`
`Reviewer: Lilliam A. Rosario PhD. NDA No.21—344
`
`VI.
`
`CARCINOGENICITY:
`
`Study title: A 2 YEAR INTRAMUSCULAR CARCINOGENICITY STUDY OF ICI 182,780
`IN THE ALBINO RAT.
`
`Key study findings:
`0
`ICI 182,780 increases the incidence of ovarian granulosa cell tumors and testicular interstital
`Leydig ademomas.
`lCI 182,780 decreases the incidence of uterine endometrial stromal polyps, mammary tumors
`(adenoma, fibroadenoma, adenocarcinoma) in females, and pituitary adenomas in females.
`Reductions in mammary gland and pituitary tumors may have contributed to the increase in
`longevity of animals administered ICI 182,780.
`
`-
`
`Study number: TClU2683
`Volume #, and page #: \N_000\2001-10-29\TCR2683 Complete Report
`
`Conducting laboratory and location:
`Test Facility:
`Test Site:
`(in vivo study)
`(Pharmacokinetics)
`——"
`AstraZeneca UK Ltd
`
`V
`
`DMPK Mereside Alderley
`Park
`Macclesfield, Cheshire
`England
`
`Test Site:
`(Electron Microscopy)
`AstraZeneca UK Ltd
`
`Safety Assessment
`Alderley
`Mereside Alderley Park
`Macclesfield,
`Cheshire England
`
`Date of study initiation: 10 November 1998
`GLP compliance: Yes
`QA report: yes (x) no( )
`Drug, lot #, and % purity:
`
`
`
`ln'ection
`
`In'ection
`
`
`
`
`
`
`
`
`
`W
`
`—_——
`
`
`
`
`
`CAC concurrence: Yes
`
`Study Type: 104 weeks in albino rats; 1M administration to the lateral compartment of the thigh
`(dose was divided in two parts (up to 0.1 mL) and administered on the right and left side).
`Species/strain: male and female Sprague Dawley (Crl:CD(SD)BR) rats (Rattus norvegicus) from
`V
`
`Number/sex/group; age at start of study: 50/sex; 28¢] days old
`
`89
`
`

`

`
`
`Reviewer: Lilliam A. Rosario PhD. NDA No.21-344 ,
`
`
`
`Animal housing: Individual
`Formulation/vehicle:
`
`Lon_ actin ; formulation
`
`
`
`
`
`
`
`1C1 182,780
`
`%w/v
`5_
`--i-
`
`—-1_
`
`Benzyl Benzoate
`15
`
`Castor Oil
`to 100
`
`Drug stability/homogeneity:
`Data from the primary stability studies indicate that fulvestrant is stable at the proposed long
`term storage condition of — '. In addition no significant change (as defined by ICH
`guideline QlA) has been observed after 6 months storage at the accelerated storage condition of
`A nor after 12 months storage at the intermediate accelerated storage conditions of
`-- -.-,,,
`and.
`.0
`
`Methods:
`Doses:
`
`Dos: Levels
`
`'
`
`Animal number
`
`11
`
`1I
`1
`0mgwkg'15days
`i
`0mg'kg‘30days
`E
`omgmg'isuays
`15 mgfkgr30 days’ 1
`10 mgxrat‘30 days 3
`I
`10 mgnus days 1
`-
`1
`
`Group No.
`ldcnli fication
`1 Vclucle control
`2 Vehicle control
`:1 same control
`.4 ICI 181730
`5 [Cl 182.7110
`
`0 10182130
`
`
`7 Health semen
`a Dosage limited by maximum injection volume 01‘02 mL'm
`‘ Control Male 1030 rcplaccd by Male 1051 following monalny during rrplaccmcm period
`
`02 eral
`OZmL'raI
`0.2 mL'ral
`03 911,15
`0.2 mL-m
`0.2 mL'rar
`-
`
`1501-1550
`1(x11—1029,1031-1051
`25012550
`E
`2001-2050
`i
`3501—3550
`i
`3001-3050
`5
`1 45014550
`40014050
`1
`1
`5001—5050
`1
`5501—5550
`:
`1
`6001-6050
`5
`6501-6550
`
`7001-7010
`7501-7510
`4*
`
`I
`5
`,
`
`The following shows the ~ actual dose (mg/kg) administered to Groups V (10
`mg/rat/30days) and Group VI (10 mg/rat/l 5 days).
`
`
`
`dose
`
`dose
`
`dose
`
`dose
`
`dose
`
`dose
`
`mg/rat/ mg/kgl mg/rat/
`Judas 30das ISdas
`
`15 days 30 days mg/rat/ mg/kg/ mg/rat/ mg/kg/ 30 days
`30das 30d3915da915das
`
`
`
`Ill-Ill I. “W
`
`
`
`
`Inn-ml..—
`.
`54
`In!
`
`
`min—— 26
`487.8
`m
`5803
`
`
`Basis of dose selection: According to the Sponsor, the dose levels selected represent the
`maximum possible doses by the
`intramuscular (1M) route based on
`strength of the formulation and
`injection volumes.
`Restriction paradigm for dietary restriction studies: n/a
`
`92
`
`

