CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`021196Orig1s000
`
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`

`

`MEMORANDUM
`
`To:
`
`File, NDA 21-196
`
`Through: Robert Temple, M.D., ODE I Office Director
`Russell Katz, M.D., Division Director, Neuropharmacologic Drug Products
`Barry Rosloff, Ph.D., Pharmacology Supervisor, HFD-120
`Anna Marie Hommonay R.Ph., Project Manager, HFD-120
`
`From:
`
`Jeri El-Hage, Ph.D., ODE I Associate Director for Pharmacology/Toxicology
`
`Subject: NDA 21-196, Xyrem®, sodium oxybate (sodium gamma hydroxybutyrate)
`Tertiary Review of Pharmacology/Toxicology Data
`
`Date:
`
`April 8, 2002
`
`The preclinical phannacology and toxicology data submitted in support of the approval ofXyrem
`suggest that the chronic administration of gamma hydroxybutyrate (GHB) to animals was
`associated minimal systemic toxicity. Therefore, I concur with Dr Rosloffs recmmnendation
`that the NDA is approvable.
`Preclinical studies submitted in suppmi of the NDA include complete genotoxicity and
`reproductive toxicity batteries and 6-month rat and 12-month dog oral toxicity studies with GHB.
`The published results of 2-year oral carcinogenicity studies conducted by the National
`Toxicology Program (NTP) with gamma-butyrolactone (GBL) in mice and rats were also
`provided . GBL is extensively converted to GHB in vivo. A separate 2-year rat carcinogenicity
`study with GHB has been recently completed and the results will be submitted as a Phase 4
`commitment.
`
`The genotoxic potential of GHB was evaluated in an Ames test, an in vitro chromosomal
`aberration assay in Chinese hamster ovary cells, and an in vivo rat micronucleus assay. GHB
`tested negative in all three assays. The NDA review (p.l 02) suggests that higher doses of GHB
`could have been utilized in the rat micronucleus assay. However, the high dose of 2000
`mg/kg/day is considered the maximum required dose for testing in the in vivo micronucleus
`assay. Therefore, the completed genotoxicity battery is adequate.
`
`The only drug-related adverse effects observed in the chronic oral toxicity studies were
`hypoactivity and mild decreases in food consumption and body weight gain in high dose rats and
`high dose dogs. The high doses tested, namely 1000 mg/kg/day in rats and 600/900 mg/kg/day in
`dogs, produce exposures comparable to (1-2 times) therapeutic exposures with the maximum
`recmmnended human dose of 9 grams/day. The animal to human exposure ratios (safety
`margins) are comparable regardless of whether the comparison is based on body surface area
`(mg/M 2
`) or actual pharmacokinetics (AUC) .
`
`The effects of GHB on fertility, reproductive perfonnance, embryo-fetal and postnatal
`development were evaluated in the standard battery of studies which included a rat fertility study,
`rat and rabbit embryo-fetal toxicity studies, and a rat pre/postnatal development study.
`No compound-related reproductive or developmental adverse effects were observed in any of the
`studies. Similar to the oral toxicity studies, the highest doses evaluated in the reproductive
`toxicity studies produce drug exposures in animals comparable to human therapeutic exposures.
`The high dose of 1200 mg/kg/day utilized in the rabbit teratology study was associated with
`decreased food consumption and significant decreases in maternal weight gain supporting the
`
`

