CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`21-344
`
`Correspondence
`
`

`

`FAX
`
`FOOD AND DRUG ADMINISTRATION
`
`DIVISION OF ONCOLOGY DRUG PRODUCTS
`
`Center for Drug Evaluation and Research, HFD-l 50
`5600 Fishers Lane, Rockville, MD 20857
`
`
`
`
`
`To:
`
`B. Jane Valas, PhD.
`
`From: Amy Baird, CSO
`
`Fax:
`
`302-886-2822
`
`Fax:
`
`(301) 594-0498
`
`Phone: 302-886-2122
`
`Phone: (301) 594-5771
`
`Pages, including cover sheet:
`
`4
`
`Date: 4—22-02
`
`Re: NDA 21-344 Faslodex.
`THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY T0 WHOM lT IS ADDRESSED AND MAY CONTAIN
`INFORMATION THAT IS PRIVILEGED, CONFIDENTIAL AND PROTECTED FROM DISCLOSURE UNDER APPLICABLE LAW.
`If
`you are not the addressee, or a person authorized to deliver the document to the addressee, you are hereby notified that any review, disclosure,
`dissemination or other action based on the content of the communication is not authorized. If you have received this document in error, please
`immediately notify us by telephone and return it to us at the above address by mail. Thank you.
`
`COMMENTS:
`
`Per the chemistry reviewer, on the following pages are comments that need to be addressed. We
`have requested that you respond to these cements in either an annual report or as a general
`correspondence/new correspondence to the NDA within 30 days of the approval of Faslodex.
`We ask that you commit to responding to these comments in the manner that we have requested
`(annual report or GC). You should provide this commitment via facsimile. Please note that
`these are not considered post-marketing commitments (phase 4), nor will they be noted in the
`approval letter. Please call should you have any questions.
`
`Thank you,
`
`\I ‘
`Amyfm
`
`

`

`Page 2
`NDA 21-344
`
`[Annual Report] = commitment to fulfill the agreement and report it in the next
`appropriate annual report.
`
`[Now] = commitment to fulfill the agreement and report it as GC/NC as soon as feasible,
`but not more than 30 days post approval.
`
`We have the following comments regarding fulvestrant drug substance:
`
`.[Annual Report] The proposed Assay specification for the. —-
`'— is 9‘% w/w and the total organic impurities is 0%. Please provide information
`regarding any additional impurities or degradants that may contribute to the remaining
`difference oi~%.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`-—-—-——
`[Annual Report] The proposed assay specification for 1
`f % w/w and the total organic impurities is specified as-%
`w/w maximum. Please provide information regarding any impurities or degradants which
`contribute to the remaining-I-Vo w/w.
`
`I—_
`[Annual Report] The proposed assay specifications for
`.——-— ranges from ~% w/w.
`- is listed as an impurity at h%
`w/w maximum. Please provide information regarding any degradants or impurities that
`contribute to the remaining - '%.
`
`[Annual Report] The proposed Assay specification for. ——
`"' , ranges from —"
`‘ This specification is rather broad it should be
`reevaluated after several commercial batch runs or one year after approval (via annual report)
`to better reflect actual batch data.
`
`[Annual Report] The proposed Assay specification for "fi
`’- %. Please provide information regarding any degradants and
`impurities that contribute to the remaining ‘- 1%.
`
`II—
`[Now] Please revise the drug substance specification for water content, ;
`-'
`specific optical rotation, microbial content, and endotoxins to reference
`appropriate USP/NF methods.
`
`_ ~— ’limit NMT- %) was
`[Annual Report]
`not detectedin any batches. This limit should be reevaluated after several commercial batch
`runs or one year after approval to better reflect actual batch data.
`
`.————- bags, which indicates that it complies with
`8. Please submit documentation for the *
`21 CFR [now]. Please describe further, the materials of construction for the
`"""""'
`-—" ‘ used for bulk packaging of fulvestrant drug substance and acceptance criteria, to
`support the use of these materials [annual report].
`
`