`

`
`
`Reviewer: Lilliam A. Rosario PhD. NDA No.21-344
`
`Route of administration: IM injection
`Frequency of drug administration: every 15 or 30 days
`Dual controls employed: Vehicle and saline controls included
`Interim sacrifices: n/a
`
`Satellite PK or special study group(s): None
`Deviations from original study protocol: Occasional minor deviations from the protocol
`occurred and were documented in the raw data and/or text. The Sponsor reports these
`deviations had no impact on the outcome of the study or upon the interpretation of the
`results.
`
`Statistical methods:
`
`First the Levene's test was used to assess the equality of the group variances followed by
`ANOVA if this test was not significant. If the Levene’s test was significant, then the
`statistical analyses were performed on the ranked transformed data.
`Survival Analysis: An overall test for homogeneity was performed on the survival
`functions of all 6 groups.
`Tumor Data: All tests for tumour incidence were one-sided looking for an increase in
`response/incidence. The Haseman (1983) principle of statistical significance was adopted
`in the formal assessment of statistically significant effects. One-sided 5% tests for
`decreasing response/incidence were also performed.
`The statistical comparisons of interest were implemented using Peto’s survival-adjusted
`trend test. Statistical comparisons were performed in three phases:
`Phase 1: Vehicle effect with dosing every 15 or 30 days: Both the 15-day and 30-day
`vehicle groups (Groups 1 and 2) were compared to the saline control group (Group 3).
`Phase 2: Treatment effect for each dosing frequency: Two vehicle groups (Groups 1 and
`2) and the two 10 mg/kg groups at 15 and 30 days frequency (Groups 5 and 6,
`respectively). Treatment groups were then compared to the appropriate vehicle separately
`for each dosing frequency.
`Phase 3: Dose effect over the 30 day dosing regimen: Group 2 (vehicle/30 days) was
`compared with the 15 mg/kg/30 days treatment group (Group 4).
`
`Observations and times:
`
`Clinical signs:
`
`Body weights:
`Food consumption:
`
`Hematology:
`
`Twice daily for mortality and clinical signs.
`A complete physical examination was performed once during
`the pretreatment period and weekly during the treatment period.
`In addition, from Week 26 onwards, all animals were examined
`for the presence of palpable masses during the detailed
`examination.
`
`Weekly.
`Weekly for the first 13 weeks of treatment, then monthly,
`thereafter.
`
`Red blood cell counts and total and differential white blood cell
`counts were performed at 12 and 18 months and at terminal
`necropsy.
`
`Clinical chemistry:
`Organ weights:
`
`Not obtained
`Not obtained
`
`93
`
`

`

`Reviewer: Lilliam A. Rosario, PhD.
`
`NDA No.2l-344
`
`Gross pathology:
`
`Histopathology:
`
`Toxicokinetics:
`
`A gross pathological examination was performed on all
`animals on this study.
`Tissues, as defined in the protocol, were examined
`histopathologically for all animals on this study. See
`addendum.
`
`Groups 4 and 5 (n=3/sex) were bled at 2, 4, 8, 12, 16 and 24
`days post close afier the 12th dose. Samples were also taken
`from 6 rats/sex (Groups 4 and 5) prior to the the 2nd, 4th, 7th
`and 10th dose.
`
`Group 6 (n=3) were bled at 2, 4, 8, 12, 16 and 24 days after the
`23th dose. Samples were also taken from 6 rats/sex from the
`same group prior to the 3rd, 7th, 13th and 19th dose.
`
`Results:
`
`Mortality:
`
`
`
`
`
` Survival
`
`(mg/W30days)
`
`da 5
`
`n=50
`
`Survival
`
`n=50
`
`Survival
`
`
`
`
`
`
`
`—mm--__nnlm 32
`
`5W
`
`‘ The ~ actual dose administered for group V and VI was calculated based on the average weight for males and females on day l.
`
`'-
`In 1997, according to the
`For control males, survival rates appear lower than expected.
`2 3, the % sun'val for male and female SD rat ranged 31 .7-61.9% and 317-6] .4%,
`respectively.
`In this study, the overall survival rate ranges between 17.1-62.9 and 24-61 .4% for
`male and females rats, respectively.
`
`Percent survival as a function of time (weeks) in d' and 9 SD rats.
`SURVIVAL 1%) - MALE
`filthVAl. 9%) - "MALES
`
` onIannual):hanuunxoouunnmunsiumm
`
`“(KS
`04aiawnxanuaouuussunannnu-nuvmm
`+5...“ +05." +Cluum +0-an +0....v +umpVI
`
`+W I + I". ll
`
`+L’lu,
`
`will“
`I + I\’
`u.”
`
`"
`
`+(u-g \
`
`+(an VI
`
`94
`
`

