CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`022501Orig1s000
`
`
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`

`

`Reviewer: Krishan L. Raheja, D.V.M., Ph.D.
`
`
`
` NDA No. 22501.000
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`
`
`
`
`
`
`
`
`
`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
`
`
`22-501
`000
`3/26/09
`
`
`
`
`
`
`
`
`
`NDA NUMBER:
`
`
`SERIAL NUMBER:
`DATE RECEIVED BY CENTER:
`
`PRODUCT:
`
`
`
`Prevention of pregnancy
`INTENDED CLINICAL POPULATION:
`Warner Chilcott Company Inc. Fajardo, PR
`
`SPONSOR:
`
`
`
`Vol. 1.1 – 1.3
`
`DOCUMENTS REVIEWED:
`
`Division of Reproductive and Urologic products
`
`REVIEW DIVISION:
`
`
` (HFD- 580)
`PHARM/TOX REVIEWER:
`
`
`Krishan L. Raheja, D.V.M., Ph.D.
`PHARM/TOX SUPERVISOR:
`
`
`Lynnda Reid, Ph.D.
`Scott Monroe, M.D.
`DIVISION DIRECTOR:
`
`
`
`Karl Stiller
`PROJECT MANAGER:
`
`
`
`
`Date of review submission to Division File System (DFS): 6-15-09
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1
`
`(b) (4)
`
`

`

`Reviewer: Krishan L. Raheja, D.V.M., Ph.D.
`
`
` EXECUTIVE SUMMARY
`
`I.
`
`
`Recommendations
`
` NDA No. 22501.000
`
`
`
`
`II.
`
`
`
`
`
`
`
`
`
`
`
`
`
`A. Recommendation on approvability: Pharmacology/toxicology data support
`approval of NDA 22-501 for
` for contraception.
`
`
`B. Recommendation for nonclinical studies: All pharmacology/toxicology data
`were reviewed under the sponsor’s approved NDA 21-871 for Loestrin® 24
`Fe (norethindrone acetate and ethinyl estradiol tablets, USP and ferrous
`fumarate tablets) for the contraception indication.
`
`C. Recommendations on labeling: As required the Labeling is in accordance with
`PLR and provided in SPL format.
`
`Summary of nonclinical findings:
`
`A. Brief overview of nonclinical findings: There are no new nonclinical findings.
`The safety of norethindrone acetate and ethinyl estradiol at concentrations of
`1.0 mg and 0.010 mg, respectively, have been established in previously
`conducted nonclinical and clinical studies.
`
`B. Pharmacologic activity: Norethindrone acetate is a progestin and ethinyl
`estradiol an estrogen.
`
`C. Nonclinical safety issues relevant to clinical use: None
`
`
`
`
`2
`
`(b) (4)
`
`

`

`Reviewer: Krishan L. Raheja, D.V.M., Ph.D.
`
`
`
` NDA No. 22501.000
`
`2.6 PHARMACOLOGY/TOXICOLOGY REVIEW
`
`
`2.6.1 INTRODUCTION AND DRUG HISTORY
`
`NDA number: 22-501
`Review number: 1
`Sequence number/date/type of submission: 000/3-25-09/original submission
`Information to sponsor: Yes ( ) No ( *)
`Sponsor and/or agent: Warner Chilcott Company Inc. Fajardo, Pueto Rico/
` Warner Chilcott (US), LLC Rockaway, New Jersey
`
`Manufacturer for drug substance: Norethindrone acetate and Ethinyl estradiol by
`
`
`
`.
`
`
`
`
`
`
`
`
`
`
`
`
`
`CAS Registry
`No.
`51-98-9
`
`Emperical
`formula
`C22H28O3
`
`57-63-6
`
`C20H24O2
`
`Molecular
`weight
`340.46
`
`296.40
`
`
`Reviewer name: Krishan L. Raheja, D.V.M., Ph.D.
`Division name: Reproductive and Urologic Products
`HFD #: 580
`
`Review completion date: 5-5-09
`
`Drug:
`
`Trade name:
`
`Generic name: Norethindrone acetate (NA) and ethinyl estradiol (EE)
`
` (1 mg NA/10 ug EE, 10 ug EE) tablets
`Code name: -
`
`
`
`
`Chemical name, CAS registry number and molecular formula/molecular weight
` are provided in the following table:
`
`Drug
`
`Norethindrone
`acetate
`Ethinyl
`estradiol
`
`
`Relevant INDs/NDAs/DMFs: IND 73,510; NDA 21-871
`
`Drug class: Norethindrone acetate, a progestin and Ethinyl estradiol, an estrogen
`
`Intended clinical population: Prevention of pregnancy
`
`Clinical formulation: Tablets
`
`Route of administration: Oral
`
`
`
`Chemical name
`
`19-Norpregn-4-en-20-yn-3-one,
`17-(acetyloxy)-, (17α)
`19-Norpregna-1,3,5(10)-trien-20-
`yne—3,17-diol, (17α)-
`
`
`
`
`3
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