`

`Page 3
`NDA 21-344
`
`9.
`
`[Now] Please provide a copy of the stability specification and tests for fulvestrant drug
`substance in the description of the stability protocol.
`
`10. [Now] Please revise the specification for the IR Identification test to indicate that it is
`compared against that obtained from the Fulvestrant Reference Standard.
`
`11. [Now] Please revise the Fulvestrant Reference Standard specification for water content,
`N ,: specific optical rotation, microbial content, and endotoxins
`to reference appropriate [TSP/NF methods.
`
`12. [Now] Please include your tests and limits for Total Organic Impurities in the Specifications
`for Fulvestrant Reference Standard.
`
`13. [Now] Please provide a commitment that —-_-— - will be performed without
`notification to the Agency.
`
`We have the following comments for Faslodex Injection drug product:
`
`1.
`
`[FIO... No action required by the applicant] We have reviewed Drug Master File (DMF)
`‘ I submitted by Vetter — GmbH & CO. KG ——
`identified several comments. The nature of these comments will be communicated to the
`
`DMF holder separately. These comments to not affect your approvability.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`and free fatty
`[Now] Please include tests for optical clarity, viscosity, extractables —-—"
`acid content in the specifications for fulvestrant drug product as they are provided in the
`stability study of fileestrant drug product.
`
`[Now] Please provide the complete regulatory specifications for FASLODEX Injection in the
`body of the stability protocol description.
`
`[Annual Report] Please provide the chemical resistance test and results for the Type 1 glass
`components (syringe barrel) as per current USP <661>.
`
`[Now] Given the solvent power of the drug product vehicle, please provide results for a one-
`time characterization of extractables from the rubber container-closure components into the
`formulation.
`
`[Annual Report] Please provide the test results for syringe barrel, rubber plunger and rubber
`tip-cap as per tests and specifications listed in V0]. 1.5, Container Closure Section of this
`application.
`
`[Annual Report] Please submit certificate of analyses from the suppliers of container
`closure for batches of drug product submitted in this application.
`
`[Now] Please provide a commitment that v - of Faslodex Injection will be
`performed without notification to the Agency.
`
`

`

`Page 4
`NDA 21 -344
`
`We recommend the following revisions to the Carton Label (2.5 mL and 5 mL) and Syringe
`Label:
`
`1.
`
`[Annual Report] At your next available printing, please revise the list of inactive ingredients
`in the Carton Label and list as: Alcohol, USP; Benzyl Alcohol, NF; Benzyl Benzoate, USP;
`
`and Castor Oil, USP.
`
`2.
`
`[Annual Report] At your next available printing, please include the following statement on
`the Syringe Label: RX only.
`
`

`

`MESSFiEE CDNF I RMPIT I ON
`
`84/22/82
`
`16: 88
`
`DRTE
`
`84/22
`
`S ! R-T 1 NE
`
`D I STRNT STRT iON ID
`
`NUDE
`
`PRGES
`
`RESULT
`
`8 1 ’ 29 "
`
`8862822
`
`CQLL I NE
`
`84
`
`OK
`
`8888
`
`I34/22/82
`
`15: 58
`
`ND. 842
`
`081
`
`FAX
`
`FOOD AND DRUG ADMINISTRATION
`
`DIVISION OF ONCOLOGY DRUG PRODUCTS
`
`Center for Drug Evaluation and Research, RFD-150
`5600 Fishers Lane, Rockville, MD 20857
`
`
`
`
`
`To:
`
`B. Jane Vaias, PhD.
`
`From: Amy Baird, CSO
`
`Fax:
`
`302-886-2822
`
`Fax:
`
`(301) 594-0498
`
`Phone: 302-886-2122
`
`Phone: (301) 594-5771
`
`Pages, including cover sheet:
`
`4
`
`Date: 4-22-02
`
`Re: NBA 21-344 Fasiodex.
`THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM H is ADDRESSED AND MAY CONTAIN
`INFORMATION THAT IS PRMLEGED, CONFIDENTIAL AND PROTECTED FROM DISCLOSURE UNDER APPLICABl .F. [.AW.
`if
`you are not the addressee, or I person authorized to deliver the document to the addressee, you ere hereby notified that my review. disclosure.
`dissemination or other action based on the content of the communication is not authorized. if you have received this document in error. please
`immediately notify us by telephone and return it to us at the above address by mail. Thank you.
`
`

`

`FAX
`
`FOOD AND DRUG ADMINISTRATION
`
`DIVISION OF ONCOLOGY DRUG PRODUCTS
`
`Center for Drug Evaluation and Research, HFD-l 50
`5600 Fishers Lane, Rockville, MD 20857
`
`
`
`
`
`
`
` To: B. Jane Valas, PhD. From: Amy Baird, CSO
`
`
`
`Fax:
`
`302—886-2822
`
`Fax:
`
`(30]) 594—0498
`
`Phone: 302-886-2122
`
`Phone: (30]) 594-5771
`
`Pages, including cover sheet:
`
`2
`
`Date: 4-18-02
`
`Re: NDA 21-344 Faslodex. Phase 4 Commitment Requests.
`THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND MAY CONTAIN
`INFORMATION THAT IS PRIVILEGED, CONFIDENTIAL AND PROTECTED FROM DISCLOSURE UNDER APPLICABLE LAW.
`If
`you are not the addressee, or a person authorized to deliver the document to the addressee, you are hereby notified that any review, disclosure,
`dissemination or other action based on the content of the communication is not authorized. If you have received this document in error, please
`immediately notify us by telephone and return it to us at the above address by mail. Thank you.
`
`COMMENTS:
`
`Attached is the latest version of three Phase 4 commitments the Division will be requesting of
`AstraZeneca. These commitments are still considered DRAFT. You do not need to reply to this
`facsimile. Call me should you have any questions.
`
`.
`
`.
`
`Thank you,
`3;“
`
`/6
`
`\r
`
`Amy Baird
`
`

