- LI expand 0.- mm mull-maul“ bun.
`b. Excludes do“ with .11 only mucus.
`
`u
`
`19
`
`n
`
`10
`
`17
`
`17
`
`v:
`0150
`-.
`20
`19( 95.0)
`3( 15.0)
`at 10.5)
`u 5.1)
`o(
`0.0)
`
`n
`
`N 0.0)
`manna)
`nuoom)
`
`(reproduced directly from eNDA 21-926, Module 4, Section 4.2, Page 7011)
`
`Offspring (malformations, variations, etc. 23
`Treatment-related changes observed:
`0 T# litters with fetuses with any alterations (9/5, 45/25, 90/50, and 90/0)
`0 T# fetuses with any alterations (9/5, 45/25, 90/50, and 90/0)
`0
`1% fetuses with any alterations/litter (90/50 and 90/0)
`
`my 2216-010: ORAL (m was) mm mm: my 0' mm succmn m ”If! m 500ml
`1! mm (W‘s STD! m: moo-m)
`mm (M 1): MENUS-m
`
`I
`0/0
`19
`19
`151
`155
`2:
`
`II
`9/5
`ll
`u
`155
`1"
`7c
`
`III
`45/25
`1.
`10
`127
`127
`0
`
`IV
`”/50
`17
`16b
`.9
`ll
`ll:
`
`V
`90/0
`15
`15
`90
`90
`0
`
`VI
`0150
`13
`13
`11‘
`u).
`3c
`
`005m mom)
`mam (mlm/m).
`H
`urn-m mm
`um mum» n W N
`mm mm
`It
`LIV.
`I
`DIAD
`ll
`nm'ns um 1mm m
`m ABM" m I“)
`m In! An unnum-
`03mm
`I m m m
`32.0 2 27.59
`33.2 g 26.5.
`10.2 g 20..
`23.0 t 30.3
`10.? 2 23.5
`WITH/m WED.
`a. mango occur-d on day. 5 though 1. o! gut-den. noun 1.- emu-u :- moron: mammalian bus.
`c
`19. Exclude- men- :13. which counted at light Wim- Inrl one dead lotus.
`an nu. 22.
`’
`. Dad locus“ «on excluded £20- gzoup avenge: and nan-um manly-up ohm-deu- lot thou conceptual are cited
`°
`significantly «Home Iro- thn which control 52m “In. (50.0!) .
`" significantly dittamt fra- thc vehicl- cmtzo]. group valu- (pg-0.01) .
`
`S( 31.6)
`
`11‘ 61.1)“
`
`11( 61.1)“
`
`13‘ 01.2)"
`
`1“ 93.3)"
`
`5‘ 30.5)
`
`"(0) 111 7.1)
`
`32( 215)"
`
`2‘( 10-5)"
`
`II( 31...)"
`
`23( 35.5)“
`
`9(
`
`0.1)
`
`6.7 g 10.5
`
`(reproduced directly from eNDA 21-926, Module 4, Section 4.2, Page 7013)
`
`Specific malformations increased: (% of fetuses)
`o
`fused caudal vertebrae (3.4% 90/50, 2.2% 90/0, 0% 0/0)
`-
`interventricular septal defect (3.4% 90750, 0% 0/0)
`
`Specific variations increased: (% of fetuses)
`9
`absent intermediate lobe of the lung (9.1% 90/50, 4.4% 90/0, 1.3% 0/0)
`0
`irregular ossification of the skull (6.8% 90/50, 5.6% 90/0, 1.3% 0/0)
`0
`incompletely ossified sternal centra (3.4% 90/50, 4.4% 90/0, 0% 0/0)
`
`145
`
`

