Reviewer: Kathleen Young, PhD.
`
`NDA No. 22-304
`
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`222
`
`

`

`Reviewer: Kathleen Young, PhD.
`
`,
`
`NDA No. 22-304
`
`Hisimical Comm] Data onNeopIasfi: Finding; ‘
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`Greater than dose-related increase in systemic exposure to test article in F at 10 to
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`Linear dose-related increase in exposure (AUC0_24) to the parent drug in the M
`Dose-proportional increase in systemic glucuronide metabolite exposure, without
`gender differences
`Exposure to parent drug, CG5 503 but not to the glucuronide metabolite was
`higher in the F than in the M
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`High intra-group variability in the TK parameters (note large Standard Deviations
`observed) may be a result of variable feeding due to the housing arrangement
`using 5 rats/cage, with possible inconsistent access to food within the caged
`groups
`
`The results of the TK evaluation on CGSSO3 and CG5503 glucuronide are
`presented in the following tables (provided from the original NDA submission):
`
`223
`
`€
`

`

`Reviewer: Kathleen Young; Ph.D.
`
`NDA No. 22-304
`
`Summary on exposure to CG5503 base in Wistar rats after daily oral doses of CG5503 in the
`diet for at least 104 weeks
`
`(mean values AUCQLM.) :1: SD. of week 4, week 13 and week 26)
`
`lmg/kgida)‘l
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`Week 13
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`i211
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`131
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`560
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`136
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`331
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`4 to 26
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`19.1
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`94
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`274
`i165
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`166
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`666
`$351
`
`1705
`11495
`
`R“ = ratio ofADC from week '26 to‘ week 4
`
`Summary on exposure to CG5503 glueuronide in Wistar rats after daily oral doses of CG5503
`in the diet for at least 104 weeks
`
`.(mean values Cm; and AUQMM i SD. of week 4, week 13 and week 26)
`Males
`Females
`
`Dose
`Week 4
`
`[mg/kg/day]
`
`
`
`
`18630
`$4778
`
`88881
`122176
`
`221058
`21:49522
`
`428530
`:167827
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`15750
`14419
`
`80647
`$20367
`
`396595
`213118
`$8960 212181995
`
`21977
`i1877
`
`94668
`£20658
`
`249068
`21266631
`
`462639
`398040
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`19312
`i6475
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`104501
`$24954
`
`495182
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`19534
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`102417
`£29299 =111166
`
`475181
`2181040
`
`16881
`$44122
`
`98980
`$32854
`
`436231
`285241
`21:95222 $150146
`
`[ugh/ml]
`
`20047
`$4563
`
`95322
`i17707
`
`249337
`271028
`
`455450
`$111894
`
`17315
`$3904
`
`94709
`$18638
`
`442669
`253973
`$64122 $132524
`
`126
`
`111
`
`10?
`
`123
`
`134'
`
`R13: ratio of AUC from week 26 to week 4 ~
`
`224
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`3.4.6. Reproductive and developmental toxicology
`
`Summagy: The potential for reproductive and developmental toxicity by tapentadol was
`evaluated in rats and rabbits. Dose selection for the main studies was based on the results
`
`of preliminary range—finding toxicity studies, conducted in pregnant or non-pregnant
`animals; The range-finding studies included assays on tapentadol given by oral gavage,
`intravenous injection, and subcutaneous injection. Pivotal reproductive toxicology
`studies were conducted by the intravenous and subcutaneous routes to maximize systemic
`exposure to the parent drug, because oral tapentadol undergoes rapid and nearly complete
`transformation, predominantly to the O-glucuronide metabolite. An additional
`preliminary study in maternal and juvenile rats given tapentadol by oral gavage was
`conducted for dose selection in the pre- and post-natal development study in maternal and
`juvenile rats. Dose range-finding studies were conducted in non—pregnant rabbits
`7
`administered tapentadol by intravenous and subcutaneous injections.