`

`MESSI—‘IGE CDNF I RMFIT I ON
`
`84/18/82 12: 49
`
`DRTE
`
`84/ 18
`
`SyR-TII’IE
`
`DISTQNT STRTIDN ID
`
`MODE
`
`PRGES
`
`RESULT
`
`88 ’ 49 "
`
`8862822
`
`CRLL I N8
`
`82
`
`UK
`
`8888
`
`. 0141/18/82
`
`12: 4'?
`
`(‘
`
`FAX
`
`FOOD AND DRUG ADMINISTRATION
`DIVISION OF ONCOLOGY DRUG PRODUCTS
`Center for Drug Evaluation and Research, RFD-150
`5600 Fishers Lane, Rockville, MD 20857
`
`N0. 82'?
`
`
`
`
`
`To:
`
`B. Jane Valas, PhD.
`
`From: Amy Baird, CSO
`
`Fax:
`
`302-886-2822
`
`Fax:
`
`(301)594-0498
`
`Phone: 302-886-2122
`Phone: (301) 594-5771
`
`
`('
`
`Pages, including cover sheet:
`
`2
`
`Date: 4-18-02
`
`Re: NBA 216“ Faslodex. Phase 4 Commitment Requests.
`'rHts DOCUMENT ls INTENDED ONLY FOR THE USE OF THE PARTY T0 WHOM IT IS ADDRESSED AND MAY CONTAIN
`INFORMATION THAT IS PRIVIU—ZGED, CONFIDENTIAL AND PROTECTED FROM DISCLOSURE UNDER APPLICABLE LAW.
`If
`you are not the addressee. or a person authorized to dellver the document to the uddresscc. you are hereby notified that any review, disclosure.
`dissemination or other action based on the content of the communication is not authorized. If you have received this document in error. ptease
`immediately notify us by tetephone and return it to us at the ehnve address by mail, Thank you.
`
`

`

`FAX
`
`FOOD AND DRUG ADMINISTRATION
`
`DIVISION OF ONCOLOGY DRUG PRODUCTS
`
`Center for Drug Evaluation and Research, HFD-l 50
`5600 Fishers Lane, Rockville, MD 20857
`
`
`
`
`
`To:
`
`B. Jane Valas, Ph.D.
`
`From: Amy Baird, CSO
`
`Fax:
`
`302-886-2822
`
`Fax:
`
`(30]) 594-0498
`
`Phone: 302-886-2122
`
`Phone: (301) 594-577]
`
`Pages, including cover sheet:
`
`2
`
`Date: 4-5-02
`
`Re: NDA 21-344 Faslodex. Phase 4 Commitment Requests.
`THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND MAY CONTAIN
`INFORMATION THAT IS PRIVILEGED, CONFIDENTIAL AND PROTECTED FROM DISCLOSURE UNDER APPLICABLE LAWI
`If
`you are not the addressee, or a person authorized to deliver the document to the addressee, you are hereby notified that any review, disclosure,
`dissemination or other action based on the content of the communication is not authorized. If you have received this document in error, please
`immediately notify us by telephone and return it to us at the above address by mail. Thank you:
`
`COMMENTS:
`
`Attached is a DRAFT version of three Phase 4 commitments the Division will be requesting of
`AstraZeneca. You do not need to reply to this facsimile. Call me should you have any
`questions.
`‘
`
`

`

`'MESSQGE CDNF I RMQT I ON
`
`84/85/82 89: 2'?
`
`DRTE
`
`84/85
`
`S r R-T 1 NE
`
`D I STRNT STRT I 8N ID
`
`MODE
`
`PRGES
`
`RESULT
`
`88 ’ 46 "
`
`8862822
`
`CRLL I N8
`
`82
`
`OK
`
`8888
`
`84/85/82
`
`89: 25
`
`N8 . 1 38
`
`D8 1
`
`FAX
`
`5600 Fishers Lane, Rockville, MD 20857
`
`FOOD AND DRUG ADMINISTRATION
`DIVISION OF ONCOLOGY DRUG PRODUCTS
`Center for Drug Evaluation and Research, HFD-l 50
`
`
`
`To:
`B. Jane Valas, PhD.
`From: Amy Baird, CSO
`
`Fax:
`302—886-2822
`Fax:
`(301)594-0498
`
`Phone: 302-886-2l22
`Phone: (301) 594-5771
`
`Pages, including cover sheet:
`2
`Date: 4-5-02
`
`Re: NBA 21-344 Faslodex. Phase 4 Commitment Requests.
`ms oocumrTNT'“ rs m‘woao omv FOR THE' use orme" PARTY—TO wow: u- rs ADDRESSED A_NDww Tow-um
`momnou THAT rs PRJvtLEGl—ID. conrroramm AND rnommn FROM orscwsuma UNDER APPLICABLE LAW,
`tr
`you are not the addressee. or a perstm authorized to deliver the document to the addressee, you are hereby notified that any review. disclosure,
`disseminltion or other action batted on the content of the communication Is not authorized.
`lt'you have received this document in error, please
`inunediately norlt‘y us by telephone and return it to us at the rthove rtddrees by mail. Thank you.
`
`6
`
`