`

`Reviewer: David B. Hawver, Ph.D.
`
`NDA No. 21-926
`
`Sponsor’s Conclusions:
`The maternal NOAEL was less than 9/5 mg/kg/day NAP/SS, due to reduced maternal
`body weight gain and food consumption in the 9/5 group during the dosing period
`compared to control group values. Cmax of SS at 9/5 was ~2.5-fold greater than human
`exposure to SS after a single dose of 100 mg SS, and Cmax of NAP was 03-fold of the
`human exposure after a single dose of 500 mg NAP.
`
`The developmental NOAEL was also less than 9/5 mg/kg/day NAP/SS, due to significant
`reduction in fetal weight in this group.
`
`Groups 90/50 and 90/0 showed significant reductions in litter size, and increases in total
`resorptions per litter, early resorptions per litter, percent of dead or resorbed conceptuses
`per litter, and in the number of does with any resorptions.
`
`Groups 9/5, 45/25, and 0/50 showed non-significant increases in numbers‘of early or late
`resorptions, average number of total resorptions, and percent ‘dead or resorbed
`conceptuses per litter.
`
`The highest percentage of fetal alterations was observed in groups 90/50 and 90/0, with
`increases in the incidences of specific malformations (interventricular septal defect in
`group 90/50, and fiised caudal vertebrae in both 90/50 and 90/0 groups) and variations
`(absent intermediate lobe of the lung, irregular ossification of the skull, and incompletely
`ossified sternal centra in both groups).
`
`The finding of two fetuses with isolated interventricular septal defects at 90/50 (and none
`in any other group) was thought to be possibly related to the increased exposures to NAP
`(AUC T43%) and SS (AUC 158%) compared to exposures in groups 90/0 and 0/50,
`respectively. [Ifevz'ewer’s./Vo/e.' [haveAUCa’zf/Qre/zces are éasea’012 Day 614065.“,
`values; however, on Day 19, AUC0_¢,, values in the 90/50 group were $6. 7% SS and
`7‘8. 7% NAP compared to those in groups 0/50 and 90/0, respectively.
`
`Reviewer ’s Comments:
`
`Except for the finding of isolated interventricular septal defects described above in group
`90/50, the toxicities reported for groups 90/50 and 90/0 are quite similar in this study,
`suggesting that the combination of SS and NAP is not likely to induce greater
`reproductive and developmental toxicity than NAP alone.
`
`It is not clear why treatment with SS alone (0/50) induced greater mortality, since,
`otherwise, it appeared to be less toxic than treatment with NAP or NAP/SS.
`
`No-effect levels for maternal and fetal toxicity (decreased body weight) were not
`established in this study. The lowest dose that induced maternal and fetal toxicity (9/5
`mg/kg NAP/SS) was associated with mean plasma exposures (AUCOM) that were 0.14
`and 1.4 times the exposures to NAP and SS, respectively, observed in humans at the
`recommended dose of TREXIMA®. However, this study did demonstrate that significant
`teratogenic effects only occurred at doses that were maternally toxic.
`
`146
`
`

`

`Reviewer: David B. Hawvera Ph.D.
`
`NDA No. 21-926
`
`The Sponsor’s conclusions omitted the findings that the number of litters with fetuses
`with any alterations, the number of fetuses with any alterations and the percentage of
`fetuses per litter with any alterations was increased with the dose of NAP i SS.
`
`Based on the pharmacokinetic information presented in the table below, the highest no-
`effect level for teratogenicity in rabbits given the NAP/SS (45/25 mg/kg) was associated
`with mean plasma exposures (AUCOm) that were 0.84 and 14 times the exposures to NAP
`and SS, respectively, observed in humans at the recommended dose of TREXIMA®.
`
`Sumatriptan Exposure Ratios
`
`Ratio
`
`n_*hr/mL
`
`
`
`
`“mun(ngmL)
`—---——
`
`
`
`1m-----
`
`
`
`
`
`
`
`
`MT400-101 *
`
`BW LOEL
`
`5 mg/kg 55
`
`BW LOEL
`
`5 mg/kg 55
`
`Rabbit NOEL
`
`45 mg/kg NAP
`
`1117
`
`Rabbit NOEL
`
`0 mg/kg NAP
`
`Rabbit
`
`90 mg/kg NAP
`
`3843
`
`15
`
`40
`
`35
`
`
`
`
`—---——
`
`
`MT400-101*
`
`BW LOEL
`
`5 mg/kg 55
`
`LOEL
`
`5mg/kg SS
`
`RabbitNOEL
`
`45 mg/ngAP
`
`102
`
`1.5
`
`1293
`
`0.84
`
`Rabbit
`
`90mg/ngAP
`
`157
`
`Rabbit
`
`90 mg/ngAP
`
`171
`
`2.25
`
`2.45
`
`1352
`
`0.87
`
`1244
`
`0.80
`
`
`
`
`
`
`
`
`
`
`(*Human Values are Geometric Means (N=8) from Clinical Study Report MT400-101)
`(Rabbit values are fi'om Day 19; Reviewer’s Tables)
`
`147
`
`