`
`The results of the oral dose range-finding study in pregnant Sprague Dawley rats (Study
`TP2767) showed maternal hypersalivation at both doses administered (300 and 400
`mg/kg/day), and reduced maternal body weight gains of -24% at 300 and —23% at 400
`mg/kg/day throughout the dosing period. There were no treatment—related effects on the
`macroscopic examination of the dams, the numbers of implantations and dead and live
`fetuses. Oral dose range—finding investigation in another study conducted for dose-
`selection in the pre- and post-natal development andjuvenile study in rats (oral doses 0,
`20, 75, and 150 mg/kg b.i.d. PO, Study TP2772) showed reduced maternal body weight
`gains and food consumption (dose-related) and F1 generation toXicity via transfer in milk
`through postnatal day (PND) 8, and by direct treatment of the pups in PND 13-26 at all
`doses. F1 toxicity included HD pup deaths in the first 4 PNDs, reduced pup body weight
`gains in female pups during lactation (up to PND 8) and in the male and female pups
`dosed directly via gavage at the HD (PND 13-26). Clinical signs observed in the pups
`included hypoactivity at the MD and HD, and sedation and coldness at the HD before
`reduction of the HD from 150 to 100 mg/kg/day.
`
`The results of the intravenous dose range—finding study in rats (Study TP2060) showed
`decreased maternal body weights at the high dose (15 mg/kg/day), and maternal deaths at
`the 7 and 15 mg/kg/day doses (2/20 rats in each group), with tonic or clonic convulsions,
`flaccid position, and hemorrhagic snout in a high dose dam. Reduced numbers of fetuses,
`implantation sites and increased late resorptions were attributed to maternal toxicity, in
`agreement with the Sponsor. No evidence of teratogenicity by tapentadol was found in
`the fetal examinations in this range-finding study.
`
`injection in pregnant rats for 2 weeks (Study TP2465) produced
`Subcutaneous tapentadol
`injection site discoloration and erythemas at the MD of 30 mg/kg/day given in divided
`doses (bid) and HD of 50 mg/kg/day (divided, b.i.d.), and weeping eroded hemorrhagic
`lesions, eschar formation, and injection site indurations at theHD in most of the dams.
`Food consumption was reduced in a dose—related manner at the MD and HD, and reduced
`motility was observed at the HD.
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`The results of the dose range-finding study in non-pregnant Himalayan rabbits
`administered tapentadol by intravenous injection at doses of 0,. 3, 7, and 15 mg/kg/day for
`2 weeks (Study TP2061) showed reduced dose-related increases in severity and duration
`of motility and flaccid position at all dose levels. Opisthotonus, increased respiratory
`rate, and reduced food consumption and body weights were observed at the MD and HD,
`and reduced respiratory volume and exophthalmus was found at the HD. Dose range—
`finding evaluation was also performed in non-pregnant rabbits by the subcutaneous route,
`at doses of 0, 10, 30 and 50 mg/kg/day (divided, b.i.d.) for 14 consecutive days (Study
`TP2464). Local toxicity was observed, similar to that in the subcutaneous toxicity study
`in the rats, at the high dose and included red or brown discoloration at the injection sites
`with subcutaneous lesions and skin thickening. Miosis and dose-related reduced food
`consumption was observed at all doses, and body weights were reduced (-18%) at the
`HD. The clinical signs also included reduced motility and abdominal position at the
`highest dose administered. The necroscopic examination in that study revealed pale liver
`and urinary bladder gritty substance at the high dose.