`

`
`
`Reviewer: Lilliam A. Rosario PhD. NDA No.21—344
`
`There were no treatment-related clinical signs, however a number
`Clinical signs:
`of animals from all treated groups and from control animals in Groups 1 and 2 (vehicle),
`exhibited cysts at the injection sites.
`Body weights:
`Overall body weights throughout the study were not affected by
`treatment. Occasional statistically significant variations in body
`weight gain across all groups (both sexes) were considered
`incidental.
`
`Body weight (g) as a function of time (weeks) for d' and 9 SD rats.
`
`(‘01, KAN m ‘mm
`«ALB
`
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`“HALLS
`
`£55§£EE§5
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`
`In);
`
`0‘IL"03)?Hllxhflllfizflflfl“TI‘VOUMIIR‘IIWHM
`WEEKS
`
`+f~v
`
`4—an
`
`*m—m
`
`+0..“
`
`—-—u—.v
`
`+n~
`
`.
`
`I
`
`I
`
`I
`
`I
`
`l
`
`I.
`
`I.
`
`r
`
`w
`
`I,
`
`v
`
`I
`
`,1
`
`Food consumption:
`
`A statistically significant reduction (7—14%) in food consumption
`was observed in both male and female animals from all treated
`
`groups, the effect being most pronounced in female rats. Effects
`were noted from Week 2 for females but did not become apparent
`in male rats until Week 20. In neither sex did the reduction in food
`
`Hematology:
`
`Clinical chemistry:
`Organ weights:
`
`——mr-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`There were no changes in hematology parameters that were
`considered to be related to treatment with ICI 182,780.
`Minor differences of some parameters, occasionally statistically
`significant, were considered incidental and unrelated to treatment
`with ICI 182,780
`No clinical chemistry was included.
`Organs were not weighed
`
`consumption result in a decrease in terminal body weight.
`RBC levels were elevated in dru -treated females. *p<0.05
`REC x
`Week 52
`Week 78
`Week 105
`103/mm3
`
`5.77
`5.32
`
`m—— 6.35
`15 mg/kg
`6.66 (T1404).
`6-84 (Tl8%)‘
`-78 (T18%)‘
`
`95
`
`

`

`
`
` Reviewer: Lilliam A. Rosario PhD. NDA No.21-344
`
`Gross pathology:
`
`<10mg/kg/30d 510mg/kg/15di
`/30d
`
`
`
`
`
` 215mg/kg
`
`U. 0
`
`LA O
`
`{J- O
`
`19
`19
`
`18
`
`Testes-pale areas
`—reduced size
`-soft texture
`
`Uterus-cyst
`-small
`
`Va ina- . ale material
`
`0 Presence of cysts at the injection sites in all groups, except saline, suggesting a vehicle effect.
`
`0 Visual inspection suggests that there was enlargement of the liver in both sexes from all drug
`treatment groups. The incidence of liver enlargement was lower in groups receiving the test
`article every 30 days (86/19) compared to animals receiving the drug every 15 days
`(106759). A small increase in the incidence of dilatation of the extrahepatic bile duct was
`noted in drug-treated females.
`
`0
`
`0
`
`In drug-treated males, there was an increased incidence of pale areas, reduced size, and soft
`texture of the testes.
`
`In drug treated females, there was an increased incidence of grossly observable ovarian and
`uterine cysts, as well as small uteri. Conversely, there was a decreased incidence of
`subcutaneous masses or thickening and pituitary masses to levels comparable with the male
`incidence. The occurrence of pituitary masses is commonly higher in female than in male rats
`of the strain and age range of this study.
`
`Histopathology:
`
`See tabular data on following pages.
`
`96
`
`

`

`NDA No.2l-344
`Reviewer: Lilliam A. Rosario PhD.
`
`Neoplastic:
`
`Animals with neoplasms
`>1 primary neoplasm
`Total primary tumors
`Ovaries n=
`Granulosa cell tumors A
`
`Abnormal follicular development
`(q/v)
`
`Hyperplasia: follicular granulosa
`cells
`Adenoma: Sertoliform tubular
`
`Uterus n=
`
`Endometrial stromal polyps
`Endometrial adenocarcinomas
`Leiomyoma
`Leiom osarcomas
`
`Mammary glands: n=
`Adenomas
`Adenocarcinomas
`fibroadenomas
`
`Pituitary gland tumors n=
`
`Adenomas
`Carcinomas
`
` All tumors n=
`
`-some 9 had > 1 primary tumor
`-l in 9
`
`“4%)
`
`2l
`
`Typically nodular in appearance with solid masses of
`granulosa cells in a pseudofollicular pattern separated by
`areas of thecal—type cells.
`Granulosa cell layer showing T cellularity with a florid
`proliferation and folding. Sometimes also proliferation of
`the ovarian interstitial cells.
`
`T incidence w/ 10 mg/rat l5 days
`
`The low incidence in Group 6 may make finding equivocal
`for dru --effect.
`
`l in tumor incidence
`
`Common tumors in elderly rats and frequent cause of death
`in this species. Most common in 95.
`i incidence in drug-txn
`i incidence in dru —txn
`
`V97
`
`