`

`adequacy of the doses tested in the rabbit. Data were not provided in the NDA review to
`demonstrate that the 1000 mg/kg/day high dose evaluated in the rat studies was adequately high
`(i.e., associated with minimal maternal toxicity).
`
`The rodent carcinogenicity studies conducted by the NTP evaluated gamma butyrolactone(GBL),
`which is extensively converted to GHB in vivo.
`2-Year Study in B6C3Fl mice: Doses evaluated were 0, 262, and 525 mg/kg/day in both sexes.
`(50/sex/dose). There was no evidence of carcinogenic potential associated with chronic oral
`administration of GBL.
`The high dose of 525 mg/kg/day GBL exceeded the maximum tolerated dose (MTD) in male
`mice since significant mortality was observed (76% at HD vs. 30% in controls). The high dose
`of 525 mg/kg/day GBL also represented the MTD in female mice since the final mean body
`weights were reduced 14-17% in HD female mice. A separate study was conducted to determine
`the plasma GHB exposures (AU C) after direct dosing with the MTD of GHB in mice (1000
`mg/kg/day) or the high dose of 525 mg/kg/day GBL tested in the 2-year mouse CA study (see
`NDA review, p. 93). This was performed to determine adequacy of the completed mouse study
`with GBL to assess the carcinogenic potential of GHB . This evaluation demonstrated that GHB
`exposures after dosing with the high dose of 525 mg/kg/day GBL in mice were approximately
`50% in males and 70% in females of those achieved after direct dosing with gamma
`hydroxybutyrate at the MTD . Therefore, it was concluded that the mouse study with GBL could
`be considered an adequate carcinogenicity assessment since it was conducted at GHB exposures
`in mice equivalent to 50% of those attained with the maximum tolerated dose of gamma
`hydroxybutyrate. (Carcinogenicity studies conducted at half the MTD are generally accepted as
`adequate).
`
`2-Year Study in F344 rats: Doses evaluated were 0, 112, 225 mg/kg/day in males; 0, 225, 525
`mg/kg/day in females (50/sex/dose). GBL produced no increases in neoplastic or non-neoplastic
`lesions in this study. However, doses of GBL evaluated in the rat did not represent a maximum
`tolerated dose (MTD) since they were not associated with excess mortality, decreased mean body
`weight, or any significant increase in tissue pathology or tumors.
`In addition, the GHB exposures in rats after administration of the high doses of GBL were only
`fractions of the AUC exposure to GHB associated direct dosing of the maximum tolerated dose
`of GHB to rats (8% in males, 35% in females; NDA review p. 96). It was concluded that the rat
`study with GBL was not an adequate assessment of the carcinogenic potential ofGHB. A 2-year
`rat study with GHB was conducted at FDA request. The 2-year rat carcinogenicity study with
`GHB has been completed and the sponsor has stated that no evidence of carcinogenic potential
`was observed. The Division has agreed to accept the results of the 2- year rat study with GHB as
`a Phase 4 commitment.
`
`Assessments of carcinogenic potential are generally required prior to approval. The Division's
`decision to allow post-approval submission of the rat carcinogenicity study results for GHB
`appears reasonable based on the other available data suggesting a minimal carcinogenic risk.
`These supportive data include:
`1)
`the absence of evidence of genotoxic potential
`2)
`the absence of tissue proliferative effects in chronic toxicity studies (i.e., no evidence for
`potential carcinogenic effects via non-genotoxic mechanisms)
`3) no evidence of carcinogenic potential in a 2-year mouse study with GBL (at GHB exposures
`half the MTD for GHB).
`
`A labeling review has been conducted (NDA review pp. 103 and 1 04) and accurately represents
`the study findings.
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/s/
`
`Jeri El Hage
`4/8/02 04:08:34 PM
`PHARMACOLOGIST
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`
`Request for Consultation
`
`_,
`
`I
`
`~--------------------------------------------------------------
`Dau~: 4/18/2002
`To: HFD-71 0/Jin/Kelly
`
`From: Neuropharmacology, HFD-120
`
`IND/NDA No. NDA 21-196
`sodium oxybate
`Xyrem
`Orphan Medical
`cataplexy
`
`Drug Name
`Trade Name
`Sponsor
`Indication
`
`Type of Document
`
`post-NDA submission
`
`Date of Document
`
`4/3/2002
`
`Reason for Request
`Orphan Medical has submitted the requested Phase IV carcinogenicty study.
`Dr. Kathy Haberny is the HFD-120 assigned pharm/tox reviewer. She has
`rr uested a stat consult of the care study results. I believe the submission is
`in the electronic document room under NDA 21-196.
`
`Thank You ,
`
`Anna Marie Homonnay
`X4-5535
`
`Signature of Requester
`
`Method of Delivery (Check One)
`( ) Mail
`( ) Hand
`
`Signature of Receiver
`
`Signature of Deliverer
`
`

`

`. \•
`' i~:<<> f
`,:
`
`Barry N. Rosloff, Ph.D.
`2/2/01
`.
`
`. . ;·
`:.. ..
`ORIGINAL SUMMARY
`
`.. ;:
`
`SPONSOR: Orphan Medica)
`13911 Ridgedale Drive
`.
`Minnetonka, Minnesota 55305
`.
`.
`DRUG: sodiurii·gamWia·'Jiydh)Jlybh;tyrat~ tGHB) (X~emTM)
`
`.
`
`.
`
`(See attached page for other names and structure)
`
`CAI:EGORY: endogenously-occuning compound; CNS depressant at pharmacologic doses;
`proposed here for narcolepsy
`.
`
`RELATED IND": 1ND
`
`<bH4> (Companion to present NDA)
`
`c
`
`

`

`CONFIDENTIAL
`Orphan Medical, Inc.
`GHB IND , CMC Section 7
`
`..
`
`7 .1 . 2 Descrip.tion, Including Physical and Chemical
`
`Chara~teristi cs and Stability.
`
`a .
`
`Nome nc.l a ture
`
`Chemical Names .: Sodium Oxybate
`
`Sodium Gamma Hydroxybutyrate
`
`4 -hydro~ybu.tanoic acid
`
`<bH4lsodi urn sal t
`
`CAS Nuni.ber:
`
`502'-85-2 .
`
`Abbreviation:
`.
`. '
`
`GHB
`
`Trade Name:
`
`Xyrem1 M
`
`Generic Name:
`
`Sodium Gamma Hydroxybutyrate
`
`;q: I!(J
`
`b.
`
`Chemi.cal · Structure
`
`HO
`
`·c:P Na~
`
`... • >
`,c•' (. t-1
`J
`
`., ..
`
`,.
`
`. . i .
`. , r -'
`
`·. ' "'
`
`I){, · 01
`
`...
`
`· r:\ghb\ind\ghbind7. doc .
`
`1/9/96
`
`

`

`TABLE OF CONTENTS
`
`Page
`
`6 Month P.O. Toxicity in Rats ............................. ~
`12 Month P.O. Toxicity in Dogs .......................... ~
`Segment I Reproduction in Rats .......................... 1 ,~
`Segment II Reproduction in Rats ......................... ;to
`Segment II Reproduction in Rabbits ................... 3 q
`Pre-and Post-Natal Development in Rats ........... .sl
`Genotox1c1ty ........................................................ C,_f
`
`Summary and Evaluation
`Pharmacodynamics/ADME .......................... ~ ~
`Chronic toxicity............................................
`' (,
`Carcinogenicity............................................ ~R-1
`Reproduction................................................ 1 o 1
`Genotoxicity ........... ~ ......... , ........................... r o)...
`
`Labeling .............................................................. ( O_J
`
`I
`
`Recommendations.............................................. I OS
`
`