`
`In the main study on potential treatment—related adverse effects on fertility and early
`embryonic development to implantation in male (M) and female (F) Wistar rats,
`'
`tapentadol was negative for adverse effects on mating and fertility at intravenOUS (IV)
`doses of up to the maximum tolerated (MTD based on toxicity, Study TP2445). The
`maternal (F0) rats were administered consecutive daily IV doses of 0 (saline vehicle
`control), 3, 6, and 12 mg/kg/day, from 28 days before mating through 9 days after mating
`in the M, and from 14 days before mating through Day 6 post-coitum in the F. The key
`study findings in the pivotal fertility study were maternal and early embryonic (F1
`generation) toxicity. Maternal toxicity was indicated by slight body weight loss and
`decreased food consumption at 6 and 12 mg/kg/day IV tapentadol. The mean numbers of
`corpora lutea were reduced by 4% and 6%, and there were decreased mean numbers of
`implantations by 8% and 11% at those doses, respectively. Additionally, there were dose
`related increases in mean percent pre-implantation and post-implantation losses, and
`dose-related decreased mean numbers of live conceptuses at all doses, compared to
`controls. No adverse treatment-related effects on mating performance and in the
`necroscopic examination ofthe reproductive organs were observed in the 4M rats. The
`embryonic developmental abnormalities (pre—implantation and post-implantation losses)
`are considered to be secondary to maternal toxicity, in agreement with the Sponsor. The
`NOAEL value for F0 toxicity was 3 mg/kg/day IV, for adverse effects on fertility in the
`F0 M and F rats was 12 mg/kg/day IV and for adverse effects on early embryonic
`development (F 1 generation) was 3 mg/kg/day IV. Toxicokinetics analyses were not
`conducted in this study; estimated systemicexposures based on the toxicokinetics
`analyses in a 4-week intravenous study in rats (PT1966) at the highest IV dose of 15
`mg/kg/day represented approximately 0.41 times in the M and 0.35 times in the F rats,
`the MRHD, on an AUC basis.
`
`Embryo-fetal development toxicity (Segment II studies) was studied in rats and rabbits
`administered tapentadol by intravenous and subcutaneous administration. Tapentadol
`was negative for teratogenicity in rats at up to maternally toxic doses, but found to
`
`226
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`increase the incidence and severity of fetal variations and malformations in the rabbit
`studies.
`
`Pregnant Sprague Dawley rats were given tapentadol by intravenous injection at doses of
`0, 3 (LD), 7 (MD), and 15 (HD) mg/kg/day on gestation days 6-17 (inclusive, Study
`TP2060). There were 2 maternal deaths each in the MD and HD groups, within 2-45
`minutes of the first injection, preceded by convulsions, exophthalmus, flaccid position
`and hemorrhagic snout. There were reduced numbers of fetuses, decreased implantation
`sites and increased late resorptions that correlated with decreased maternal body weights
`and severe maternal clinical signs. There were no treatment-related effects on sex
`.
`distribution, placenta weight, fetal weight, fetal deaths, incidence of runts, and no
`external, skeletal and soft tissue malformations, variations and retardations. Subsequent
`investigation of embryotoxicity by tapentadol in using the subcutaneous route (Study
`TP2510) at doses of 0, 5 (LD), 10 (MD), and 20 (HD) mg/kg bid. (10, 20, and 40
`mg/kg/day) on Gestation days 6-17 (inclusive) showed maternal toxicity at all dose
`levels, with dose-related increases in severity and duration of reduced body weight gain,
`abdominal position lasting 1-2 hours, and at the MD and HD local toxicity (eschar
`formation and hemorrhagic foci). No treatment-related malformations or variations were
`observed in this study. However, tapentadol was embryotoxic at the HD (representing
`systemic exposure of approximately 3 times the clinical systemic exposure at the MRHD,
`on an AUC basis). There were observations indicative of treatment-related
`developmental delay (skeletal retardation), with increased incidence of incomplete or
`missing ossification of the stemebra and caudal vertebral bodies when compared to
`control fetuses. A relationship of the observed embryotoxicity to maternal toxicity,
`particularly to treatment-related reduced food consumption and body weight gain is
`likely. The NOAEL for embryotoxicity was 20 mg/kg/day (representing systemic
`exposure of approximately 1.5 times the clinical systemic exposure at the MRHD, on an
`AUC basis). Exposure to the O-glucuronide metabolite at the highest dose tested was
`approximately equivalent to clinical exposure to the metabolite at the MRHD, on an AUC
`basis.
`
`An early embryo-fetal toxicity study in Himalayan rabbits (Study TP2061) evaluated
`intravenous doses of O, 1 (LD), 3 (MD), and 9 (HD) mg/kg/day from Gestation Days 6-
`20, inclusive (Study TP2062). Maternal toxicity, noted at the HD, included flaccid
`position, increased respiratory rate, opisthotonus and tremor. There was one abortion at
`the HD on Gestation Day 26 (within range of historical background incidence). This
`study was negative for external, visceral and skeletal malformations, variations and
`retardations by IV tapentadol administration, although there was a treatment-related
`decrease in number of live fetuses and increased post-implantation loss at the HD, due to
`the deaths of 10 fetuses in 2 of the 16 litters evaluated. Toxicokinetic evaluation results
`
`were not provided.