`

`
`Reviewer: Lilliam A. Rosario Ph.D.
`NDA Noll-344
`
`Liver: n=
`
`Adenomas
`Carcinomas
`
`Lymphoid tissue (n=
`Malignant lymphoma C
`H stioc tic sarcomata C
`
`Endocrine organs n=
`Adrenal conical or medullary
`carcinoma
`
`Adrenal conical or medullary
`adenoma
`
`
`
`No txn effect
`
`Appears more prevalentm Group 5
`
`
`
`
`
`
`
`Thyroid follicular or C—cell
`carcinoma
`Thyroid follicular or C-cell
`adenoma
`Pancreatic islet carcinoma
`Pancreatic islet adenoma
`Subcutaneous tissue n=
`Fi broma
`Fibrosarcoma
`Uncommon tumors. Background instances in this lab vary from 0/120 to l/l20 (0.2%) Study w/ same strain1and source n= 4493 0.3%. Other strains 1 -3%
`5 Background incidencesIn this lab: l/60 to 6/120 (0.02-0. 05)
`C Comparison of the incidencesIn treated groups with the appropriate control groups (Groups 4 and 5 against Group 2 and Group 6 against Group 1) shows that that spontaneous
`pituitary tumor incidence in these groups was reduced to levels comparable to that seen in both control and treated male animals. The reduction in number of pituitary masses seen at
`necropsy (qv) was greater than that for histologically diagnosed pituitary tumours (above) suggesting tumours in drug--treated females were smaller thanIn untreated or male animals
`I)Spontaneous tumors in aged rats and associated w/ death
`
`in both sexes and all doses
`In both sexes and all doses
`
`
`
`
`
`
`
`
`

`

`Reviewer: Lilliam A. Rosario PhD.
`NDA No.21-344
`
`Non-Neoplastic
`
`
`
`Ovaries n=
`
`Corporea lutea reduced or absent
`Prominent follicles
`
`Abnormal follicular development "
`Hyperplasia: granulosa cells‘
`Hyperplasia: sertoliform tubular
`Hyperplasia: stromal
`
`Cyst: follicular
`Cyst: hemorrhagic
`
`Uterus n=
`
`Hypertrophy: Stromal
`Cyst: endometria;
`Dilatation: lumen
`
`Atrophy: Endometrial
`Atroh : Myometrial
`
` Normal rat ovarian structure in aged animals
`
`is typified, by a l or absence of corpora
`lutea, by the presence of follicular cysts
`(small to grossly distended in size) and
`occasional sertoliform tubular hyperplasia in
`the interstitium.
`
`Absent corpora lutea in drug-treated rats.
`Follicles showed degrees of abnormal
`development, contained oocytes, and tended
`to include unusually prominent granulosa
`cell layers.Note:
`In anestrous rats of this
`age range, follicles of any stage of
`development sare rarely seen.
`Discussed inprevious table.
`Discussed inprevious table.
`l incidence in treated animals
`T incidence of unusual stromal hyperplasia
`not observed in untreated animals.
`
`T incidenceof follicular cysts in treated rats.
`Presence of hemorrhagic cysts in drug-
`treated rats.
`
`In aged 9 rats, normal uteri show i
`endometrial glands with occasional
`development of glandular cysts. Lumenal
`dilatation and stromal hypertrophy may be
`present.
`Absence of typical age-related changes.
`Absence of typical age-related changes.
`Absence of typical age-related changes.
`T incidence in treated rats.
`T incidence in treated rats.
`
`p39
`
`
`
`