`

`"'· .
`
`I
`
`I
`
`6 MONTH P.O. TOXICITY IN RATS
`
`A) Dosage
`
`20/sex at 0, 150, 350, or 1000 mglkg/day, by gavage.
`
`Strain: Sprague - Dawley Crl: CD BR
`
`Laboratory:
`
`Drug Lot #: 950 1
`
`B) Results
`
`.} ) Observed signs
`
`"Hypoactivity'' seen in 11 HD M and 14 HD F. This was seen quite sporadically, i.e. on 1-
`6 days each among HD M and o·n 1-11 days each among HD F. lt was seen only in the first
`2 (M) or 3 (F) months of the study.
`
`2) Mortality
`
`One control F, 3 LD F, and 1 HD F died, not considered drug-related.
`
`3) Bodyweight gain
`
`Weights at HD were below controls beginning w eeks 3-4; mean weights near end of study
`were - 90% of control. Weight gain was slightly less than controls in LD and MD M; this
`was not dose-related and mean weights were not statistically significantly different from
`controls.
`
`4) Food Consumption
`
`Decreased at HD periodically over most of the treatment period. Overall consumption 97%
`and 92% of control in HD M an:d HD F, respectively.
`
`5) Ophthalmoscopic exam
`(Done pre-study and during week 26)
`
`·No drug effects
`
`6) Hematology
`(Done at termination)
`
`

`

`1) Total WBC, and numbers oflymphocytes and segmented neutrophils, were
`slightly decreased in HD M; mean~ 75% of control. A slight/ equivocal
`decrease in total WBC and lymphocytes seen in HD F.
`
`2) RBC, Hb, and HCT were very slightly below controls in all M groups, not
`clearly D-R.
`
`3) Other parameters measured: platelets, PT, APTT, rest of differential.
`
`7) Clinical chemistry
`(Done at termination)
`
`No clear/pronounced drug effects. Very slight/equiv?cal effects included
`decreased total protein, albumin, and potassium in HD M, and decreased
`phosphorus in HD F.
`
`.
`.
`morgamc
`
`Other parameters measured: AL T, AST, AP, GGT, total bilirubin, glucose,
`urea N, ~reatinine, globulin, amylase, Ca, Na,-Cl.
`
`8) Urinalysis
`(Done at termination)
`
`Text states the results were "generally unremarkable and comparable between the
`groups." Summary tables were not presented; from the individual animal data it is
`evident that urine pH was greater than controls in all M groups and in HD F; mean
`values were approximately 1-1.5 units above control at HD.
`
`Other parameters measured: volume, SG, appearance, glucose, ketones, protein,
`occult blood, microscopic exam of sediment.
`
`9) Organ weights
`
`No clear drug effects aside from changes in absolute or relative weights
`at HD likely secondary to decreased bodyweights.
`
`1 0) Gross pathology
`
`No drug effects
`
`11) Microscopic pathology
`
`(Routine exam in controls and HD only. Gross lesions, lung, liver, and
`kidney were examined in all groups).
`
`No drug effects.
`
`12) Plasma drug levels
`
`

`

`Samples taken duririg ·week 26 at 0.5, 1, 2, 4: and 24 hours post-dose; N=3/time
`point. Results are shown in the attached tables. AUCs increased proportionally to dose
`between LD and MD F, but greater than proportionally i.n other cases. Levels in M .and F
`were similar.
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`.
`Text Table 3
`Exper imental Val uei of Pharm~co kihet ic Pa~ameters and Res ul ts of
`~tatisiica l Analysei
`
`· AUMC 0 _2.4 MRTo-z4 cmax Tmax · AUC 0_24JOose
`Group Dose Sex AUC 0 _24
`ISO H . 34 . 755
`0. 2317
`24.830 0. 7144 39.70 0.5
`350 H 197 . 825 238 . 900 1 . 2076 11 1. 50 1.0 .. 0. 5652 .
`I .1771
`1000 M 1177. 11 0 2389.607 · 2.0301 369.67 2.0
`-
`79.673 1. 0347 102.07 0.5
`77.005
`150 F
`350 F 180.042 }63. H,l3 0.9064 155 . 03 0.5
`1000 F 1032.867 2079 . 633 2.0135 479.00 1.0
`
`2
`3
`4
`
`2
`3
`4
`
`cmaxfOose
`
`0. 2647
`0.3186'
`0.3697-
`
`"
`
`0.6805
`0.443.0
`0;4790
`
`.0.5134
`0.5144
`1. 0329
`
`Statistical Resul ts of ANOVA
`Gr oup p- va 1 ue
`Sex -val ue
`
`.0599
`.9969
`
`. 1875 .0784
`.2254 .8440
`
`. 7797
`. 1621
`
`

`

`12 MONTH P.O. TOXICITY IN DOGS:
`
`. I
`
`· A) Dosage
`
`4/sex at 0, 150, 350, and 600 ~· 900 mg/kg/day, by oral intubation.
`
`The dosage increase at HD began week 32.
`
`Strain: Beagle ·
`
`r - - - - - - - - - -- ,(b)(41
`
`(b)(4); - - - - - - - '
`
`Drug Lot# : 9501
`
`B) Results
`
`1) Observed signs
`
`a) All HD F had hypoaetivity and ataxia on a very few occasions, mainly near the
`beginning of the study anp/oi after the dosage was increased to 900 mg/kg at week
`32. One HD F also had prostration week 1 and another had slight convulsions week 33.
`One HD M ha(i ataxia on 3 occasions near the begitming of treatment.
`
`b) Increased incidence/frequency of diarrhea in MD and HD M and HD F.
`
`c)· .Emesis was seen in most animals~ frequency was greater than controls in 1 MD F and
`IHDF.
`.
`.
`.
`d) Thin appearance seen in 1 MD M, 1 HD M, and 2 HD F near the beginning of the
`study; decreased appetite seen sporadically in most of these.
`
`2} Mortality
`
`None
`
`3)· Bodyweight
`
`Decreased gain in MD and HD M and HD F early in the. study. Weights in M remained
`below control throughout the study (final weights 95% and 91% of control in MD M
`and HD M, resp~); weights in HD F retumed to control level by week 14. (One HD F
`lost ·a relatively large amount of weight, 1.7 kg, shortly after increase in dosage, but
`reboui1ded rapidly).
`·
`·
`·
`·
`
`