`
`A second embryo-fetal development study on tapentadol was conducted in Himilayan
`rabbits, dosed twice daily by the subcutaneous route at doses of 0, 4 (LD), 10 (MD), and
`24 (HD) mg/kg/day (Study TP251 1). There were dose-related increases in incidence and
`severity of maternal toxicity, indicated by miosis, abdominal position and reduced body
`
`227
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`weight gain and food consumption at all doses administered. Statistically significant
`reductions in fetal body weights were found at the MD (~10%) and HD (~13%). The
`fetal examinations also revealed dose-related decreases in fetal viability, with increased
`post-Caesarian deaths during the 24-hour incubator stay at he MD (9'fetal deaths) and
`HD (7 fetal deaths), when compared to the control and LD groups (3 deaths each).
`There were 4 runts at the HD (compared to 2 in the control group),_all of which died
`during the 24 hour post-Caesarian incubator stay. Increased incidence of multiple
`internal malformations, with gastroschisis or thoracogastroschisis, prolapsed organs,
`. amelia, and phocomeliawere observed at the MD (+0.9% incidence compared to
`controls) and HD (+1.7% incidence compared to controls). Encephalocele was seen in 1
`HD runt, spina bifida in 1 HD‘runt, kyphosis in 1 HD runt, ablepharia in 3 HD‘fetuses
`from 1 litter, and cleft palate in 1 MD fetus (0.9%), 3 fetuses from 1 HD litter and 1
`additional fetus from another HD litter (3.4%). Skeletal variations (accessory 13th rib,
`shortened ribs, caudal vertebral bodies misaligned or fused, unossified parietal area of the
`skull and sternum fused or misaligned), and skeletal retardations (incomplete ossification
`in the frontal, parietal, interparietal, and supraoccipital skull, unossified hyoid,
`incomplete or unossified small sternum, and reduced, unossified or dumbbell-shaped
`vertebral bodies) were found with statistically significant increases at the HD compared
`to control incidence. The NOAEL for teratogenicity in this study was 4 mg/kg/d SC,
`representing exposures in the dams that were approximately equivalent to the clinical
`systemic exposure at the MRHD ,on an AUC basis. The embryo-fetal toxicity was
`observed in the litters from dams showing severe clinical signs, body weight loss, and
`reduced body weight gain and food consumption, although not all dams showing toxicity
`had adversely affected fetuses. A possible relationship of the observed fetal toxicity to
`maternal toxicity, along with the incidence Of these findings within the upper limit of the
`historical range of background incidence for the' performing laboratory suggest that the
`findings in this study may not be entirely related to direct effect of tapentadol-on embryo-
`fetal development in rabbits, although a direct treatment-related teratogenic effect cannot
`be ruled out, either.
`
`Pre— and post-natal developmental toxicity by tapentadol was investigated in Sprague-
`Dawley rats at maternal (F0 generation) oral gavage doses of 0, 10 (LD), 25 (LMD),
`75(HMD), and 150 (HD) mg/kg b.i.d. (20, 50, 150, and 300 mg/kg/day) administered
`from Gestation Day (GD) 6 through Post-Partum Day (PPD) 21, inclusive. Maternal
`toxiCity was indicated by deaths (4 HD dams found dead and the remaining maternal
`deaths by sacrifice in extremis) in 6 HD, 1 HMD, l LMD, and 2 LD dams, and clinical
`signs of ptyalism (HD), piloerection and round back (HD, HMD), reduced body weight
`and body weight gain (BWG, -22% at the HMD and -24% at the HD), and reduced food
`consumption at the HMD and HD throughout the dosing period. There were no
`treatment-related effects on pregnancy and parturition. There was a statistically
`significant treatment-related reduction in the viability index indicating increased pup
`mortality, with complete litter deaths in l HMD litter and 2 HD litters, and increased
`numbers of pup deaths at the HMD (16 pups) and HD (18 pups) compared to 2 control
`pup deaths. Statistically significant reduction in pup body weights and body weight gains
`were also observed at the HD from PPDl throughout lactation. Unossified 6th centrum of
`the cervical vertebrae was noted in 50% of theHD pups that were found dead during PPD
`
`228
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`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`l-4, and there were non-ossified or incomplete ossification in other bones in several pups,
`probably due to lower body weights in these pups.