`

`Reviewer: Lilliam A. Rosario, Ph.D.
`
`NDA No.21-344
`
`Mammary Gland n=
`Hyperplasia
`
`
`
`In treted 9, the incidence of mammary
`hyperplasia wasl and approached the
`incidence in 6' animals.
`
`In a some treated rats mammary glandular
`tissue was not discernible or was atrophic.
`These changes may be treatment related or a
`consequence of l incidence of pituitary
`neoplasia. Note: Pituitary cells. normal or
`neoplastic, under the influence of estrogen
`produce prolactin levels that are implicated
`in mammary gland proliferation, an effect
`that can be inferred absent in treated rats.
`Cysts were absent in saline controls.
`Cysts were typically multiple and
`moderately large with thin fibrous walls and
`appeared to be empty. Commonly located in
`the adipose tissue adjacent to muscle blocks
`or in the connective tissue of the muscle
`fascia and often occurred in connective
`tissues immediately adjacent to nerve
`bundles located in the vicinity of the
`injection site.
`Vvarying degrees of atrophy or
`degeneration of muscle fibers possibly due
`to the physical presence of the large cysts.
`Mild cell infiltration that appeared more
`frequent in Group 6 {10 mg/rat every l5
`days) 95.
`Mild cell infiltration that appeared more
`frequent in Group 6 {l0 mg/rat every I5
`da 5 95.
`No treatment effect on the incidence of
`basophilic or eosinophilic hepatocellular
`foci.
`
`T incidence of foci or areas oftension
`lipidosis in Group 6 (IO mg/rat every 15
`
`Woo
`
`days)..
`
`Atrophy
`
`Injection sites: n=
`Cyst
`
`Atrophy/degeneration Myofibers
`
`Inflammation: muscle
`
`Inflammation: Fat/connective tissue
`
`Liver n=
`
`Basophilic cell foci
`
`Eosinophilic cell foci
`Eosin cells: cystic degeneration
`Clear cell foci
`
`

`

`Reviewer: Lilliam A. Rosario PhD.
`N DA No.2l-344
`
`Tension lipidosis
`
`
`
`T incidence in drug-treated rats. This
`change is a specific focal lesion generally
`considered to be associated with prolonged
`tension by supporting ligaments acting on a
`particular subcapsular area of hepatocytes
`In a smal 1 number of treated animals,
`especially 9, dilatation of the extrahepatic
`bile ducts was recorted.
`
`T incidence in treated rats.
`
`T incidence in treated rats.
`T incidence in treated rats.
`T incidence in treated rats.
`
`T incidence in treated rats.
`
`T incidence in in Group 6 (l0 mg/rat/l 5
`days). In 9, T in cystic degeneration (all
`treated groups).
`
`In of, T incidence of vacuolation in the pars
`distalis.
`
`T incidence in treated 0" rats while a i
`incidence in 9 rats.
`
`i in pigment deposition (hemosiderosis) in
`9 animals to levels com arable with d'.
`
`T incidence in Group 6 males (l0 mg/rat
`every l5 days) compared to vehicle or saline
`controls and in all 9 vehicle control and
`treated animals comared to saline controls.
`
`50
`45
`
`2 1
`
`7
`50
`42
`
`50
`
`50
`46
`
`I l
`
`l
`
`40
`
`50
`
`2 5
`
`0
`12
`
`0 5 5
`
`0
`
`50
`4
`
`50
`
`50
`
`8 0 8 5
`
`8 5
`
`8
`
`0
`
`0
`
`50
`2
`50
`8
`0
`
`50
`6
`50
`2
`
`3
`
`50
`l
`
`50
`2]
`3
`
`50
`I7
`3
`
`50
`18
`I
`
`50
`I9
`3
`
`50
`15
`2
`
`50
`28
`12
`
`Hyperplasia: bile duct
`
`Bile ducts n=
`Dilatation
`Testes n=
`Atrophy: seminiferous tubules
`Hyperplasia: interstitial cells
`Inflammation: vascular
`
`Epididymis:
`Oligo/aspennia
`Endocrine tissues: Adrenals n=
`Hyperplasia: cortex
`
`Deeneration: c stic
`
`Pituitary n=
`Vacuolation: pars distalis
`
`Kidneys: n=
`Chronic progressive nephropathy
`
`Spleen n=
`Deposits: pigment
`
`Skin n=
`Ulceration
`Joint: ulceration plantar
`
`Incidental changes:
`0
`Endocrine tissues — adrenal cortical congestion and sinusoidal dilatation, thyroid C-cell proliferation, thyroid follicular cysts.
`Gastrointestinal tract - ulceration, primarily in the stomach, mucosa] and submucosal inflammation.
`Liver —sinusoidal congestion, hepatocellular vacuolation, basophilic, eosinophilic and clear cel l foci, foci or areas of necrosis.
`Lungs — focal aggregations of alveolar macrophages, congestion and edema.
`Urinary tract —interstitial inflammation, pelvic inflammation, pelvic dilatation, urinary bladder transitional epithelial hyperplasia..
`
`
`
`