`

`FAX
`
`FOOD AND DRUG ADMINISTRATION
`
`DIVISION OF ONCOLOGY DRUG PRODUCTS
`
`Center for Drug Evaluation and Research, HFD-ISO
`5600 Fishers Lane, Rockville, MD 20857
`
`
`
`
`
`To:
`
`B. Jane Valas, PhD.
`
`From: Amy Baird, CSO
`
`Fax:
`
`302-886-2822
`
`Fax:
`
`(301) 594-0498
`
`Phone: 302-886-2122
`
`Phone: (301) 594-5771
`
`Pages, including cover sheet:
`
`2
`
`Date: 3-22-02
`
`Re: NBA 21-344 Faslodex. Proposed announcement for ASCO.
`THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY T0 WHOM IT IS ADDRESSED AND MAY CONTAIN
`INFORMATION THAT IS PRIVILEGED, CONFIDENTIAL AND PROTECTED FROM DISCLOSURE UNDER APPLICABLE LAW.
`If
`you are not the addressee, or a person authorized to deliver the document to the addressee, you are hereby notified that any review, disclosure,
`dissemination or other action based on the content of the communication is not authorized. If you have received this document in error, please
`immediately notify us by telephone and return it to us at the above address by mail. Thank you.
`
`COMMENTS:
`
`Attached is the proposed announcement that we will send to ASCO membership the day that
`Faslodex is approved. Please review and comment.
`
`Thank you,
`A
`
`n/o/
`
`Amy Baird
`
`

`

`MESSPIGE CUNF I RMPIT I DH
`
`83/22/82 11 : 88
`
`DQTE
`
`83/22
`
`S . R-T I ME
`
`DI STRNT STRT I ON I D
`
`MODE
`
`PQGES
`
`RESULT
`
`88 ’ 58 "
`
`8862822
`
`CRLL I N8
`
`82
`
`OK
`
`8888
`
`/ "3/22/82
`
`18:59
`
`FAX
`
`FOOD AND DRUG ADMINISTRATION
`
`DIVISION OF ONCOLOGY DRUG PRODUCTS
`Center for Drug Evaluation and Research, HFD-l SO
`5600 Fishers Lane, Rockville, MD 20857
`
`
`
`
`
`To:
`B. Jane Valas, PhD.
`From: Amy Baird, CSO
`
`
`Fax:
`302-886-2822
`Fax:
`(301) 594-0498
`
`
`Phone: 302-886~2122
`Phone: (301) 594-5771
`
`
`
`
`
`
`2Pages, including cover sheet: Date: 3-22-02mm
`
`Re: NBA 21-344 Fulodex. Proposed announcement for ASCO.
`THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND MAY CONTAIN
`INFORMATION THAT IS PRWILEOED, CONFIDENTIAL AND PROTECTED FROM DISCLOSURE UNDER APPLICABLE LAW.
`If
`you are not the addressee, or e person wthorlzed to deliver the document to the addreme, you are hereby notified that my review. disclosure,
`disscmlnmion or other action tuned on the content of the communication is not authorized.
`[1‘ you have received this document in em, please
`immediately notify us by telephone and return It to us at the nbmre address by mail. Thank you.
`
`

`

`FAX
`
`FOOD AND DRUG ADMINISTRATION
`
`DIVISION OF ONCOLOGY DRUG PRODUCTS
`
`Center for Drug Evaluation and Research, HFD-ISO
`5600 Fishers Lane, Rockville, MD 20857
`
`
`
`
`
`
`To:
`B. Jane Valas, PhD.
`horn: Amy Baird, CSO
`
`
`Fax:
`302-886-2822
`Fax:
`(301) 594-0498
`
`Phone: 302-886-2122
`
`Phone: (30]) 594-5771
`
`Pages, including cover sheet:
`
`6
`
`Date: 2-21-02
`
`Re: NBA 21-344 Faslodex. Carcino enici Review.
`THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND MAY CONTAIN
`
`INFORMATION THAT IS PRIVILEGED, CONFIDENTIAL AND PROTECTED FROM DISCLOSURE UNDER APPLICABLE
`LAW. If you are not the addressee, or a person authorized to deliver the document to the addressee, you are hereby notified that any
`review, disclosure, dissemination or other action based on the content of the communication is not authorized.
`If you have received
`this document in error, please immediately notify us by telephone and retum it to us at the above address by mail. Thank you.
`
`COMIVIENTS:
`
`Attached are the oflicial minutes from the Carcinogenicity Committee review meeting on Faslodex.
`Please call should you have any questions.
`
`Thankyou,
`
`