`

`Reviewer: David B. Hawver, Ph.D.
`
`NDA No. 21-926
`
`Additional details on does found dead, sacrificed early, or aborting:
`45/25 NAP/SS: 1/20 found dead (FD) DG 24; 1/20 aborted DG 26
`
`(Doe 259: FD DG 24; soft/liquid feces DG 20-24; scant feces DG 23-24; head tilt DG
`24; BW loss DG 17-24; JrFC DG 18-24; black regions in all areas of stomach; 2 cm
`perforation in cardiac region of stomach, with thin surrounding tissue; litter consisted
`of 3 early and 4 late resorptions)
`
`(Doe 257: aborted & sacrificed DG 26; soft/liquid feces DG 13-18, 22-25; scant feces
`Dg 19-21, 23-25; red substance in cage pan DG 26; BW loss DG 9-26, JvFC DG 10-26;
`red substance in stomach; 2 early resorptions, 2 implantation sites assumed
`cannibalized, 3 fetuses (partly cannibalized) and one placenta found in cage pan; 2
`fetuses had unossified pubic bones, 3 appeared normal)
`
`90/50 NAP/SS: 1/20 aborted DG 21
`
`(Doe 276 aborted & sacrificed DG 21; scant feces DG 10-15, 19-21; no feces DG 16-
`18; soft/liquid feces DG 20-21; red substance in cage pan DG 21; BW loss, JrFC DG7-
`21; 9 implantation sites and 8 placentas found in cage pan)
`
`90/0 NAP/SS: 1/20 FD DG19; 1/20 aborted DG 21
`
`(Doe 300: FD DG 19; soft/liquid feces DG 12-18; scant feces DG 14-18; dehydration
`and red substance found in cage pan DG 18; BW loss DG 7-18; iFC DG 6-19; not
`pregnant)
`
`(Doe 296 aborted & sacrificed DG 21; soft/liquid feces DG 18-21; scant feces DG 10,
`20-21; red substance in cage pan DG 21; 1 conceptus, 1 early resorption, 1 late
`resorption found in utero, and 1 conceptus and 1 placenta found in cage pan; remaining
`4 conceptuses presumed cannibalized)
`
`0/50 NAP/SS: 2/20 FD DG 12 & 18; 2/20 sacrificed moribund (SM) D18 & 28; 1/20 FD
`DG 14 (Doe 313: dosing accident); 1/20 aborted DG 26
`
`(Doe 314: SM DG 28; soft/liquid feces DG 15, 23-26; scant feces DG 27; tan
`gelatinous substance in cage pan DG 28; BW loss and iFC DG 22-28; tan areas on all
`lobes of liver; black areas in stomach; tan caseous material adhered to lining of uterus;
`rough mottled placenta; pale spleen; litter consisted of 7 apparently normal live fetuses
`and 4 late resorptions)
`
`(Doe 317: FD DG 18; soft/liquid feces DG 12-15, 17; scant feces DG 16; dehydration,
`salivation DG 17; BW loss and lFC DG 11-18; 9 fetuses in litter)
`
`148
`
`