`

`
`
`Reviewer: Lilliam A. Rosario PhD. NDA No‘21-344
`
`Heart— occasional instances of myocarditis myocardial fibrosis, and atrial thrombosis
`0
`Lymphoid organs — plasmacytosis, sinus histiocytosis and lymphoid hyperplasia were present to varying degreesin many lymph
`nodes. Thymic atrophy associated with normal aging was seen in the majority of animals
`
`Toxicokinetics:
`
`The following shows the ~ actual dose (mg/kg) administered to Groups V (10 mg/rat/3O days)
`and Group VI (10 mg/rat/l 5 days).
`
`
`
`“—
`BW(g) 'Actual BW(g)Ami-1
`3w(g)
`BW(g)
`~Actual
`dose
`dm—se dose
`dose
`dose
`dose
`III‘° IImyrat/ mg/kg/ mg/rat/
`
`
`
`
`
`——
`
`
`lSdays 30 days mg/rat/ mg/kg/ mg/rat/ mg/kg/ 30 days
`30das 30das lSdas lSdas
`153.
`
`
`
`30das 30das lSdas
`1923
`
`—29
`
`——
`_-
`-- 4878
`n-
`
`0
`
`Systemic exposure to ICI 182,780 was demonstrated in Group 4 (15 mg/kg/30days), Group 5
`(10 mg/rat/30days) and Group 6 (10 mg/rat/l 5days) afier a dosing period of ~12 months.
`
`/
`
`Mean trough plasma concentrations of ICI 182,780
`
`Group 4 (15 mg/kg/SO days)
`
`Group 5 (10 mg/rat/30days)
`
`Group 6 (10 mg/rat/lSdays)
`
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`0 Trough plasma concentrations were monitored over the first 9 months of dosing in all groups
`(see Figures above) showing a steady increase up to 4 months, consistent with accumulation,
`followed by a flattening of the profile thereafter, suggesting that steady state
`phannacokinetics had been achieved.
`
`102
`
`

`

`
`
`Reviewer: Lilliam A. Rosario PhD. NDA No.21-344
`
`
`Group-—-
`
`
`23
`
`
`———
`l5 mg/kg/30d
`lO mg/rat/30d
`10 mg/rat/lSd
`2]
`'5
`12 -- 34
`nu
`
`Dose and frequency
`Estimated actual
`
`dose (mg/kg/30 d)
`
`
`
`
`
`
` Cm ("s/ml)
`—m In —
`
`—-IlI---
`on
`
`
`
`
`
`
`0‘
`
`
`
`(23:.—6,wo0
`
`U!
`
`
`
`2135
`23-5
`ma)
`AUC was calculated over 30 days in Groups 4 and 5, and over 16 days in Group 6.
`0 The higher Cmax values (1.6-2.3-fold) observed in Group 6 compared to Groups 4 and 5 may
`reflect drug accumulation due to more frequent dosing (every15 days).
`0 After ~ 12 months of dosing (i.e., dose 12 in Groups 4 and 5, and dose 23 in Group 6), Cmax
`values for females in groups 5 and 6 were ~2-fold higher than males.
`
`I‘"\
`
`0 Due to differences in the dosing criteria (mg/kg versus mg/animal) and the duration of the
`dosing interval (15 versus 30 days) comparison of exposure across the groups was not
`feasible.
`
`0 AUC values for female rats in groups 5 and 6 are ~2-fold higher than male values but there is
`no difference between the sexes for rats in Group 4. The Sponsor suggests that the sex
`difference resulted from females receiving relatively higher mg/kg dose in Groups 5 and 6
`compared to male animals due to lower female body weights.
`
`0
`
`If AUC values in the 3 dose groups are normalized for dose and body weight, the relative
`exposure between Groups 4 and 5 appears similar (see table below). Both groups received a
`similar dose level (~20 mg/kg for females and l 1.9 mg/kg for males in Group 5 compared to
`15 mg/kg in Group 4) over the same time interval of 30 days.
`
`CFBR Project number 88579, AstraZeneca Reference number
`Table l
`TCR2683. AUC values normalised for body weight, dose and time
`
`Group 4
`(lSmg/kgBOdays)
`Dose l2
`
`Group 5
`(10 mg/m/30days)
`Dose 12
`
`Group 6
`(IO mg/rnt/IS days)
`Dose 23
`
`Parameter
`Males
`Females Mala
`Females Males
`Females
`
`Mean Weight (g)
`823
`50!
`843
`500
`795
`513
`Ntmmlised Dose
`15.0
`IS.0
`l 1.9
`20.0
`12.6
`I9.5
`(ms/k8)
`Observed AUC
`(fled/ml)
`
`4l7
`
`497
`
`427
`
`BIS
`
`538
`
`830
`
`85.l‘
`85.4'
`40.8
`35.9
`33.!
`27.8
`Normalised AUC
`(ns-d/mI/ms/ks)————________—_____________
`‘AUC ulna in Group 6 were mrmaliscd and then doubled in order to assess the exposure for 2 doses over
`a 30 day period
`
`103
`
`