`

`' 4) Food consumption
`
`Decreased in HD M (~ 60-75% of control, mainly due to a large effect in 1 dog) and HD F
`(~30-60% of control) during first 3-4 weeks. The HD F mentioned above which transiently
`lost weight upon dosage escalation a:lso had a
`transiently reduced food consumption at this
`time.
`
`5) Ophthalmoscopic exam
`(Done pre-study and week 52)
`
`No drug effects
`
`6)EKG
`(Done pre-study and "during" weeks 26 and 52; the time relative to
`dosing when this was done was not stated).
`
`It was stated that EKGs were within riormallimits; no results were shown.
`
`7) Hematology
`(Done pre-study and weeks 13, 26, 39, and 52)
`
`No clear drug effects.
`
`· Parameters measured: RBC, Hb, Hct, platelets, PT, APTT, WBC,
`differential
`
`8) Blood chemistry
`(Done pre-study and weeks 13, 26, 39, and 52)
`
`No clear drug effects. Chloride was equivocally slightly
`decreased (mean 2 meq/L below control) in HD M at most times
`during treatment.
`
`Other parameters measured: ALT, AST, total bilirubin, GGT, total
`protein, albumin, globulin, glucose, urea N, creatinine, Ca, Pi, Na, K
`
`9) Urinalysis
`(Done pre-study and weeks 13, 26, 39, and 52)
`
`Text states that results were "generally unremarkable and comparable between the control and
`treated groups". Summary tables were not presented; from the individual animal data it is
`evident that urine pH was greater than controls i1,1 HD M and MD and
`HD F at all times during treatment; sporadic increases were also seen at the lower doses.
`Mean values averaged ~ 1-1.5 units above control. Also, urine SG was slightly below control
`in HD M weeks 39 and 52.
`
`Other parameters measured: appearance, glucose, ketones, protein,
`bilirubin, occult blood, sediment exam.
`
`

`

`••
`
`,
`
`I
`
`1 0) Organ weights
`
`Absolute and relative liver weights slightly increased in HD M . (Rei. wt. 1.24 x
`control). Relative kidney weight ·siightly increased in HD M (1 .1 9 x control).
`
`11) Gross pathology
`
`Pale/dark raised area in lung seen in 1 MD M, 2 HD M, and 1 HD F. See below
`for histology.
`
`12) Microscopic pathology
`(Routine exam done in all animals)
`
`a) Lung- Chronic active inflammation seen in the 4 dogs with gross lesions noted
`above. Two of the~e dogs (1 MD M and 1 HD M) also had pi gmented
`macrophages. The text states that these lesions "could be related to the irri tation
`caused by the aspirated test article."
`
`b) Esophagus- atrophy of submucosal gland seen in 7/8 MD and
`8/8 HD; none in other groups. "Moderate" or "moderately severe" in
`most cases.
`
`c) Mandibular salivary gland- atrophy in 6/8 MD and 7/8 HD;
`none in other groups. Severity ranged from "minimal" to "moderately
`severe".
`
`13) Plasma drug levels
`
`(Samples taken weeks 4, 30, 32, and 52, at 0.25, 0.5, 1, 2, 4 , 8, and
`24 hr. post-dose [with the exception that no samples were taken at 8 hours post(cid:173)
`dose at week 4]. The samples at week 32 were presumably taken on the first
`day of the dosage increase, at HD to 900 mglkg).
`
`R esults are shown in the attached tables. (Note that no results were shown
`for LD and MD at weeks 30 and 32; the study report is contradictory as to whether or
`not samples were taken at these times in these groups).
`
`The following conclusions may-be drawn regarding the AUC values;
`however, note that these caMot be said to be well-established in v.iew of the small
`sample sizes and large inter-animal variation (e.g. see "Text Table 1"):
`
`a) AUCs increased much greater than proportionally to dose between LD (150
`mglkg) MD (350 mglkg), but equal to or less than proportionaJJy betWeen
`MD and HD ( 600/900 mglkg).
`
`