`

`
`
`Reviewer: David B. Hawver Ph.D. NDA No. 21-926 _
`
`
`
`(Doe 319: SM DG 18; soft/liquid feces DG 12—13, 15-17; scant feces DG 12-14, 16-18;
`~Lmotor activity, clear perinasal substance, lateral recumbency, labored breathing DG
`18; BW loss and JrFC DG 10-18; thin area in mucosal lining within cardiac region of
`stomach; 3 dead fetuses and five late resorptions in litter)
`
`(Doe 320: FD DG 12; soft/liquid feces DG 6-11; Jvmotor activity DG 10; dehydration,
`emaciation, scant feces DG 10-11; BW loss and ~LFC DG 6-12; 12 early resorptions in
`litter)
`
`(Doe 316 aborted & sacrificed DG 26; soft/liquid feces DG 13-19, 22-24; scant feces
`DG 16-24; dehydration, emaciation DG 25-26; red substance in cage pan DG 26; BW
`loss and loFC DG 9-21; red substance in stomach; dark firm areas in lungs; 6 late
`resorptions found in cage pan; 1 more late resorption aborted prior to sacrifice)
`
`Appears This WGV
`On Original
`
`149
`
`

`

`
`
`Reviewer: David B. Hawver Ph.D. NDA No. 21-926
`
`Oral (Stomach Tube) Dosage-Range Developmental Toxicity Study of MT 400 in
`Rabbits
`
`(POZEN Study #MT400-T10; — Protocol #2216-010P; Completed 10 OCT
`2003; GLP; QA; Naproxen Sodium (NAP) Lot #NPXNAM-126, Purity 99.5%;
`Sumatriptan Succinate (SS) Lot QTO 1002, Purity 99.4%, dosed calculated as base;
`eNDA 21-996, Module 4, Page 6794)
`
`Methods:
`
`Five presumed pregnant F New Zealand White [Hra:(NZW)SPF] rabbits were assigned to
`each of the following groups: 0/50, 90/1, 90/5, 90/ 15, 90/50, and 90/0 mg/kg/day
`NAP/S S, and treated via gavage at 10 mL/kg once daily on DG 6-18 (days of gestation).
`Observations included viability checks (2X/day), clinical signs (for ~1 hr postdose), body
`weight (BW, daily), and food consumption (FC, daily). All surviving rabbits were
`sacrificed on DG 29 and examined for the number and distribution of corpora lutea,
`implantation sites, and uterine contents. Gross necropsy of the thoracic, abdominal, and
`pelvic viscera was performed. Fetuses were weighed and examined for gross external
`alterations and sex.
`
`Results:
`
`No mortality or abortions were observed, except for one at 90/ 15 , which aborted and was
`sacrificed DG 24, with soft/liquid feces DG17-20 and 22-24, fluctuating BW, and
`reduced FC during the dosing period. Necropsy of this doe showed firmness and
`discolorations (dark red, tan, green) in right cardiac and distal end of lefi apical lobes of
`lung. The litter consisted of two dead fetuses (appearing normal) and three late
`resorptions in utero (too much autolysis for examination).
`
`Treatment-related clinical signs included sofi/liquid/scant feces in 1-3 does/group at 90/5,
`90/ 15, and 90/50, and ungroomed coat in 1/5 at 90/50. Maternal BWG was dose-
`dependently reduced in combination groups during the dosing period (+0.13, +0.14,
`+0.07, and -0.12 kg in groups 90/ 1, 90/5, 90/ 15, and 90/50, respectively, compared to
`+0.25 and +0.23 kg in groups 0/50 and 90/0, respectively). No significant differences in
`final BW were observed. Food consumption was reduced in groups 90/1, 90/ 15, and
`90/50 vs. comparators, but only during the dosing period.
`
`Increases in numbers of early resorptions, numbers of litters with resorptions, and
`percentage of resorbed conceptuses per litter were observed in groups 90/1, 90/5, 90/15,
`90/50, and 90/0 compared to group 0/50. These parameters showed greater increases in
`the 90/50 group compared to the 90/0 group. Mean fetal BW was reduced only at 90/50
`(based on only 14 fetuses). Gross external malformations were observed in two fetuses at
`90/1 (one with gastroschisis and one with a short tail), and in two fetuses (one with
`gastroschisis and one with a short tail) and two late resorptions (one with acrania,
`gastroschisis, medial rotation of right hindlimb, short tail, and fused forepaw digits; and
`one with gastroschisis, downward flexed forepaws, absent tail, no anal opening, and no
`external urogenital area) at 90/50.
`
`150
`
`

