CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`204654Orig1s000
`
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`204654Orig1s000
`
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`MEMO
`
`
`
`
`Division of Reproductive and Urologic Products
`Center for Drug Evaluation and Research
`
`
`
`
`
` FOOD AND DRUG ADMINISTRATION
`
`
`Date: 5/16/2013
`Reviewer: Alex Jordan, PhD
`
`
`
`
`NDA #/SS#/date: 204654
`
`Sponsor: Warner Chilcott
`
`
`
`
`
`Drug Product: Norethindrone acetate/ethinyl estradiol/FE tablets
`
`
`
`Indication: Contraception
`
`Recommended Action: Approval
`
`
`
`Background: I agree with the primary reviewer Dr. Raheja that NDA 204654 is approvable for
`contraception from a pharmacology standpoint.
`
`
`
`
`
`Reference ID: 3309616
`
`1
`
`
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ALEXANDER W JORDAN
`05/16/2013
`
`Reference ID: 3309616
`
`
`
`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA/BLA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`
`204654
`e-submission
`9/27/2012
`9/28/2012
`Norethindrone acetate NA) / Ethinyl estradiol
`(EE)/FE tablets
`
`Prevention of pregnancy
`Indication:
`Applicant: Warner Chilcott
`Review Division:
`RUDP
`Reviewer:
`Krishan L. Raheja, D.V.M., Ph.D.
`Supervisor/Team Leader:
`Alex Jordan, Ph.D.
`Division Director:
`Hylton, Joffe, M.D. MMSc
`Project Manager:
`Pamela K. Lucarelli
`Review entered in DARRTS: 4/19/2013
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 204654 are owned by Warner Chilcott or are data for
`which Warner Chilcott has obtained a written right of reference.
`Any information or data necessary for approval of NDA 204654 that Warner Chilcott
`does not own or have a written right to reference constitutes one of the following: (1)
`published literature, or (2) a prior FDA finding of safety or effectiveness for a listed drug,
`as reflected in the drug’s approved labeling. Any data or information described or
`referenced below from reviews or publicly available summaries of a previously approved
`application is for descriptive purposes only and is not relied upon for approval of NDA
`204654.
`
`Reference ID: 3296075
`
`1
`
`(b) (4)
`
`
`
`NDA/BLA # 204654Reviewer: Krishan L. Raheja, D.V.M., Ph.D.
`
`
`1
`
`Executive Summary
`
`Introduction: This NDA provides for a new method of administration for a low
`1.1
`dose oral contraceptive consisting of one chewable tablet containing 1 mg
`norethindrone acetate and 10 ug ethinyl estradiol (
`1/10 chewable tablets)
`taken daily for 24 days followed by one tablet containing 10 ug ethinyl estradiol alone
`taken daily for 2 days, and one ferrous fumarate tablet taken daily for 2 days to facilitate
`28-day regimen.
`1/10 chewable tablets may be
` chewed before
`swallowing and followed with liquid; the 4 remaining tablets are swallowed. In lieu of
`nonclinical pharmacology and toxicology information, this application makes reference
`to sponsor’s NDA 022501 approved on 10/20/2010 for Lo Loestrin Fe which consists of
`the same regimen and daily doses of active ingredients as in
` but in which all
`28 tablets are swallowed.
`
`Brief Discussion of Nonclinical Findings: All nonclinical pharmacology/toxicology
`1.2
`information referred to sponsor’s approved NDA 022501 for Lo Loestrin Fe.
`
`1.3 Recommendations:
`
`1.3.1 Approvability: Pharmacology/Toxicology recommends approval of
`under NDA 204654 for the indication of prevention of pregnancy
`
`1.3.2 Additional Non Clinical Recommendations: None
`
`1.3.3 Labeling: Sponsor has provided drug label in PLR format which is acceptable
`from the Pharmacology/Toxicology perspective.