`

`
`
`Reviewer: Lilliam A. Rosario PhD. NDA No.21-344
`
`F‘“
`
`0
`
`Inspection of the plasma concentration—time profiles indicated that following the peak in
`Groups 4 and 5, ICI 182,780 declined monoexponentially with a long half-life (21.5 and 28.9
`days). For purposes of calculating AUCMOd it was assumed that steady state kinetics had
`been achieved prior to dosing at 12 months and the predicted concentrations at 30 days were
`therefore substituted as pre—dose values. For Group 6 the AUC was calculated from time 0 to
`16 days; there were insufficient data points to calculate a half—life.
`
`0 No significant levels of sulphone and 17-ketone metabolites of 1C1 182,780 were measured
`(below the assay limit of quantification of-ng/ml for sulphone and ’ng/ml for 17-ketone).
`
`Summary of individual study findings:
`Adequacy of the carcinogenicity study and appropriateness of the test model:
`0 Despite the lower than expected survival rates for control males, there are an adequate
`number of animals that survived to the end of the study.
`0 The duration of the study (2 years) is appropriate.
`On July 28, 1998, the Sponsor obtained dose concurrence from the Executive CAC for the
`proposed carcinogenicity protocol.
`
`Evaluation of tumor findings:
`Administration of ICI 182,780 resulted in changes in the incidence (increased and decreased) of
`both neoplastic and non-neoplastic findings. Several of the changes in the ovaries, uterus,
`mammary glands, pituitary gland, and testes are considered to be related to the pharmacological
`activity ofICI 182,780.
`
`ICI 182.780 increases the incidence of ovarian granulosa cell tumors and testicular interstital
`Leydig cell ademomas.
`
`Ovaries: An increase in the incidence (14%) of ovarian granulosa cell tumors was recorded in
`the high dose female animals (7/50 rats at 10 mg/rat/ 15d). This was also associated with an
`increased incidence of hyperplasia of follicular granulosa cells in these animals. Also in the
`ovaries, there was an increase incidence of abnormal follicular development and a reduction in
`sertoliform tubular hyperplasia. Spontaneous incidence of granulosa cell tumors for this strain of
`rat is 0.06% (n=l729) (Giknis and Clifford, 2001
`-""""
`, The conducting
`laboratory reports background instances varying from 0/ 120 to 1/ 120 (0.2%). Another study (n=
`4493) with the same strain and source reports 0.3% (Gregson and Abbott, 1984).
`
`Testes: There was an increase (2-12%) incidence of interstitial Leydig cell tumors (adenomas) in
`drug-treated animals. These tumors were present at a low incidence (4%) in the saline control
`group and absent in the vehicle control groups. The incidence in the high dose group was similar
`to controls (2%) while increased (8-12%) in the two lower dose groups. Spontaneous incidence
`for this tumor in this strain of rat is 2.35%.
`
`ICI 182,780 decreased the incidence of uterine endometrial stromal polyps, mammary tumors
`(adenoma, fibroadenoma, adenocarcinoma) in females, and pituitary adenomas in females.
`Reductions in mammary gland and pituitary tumors may have contributed to the increase in
`longevity of animals administered ICI 182,780.
`
`104
`
`

`

`
`
`Reviewer: Lilliam A. Rosario PhD. NDA No.21-344
`
`Carcinogenicity summary:
`ICI 182,780 (fulvestrant-Faslodex) is a steroidal estrogen receptor antagonist. The compound is
`negative in in vitro and in vivo genotoxcity assays. The purpose of this study was to investigate
`the carcinogenic potential of ICI 182,780 following intramuscular injection to Sprague-Dawley
`rats once every 15 or 30 days over a minimum period of 104 consecutive weeks. According to
`the Sponsor, the highest dose level selected represent the maximum possible dose administerable
`by the intramuscular route based on strength of the formulation and injection volume.
`
`Survival of drug-treated rats was increased compared to controls. It is noteworthy that survival
`rates for control males appear lower than expected. There were no treatment—related clinical
`signs, however a number of animals from all treated groups and fiom control animals in Groups
`1 and 2 receiving vehicle, exhibited cysts at the injection sites. Overall body weights throughout
`the study were not affected by treatment even though there was a statistically significant
`reduction (7—14%) in food consumption in both male and female animals from all treated groups.
`Hematology parameters were unaffected by treatment.
`
`Phannacokinetic analysis showed systemic exposure to lCI 182,780 in drug-treated rats after a
`dosing period of ~ 12 months. Over the first 4 months of dosing, trough plasma concentrations
`increased steadily; subsenquently concentrations leveled off suggesting that steady state
`pharmacokinetics had been achieved. Similar to previous studies in rats (1 and 6 month), plasma
`concentrations of ICI 182,780 were higher in female rats compared to males in all groups.
`Plasma levels in Group 5 (10 mg/rat/30 d) and 6 (10 mg/rat/l 5 (1) females were significantly
`greater than in males. This effect may result from higher mg/kg dose exposure due to lower body
`weights in females. Given the study design, in group 5 and 6 (10 mg/rat) the actual dose
`administered decreases with increasing weight. Thus, by dose 12/23, the actual dose
`administered to males (~13 mg/kg) is not significantly different than in Group 4 (15 mg/kg).
`Consequenlty, PK parameters are not different in males between Groups 4 and 5.
`
`Administration of ICI 182,780 resulted in changes in the incidence (increased and decreased) of
`both neoplastic and non-neoplastic findings. ICI 182.780 increases the incidence of ovarian
`granulosa cell tumors and testicular interstital Leydig ademomas while decreasing the incidence
`of uterine endometrial stromal polyps, mammary tumors (adenoma, fibroadenoma,
`adenocarcinoma) in females, and pituitary adenomas in females. Reductions in mammary gland
`and pituitary tumors may have contributed to the increase in longevity of animals administered
`lCI 182,780.
`
`Non-neoplastic changes included an increased prominence of ovarian follicles with the presence
`of abnormal follicles and granulosa cell proliferation in drug-treated groups. There was increased
`numbers of follicular cysts (also more hemorrhagic cysts) and increased interstitial cell stromal
`hyperplasia while age-related sertoliforrn tubular hyperplasia was decreased. There was an
`extensive uterine endometn'al and myometn'al atrophy and an extensive atrophy of mammary
`tissues in females. In males, testicular seminiferous tubular atrophy was associated with vascular
`inflammatory changes and epididimal oligo/aspermia.
`
`Adrenocortical hyperplasia and cystic degeneration were seen primarily in high dose females. A
`decreased incidence of chronic progressive nephropathy was seen in females with a slight
`corresponding increase in males. There was evidence for a decreased splenic hemosiderosis in
`
`105
`
`