`

`b) At LD, AUCs were similar between weeks 4 and 52; at MD, AUC at 52
`weeks was about 2/3 that at 4 weeks. At HD, AUC decreased by abdut half
`between weeks 4 and 30; when the dose was increased to 900 mglkg at
`week 32, AUCs were similar to those seen at week 4 (at 600 mglkg).
`
`c) AUCs were roughly similar between sexes.
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`~J ·
`
`43
`
`,, . -~,
`
`"
`
`..
`~ "
`
`Group Sex
`M
`2
`M
`2
`M
`2
`M
`2
`
`·Animal
`33507 .
`33508
`,33509
`335.10
`
`. .
`Text Table 1 - AUC'H, (~gxhour/qt{_)
`.Week 4
`Week32
`Week 30
`231-.275
`196.250
`233.450
`265.750 .
`
`2
`2
`2
`2
`
`3
`3
`3
`3
`
`3
`3
`3
`3
`
`4 .
`4
`4
`4
`
`4
`4
`4
`4
`
`F
`F
`. F
`. F
`
`M
`M
`M
`M
`
`F
`F
`F
`F
`
`M
`· M
`M
`M .
`
`F
`F
`F
`F
`
`335 11
`33512 .
`33513
`335 14
`
`335 15
`335 16 .
`335 17
`335 18
`
`33519
`33520
`3352 1
`33522
`
`33523
`33 524
`33525
`33526
`
`33547 ..
`33528
`33529
`33530
`
`192.875
`31.245
`0.833
`237.300
`
`3353.375
`1401.525
`1994.125
`364'6. 125
`
`2051.375
`4138.625
`2942.250
`324.450
`
`4 152.625
`2675.625
`3466.750
`5733.3 7.)
`
`2705.250
`288 1.12.5
`4911.62.5
`)3ltR 750
`
`2705.300
`2515.400
`1093.150
`2222.000
`
`.).761.250
`169.925
`. 2683.500
`i98 1.750
`
`4987.875
`5708.250
`3990.825
`4630.250
`
`3084.625
`4803.125
`772.550
`5050.925
`
`Week 52
`313.325
`259.575
`471.550
`372.475
`
`434.300
`13.625
`74.050
`351.675
`
`1962.000
`2 ll 9. l25
`971.125
`1933.700
`
`.. 466.650
`n22.15o
`2538.875
`129.538
`
`5321.875
`267 l.l 25
`4611.625
`847.575
`
`. 4'021.250
`620 .. 025
`4703:625 .
`5.180.500
`
`~
`
`

`

`
`
`13000
`
`.
`
`'
`
`46
`
`5627413 ,_
`
`
`Tax! Table 4 - C 1 mL)
`
`
`Own
`3611.
`Animal Wadi“ -
`0:661:30
`Week 32
`' WOCKSZ-
`
`2
`M .
`33507
`_ 123.00
`"
`'
`’
`'
`'
`172.00
`2
`M
`33503
`133.00
`202.00
`2
`M
`33509
`162.00
`215.00
`
`.
`
`5
`1F
`,1
`
`1
`
`I
`
`{
`
`2
`2
`2
`2
`2
`
`3
`'3
`
`3 ,
`3
`
`3
`3
`3
`3
`
`4
`4
`4
`
`4
`
`4
`4
`4
`4
`
`-
`
`M
`F
`1-"
`F
`' F
`
`M
`M
`
`M
`M
`
`F
`F
`F
`' F
`
`M
`M
`M
`
`M
`
`33510
`' 33511
`33512
`33513
`33514
`
`33515
`33516
`
`33517
`33513
`
`33519
`33520
`33521
`33522
`
`33523
`33524
`33525
`
`33526
`
`- 164.00
`151.00
`93.10
`2.22
`159.00
`
`619.00
`- 216.00
`
`321.00
`522.00
`
`211600
`536.00
`453.00
`190.00
`
`626.00
`294.00
`. 651.00
`
`'
`'
`
`'
`
`-
`
`-
`
`_
`
`-
`
`,
`
`'
`
`'
`
`610.00
`725.00
`252.00
`
`752.00
`710.00
`446.00
`
`-
`
`'
`
`.
`
`132.00
`192.00
`10.60
`32.60
`192.00
`
`468.00
`662.00
`
`137.00
`404.00
`
`,. 223.00-
`65.3.00
`670.00
`62.70
`
`615.00
`553.00
`914.00
`
`362.00
`
`'
`
`620.00
`
`227.00
`
`_
`
`250.00
`
`F
`33522
`512.00
`531.00
`608.00
`202.00
`F
`33523
`579.00
`123.00
`' 226.00
`263.00
`F
`33529
`324.00
`633.00
`263.00
`399.00
`1039.0 33530 4?2.00 _ 651.09 930.00
`F
`
`
`
`
`
`
`
`~-
`
`