`

`Executive CAC
`
`Date of Meeting; December 4, 2001
`Rat Carcinogenicity Study
`
`Committee:
`
`Joseph DeGeorge, Ph.D., HFD-024, Chair
`Joseph Contrera, Ph.D., RFD-90], Member
`Timothy McGovern, Ph.D., RFD-170, Alternate Member
`David Morse, PhD. Supervisory Pharmacologist, RFD-150
`Lilliam Rosario, Ph.D., Pharm-Tox Reviewer, HFD-ISO
`
`Author of Draft: Lilliam Rosario, Ph.D.
`
`The following information reflects a brief summary of the Committee discussion and its
`recommendations. Detailed study information can be found in the individual review.
`
`NDA # 21,344
`
`Drug Name: Faslodex (Fulvestrant; ICI 182,780
`Sponsor: Astra Zeneca Pharmaceuticals
`
`Mouse Carcinogenicig Study: Not conducted
`
`Background
`This 2-year carcinogenicity study in rats was submitted to NDA 21,344. This NDA proposes the
`use of ICI 182,780 (fulvestrant) for the
`'pra ft
`a
`
`- I The—recommended dose of Faslodex is 250 mg to be administered intramuscularly (1M)
`monthly.
`
`The Sponsor indicates fulvestrant is an antiestrogenic agent, which acts by downregulation of the
`estrogen receptor (ER). Fulvestrant binds ER in a competitive manner with a high affinity
`comparable to estradiol. Further, the Sponsor suggests that Fulvestrant is a non-agonist
`antiestrogen which blocks the uterotrophic action of estradiol in mice, rats and monkeys without
`itself having any partial agonist estrogen- like activity.
`
`Genotoxicity
`The mutagenic and clastogenic potential of ICI 182,780 has been studied in bacterial mutation
`assays in strains of Salmonella typhimurium and Escherischia coli, an in vitro cytogenetics assay
`in cultured human lymphocytes, a mouse lymphoma mutation assay, and an in viva rat
`micronucleus test. ICI 182,780 has shown no evidence of genotoxic/clastogenic potential in this
`battery of tests.
`
`

`

`Rat Carcinogenicity Study:
`
`Study Design:
`
`0 Dose concurrence was obtained on July 28, 1998.
`o The Sponsor selected the high dose level to represent the maximum possible dose by the IM
`route (maximum feasible dose).
`
`w»
`0 There were 6 groups (50 sex/group); Sprague Dawley rats r —-—-—
`Control-l (C 1):
`Vehicle/ 15 days
`Control-2 (C2):
`Vehicle/30 days
`Control-3 (C3):
`Saline/15 days
`Low Dose (LD):
`15 mg/kg/3O days
`Middle Dose (MD):
`10 mg/rat/30 days
`High Dose- (HD):
`10 mg/rat/ 15 days
`
`The following table shows the ~ actual dose (mg/kg) administered to Groups V (10
`mg/rat/30days) and Group VI (10 mg/rat/l 5 days). For comparison purposes, these values have
`also been normalized for frequency of administration (from every 15 days to every 30 days)
`
`10 m_/rat/30 da 5
`
`10 m rat/15 da s
`
`Week Body
`weight
`
`Body mg/kg/ mg/kg/30
`mg/kg/
`30 days weight
`15 days
`days
`
`
`
`
`
`
`
`Statistical Methods:
`
`0 All tests for tumor incidence were one-sided looking for an increase in response/incidence.
`0 The Haseman (1983) principle of statistical significance was adopted; a rare tumor (<1 %
`spontaneous incidence) will be deemed statistically significant if p<0.05, and a common
`tumor shall be deemed significant if p<0.01.
`0 The statistical comparisons of interest were implemented using Peto’s survival-adjusted trend
`test.
`
`0 Note that the significance values used by the Sponsor are in accordance with those employed
`by CDER when only a single carcinogenicity study is conducted. The probability levels for
`determining significance of tumor incidence has not been adjusted for multiple statistical
`comparisons as would be appropriate to maintain a constant error rate over multiple studies.
`
`