`
`
`
` Drug Information
`
` 2
`
`2.1 Drug
`CAS Registry Number (Optional)
`
`For norethindrone acetate CAS number: 51-98-9
`For ethinyl estradiol CAS number: 57-63-6
`
`Generic Name: Norethindrone acetate, ethinyl estradiol, ferrous fumarate
`
`Code Name:
`
`
`
`
`Reference ID: 3296075
`
`2
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`
`
`NDA/BLA # 204654Reviewer:
`
`Krishan L. Raheja, D.V.M., Ph.D.
`
`Chemical Name:
`
`For norethindrone acetate- 19-Norpregn-4-en-20-yn-3-one, 17-(acetyloxy- (1 7a)
`1 7—Hydroxy—19—nor—1 7a—pregn—4-en—20—yn-3-one acetate
`
`For ethinyl estradiol
`
`19- Norpregna-1 ,3,5(10)-trien-20-yne-3,17—diol, (17a)-
`19-No-17a-pregna-1 ,3,5(10)-trien-20-yne-3,17-diol
`
`Molecular Formula/Molecular Weight
`
`For norethindrone acetate- C22 H28 03 (340.46)
`For ethinyl estradiol- C20 H24 02 (296.40)
`
`Structure or Biochemical Description: Norethindrone acetate/ethinyl estradiol is an oral
`contraceptive.
`
`Pharmacologic Class: Norethindrone acetate is a progestin and ethinyl estradiol is an
`estrogen
`
`Relevant INDs, NDAs, BLAs and DMFs : NDA 022501 (Lo Loestrin, which has the same
`daily doses as
`M". DMF
`“m for norethindrone
`acetate USP); DMF
`“m for ethinyl estradiol; DMF
`for norethindrone acetate); DMF
`M" for ethinyl
`
`(”"9
`
`estradiol).
`
`Warner Chilcott has also referred to their other approved NDAs using active ingredients
`as in
`“M tablets shown in table below:
`
`Reference ID: 3296075
`
`
`
`NDA/BLA # 204654Reviewer: Krishan L. Raheja, D.V.M., Ph.D.
`
`
`Warner Chilcott NDAs Using Active Ingredients in
`
`Inactive ingredients
`
`Product
`
`Regimena
`NA(mg) / EE(mg)
`
`Indication(s)
`
` Tablets
`
`NDA 022501
`
`Lo Loestrin Fe
`
`1 / 0.10x 24 days
`0 / 0.10 x 2 days
`
`Prevention of pregnancy
`
`NDA 21-871
`
`NDA 17-876
`
`NDA 17-875
`
`NDA 17-354
`
`NDA 17-355
`
`NDA 20-130
`
`Loestrin 24 Fe
`
`1 / 0.020x 24 days
`
`Prevention of pregnancy
`
`Loestrin 21
`
`1 / 0.020 x 21 days
`
`Prevention of pregnancy
`
`Loestrin 21 1.5/30
`
`1.5 / 0.030 x 21 days
`
`Prevention of pregnancy
`
`Loestrin Fe
`
`1 / 0.020 x 21 days
`
`Prevention of pregnancy
`
`Loestrin Fe 1.5/30
`
`1.5 / 0.030 x 21 days
`
`Prevention of pregnancy
`
`Estrostep® Fe
`
`1 / 0.020 x 5 days
`1/ 0.030 x 7 days
`1 / 0.035 x 9 days
`
`1 / 0.020 x 5 days
`1/ 0.030 x 7 days
`1/ 0.035 x 9 days
`
`0.5 /0.0025 x 28 days
`1/ 0.005 x 28 days
`
`Prevention f pregnancy
`
`Prevention of pregnancy
`
`Treatment of vasomotor
`symptoms
`Prevention of
`osteoporosis
`
`
`
`Estrostep Fe
`
`NDA 21-065
`
`Femhrt®
`
`
`
`2.3 Drug Formulation: Tablets
`
`2.4 Comments on Novel Excipients: None
`
`Inactive ingredients: All inactive ingredients in
` 1/10 chewable tablets,
`WC3016 EE10 tablets and ferrous fumarate tablets are described as either compendial
`or generally recognized as safe per 21 CFR regulations and are listed in the FDA
`Inactive Ingredients Database, which provides the maximum amount of inactive
`ingredient for each route/dosage form of FDA-approved drug products containing that
`ingredient. As shown in tables below, all inactive ingredients in
`1/10 chewable
`tablets, WC3016 EE10 tablets and ferrous fumarate tablets have quantities equal to or
`below those listed in the database for a chewable oral tablet or an oral tablet.