`

`
`
`Reviewer: Lilliam A. Rosario PhD. NDA No.21-344
`
`females and a slight increase in the incidence of altered eosinophilic foci or areas of tension
`lipidosis in the liver of both males and females. The injection site exhibited multiple, thin walled
`cysts occasionally associated with minor degrees of local inflammation and degeneration or
`atrophy of skeletal muscle. Similar cystic structures were occasionally seen in perineural tissues
`of sciatic nerve distal to the injection sites.
`
`Carcinogenicity conclusions:
`The Sponsor concluded that 1C1 182,780, administered intramuscularly to rats for 2 years at
`doses of 15 mg/kg/30 days, 10 mg/rat/30 days and 10 mg/rat/ 15 days, showed no evidence of
`direct carcinogenic activity. The Sponsor also suggests that induction of ovarian granulosa cell
`tumors and testicular Leydig cell tumors was consistent with the pharmacological activity of an
`anti-estrogen. The Sponsor notes that ICI 182,780-treated rats showed increased survival, “near
`abolition” of mammary tumors, and a reduction in the incidence of pituitary neoplasms.
`
`On December 4, 2001, the results of this study were presented to the Executive Carcinogenicity
`Assessment Committee (Meeting minutes on Appendix A). After careful evaluation of the study,
`the Committee concluded that Fulvestrant increases the incidence of ovarian granulosa cell
`tumors in female rats, and the incidence of interstitial Leydig cell tumors in male rats. The
`increase incidence of granulosa and Leydig cell tumors should be included in the product
`labeling for fulvestrant.
`
`The Committee also noted that while fulvestrant appears to have a negative profile for
`genotoxicity potential on a standard battery of tests, the Sponsor did not perform the defining
`studies to determine fulvestrant is not genotoxic. The Committee recommended that the Sponsor
`be asked to perform 32? post-labeling study to determine if fulvestrant and/or its’ metabolites
`may form adducts with cellular DNA. We agree that a 32F post-labeling study will be valuable in
`assessing possible genotoxic potential of Fulvestrant. However, given that the current indication
`for Fulvestrant is '
`F‘—
`
`the request for this study maybe postponed. If the indication of Fulvestrant was to change to
`include any other population, the Sponsor is strongly recommended to conduct a 32P post-
`labeling study to ensure that Fulvestrant is non-genotoxic.
`
`106
`
`

`

`
`
`Reviewer: Lilliam A. Rosario PhD. NDA No.21-344
`
`Labeling Recommendations:
`The Sponsor proposed the following carcinogenesis labeling:
`Carcinogenesis:
`
`DMFPFE
`
`pu..--.
`
`FDA Recommendations:
`
`A two-year carcinogenesis study was conducted in female and male rats, at intramuscular doses
`of 15 mg/kg/30 days, 10 mg/rat/3O days and 10 mg/rat/l 5 days. These doses correspond to
`approximately 1-, 3-, and 5-fold (in females) and 1.3-, 1.3-, and 1.6-fold (in males) the systemic
`exposure [AUCMO days] achieved in woman receiving the recommended dose of 250 mg/month).
`An increased incidence of benign ovarian granulosa cell tumors and testicular Leydig cell tumors
`was evident, in females dosed at 10 mg/rat/15 days and males dosed at 15 mg/rat/3O days,
`respectively. Induction of such tumors is consistent with the pharmacology—related endocrine
`feedback alterations in gonadotro