`

`RAT TUMOR FINDINGS:
`
`It appears that the [M administration of IC] 182,780 (fulvestrant) for 24 months increased the
`incidence of ovarian granulosa cell tumors and testicular Leydig cell tumors in female and male
`rats, respectively.
`
`Ovaries:
`
`A 14% increase in the incidence of a rare ovarian granulosa cell tumors in the high dose
`female animals (7/50 rats at 10 mg/rat/l 5d; p=0.01887).
`Spontaneous incidence of granulosa cell tumors for this strain of rat is 0.06% (n=l 729)
`(Giknis and Clifford, 2001 ""'~
`The conducting laboratory reports background instances varying from 0/ 120 to l/ 120 (0.2%).
`Another study (n=4493) with the same strain and source reports 0.3% (Gregson and Abbott,
`1984).
`
`Testes:
`
`There was increase incidence (2-1 2%) of interstitial Leydig cell tumors (adenomas-common)
`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 slightly increased (8-12%) in the two low dose groups.
`In Group 4 (15 mg/kg/3O days), interstitial cell tumors were increased significantly
`(p=0.01922)
`
`Spontaneous incidence for this strain of rat is 2.35%
`
`-————
`
`The reviewer proposed 3 questions for the EXEC CAC committee:
`
`1. Are the survival rates observed in control and drug—treated groups adequate to determine the
`carcinogenic potential of ICI 182,780 (fulvestrant)?
`
`0 Even though survival rates appear lower than expected for control males, the Committee
`agreed that the rate of mortality is adequate to determine the carcinogenic potential of ICI
`182,780.
`
`Does the Committee agree that administration of ICI 182,780 increases the incidence of
`granulosa cell tumors and interstitial Leydig cell tumors?
`
`The Committee
`
`0
`
`0
`
`0
`
`0
`
`agreed that administration of ICI 182,780 increases the incidence of both granulosa cell
`tumors and interstitial Leydig cell tumors, in females and males, respectively.
`recommended the statistical evaluation of these results take into consideration that only
`one carcinogenicity study was submitted.
`
`recommended to carefiilly examine the pharmacological data submitted to support the
`claim that ICI 182,780 is a “non-agonist” antiestrogen. The increase incidence of
`interstitial Leydig cell tumors in males may suggest a drug-induced estrogenic effect.
`noted that while the carcinogenicity study was acceptable, the Sponsor did not perform
`the defining studies for an anti-estrogen to determine if the compound is non-genotoxic.
`
`

`

`The Committee suggested that a 32F post labeling study to determine whether ICI 182,780
`induces DNA adducts.
`
`3. Does the Committee agree that these findings should be included in the product labeling for
`ICI 182,780 (fulvestrant)?
`The Committee agreed that the increase incidence of both granulosa cell tumors and
`interstitial Leydig cell tumors, in females and males, respectively be included in the product
`labeling for ICI 182,780 (fulvestrant).
`
`Additional comments from the Committee:
`The Committee
`
`0
`
`0
`
`pointed out that, unlike tamoxifen, the incidence of liver tumors was not changed in ICI
`182,780-treated rats.
`
`suggested that, since male rats in the high dose group lost weight, the mid-dose male group
`should also be considered in evaluation of carcinogenic response.
`
`Executive CAC Recommendations and Conclusions:
`
`1) Fulvestrant increases the incidence of ovarian granulosa cell tumors in female rats, and the
`incidence of interstitial Leydig cell tumors in male rats.
`2) The increase incidence of granulosa and Leydig cell tumors should be included in the product
`labeling for fulvestrant.
`3) The Committee recommended that the Sponsor be asked to perform 321’ post-labeling study to
`determine if fulvestrant and/or its’ metabolites may form adducts with cellular DNA.
`
`Joseph DeGeorge, Ph.D.
`Chair, Executive CAC
`
`cc:\
`
`/Division File, HFD-ISO
`/David Morse, PhD. Supervisory Pharmacologist, HFD-ISO
`/Lilliam Rosario, Ph.D., Pharm-Tox Reviewer, I-IFD-150
`
`IAmy Baird, HFD-l 50
`/Adele Seifried, HFD-024
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/5/
`
`Joseph DeGeorge
`12/11/01 08:31:08 AM
`
`

`

`MESSFIGE CDNF I RMFIT I ON
`
`82/21/82 89:32
`
`DRTE
`
`82/2 1
`
`S.R—TIME
`
`DISTRNT STRTION ID
`
`NUDE
`
`PRGES
`
`RESULT
`
`8 1 ’ 56 "
`
`8862822
`
`CRLL I N8
`
`86
`
`OK
`
`8888
`
`82/21/82
`
`89:29
`
`NE]. 821
`
`081
`
`FAX
`
`FOOD AND DRUG ADMINISTRATION
`
`DIVISION OF ONCOLOGY DRUG PRODUCTS
`
`Center for Drug Evaluation and Rmh, RFD-150
`5600 Fishers Lane, Rockville, MD 20857
`
`
`
`
`
`To:
`
`B. Jane Valas, PhD.
`
`Worn: Amy Baird, CSO
`
`Fax:
`
`302-886-2822
`
`Fax:
`
`(301) 594-0498
`
`Phone: 302-886-2122
`
`Phone: 301) 594-5771
`
`Pages, including cover sheet:
`
`6
`
`Date: 2-21-02
`
`Re: NBA 21-344 Faslodex. Carcino enicl Review.
`
`THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY 'IO WHOM IT IS ADDRESS!!!) AND MAY CONTAIN
`INFORMATION THAT Is PRIVILEGED, CONFIDENTIAL AND PROTECTED FROM DISCLOSURE UNDER APPLICABLE
`LAW. If you are not Ibo Iddrouoc, or a person unburied to deliver the document In the addrn-ee, you are hereby notified Lhnl any
`review. disclosure, diileminntian or other action band on the content of the communication in not omhorizod.
`If you hove rccoivcd
`
`