`

`Reviewer: David B. Hawvera PhD.
`
`NDA No. 21-926
`
`Conclusions:
`
`The proposed high dose of 90/50 mg/kg/day NAP/SS is expected to produce tolerable
`maternal and fetal toxicity in the definitive developmental toxicity study in rabbits
`(reduced maternal BWG during treatment at 90/ 1, 90/5, 90/15, and 90/50; reduced fetal
`BW in at 90/50 mg/kg/day NAP/SS ; and increased malformations at 90 mg/kg/day NAP
`i SS).
`
`meflinfl: DMMHWWWDWMTWIWWHTWDN mm
`«mm mmwulm: KIND-“U!
`
`MATERNAL BODY WEIGHTS
`
`Figure 1
`
`
`
`lli7!910111113141516171I1lm21n232‘25252782!
`DAYOFGESTATION
`
`(reproduced directly from eNDA 21-996, Module 4, Page 6803)
`
`Appears This Way
`0n Original
`
`151
`
`

`

`Reviewer: David B. Hawvera Ph.D.
`
`NDA No. 21-926
`
`Emmi: 2215-0100: can cm 1'00!) "-00“ mm mm m 01' '1' 000 11! 0000175
`(W's 5110)! mm.
`In 000-210)
`1m 0 ("an 1): mmmmm-m
`
`1
`0/50
`5
`$000.0)
`0| 0.0)
`
`I
`"(fl
`I“)
`
`11
`90/1
`5
`5(100.0)
`DI 0.0)
`
`III
`90/5
`5
`0! 00.0)
`0! 0.0)
`
`IV
`90/15
`5
`5(100.0)
`1( 20.0)
`
`V
`90/50
`5
`5(100.0)
`0! 0.0)
`
`VI
`00/0
`5
`51100.0)
`0l 0.0)
`
`fl
`“55.0.
`”95.0.
`ml).
`ll
`ml).
`I
`m.0.
`II
`“0.0.
`I
`ml).
`I“)
`
`5
`10.0 g
`9.5 g
`9.0 g
`07
`9.0 g
`0
`0.2 i
`0
`0.0 g
`1
`0.2 g
`1! 20.0)
`
`1.0
`1.7
`1.7
`
`1.7
`
`0.0
`
`0.0
`
`0.0
`
`5
`9.0 g
`9.2 g
`5.5 g
`33
`5.5 g
`0
`2.5 g
`11
`1.2 g
`2
`0.0 g
`0( 00.0)
`
`1.0
`1.9
`3.0,
`
`3.0
`
`1.0
`
`1.0
`
`0.5
`
`0
`10.0 g
`0.0 g
`3.2 g
`13
`3.2 g
`0
`5.5 g
`22
`5.5 a
`0
`0.0 g
`3! 75.0)
`
`0.0
`1.0
`3.5
`
`3.5
`
`0.0
`
`0.0
`
`0.0
`
`0
`0.5 g
`0.5 g
`5.5 0
`25
`5.5 g
`0
`2.0 g
`5
`1.5 g
`2
`0.5 a
`3( 75.0)
`
`1.3
`1.3
`2.9
`
`2.9
`
`1.5
`
`1.9
`
`1.0
`
`5
`0.2 g
`7.0 g
`0.5 g
`23
`0.5 g
`0
`3.2 g
`11
`2.0 5
`0
`0.0 g
`5(100.0)
`
`2.3
`2.0
`3.0
`
`3.0
`
`1.3
`
`1.0
`
`0.0
`
`5