`

`·I ~-efyY-
`
`~bj
`
`' 52
`
`I ~ ..
`
`-~
`
`I
`& I
`I ·.;
`
`r~x( T&bl ~ 9 • Heeo end Standard Oevi• tion (SO ) br Gr~1 Sex, end \leek
`, ....
`AUC1.11to
`c,,tl>
`c ...
`>.
`AVHC'1 . u . HilT I ·U
`tu:z
`0 .86083
`1. 54454 . o. 97833 .
`..e.AW 0 .62500 146.750
`263.81
`I. B roo
`0.80958
`' 42.44
`0 . 11543
`0 . 15603
`0. 17078
`0. 18932
`0. 25000
`19 . 75S
`0. 13170
`
`AUCa ·t l
`231. 68
`28.40
`
`G s
`
`\J(
`
`2 H
`
`z " <
`' so
`2 " 52
`..e.AH 0 .87'500, 195.250
`2 H 52 so
`0 .25000
`1 8.~90
`r
`f
`
`2
`2
`
`..e.AH 0.43750 102 . 56{)
`4
`4 so
`0 .12500
`' 72. 157
`
`354 . 23
`90:79
`
`521.7'5
`l26.90
`
`1.4J2 11
`0.41317
`
`0.81895
`0.4487l
`
`0.99501
`0. 36670
`
`2.36154
`0.60528
`
`1.30167
`0. 12393
`
`115.56
`1 17.00
`
`119.38
`' 133.44
`
`0 .74949
`0 .39269
`
`<U8894 O.SU39
`2.25357-
`·0 .34288
`
`0.77042
`0.78003
`
`0.68387
`0 .48105
`
`2
`2
`
`..e.AH 0 .87500 121.800
`52
`52 so
`89.663
`0 .25000
`
`2 16 . 4 1
`205.87
`
`284.81 1.03801
`299.18
`0 .391.52
`
`0. 89~68
`0. 74430.
`
`1 . 17005
`0.75620
`
`1.45608
`1. 37245
`
`0. 81200
`0 .59775
`
`II
`
`3
`J
`
`7970.96
`JZ72. IS
`
`3 .07'913
`_0. 127?4
`
`0 . 35369 ' 2 . 0 1314
`0.0721 1 O.JSO IS
`
`5. 71'508
`2.38837
`
`0. 96000
`0.39220
`
`4454.98
`1Z7S. 31
`
`2. 56812
`0. 19789
`
`0 . 33084
`0 . 23576
`
`3.76643
`J.76i94
`
`3.86108
`I . 16290
`
`0 . 95611
`0 .43507
`
`7461.66
`5683 .14
`
`:?.66719
`1.06868
`
`1 .66 154
`0.<6566
`0. 20037 ' 0.5451.3
`
`5 . 25372
`3.56969
`
`0 . 61667
`0,. 35073
`
`I .6$71. 1
`0.1;4965
`
`3 :53212
`3.38506
`
`0 .89650
`0.681.35
`
`-4
`IIE)JI 1.00000 432.000 2598.79
`3
`J " 4 so
`to7t. .n
`0 . 707 11
`176.490
`J H 52 ~ 1.25000 4J0. 2SO 1746. 49
`3 H 52 so
`523.30
`0.50000 . 195.783
`·.
`I<EAII 1.37'500 367.500 2364. 16
`4
`• 4 ·so
`0 . 7'5000 157.830 1606.36
`' 52
`I<EAH 1.00000 403 .425 1589.45
`f 52 so
`0 .00000 307.960 1523.26
`
`J
`3
`
`4247.69 . 2 .03961 · O. Q975
`t.615 . 95
`o.9o8S5
`0.09557
`
`I. H
`4 H
`
`t. 25000 606 . 250 4007.09 12?01.22
`4013 .65
`0.50000 234.723 1299.49
`
`4
`t<EAII
`4 so
`4 H 30 NOAH 1. 75000 565.500 2133.96 m~ . 2a
`0 . 50000 210.961
`721.79
`1813 .91
`
`4
`
`1 . 54765 152.690
`
`716 . 56
`
`3661. n
`
`0. 50000 272.2S8 2016.79
`
`12755 ;S·I
`l0$10 .67
`
`I. " 30 so
`4 " 32 H€ AH 1.67500 671.250 1.829. 30 21664.26
`II 32 so
`4 " 52 . I<EAII 1.75000 583.000 336J . OS
`I. · " 52 so
`(.
`4 HE,_,) 0.75000 596.750 3471.69 10039.39
`IS 7.800 1002.74
`3 174 . 57
`0.28868
`~.,·
`
`3.05301
`0.20233
`
`0.31.762
`0.087(]
`
`2.06426
`0.48785
`
`6.67849
`2,16581
`
`1.01375
`0.39121
`
`2.47508
`0.29685
`
`{, , 1.9537
`0. 52571
`
`0 . 51.435
`0 . 31231
`
`2. 78359
`3 . 56355
`
`3 . 55660
`1.20299
`
`0.94250
`0.35160
`
`o. 24300
`0.06079
`
`3 : 0261.8
`0.93M7
`
`5 .36569
`0.79617
`
`0.74583
`0.16966
`
`3.26292
`1.22156
`
`0.52170
`0.33535
`
`1.81803 3.nbn
`1. 15643
`2 . 24088
`
`0 . 64T78
`0 .30251
`
`' so
`f 30 NOAA 1.62500 499.500 1649 . 11
`r 30 so
`0. 75000 256 . 573 1061.63
`' 32 HCAII 1.50000 656 . 750 3427.81 125tt.o9. 3 . 25202
`4
`I. F 32 so. o.5ms 303.385 1974.35
`
`4
`4
`
`3617.45
`2599.65
`
`1. 90275
`0 .6 1072
`
`8537.63
`
`0.9298<
`
`2 .&7S:Y.
`0 . 16350
`
`0.3.9364
`0 . 10689
`
`1.865 14
`0.62174
`
`5. 78615 Q.99458
`1.67124
`·o. 26300
`
`0. 75489
`0.31.756
`
`1. 08978
`0 . 53536
`
`2 . 74651
`1. 76938
`
`0.83250
`0.'2762
`
`0. 422t.3
`0. 10968
`
`I. 732 18
`0.47713
`
`3 . 80867
`2. 19372
`
`0.72972
`0 .33709
`
`I<EAN 1.37500 726 . 750 363 1. 35 125". 98
`7675.31
`0.75000 336 : 230 2063. IS
`
`4 F 52
`
`' F 52 so
`c = Croui:>
`S = Sex
`U(
`: Ueel
`.o.uc,.,,;o • AUC0 • 7, /0ose
`C •• .IO = C. , . /Oose
`
`3.0 1627 O.H830
`1.09191
`0. 109M
`
`4 .03483
`2.31"75
`1.09524 . 2.29239
`
`0.80750
`0.37359
`
`