`

`FAX
`
`FOOD AND DRUG ADMINISTRATION
`
`DIVISION OF ONCOLOGY DRUG PRODUCTS
`
`Center for Drug Evaluation and Research, HFD-l 50
`5600 Fishers Lane, Rockville, MD 20857
`
`
`
`
`
`
`To:
`E. Jane Valas, PhD.
`From: Amy Baird, CSO
`
`
`Fax:
`302-886-2822
`Fax:
`(301) 594-0498
`
`
`Phone: 302-886-2122
`Phone: (301) 594-5771
`
`
`
`
`
`2Pages, including cover sheet: Date: 2-15-02
`
`Re: NDA 21-344 Faslodex. Repro tox labeling issue.
`THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY T0 WHOM IT IS ADDRESSED AND MAY CONTAIN
`INFORMATION THAT IS PRIVILEGED, CONFIDENTIAL AND PROTECTED FROM DISCLOSURE UNDER APPLICABLE LAW.
`If
`you are not the addressee, or a person authorized to deliver the document to the addressee, you are hereby notified that any review, disclosure,
`dissemination or other action based on the content of the communication is not authorized. If you have received this document in error, please
`immediately notify us by telephone and return it to us at the above address by mail. Thank you.
`
`COMMENTS:
`
`On the following page is a statement from the pharmacology review team regarding Warnings
`section of the labeling. Please call should you have any questions.
`
`Thank you,
`A
`/_.
`
`J}\
`
`Amy Baird
`
`

`

`Page 2
`NDA 21-344
`
`We agree that in this study, the percentage incidence of fetuses and litter with an extra 13‘” rib, in
`both the control and the high dose group, was high possibly indicating a normal variation within
`this strain of rabbits. However, there is a significantly increased fetal incidence of backwards
`displacement of the pelvic girdle in animals treated with 0.25 mg/kg/d fulvestrant [24 out of 102
`fetuses (23.5%) in fulvestrant-treated rabbits compared to 16 out of 152 fetuses (10.1%) in the
`control animals showing a doubling in fetal incidence]. Similarly, there was a significantly
`increased fetal incidence of 27 pre-sacral vertebrae [24 out of 102 fetuses (23.5%) in fulvestrant-
`treated rabbits compared to 19 out of 152 fetuses (12%) in the control animals]. The possibility
`that these results may represent a random effect on variations cannot be examined since you did
`not conduct a full histomorphological assessment of all the doses tested in this study. Thus, the
`increased incidence of the above-mentioned variations should be included in the product label.
`
`Point of clarification, this study in rabbits was considered inadequate to fully define the possible
`adverse effects on fetal development because administration of fulvestrant (up to 0.25 mg/kg/d)
`to pregnant rabbits did not result in any maternal toxicity and you did not evaluate the skeletons
`of fetuses from the lower two dose groups.
`
`Please refer to the Warning section of the label. In the following sentence
`
`i’rofoSQJ Ln be h’nj
`
`We agree that the skeletal effects seen in the drug treated rabbits should be described as in
`‘increased incidence of skeletal variations, '
`'
`..”—-— '
`
`

`

`MESSFIGE CDNF I RMPIT I ON
`
`82/15/82
`
`11 :81
`
`DRTE
`
`82/15
`
`S . R—T I ME
`
`D I STFINT STQT ION 1D
`
`MODE
`
`PQGES
`
`RESULT
`
`88 ’ 49 "
`
`8862822
`
`CFILL 1 N6
`
`82
`
`OK
`
`8888
`
`82/15/82
`
`11:88
`
`FAX
`
`FOOD AND DRUG ADMINISTRATION
`DIVISION OF ONCOLOGY DRUG PRODUCTS
`Center for Drug Evaluation and Research, HFD-ISO
`5600 Fishers Lane, Rockvillc, MD 20857
`
`
`
`
`
`To:
`B. Jane Valas, PhD.
`From: Amy Baird, CSO
`
`
`Fax:
`302-886-2822
`Fax:
`(301) 594-0498
`
`
`Phone: 302-886-2122
`Phone: (301) 594-577 I
`
`
`Date: 2-15-02
`2
`Pages, including cover sheet:
`-—————————_——.—.____________—__________
`
`Re: NBA 21-344 Faandex. Repro tox labeling issue.
`THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY T0 WHOM IT IS ADDRESSED AND MAY CONTAIN
`INFORMATION THAT IS PRMLEGED. CONFIDENTIAL AND PROTECTED FROM DISCLOSURE UNDER APPLICABLE LAW.
`If
`you m not the addressee. m a person authoriud to deliver tha document to the addressee, you are hemby notified that any review, disclosure.
`dissemination or other anion based on the comm om oommunictuicm in not authorized. ”you hlvc received this document in m, please
`immediately notify us by teIephone and mum It to us a: the above addnss by mail. Thank you.
`
`