`10.0 g
`10.5 g
`0.5 g
`03
`0.5 g
`0
`2.0 g
`5
`1.2 g
`0
`0.0 g
`3[ 50.0)
`
`3.0
`2.5
`2.1
`
`2.1
`
`1.5
`
`1.3
`
`1.3
`
`0005 m m 0501??!“
`0035 um I“. mm
`0( 0.0)
`DI 0.0)
`0( 0.0)
`1( 25.0)
`0( 0.0)
`0! 0.0)
`I")
`mm
`5(100.0)
`50.00.01
`0(100.0)
`3! 75.0)
`5(100.0)
`5(100.0)
`0025 In: vnuu mm In)
`sum) 0)
`5(100.0)
`01100.0)
`3(100.0)
`5(100.0)
`5|100.0)
`Pm mum mum.
`1H0]
`I. hang. «and on any! 5 5W 10 of gent-um. hung: in mud n nnpxoun ladiul/Iunttiptn hm.
`
`mm
`m ovum/m).
`nun: new
`Pm
`mom:
`0000115 Pm In
`tannins-5mm
`0! m 29 O! mamas
`0000000 mm
`1mm
`m an:
`LIVE mum
`
`nm must:
`mos
`mm “salmon
`
`“Tl 03000711“
`
`(reproduced directly from eNDA 21-996, Module 4, Page 6812)
`
`5mm 2215-0109:
`
`rm 0 (PM! 1):
`
`0001. (am Tull) Dom-nu mun-I'm. MCI“ my DY '1' 000 ll 0000115
`(5mm mt man.
`)u' 000-?10)
`1.1111: 03mm (mun-mm m) - 5m
`
` “0.0.
`
`1.7
`
`9.0 g
`21
`
`3
`
`an nu mu:
`u m m
`mag/um
`m m1. 000! mm
`07.10 g 0.00
`(“)1m m.D.
`07.00 g 0.57
`m "was
`”55.0.
`mm “5.0. 05.32; 3.09
`
`mm.
`
`«.2 .
`
`3.1
`
`3.0
`
`5.5 ¢
`:9
`
`3.5
`
`0.3 g
`I
`
`2.0
`
`5.5 a
`n
`
`3.0
`
`0.5 g
`u
`
`2.1
`
`0.5 g
`u
`
`“.4 g no.2
`
`70.0 . 25.0
`
`‘
`
`51.2 . 19.0
`
`11.: 1. a“
`
`59.1 g
`
`1.5.:
`
`05.51 3 3.35
`07.55 a 2.00
`05.00; 0.02
`
`09.70 g 7.50
`00.71 g 0.07
`05.30; 2.10
`I “E
`05.3 a 00.5
`
`05.05 g 1.20
`05.00 g 7.30
`05.05; 7.03
`
`25.1; 23.5
`
`03.09 g 9.70
`02.70 g 11.39
`00.70* 3.03
`I 3):
`05.0.; 30.1
`
`05.30 g 3.00
`05.30 g 0.03
`07.00. 1.90
`
`15.25 20.1
`
`1.0;
`
`0.5
`
`30.1; 27.2
`
`mun-m “5.0.
`I l - mm 07 VII-005 m
`a. Design occur“ on any. 5 M 10 a! mating. Dang. in mood I. m ”dim/mud)!“ but.
`3. us»: 0051 had no {”10 lama.
`c. Litton 0071 and 0073 1nd no Emlq teen-co.
`
`(reproduced directly from eNDA 21-996, Module 4, Page 6812)
`
`152
`
`