`

`SEGMENT I REPRODUCTION IN RATS: ·
`
`A) Dosage
`
`20/sex at 0, 150, 350, or 1000 mglkg/day, by gavage.
`
`Males were treated for 10 weeks beginning 4 weeks pre-mating. Females were ·treated from 2
`weeks pre-mating through day 13 of gestation, at which time they were sacri ficed/ caesarian
`·
`sectioned. Mating ratio= 1:1.
`
`Strain:
`
`Sprague-Dawley Crl: CD BR
`
`Laboratory:
`
`Drug Lot #:
`
`9501
`
`·B) Results
`
`1) Observed signs
`
`Five HD M and 6 HD F had "hypoactivity"; in 9.ofthese rats this was seen only on a single
`·
`day; in the other 2 rats it was seen on 2 dayl?.
`
`2) Bodyweight
`
`D ecreased weight gain in HD M (weights 90-95% of control).· No d ear effects in F. (Weights
`in HD F were slightly below controls during treatment, but initial weights were lower to a
`similar degree).
`·
`
`3) Food Consumption
`
`Decreased in HD M (- 92% ofcoritrol).
`
`4) Male organ weights
`
`No effect on weight of testes, epididymis, seminal vesicles, prostate.
`
`5) Sperm analysis
`· ( I 0/sex/group)
`
`No drug effect on sperm count, motility, or morphology
`
`6) Mating
`
`No drug effect on estnts cycling, mating performance, or successful matings.
`
`

`

`7) ca·esarian sc<:tion data
`
`No drug effects. (See attached table).
`
`'
`
`,
`
`APPEARS THIS WAY ON
`ORIGINAL
`
`

`

`APPEARS TillS WAY ON ORIGINAL
`
`

`

`Orphan !oledlea \
`
`TABLE 11
`.
`STUDY OF' FERTILI TY ANO EARLY EMBRYONIC DEVELOPMENT TO IMPLANTAT ION !N RATS
`.
`SUMMARY OF CESAREAN S'ECTION DATA
`.
`.
`--------------------------------------------------------------------------------------------------------------------------------·---
`.
`DOSE LEVEL
`GROUP 1
`GROUP 2 .
`GROUP 3
`GROUP 4
`0 MG/KG/DAY
`150 MG/KG/OAY
`350 HG/KG/OAY
`1000 MG/KG/OAY
`-- - ---~- ---- - --~---~ -- ---------- -- ---------- --- ------------------ ---- ------------- ---- ------ ---~------ -------~----7·----------------
`19
`N
`Pregnant at C-secilon
`20
`1.9
`19
`HEAN
`Resorpt ions: Tota l
`0.6
`0. 7
`1.3
`s .0 .
`0.7
`0.9
`1.3
`N
`19
`20
`19
`TOTAL
`12
`24
`14
`MEAN X
`9.9
`9.7
`3.8
`S.D.
`!5.8
`22 .6
`5.3
`
`1.3
`1. 5
`19
`24
`11. 1
`22.3
`
`'
`®
`
`Early
`
`·Late
`
`Oead Fetuses
`Postlmpl antat lon Loss
`
`MEAN
`s .0.
`N
`TOTAl
`MEANY.
`S. D.
`
`MEAN
`s .0.
`N
`TOTAL
`HE ANY.
`S.D.
`
`TOTAL
`MEANY.
`S. D.
`
`0.7
`0.7
`20
`14
`9.l
`22.6
`
`0.0
`0. 0
`20
`0
`0 .0
`o.o.
`
`0
`9.7
`22.6
`
`1.3
`l. S
`19
`24
`11. 1
`22.3
`
`0.0
`0 . 0
`19
`0
`0.0
`0. 0
`
`0
`11 . I
`22.3
`
`0.6
`0.9
`19
`12
`3.6
`5.3
`
`0.0
`0 . 0
`19
`0
`0.0
`0.0
`
`0
`3.8
`5.3
`
`1.3
`1.3
`19
`24
`9.9
`15.6
`
`0.0
`0 .0
`19
`0
`0.0
`0.0
`
`0
`9.9
`15.8
`
`- - - ----- ·--------~------------------------------- --- ---------------- ----------------------------- --- ----~------------------------ ---
`S l G~ IF !CA~iLY DIFFERENT FROM CONTROL: * • P~O . OS ; ** • P~O.Ol.
`
`
`
`. · .~ .. . ,;.,._
`
`

`

`. TABLE 11
`STUDY OF FER Till TY AND EARLY EMBRYON.IC O£VEtOPMEIIT. TO IMPLANMT!ON JN. RATS
`SUMMARY OF CESAREAN S.ECTIOH OATA
`.
`.
`·---- - ------~- ~-- ---- ------- --- ---- ---- - -------- -----------------~------------ -----~---- --------------- --~---~----------------------
`DOSE LEVEL
`GROUP 1 '
`GROUP 2
`GROUP 3
`GROUP 4
`· 0 MG/KG/OAY
`ISO MG/KG/OAY
`350 MG/KG/OAY
`1000 MG/KG/OAY
`------------- -- - -- - - -------------------------------------·---- -- ----------------~------------------- ------------------------ - --------
`20.
`19
`1'9
`!9
`Pregnant at C-sect ion
`N
`
`Orphan Hedlc!'1
`
`Lt ve Fetuse·s
`
`.
`
`HEAN
`S.D.
`N
`TOTAL
`MEANY.
`S.D.
`
`!4 . 4
`4.6
`20
`289
`90.3
`22.6
`
`.
`.
`----·---------·--------------------------------------------------------------------------~--~---------------------------------- ---- --
`SIGNifiCANTLY Dl FFERtNT FROM CONTROL:· • • P~0. 05; •• • P~O.O l ,
`
`14 .6
`4.0
`19
`277
`88.9
`22 .3
`
`15.4
`1.8
`19
`312
`96. 2
`5.3
`
`14 .0
`3 i~
`266
`90. 1
`15.8
`
`