`
`Reference ID: 3296075
`
`4
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`
`
`NDA/BLA # 204654Reviewer:
`
`Krishan L. Raheja, D.V.M., Ph.D.
`
`Quantities of inactive ingredients in
`
`m" 1 I10 chewable tablets
`
`Quantity per
`M" 1/10 tablet
`
`Maximum potency
`in FDA database
`
`(ma)
`
`m
`
`(ma)a
`
`"”‘"
`
`Inactive ingredient
`
`Mannitol, USP
`Mannitol, USP
`Microcrystalline cellulose, NF
`
`“M"
`(”"9
`
`"M"
`
`
`
`FD&C Blue No. 1 aluminum Lake
`
`Sodium starch cl colate, NF
`Magnesium stearate, NF
`Povidone, USP
`Vitamin E, USP
`Lactose monoh drate, NF,
`S earmint flavor
`
`Sucralose, NF
`
`
`
`“M"
`"'""
`“m
`
`a For an uncoated chewable tablet unless otherwise noted.
`
`b maximum potency for an oral tablet (not available for an uncoated, chewable tablet)
`
`Quantities of inactive ingredients in WC3016 EE10 tablets
`
`Inactive ingredient
`
`Mannitol, USP
`Mannitol, USP
`Microcrystalline cellulose, NF
`
`W”
`“M"
`
`“M"
`
`
`
`Sodium starch l colate, NF
`
`Quantity per
`WC3016 EE10
`tablet (ma)
`“M"
`
`Maximum potency
`in FDA database
`8
`(W,
`
`Manesium strearte, NF
`“9‘"
`Povidone, USP
`“"0
`Vitamin E, USP
`(W)
`Lactose monoh drate,
`a for a tablet unless otherwise noted
`
`
`
`
`
`Quantities of inactive ingredients in ferrous fumarate tablets
`
`Inactive ingredient
`
`Ferrous fumarate, USP
`
`Mannitol, USP
`
`Quantity per ferrous Maximum potency
`fumarate tablet (mg)
`in FDA database
`m a
`
`Reference ID: 3296075
`
`
`
`
`
`
`
`NDA/BLA # 204654Reviewer: Krishan L. Raheja, D.V.M., Ph.D.
`
`Povidone, USP
`Microcrystalline cellulose, NF
`
`Sodium starch glycolate, NF
`Magnesium stearate, NF
`Sucralose, NF
`Spearmint flavor
`a for an oral tablet unless otherwise specified
`b maximum potency for povidone
`
`2.5 Comments on Impurities/Degradants of Concern: None
`
`Proposed Clinical Population and Dosing Regimen: Clinical population will
`2.6
`include women who want to use low dose COC. The dosing regimen consists of a
`chewable tablet containing 1 mg NA and 10 ug EE taken daily for 24 days followed by
`one tablet containing 10 ug EE alone taken daily for 2 days, and one ferrous fumarate
`tablet (placebo) taken daily for 2 days to complete 28-day regimen.
`
`2.7 Regulatory Background: -
`
`Studies Submitted: None. All referred to NDA 022501 for Lo Loestrin Fe.