`

`
`
`Reviewer: David B. Hawver Ph.D. NDA No. 21-926
`
`Oral (Gavage) Dosage-Range Developmental Toxicity Study of MT 400 in Rats
`
`(POZEN Study #MT400-T09; — Protocol #2216-009P; Completed 10 OCT
`2003; GLP; QA; Naproxen Sodium (NAP) Lot #NPXNAM-l26, Purity 99.5%;
`Sumatriptan Succinate (SS) Lot QTO 1002, Purity 99.4%, dosed calculated as base;
`eNDA 21-996, Module 4, Page 6647)
`
`Methods:
`
`Five presumed pregnant F ‘CD®(SD)IGS BR VAF/Plus® rats were assigned to each
`of the following groups: 0/1000, 25/50, 25/250, 25/500, 25/ 1000, and 25/0 mg/kg/day
`NAP/SS, and treated via gavage at 10 mL/kg once daily on DG 7-17 (days of gestation).
`Observations included viability checks (2X/day), clinical signs (for ~1 hr postdose), body
`weight (BW, daily), and food consumption (DG 0, 7, 10, 12, 15, 18, and 21). All
`surviving rats were sacrificed on DG 21 and examined for the number and distribution of
`corpora lutea, implantation sites, and uterine contents. Gross necropsy of the thoracic,
`abdominal, and pelvic viscera was performed. Fetuses were weighed and examined for
`gross external alterations and sex.
`
`Results:
`
`No treatment-related mortality or clinical signs were observed. Maternal body weight
`gains were reduced during the dosage treatment period (DG 7-18) in combination dosage
`groups (68.0, 57.4, 66.2, and 41.6 g at 25/50, 25/250, 25/500, and 25/ 1000 mg/kg/day
`NAP/SS, respectively) compared to NAP alone (73.0 g at 25/0) and SS alone (70.4 g at
`0/ 1000) groups. No significant differences in final BW were observed (”o/e [fie lack ofd
`Vééz'c/e comm/grog”). Food consumption was reduced in the 25/ 1000 groups compared
`to all other groups, but only during the dosing period. No dead fetuses were observed. All
`C-section and litter parameters examined were comparable among groups, except that
`fetal body weights were dose-dependently reduced in the 25/250, 25/500, and 25/ 1000
`mg/kg/day groups compared to groups 0/ 1000 and 25/0. No treatment-related fetal gross
`external malformations or variations were observed. One fetus with a cleft palate from a
`dam treated at 25/5 00 mg/kg/day was not considered treatment-related.
`
`Conclusions:
`
`Based on these results, dosages of up to 25/ 1000 mg/kg/day NAP/SS are expected to
`produce tolerable maternal and fetal toxicity in rats (reduced maternal BWG during
`treatment, and reduced fetal BW at ,>_ 25/250 mg/kg/day NAP/S S).
`
`153
`
`