`

`EGMENT II REPRODUCTION IN RATS:
`
`A) Dosage
`
`25 F at 0, 150, 350, or 1000 mglk.glday, by gavage, days 6-17 of gestation
`
`Dams sacrificed day 20 of gestation. All fetuses examined externally. One half of fetuses
`processed for visceral exam by Wilson teclmique. Remaining fetuses processed for skeletal
`·exam by Alizarin Red S staining method.
`·
`
`Strain:
`
`Sprague-Dawley Crl: CD BR
`
`r - - - - - - - - .(b)(41
`Laboratory:
`
`Drug Lot # : 9501
`
`B) Results
`
`1) Observed signs ·
`
`"Hypoactivity" seen in 5 HD F (on 1 day each in 3; on 2 days each in 2). Ataxia was
`also seen in 2 of the above on 1 day each. Prostration was seen in an additional HD on a $ingle
`day.
`
`2) Body weight
`
`No drug effect ·
`
`3) · Food consUmption
`
`Equivocal slight decrease at HD during first week of treatment;
`mean values 6-8% below controls, generally not statisti~ally significant
`
`4) Gravid uterine weight
`
`No drug effects
`
`5) Reproductive parameters
`
`No drug effects on resorptions, live or .dead fetuses, or post-implantation loss.
`
`

`

`Fetal weights were slightly greater than controls in all drug groups, not clearly
`
`dose-related
`
`· 6) Fetal exams
`
`Results shown in attached tables.
`
`There were no clear drug effects with the possible exception of an
`increase in "wavy/bent rib(s)" (fetal incidence 0, 1.7, 4.2, and 4.1% in control, LD, MD, and
`HD, resp.; litter incidence = 0, 8, 14, and 21%, resp.). (Historical control values not given,
`although it was stated that the skeletal variations ''were generally of the type and frequency
`commonly noted in this strain of rat.").
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`.. ,/•
`
`......
`
`\
`
`Table 9A
`Summary of Fetal External Variations
`Rat Developm,ntal Toxi~ity Study
`
`

`

`.· .....
`
`,.,. ',
`Orphan Hedi'ca 1 Proj ect
`' \"·
`
`'
`
`TABLE 9A
`RAT. DEVELOPMENTAL TOXIC ITY STUDY
`.
`SUMMARY OF FETAL EXTERNAL . VARIATIONS
`.
`- - ----- - - - -------------- - - --------- - - - -- - ------ - --- - ---- -- ---- - -------- -- --- - -------- - - ----------- - ------~ --------- - -- - ---------- - --
`DOSE LEVEL
`GROUP 1
`GROUP 2
`GROUP 4
`GROUP 3
`1000 HG/KG/OAY
`150 MG/KG/OAY
`0 MG/KG/DAY
`350 HG/KG/OAY
`------------------ ---- ---------- ------------------------~--------- ------ -- --- --- - -~-- ----- ------------ ------------------~-----------
`24
`Litter s Eval uated
`25
`22
`N
`23.
`Fetuses Evaluated
`332
`293
`333
`331
`N
`332
`Li ve
`33 1
`293
`N
`333 '
`Dead
`0
`0
`0
`0
`N
`TOTAL f ETAL EXTERNAL
`VAR IATIONS
`Fetal Inc idence
`N.
`Y.
`N
`1.
`
`0
`0. 0
`0
`0.0
`
`0
`0.0
`0
`0.0
`
`Ll t ter 1 nc I dence
`
`0
`0.0
`0
`0.0
`
`0
`0. 0
`0
`0.0
`
`N • Number
`
`. ·-·· ...... ~ .... .. .
`
`.,.;~_ ., .e ... : .. ~ - ·
`
`4
`
`. ,.._ .. _______ , ______ _
`
`- ---.:-~ :._:.:..:.:..:..: ~ ~
`
`.,......,,,.
`· r ·. ·!1
`"
`~
`
`....
`
`, . ..
`
`U'1
`0
`
`"'" ... ' .' :::: .. _.,,~!'";;;;~-~. xS il
`
`.
`
`-~
`
`'
`
`,,..,I'. •
`·'
`
`'
`
`'!'E!!L
`
`

`

`:· ..
`
`Orphan Medical rJ.'ro,j.~ct
`
`\@·I . ..:t:
`
`/
`
`\
`
`Tab.l e 98
`Summary of Fetal txternal Malformations ..
`Rat Devel9pment~l Toxi city St~dy
`
`.• .
`
`i .
`
`

`

`•
`
`I
`
`. ..- ( '
`""'
`, ,:.'· .
`•, . .
`... ,
`
`\
`
`.....
`
`Crphan Hedical Project No,
`t'·
`,.,. · .
`
`OOSE LEVEL
`
`TABLE 96
`RAT DEVELOPMENTAL TOXICI TY STUDY
`SUMMARY OF FETAL EXTERNAL
`HALFORHATIONS
`GROUP 4
`GROUP 3
`GROUP 2
`GROUP I
`1000 HG/KG/OAY
`350 MG/KG/OAY
`0 HG/KG/ DAY
`150 HG/KG/ OAY
`- -·- - - -- - - - ~--- - · - - -- --· - - - ------------- --- -- - - --- ----- - - --- --- - --------·----- ---~------- ------------------ ------ --------------------
`l itters Eval uated
`24
`25
`22
`23
`N
`293 .
`332
`Fetuses Evaluated
`331
`333
`N
`'293
`331
`332
`333
`Live
`H
`Oead
`0
`tl
`0
`0
`0
`ANOPHTHALMIA
`Fetal Incidence
`
`I
`
`-®
`
`Lt tter Inc idence
`
`BRACHYGNATHIA
`Fetal Incidence
`
`Li tter Incidence
`
`NOSE MALFORMED
`Fetal Inc I dance
`
`l i tter Inci