CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`
`
`APPLICATION NUMBER:
`203752Orig1s000
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`PHARMACOLOGY REVIEW(S)
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`RESEARCH
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`APPLICATION NUMBER:
`203752Orig1s000
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`PHARMACOLOGY REVIEW(S)
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`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
`
`Indication:
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`
`203752 SS# 0000
`e-submission
`12/29/2011
`12/29/2011
`
`Proposed Proprietary name as
`(Estradiol transdermal system).was considered
`unacceptable by Division of Medication Error
`Prevention & Analysis.
`For treatment of moderate to severe vasomotor
`symptoms associated with menopause
`Noven Pharmaceuticals, Inc, New York, NY
`Applicant:
`Reproductive & Urologic Products
`Review Division:
`Krishan L. Raheja, D. V. M. Ph.D.
`Reviewer:
`Alex Jordan, Ph.D.
`Supervisor/Team Leader:
`Audrey Gassman, M.D.
`Division Director:
`George Lyght, RPh.
`Project Manager:
` Date entered in Darrts 5/9/2012:
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 203752 are owned by Noven Pharmaceuticals Inc. or
`are data for which Noven Pharmaceuticals Inc. has obtained a written right of reference.
`Any information or data necessary for approval of NDA 203752 that Noven
`Pharmaceuticals 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 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 203752.
`
`Reference ID: 3128241
`
`
`
`1
`
`(b) (4)
`
`
`
`NDA # 203752
`
`Reviewer: Krishan L. Raheja, D. V. M., Ph.D.
`
`1
`
`Executive Summary
`
`“m NDA is a 505b(1) application with a right of
`Introduction: The
`1.1
`cross-reference to Novartis’s Vivelle and Vivelle-Dot NDA 20-323 and NBA 20-
`538, respectively.
`m“) is a multipolymeric adhesive, estradiol transdermal
`system (ETS) that releases 17B-estradiol continuously upon application to intact“)
`skin.
`
`WIS-estradiol is the primary estrogenic hormone secreted by the human ovary. Loss of
`ovarian estrrdiol secretion at the onset of menopause or after bilateral oophorectomy is
`associated with vasomotor symptoms as hot flashes and night sweats. Systemic
`hormone therapy is considered as standard therapeutic option for the treatment of hot
`flashes. Treatment of moderate to severe menopausal symptoms is the primary
`indication for systemic hormone therapy.
`
`m" is for the treatment of moderate to severe
`The proposed indication for
`vasomotor symptoms associated with menopause. Data to support the use of
`for the proposed indication comes from previous conducted clinical trials with Vivelle.
`
`(b) (4)
`
`Brief Discussion of Nonclinical Findings: Based on discussion with the
`1.2
`sponsor in a prelND meeting on 9/11/07, it was agreed that no additional
`preclinical studies for
`“m were necessary to support its marketing
`registration because:
`
`(5) (4)
`
`2. Preclinical studies have shown that Vivelle-Dot is neither a primary skin irritant nor a
`dermal sensitizer.
`
`3. The nonclinical pharmacology, pharmacokinetics, and toxicology of 17B—estradiol
`delivered via an estradiol transdermal system are well characterized as summarized in
`the current Package Inserts for Vivelle and Vivelle-Dot.
`
`Reference ID: 31 28241
`
`
`
`2.5 cm2
`3.75 cm2
`5.0 cm2
`7.5 cm2
`10 cm2
`
`
`0.39 mg
`0.585 mg
`0.78 mg
`1.17 mg
`1.56 mg
`
`
`2.48 cm
`3.30 cm2
`4.95 cm2
`6.60 cm2
`
`
`
`0.62 mg
`0.83 mg
`1.24 mg
`1.65 mg
`
`2.17 mg
`3.28 mg
`4.33 mg
`6.57 mg
`8.66 mg
`
` dosage forms:
`
`Vivelle
`
`Vivelle-Dot
`
`
`
`NDA # 203752 Reviewer: Krishan L. Raheja, D. V. M., Ph.D.
`
`
` strengths that have been designed
` is available in
`As shown in table below,
`to deliver the same dosage levels of estradiol as Vivelle-Dot, but from a smaller active
`surface area.
`
`Vivelle, Vivelle-Dot and
`
`Strength
`
`Active surface area/patch size
`7.25 cm2
`0.025 mg/day
`11.0 cm2
`0.0375 mg/day
`14.5 cm2
`0.05 mg/day
`22 cm2
`0.075 mg/day
`29cm2
`0.1 mg/day
`
`
`Estradiol
`content/unit
`0.025 mg/day
`0.0375 mg/day
`0.05 mg/day
`0.075 mg/day
`0.1 mg/day
`
`Note: Vivelle-Dot was approved under NDA 20-538 on 7/31/1996.based on
`bioequivalent to Vivelle. Vivelle was approved under NDA 20-323 on 10/28/1994.
`1.3 Recommendations
`1.3.1 Approvability: Based on the results of the preclinical studies demonstrating
`lack of skin irritation in rabbit and delayed sensitization in guinea pig and patch safety in
`clinical trials, Pharmacology/Toxicology will recommend approved of NDA 203752 for
` for treatment of moderate to severe vasomotor symptoms associated with
`menopause.
`
`1.3.2 Additional Non Clinical Recommendations: None
`
`1.3.3 Labeling: Sponsor has provided Draft Labeling Text
`
`
`Reference ID: 3128241
`
`
`
`3
`
`(b) (4)
`
`(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
`05/09/2012
`
`ALEXANDER W JORDAN
`05/09/2012
`
`Reference ID: 3128241
`
`
`
`45 Day NDA Meeting Checklist
`Pharmacology/1'oxicology
`
`NDA Number:
`
`203752
`
`M“) (estradiol transdermal system)
`Drug Name:
`Sponsor: Noven Pharmaceuticals Inc.
`
`Date: 2—13—2012
`
`Reviewer: Krishan L. Raheja
`
`Date CDER Received: 12-29-2011
`
`Filing Date: 2—27—2012
`User Fee Date:
`
`Expected Date of Draft Review: —
`
`0n initial overview of the Pharm/l‘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?
`
`In a pre—lND meeting on 9-11-2007 it was
`agreed that no additional preclinical studies
`for
`M“) were necessary to support its
`marketing registration because:
`
`1_
`
`(b) (4)
`
`and submitted in this NDA?
`
`2. Preclinical studies have shown that
`
`Vivelle-Dot is neither a primary skin irritant
`nor a dermal sensitizer.
`
`3. The nonclinical pharmacology,
`pharmacokinetics, and toxicology of 176-
`estradiol delivered via an estradiol
`
`transdermal system are well characterized
`and are summarized in the current Package
`Inserts for Vivelle and Vivelle-Dot.
`
`Is the Pharm/Tox section of the NDA
`
`indexed and paginated in a manner to
`allow substantive review to begin?
`
`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: 3086717
`
`
`
`
`
`NA
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`
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`NA
`
`
`
`NA
`
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`YES
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`NO
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`YES
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` 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: 3086717
`
`
`
`---------------------------------------------------------------------------------------------------------
`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
`02/13/2012
`
`ALEXANDER W JORDAN
`02/13/2012
`
`Reference ID: 3086717
`
`
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