`'
`
`Pup (F 1 generation) post-weaning physical development measurements shoWed reduced
`body weights and body weight gains in the F1 HD M from PPD22 to the end of the study
`(pup ages 10—11 weeks), and in the MD (PPD22-37) and HD (PPD22-ages 10-11 weeks)
`F compared to controls. There were slight, but not significant increases in horizontal
`movements and rearing at the MD and HD in the M (+7% and +10%, respectively) and F
`at all dose levels (+2%-+20%). The results of the T-maze test on the F1 generation
`showed slight, but not significant increases in test time in the learning phase in M at the
`HMD (+63%) and HD (+52%), and in the memory phase at the HD (+12%), compared to
`controls. No treatment-related effects on F1 generation sexual development, auditory
`function and pupil constriction were found. Specifically, there were no treatment-related
`effects on F mating, mean numbers of days to mate, fertility data pregnancy status,
`hysterectomy data (e.g., corpora lutea, implantations, concepti, etc). There was a failure
`to mate in 2, l, and 1 F] M at the LD, MD, and HD, respectively, that is unlikely related
`to treatment due to absence of dose-effect. Toxicokinetic evaluation showed dose-
`
`related linear increases in exposure to parent drug and the glucuronide metabolite in the
`F1 pregnant dams, with increased exposure to the parent drug with repeated dosing at all
`but the HD, and to the glucuronide at all doses, suggesting accumulation. The NOAEL
`for F0 maternal toxicity was 50 mg/kg/day PO, based on reduced BWG and food
`consumption (representing systemic exposure of approximately 1.5 times the clinical
`exposure at the proposed MRHD on an AUC basis). The NOAEL for treatment-related ‘
`abnormalities in pup development was 20 mg/kg/day PO, due to pup deaths from PPD l-
`4 (exposure of approximately 0.3 times the clinical exposure at the MRI-ID, on an AUC
`basis). The NOAEL for the F1 generation was 300 mg/kg/day (systemic exposure of
`approximately 10 times the clinical exposure to the parent drug at the MRHD, on an
`AUC basis); although body weights were reduced, there were no effects on mating,
`fertility, and neurobehavioral parameters. Maternal systemic exposure to the main 0-
`glucuronide metabolite at the NOAEL represented approximately 35 times the clinical
`exposure to the metabolite at the MRHD, on an AUC basis.
`
`In conclusion, the results of the studies on reproductive toxicity in rats and rabbits
`suggested potential adverse effects by tapentadol on the developing fetus and newborn,
`although these effects may be related in part to drug-related poor maternal condition,
`such as nutritional deficiencies, due to decreased appetite and food consumption, and
`resulting weight loss. No direct effects on fertility were observed in male and female rats
`at doses up to the maximum tolerated, based on treatment-related toxicity and
`representing systemic exposure that were approximately equivalent to clinical exposure at
`the MRHD of 700 mg/day, using AUC comparison. No clear, treatment-related
`teratogenic effects were observed in rats (given subcutaneous and intravenous doses) and
`rabbits (given intravenous doses) at doses up to the maximum tolerated based on
`maternal toxicity during organogenesis (approximately 3 times in rats and 10 times in
`rabbits, the clinical exposure at the MRHD on an AUC basis); however, tapentadol was
`embryotoxic in these studies. However, malformations were seen in the subcutaneous
`study on embryo-fetal development in the rabbits. The degree to which maternal toxicity,
`
`229
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`'
`
`_
`
`NDA No. 22-304
`
`known to affect embryofetal development in rodents, was responsible for these findings,
`vs. direct teratogenicity by tapentadol is not known. The Segment II studies revealed
`developmental delay in the rats, indicated by incomplete or non-ossification of the
`stemebrae and caudal vertebral bodies. In the rabbits, decreased viability, developmental
`delay (delayed ossification of fetal skeleton), and slight dose-related increased incidence
`of variations and malformations were observed, although predominantly in the litters of
`dams showing severe treatment-related toxicity. The malformations seen in the fetal
`rabbits were within the upper range of historical incidence. Tapentadol exposure in utero
`and during lactation (Segment III) increased rat pup mortality in the days following birth,
`reduced pup body weight gain and skeletal development, and suggested a slight but not
`significant effect on learning and memory, probably due to secondary effects of maternal
`toxicity and treatment-related CNS sedation, in the offspring, at maternal doses higher
`than those representing exposure approximately equivalent to the clinical exposure at the
`MRHD on an AUC basis.