` NDA No. 22501.000
`
`Reviewer: Krishan L. Raheja, D.V.M., Ph.D.
`
`
`Disclaimer: Tabular and graphical information are constructed by the reviewer unless
`cited otherwise.
`
`Data reliance: Except as specifically identified below, all data and information
`discussed below and necessary for approval of NDA 22-501 are owned by Warner
`Chilcott Company Inc. or are data for which Warner Chilcott Company Inc. has obtained
`a written right of reference. Any information or data necessary for approval of NDA 22-
`501 that Warner Chilcott, Inc. 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 described in the drug’s approved labeling.
`Any data or information described or referenced below from a previously approved
`application that Warner Chilcott, Inc. does not own (or from FDA reviews or summaries
`of a previously approved application) is for descriptive purposes only and is not relied
`upon for approval of NDA 22-501.
`
`Studies reviewed within this submission: None. All pharmacology/toxicology studies
`were referenced to the sponsor’s approved NDA 21-871 for Loestrin ® 24 (norethindrone
`acetate/ethinyl estradiol) tablets for contraception.
`
`Studies not reviewed within this submission: none
`
`
`
`OVERALL CONCLUSIONS AND RECOMMENDATIONS
`
`Conclusions: There are no safety concerns as the sponsor’s product Loestrin® 24 has
`been previously approved for contraception under NDA 21-871. Both products have the
`same active ingredients. The amount of norethindrone acetate is 1 mg/tablet for both
`Loestrin® 24 and
` However, while the amount of ethinyl estradiol is 20
`ug/tablet in the approved Loestrin® 24, it is reduced to 10 ug under NDA 22-501. The
`dosing regimen for both formulations consists of continuous dosing for 24 consecutive
`days followed by 4 days on placebo tablets containing 75 mg ferrous fumarate. The
`safety of inactive ingredients in
` is established by showing that the
`quantity of inactive ingredients used in the manufacture of tablets is below the maximum
`potency outlined in FDA’s Inactive Ingredients Database or otherwise that the inactive
`ingredients are generally recognized as safe per 21 CFR regulations.
`
`Unresolved toxicology issues (if any): None
`
`Recommendations: Pharmacology /toxicology data support approval of NDA 22-501.
`
`Suggested labeling: Suggested Labeling is in accord with PLR and provided in SPL
`format. Section No. 13 Nonclinical toxicology and 13.1 Carcinogenesis, Mutagenesis and
`Impairment of Fertility were not included in the draft labeling, which is mandatory and
`needs to be included. Sponsor will need to provide recommended labeling consistent with
`other combined oral contraceptives.
`
`
`
`
`4
`
`(b) (4)
`
`(b) (4)
`
`

`

`Reviewer: Krishan L. Raheja, D.V.M., Ph.D.
`
`
`
`
` NDA No. 22501.000
`
`
`
`
`5
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`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
`6/16/2009 01:17:01 PM
`PHARMACOLOGIST
`
`Lynnda Reid
`6/22/2009 01:37:18 PM
`PHARMACOLOGIST
`
`

`

`ITEM
`
`
`
`1)
`
`
`On its face, is the Pharm/Tox section of
`the NDA organized in a manner to allow
`substantive review to begin?
`
`
`YES / NO
`
`Yes
`
`COMMENTS
`In lieu of nonclinical P/T information,
`sponsor has made reference toWarner
`Chilcott NDA 21-871 for Loestrin® 24 Fe
`(norethindrone acetate and ethinyl estradiol
`tablets, USP and ferrous fumerate tablets)
`which is an approved oral contraceptive
`containing NA and EE. It is low dose
`contraceptive consisting of new dose with
`less EE and new regimen of the
`combination of NA and EE.
`
`
`45 Day NDA Meeting Checklist
` Pharmacology/Toxicology
`
`Date: 4-22-09
`Reviewer: Krishan L. Raheja
`
`
`NDA Number: 22-501
`Drug Name:
`
`Sponsor: Warner Chilcott Company, Inc.
`
`Date CDER Received: 3-26-09
`Filing Date: 5-25-09
`User Fee Date:
`Expected Date of Draft Review:
`
`On initial overview of the Pharm/Tox portion of the NDA application
`
`
`
`NA
`
`NA
`
`NA
`
`NA
`
` 2)
`
`Is the Pharm/Tox section of the NDA
`indexed and paginated in a manner to
`allow substantive review to begin?
`
` 3) 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?
`
`
`
`
` 4) Are all necessary and appropriate studies
`for this agent, including special
`studies/data requested by the Division
`during pre-submission
`communications/discussions, completed
`and submitted in this NDA?
`
`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?
`
`
`
`
`
` 5)
`
`
`
`
`
`
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`
`
`
`No. 13 Nonclinical toxicology and 13.1
`Carcinogenesis, Mutagenesis and
`Impairment of Fertility which are not
`included in the draft label, need to be
`included or explained.
`
`
`
`NA
`
`NA
`
`NA
`
`Yes
`
`
`No
`
`
`
`
`NA
`
`Yes
`
` 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:
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`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
`4/30/2009 11:51:20 AM
`PHARMACOLOGIST
`
`Lynnda Reid
`4/30/2009 12:16:02 PM
`PHARMACOLOGIST
`
`