`

`
`
`Reviewer: David B. Hawver Ph.D. NDA No. 21-926
`
`PMOW. 221m»: ORAL (MVA-a)W“ MOPMALmmm 0' mm '0 M78
`momma STUDYman: Inmm!)
`
`MATERNAL BODY WEIGHTS
`Figure 1
`
`+
`
`a
`
`7
`
`a
`
`s
`
`an
`
`11
`
`t:
`
`u
`13
`DAYOFGESTATION
`
`1:
`
`1:
`
`17
`
`n
`
`:1
`n
`n
`I. mauwmm
`
`1mm MGMAV a
`
`(reproduced directly from eNDA 21-996, Module 4, Page 6656)
`
`010200)!- 2215-0005:
`
`0001: (GIVE!) wen-m mum MCI“ cm 07 If! 000 11 ”1‘5
`team's 511!!! mm.
`)I'l' 000-109)
`rm 0 (no! 1): unit more (mini-mm) -m
`
`fl
`“5.13.
`N
`”95.0.
`H
`
`I
`0,1000
`
`5
`15.5 g
`70
`15.5 g
`00
`
`11
`25/50
`
`'
`
`5
`10.0 g
`73
`10.5 g
`35
`
`1.3
`
`0.0
`
`2.5
`
`2.7
`
`III
`25/250
`
`0
`15.2 g
`‘0
`15.0 g
`29
`
`1.2
`
`1.0
`
`IV
`25/500
`
`0
`17.5 g
`GI
`17.0 g
`35
`
`3.3
`
`2.0
`
`V
`25/1000
`
`5
`15.5 t
`72
`10.0 g
`03
`
`1.1
`
`1.1
`
`VI
`25/0
`
`5
`17.5 g
`I5
`11.0 g
`39
`
`1.5
`
`3.1
`
`55.7 g 12.0
`
`00.1 3 11.5
`
`00.9 g 10.7
`
`50.5 g 15.5
`
`50.1 t 20.0
`
`05.5 t
`
`5.5
`
`Gm
`nous W/mm)£,h
`W 031'! ml 02
`m 1.1“ rams
`1mm
`mm mun:
`
`hm nu mm
`0 1.1V! mm
`mm WJD.
`nm rm ND! man:
`(mm “5.0.
`mums WA).
`man man: m.0.
`
`5.23 g 0.23
`5.30§ 0.21
`5.10 g 0.25
`
`3.1;
`
`0.0
`
`5.11 g 0.33
`5.21; 0.31
`5.02 g 0.37
`
`0.95 g 0.50
`5.05 g 0.10
`5.505 0.20 \ 5.00. 0.52
`5.33 g 0.12
`0.05 g 0.55
`
`0.00 g 0.20
`5.00; 0.15
`0.72 g 0.20
`
`0.02
`0.05 g
`0.92 g 0.05
`0.01 g 0.02
`
`mum "55.0.
`
`0.5
`7.3;
`3.0
`2.63
`2.0
`7.5.
`3.2
`1.0.
`mmuflmmmnmnmumsmmml
`I. non-gt «and on day- ‘l m 11 of gauntlet.
`b. bound on Inputs “flu/muim bun.
`
`5.0.
`
`3.0
`
`(reproduced directly from eNDA 21-996, Module 4, Page 6665)
`
`154
`
`

`

`Reviewer: David B. Hawvera Ph.D.
`
`NDA No. 21-926
`
`2.6.6.7 Local tolerance
`
`No local tolerance studies were submitted.
`
`2.6.6.8 Special toxicology studies
`
`No special toxicology studies were submitted.
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`Appears This way
`On Original
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`Reviewer: David B. Hawver, Ph.D.
`
`NDA No. 21-926
`
`2.6.6.9 Discussion and Conclusions
`
`Repeat-Dose Toxicology Studies
`In the pivotal 90-day repeat-dose toxicology study in mice (MT400-T19), high dose
`naproxen sodium (NAP) induced gastrointestinal toxicity characteristic of NSAIDs:
`ulcer, erosion, and inflammation of the glandular stomach. In female mice, the GI
`toxicity induced by NAP (50 mg/kg/day) was observed in the presence or absence of high
`dose sumatriptan sodium (SS, 320 mg/kg/day reduced to 210 mg/kg/day in Wk 4), but
`was increased in incidence and severity in the presence of SS, despite a 31% lower Day
`90 NAP AUC in the presence of SS. In the absence of other explanations, the
`exacerbation of NAP-induced GI toxicity by SS must be considered as a real possibility.
`
`Male mice in study MT400-T19 treated with HD NAP (100 mg/kg/day) alone showed no
`GI toxicity, while those given the HD combination (320/100 mg/kg/day SS/NAP)
`characteristic NAP-related toxicity. The difference in toxicity between these two groups
`could be related to the 37.5% higher NAP exposure in the SS/NAP group (Day 90 AUC).
`Also, it is not clear why females in the HD SS/NAP group showed greater toxicity than
`the males, since their NAP exposures appeared to be similar (Day 90 AUC0_0° = 381
`ug*hr/mL F, 363 ug*hr/mL M).
`
`Other treatment-related findings in study MT400-T19 were consistent with compensatory
`changes secondary to the GI toxicity induced by NAP: mild increases in WBC count,
`neutrophils, reticulocytes and platelets; increased absolute and relative spleen weights
`(correlated with increased erythroid extramedullary hematopoiesis); mild reductions in
`RBC count, HGB, and HCT;