`
`Dose range-finding studies:
`
`Dose range finding studies were conducted in pregnant rats and rabbits. The results of
`two embryo-fetal toxicity studies (Studies 10434 (TP 2060) and TP2062) were reviewed
`under the original IND submission (IND 61,345, SNOOO, December 1, 2000, Kathleen
`Haberny, Ph.D., now Kathleen Young, Ph.D., Pharmacology and Toxicology Reviewer).
`The previous study reviews are provided, below.
`
`Examination of the influence of Slit-200 on the Pregnant Rat and the Fetuses by
`intravenous Administration - Embryotoxicity Study: study 10434/97
`
`Amendment #000, Vol #4, Page #1
`
`gianducting laboratory and location: Testing facility: C,
`a...
`.
`2””
`”E
`Date of study initiation: May 6, 1997
`GLP compliance: Signed and present
`QA- Report Yes (x ) No ()
`Protocol reviewed by Division Yes ( ) No (x)
`
`j?
`,l
`
`”(4)
`
`230
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`‘
`
`»
`
`NDA No. 22-304
`
`Mgthods: Pregnant Sprague—Dawleyrg SPRDI‘ats (;
`
`7 ages 7 wee s, weights 184-231 g,
`“(W 'fi
`‘n’2/2tlidose) were used in this study. The Fats were administered BN-200 (presently
`known as (365503, Batch #06, purity 98% by TLC, in physiological saline) at doses of 0,
`3, 7 and 15 mg/kg/day by intravenous bolus injection at 'lD ml/kg over 1 minute, daily
`from the 6‘h to 17‘“ day of pregnancy.
`
`d 3
`
`“4)
`
`The maternal observations Were mortality (daily), clinical signs (daily). body weights
`(daily), and food and water consumption (daily).
`
`The necropsy evaluations, conducted on gestation day 20, were uterine weights,
`examination of maternal internal organs, numbers of alive and dead fetuses, placentae
`count, sex and viability of fetuses, number and size of resorptions, corpora lutea in the
`ovaries, implantations, locations of fetuses in the uterus, gravid uterus weight, Weights
`of fetuses and placentae, external and internal inspection of fetuses for skeletal, internal
`organ, and soft tissue damages/malformations, variations, and retardations. The
`parameters were corpora lutea, implants, resorptions, placental weights, fetal weights,
`number of alive and dead fetuses per dam, per group and per sex, distribution of
`fetuses in uterine horns, runts, malformed fetuses, malformation rate, variations and
`variation rate, retardations and retardation rate, rare—implantation loss and post-
`implantation loss. No toxicokinetic analysis was conducted.
`
`Results: There were 2 maternal deaths each in the mid-dose (7 mglkgld] and high-
`dose (15 mglkg/d) groups. The mortalities occurred within 245 minutes of the first
`injection on gestation day 6. The deaths were preceded by tonic or clonic convulsions,
`exophthalmos, flaccid position, and in one high dose darn, hemorrhagic snout.
`
`There were no local reactions at or near the injection sites in any group. The clinical
`signs in the dams given the low dose (3 mglkgld) were decreased activity, head
`bobbing, and flaccid position beginning at 5-20 minutes after dosing and lasting 5-20
`minutes, on the first 2-3 dosing days. The treatment-related clinical signs in the mid-
`dose group were exophthalmos and flaccid position, and in one dam respiratory
`depression, beginning 5 minutes after dosing and lasting 20 minutes-2 hours on all
`dosing days.