`

`FAX
`
`FOOD AND DRUG ADMINISTRATION
`
`DIVISION OF ONCOLOGY DRUG PRODUCTS
`
`Center for Drug Evaluation and Research, HFD-l 50
`5600 Fishers Lane, Rockville, MD 20857
`
`
`
`
`
`To:
`
`B. Jane Valas,Ph.D.
`
`From: Amy Baird, CSO
`
`Fax:
`
`302-886-2822
`
`Fax:
`
`(301)594-0498
`
`Phone: 302-886-2122
`
`Phone: (301)594-5771
`
`Pages, including cover sheet:
`
`17
`
`Date: 1-29-02
`
`Re: NDA 21-344 Faslodex. Division of Medication Errors and Technical Support (DMET)
`reviews.
`THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND MAY CONTAIN
`INFORMATION THAT IS PRIVILEGED, CONFIDENTIAL AND PROTECTED FROM DISCLOSURE UNDER APPLICABLE
`LAW. If you are not the addressee, or a person authorized to deliver the document to the addressee, you are hereby notified that any
`review, disclosure, dissemination or other action based on the content of the communication is not authorized.
`If you have received
`this document in error, please immediately notify us by telephone and return it to us at the above address by mail. Thank you.
`
`COMNIENTS:
`
`Regarding the proposed trademark name Faslodex (fulvestrant injection), attached are the DMET
`reviews.
`Ifyou wish DMET to reconsider the acceptability of the name Faslodex, you should respond
`to the concems expressed in the attached reviews with information that shows the improbability of
`
`misadministration. Please call should you have any questions.
`
`Thank you,
`A
`
`Amy Baird
`
`. [8/
`
`

`

`MESSQGE CUNF I RMQT I ON
`
`81/38/82
`
`15:38
`
`DQTE
`
`81/36
`
`SyR—TIME
`
`DISTRNT STRTIUN ID
`
`MODE
`
`PRGES
`
`RESULT
`
`BS’SB”
`
`8862822
`
`CQLLING
`
`17
`
`OK
`
`0088
`
`Q1/3B/B2
`
`15:29
`
`NEBBS
`
`081
`
`FAX
`
`FOOD AND DRUG ADMINISTRATION
`
`DIVISION OF ONCOLOGY DRUG PRODUCTS
`Center for Dmg Evaluation and Rwearch, RFD-150
`5600 Fishers Lane, Rockvillc, MD 20857
`
`
`
`
`
`To:
`B. Jane Valas,Ph.D.
`From: Am Baird, CSO
`
`
`302-886-2822
`Fax:
`(301) 594-0498
`
`
`Phone: 302-886-2122
`
`Phone: (301)594-5771
`
`Pages. including cover sheet:
`
`17
`
`Date: 1-29-02
`
`Re: NBA 21-344 Fulodex. Division of Medication Errors and Technical Support (DMET)
`reviews.—___________——.___.———————————-—-——~——-——-
`THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND MAY CONTAIN
`INFORMATION THAT IS PRIVILEGED. CONFIDENTIAL AND PROTECTED FROM DISCLOSURE UNDER APPLICABLE
`. :.- -- -I.-- -....-.... L---.4 _. .L- ......... .I yL. a--.“nn.5...;M. :. an! ... mad-”A If van in.» m‘w-d
`LAW.
`If.you are not the addrenuc, or I pcnm authorized to deliver the document to the lddreuec, ynu are hereby notified (ha! my
`
`

`

`FAX
`
`FOOD AND DRUG ADMINISTRATION
`
`DIVISION OF ONCOLOGY DRUG PRODUCTS
`
`Center for Drug Evaluation and Research, HFD-l 50
`5600 Fishers Lane, Rockville, MD 20857
`
`
`
`
`
`To:
`
`B. Jane Valas, PhD.
`
`From: Amy Baird, CSO
`
`Fax:
`
`302-886-2822
`
`Fax:
`
`(301) 594-0498
`
`Phone: 302-886-2122
`
`Phone: (301) 594-5771
`
`Pages, including cover sheet:
`
`2
`
`Date: 1-25-02
`
`Re: NDA 21-344 Faslodex. Labeling.
`THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND MAY CONTAIN
`INFORMATION THAT IS PRIVILEGED, CONFIDENTIAL AND PROTECTED FROM DISCLOSURE UNDER APPLICABLE LAW.
`If
`you are not the addressee, or a person authorized to deliver the document to the addressee, you are hereby notified that any review, disclosure,
`dissemination or other action based on the content of the communication is not authorized. If you have received this document in error, please
`immediately notify us by telephone and return it to us at the above address by mail. Thank you
`
`COMMENTS:
`
`The first sentence of the DESCRIPTION section of the labeling reads as follows:
`
`“FASLODEX (fulvestrant) Injection for intramuscular administration is a
`
`.-
`
`FDA Comment: We are not yet convinced that the