`
`
`
` 3
`
`
`12 Appendix/Attachments: None
`
`
`
`Reference ID: 3296075
`
`6
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`KRISHAN L RAHEJA
`04/19/2013
`
`ALEXANDER W JORDAN
`04/19/2013
`
`Reference ID: 3296075
`
`
`
`NDA Number: 204654
`
`Date: 10-1 1-2012
`
`45 Day NDA Meeting Checklist
`Pharmacology/1'oxicology
`
`”(o
`
`Reviewer: Krishan L. Raheja
`
`Drug Name: Norethindrone acetate/EE/FE
`Sponsor: Warner Chilcott
`
`Date CDER Received: 9-28-2012
`
`Filing Date: 11-12-2012
`User Fee Date: 7-28-2013
`
`Expected Date of Draft Review: 3-15-2013
`
`0n initial overview of the Pharmfl‘ox portion of the NDA application
`
`On its face, is the Pharm/Tox section of
`the NDA organized in a manner to allow
`substantive review to begin?
`
`Is the Pharm/Tox section of the NDA
`
`indexed and paginated in a manner to
`allow substantive review to begin?
`
`This NDA provides for a new method of
`administration for low dose 0C consisting
`of one chewable tablet containing 1 mg
`NETA and 10 ug EE
`”(4) 1/10) taken
`daily for 24 days followed by one tablet
`containing 10 ug EE alone taken daily for 2
`days, and one ferrous fumarate tablet taken
`daily for 2 days to facilitate 28-day
`regimen.
`(m4) 1/10 chewable tablets
`may be
`“@chewed before
`swallowing and followed with liquid; the 4
`remaining tablets are swallowed. In leu of
`nonclinical pharmacology and toxicology
`information, this application makes
`reference to sponsor’s NDA 022501
`approved on 10/20/2010 for Lo Loestn'n Fe
`which consists of the same regimen and
`daily doses of active ingredients as in
`0"“) but in which all 28 tablets are
`swallowed.
`
`and submitted in this NDA?
`
`On its face, is the Pharm/Tox section of
`the NDA legible so that substantive
`review can being? Has the data been
`presented in an appropriate manner?
`
`Are all necessary and appropriate studies
`for this agent, including special
`studies/data requested by the Division
`during pre-submission
`communications/discussions, completed
`
`Reference ID: 3203204
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`NA
`
`
`
`
`
`
`NA
`
`
`
`NA
`
`
`
`NA
`
`
`Yes
`
`
`Yes
`
`
`
`NA
`
`
`YES
`
` 5)
`
`If the formulation to be marketed is not
`identical to the formulation used in the
`toxicology studies (including the
`impurity profiles), has the Sponsor
`clearly defined the differences and
`submitted reviewable supportive data?
`
`
`
`
` 6) Does the route of administration used in
`animal studies appear to be the same as
`the intended human exposure? If not,
`has the sponsor submitted supportive
`data and/or an adequate scientific
`rationale to justify the alternative route?
`
` 7) Has the sponsor submitted a statement(s)
`that all the pivotal Pharm/Tox studies
`have been performed in accordance with
`the GLP regulations (21 CFR 58) or an
`explanation for any significant
`deviations?
`
` 8) Has the sponsor submitted a statement(s)
`that the Pharm/Tox studies have been
`performed using acceptable, state-of-the-
`art protocols which also reflect agency
`animal welfare concerns?
`
` 9) Has the proposed draft labeling been
`submitted?
`
`Are the appropriate sections for the
`product included and generally in
`accordance with 21 CFR 201.57?
`
`Is information available to express
`human dose multiples in either mg/m2 or
`comparative serum/plasma AUC levels?
`
`10) From a Pharm/Tox perspective, is this
`NDA fileable? If not, please state in
`item #11 below why it is not.
`
`11) Reasons for refusal to file:
`
`
`
`
`
`
`
`
`
`Reference ID: 3203204
`
`
`
`
`
`
`Reference ID: 3203204
`Reference ID: 3203204
`
`
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`KRISHAN L RAHEJA
`10/15/2012
`
`ALEXANDER W JORDAN
`10/15/2012
`
`Reference ID: 3203204
`
`
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