`In the high-dose group, the clinical signs were tendency toward
`convulsions, flaccid position, and exophthalmos. Body weights were decreased slightly
`(-9% compared to controls) in the high-dose dams on gestation days 8-20 and body
`weight gain was reduced (57% increase compared to 69% increase in controls) on days
`6-9 and 9-12, Food consumption was reduced in the high-dose group on gestation
`days 8 and ‘12. There were no systemic necropsy findings in the dams that survived to
`necropsy. Dark-red discolored lungs were observed in the necropsy examination of the
`animals that died. The uterus weight was decreased in the mid—dose and high—dose
`dams.
`
`APPEARS TH is
`0N omcmALWAY
`
`231
`
`

`

`Reviewer: Kathleen Young, PhD.
`
`NDA No. 22-304
`
`The reproduction data of the dams is presented in the following table (reproduced from
`the original IND submission):
`
`
`
`
`_ Dose (marks/day)
`—‘-——-_
`
`
`Corpora Iutea
`total
`258
`256
`262
`235
`
`
`uer dam
`12.9
`12.8
`13.1
`11.8
`
`uer dam
`
`er dam
`
`- er clam
`
`per dam
`
`12.9
`
`1.1
`
`0.3
`
`0.8
`
`12.8
`
`1.0
`
`0,5
`
`0.4
`
`.
`
`12.6
`
`1.1
`
`0.4
`
`0.7
`
`11.6
`
`0.6
`
`0.2
`
`11.5
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`11.1
`11.7
`11.8
`erdam
`mean °/o mi-
`Pre-im-Iantation loss
`.
`.
`
`
`mean % “—11-“
`Post-in) Iantation loss
`‘Signtficantly different from controls at 050.05
`”Significantly different from controls at ps0.01
`
`Implantation sites were decreased at the mid-dose and high-dose. Late resorptions and
`number of live fetuses were decreased in the high-dose animals.
`
`The examination of the fetuses revealed no treatment—related effects on sex
`distribution, mean placental weights, and mean fetal weights. The external examination
`showed encephalocele in one control fetus. and an abdominal hematoma in one low-
`dose fetus. There were 5 dead fetuses (1 control. 3 at 3 mglkgld, and 1 at 7 mglkgld).
`There were 4 runts (2 control, 1 at 3 mg/kgld, 'I at 15 mglkg/d).
`In the skeletal
`examination of the fetuses, there were no mattdrmations. Skeletal variations included
`accessory 14“h ribs, stemum bipartite and misaligned sternebrae in similar incidence
`among the control and treatment groups. Skeletal relardations were also observed to a
`similar extent (degree and incidence) in all groups and included incomplete ossification
`APPEARS THIS WAY
`0“ ORIGINAL
`
`of the skull and hyoid, incomplete and missing ossification or reduced size of
`sternebrae, incompletely ossified or dumbeII-shaped and bipartite thoracic, lumbar'and
`caudal vertebral bodies, and unossified 5‘h metacarpatia and 5‘“ metatarsalia. There
`were no treatment-related soft tissue malformations or variations in any group.
`
`Key Study Findings:
`0 High dose (15 mgl'kgld) resulted in matemal toxicity (tremor, convulsions, flaccid
`position, exophthalmos, decreased body weights and decreased food consumption)
`0 Reduced number of fetuses correlated with decreased matemal body weights in the
`high-dose group
`. Decreased implantation sites and late resorptions. probably related to maternal
`toxicity. at 15 mg/kgfd
`o No treatment-related effects on sex distribution, placenta weight, fetal weight, fetal
`deaths and incidence of runts
`. No effects of BN-200 on external, skeletal and soft tissue malformations, variations
`and retardations at doses ranging from 3-15 mgi‘kgl'cl IV, when administered on
`gestation days 6-17 in rats
`
`232
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`Examination of the Influence of BN-200 on the Pregnant Rabbit and the Fetus by
`Intravenous Administration - Embryotoxicity Study: Study TP 2062
`
`Amendment #000, Vol #3, Page #1
`
`I;
`
`Date of study'initiation: June 17, 1997
`GLP compliance: Signed and present
`QA— Report 'Yes (x ) No ()
`Protocol reviewed by Division Yes ( ) No (x)
`
`Mair
`”.2
`
`M4)
`
`Methods: Pregnant Himalayan rabbits (own breed ages 5 57 months, weights 2.53-
`3.60 kg, n=161dose) were usedIn this study. The rabbits were administered BN-200
`(presently known as 065503, Batch #06 purity 98% by TLC in physiological saline) at
`doses of 0. 1 3 and 9 mg/kgiday by intravenous bolus injectionIn an ear vein at 3 mlikg
`over 1 minute daily from the 6‘h to 20‘“ day of pregnancy.
`
`The maternal observations were mortality, local tolerance at the injection site, clinical
`signs, body weights, and food and water consumption.
`
`Necroscopic examination on gestation day 29 inclirded number of dead and alive
`fetuses, placental count, fetal viability (after S—h and 24-h stay in incubator), number and
`size of resorptions, corpora lutea in ovaries, and implantations, and location of fetuses
`in uterus, fetal weights, placental weights, extemal inspection for fetal damage
`(malfomiations, variations, retardations), fetal dissection for location, size and condition
`of the intemal organs, abnormalities of soft tissue, internal head structure and brain, APPEARS firms WAY
`Oil ORIGltlAL
`
`fetal sex, and skeletal retardations, variations and malformations. The evaluations were
`corpora lutea, implants, resorptions, weight of placentae, weight of fetuses, live and
`dead fetuses, runts, malformed fetuses, malformation rate per group, fetuses with
`variations, variation rate, fetuses with retardations, retardation rate, pre-implantation
`loss, and post-implantation loss.
`
`* Blood was withdrawn for toxicokinetic analysis before closing and at 15, 60 and 120
`minutes on pregnancy days 6 and 20, from 3 rabbits per group.
`
`Results: There were no maternal deaths, and no local reactions at or near the injection
`sites in any group. Clinical signs were observed in all dams at the high dose of 9
`mglkgld N on several dosing days, and included opisthotonus (spasm consisting of
`‘hyperextension of the body), flaccid position, and increased respiratOIy rate. Tremor
`was occasionally observed, and there was one abortion on gestation day 26 at the high
`close, There were no treatment-related effects on body weights, body weight changes,
`food and water consumption, and no pathologic findings at the iniection site in the
`necropsy examination. The systemic necropsy showed liver discoloration in one dam
`each in the low-dose {1 mgikgfd) and high-dose (9 mgi'kgld) groups.
`In one high dose
`dam, there was a hemorrhage in the right uterine horn, with a thickened, malshaped
`placenta; all fetuses were found dead in this dam. The single abortion contained 2
`normal appearing fetuses with l placenta: 7 dead fetuses ands placentae remained in
`the uterus Net weIght change from days to necropsy Nas slightly IeducedIn the high
`dose clams
`
`233
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`.
`
`NDA No. 22-304
`
`The reproduction data of the dams is presented in the following table (reproduced from
`the original IND submission):
`-
`
`
`
`
`
`
`implantation sites
`
`
`
`_ Dose (mglkgldav)
`
`
`—__-__‘-
`
`Corpora lutea
`total
`152
`142
`145
`141
`- er dam
`9.5
`8.9
`9.1
`9.4
`total
`137
`133
`131
`128
`
`per dam
`8.6
`8.3
`8.2
`8.5
`Resorptions
`total
`
`
`10
`
`Early resorptions
`
`
`
`
`
`
`7.2
`7.6
`7.4
`7.4
`per dam
`'
`
`
`—-“-§_
`
`
`
`Post—implantation loss
`mean %
`*Significantly different from controls at ps0.05
`*‘Slgnificantly different from controls at ps0.01
`
`- er dam
`
`0.7
`
`0.7
`
`0.9
`
`Post-implantation loss was increased, although not significantly, in the high dose group
`due to the significant decrease