CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`
`APPLICATION NUMBER:
`203752Orig1s000
`
`
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`

`

`Biopharmaceutics Review Addendum
`Office of New Drug Quality Assessment
`
`
`
`Strength(s), and Dosing Regimen:
`
`0.1, 0.075, 0.05, 0.0375.
`twice weekl
`
`mg/day;
`
`Indication: Treatment of moderate to severe vasomotor
`
`symptoms (VMS) associated with
`meno o ause
`
`0ND Division: D1v1310n of Reproductlve and Urologrc
`Products (DRUP)
`
`Reviewer Ta ash Ghosh, Ph.D.
`
`'
`
`SYNOPSIS
`
`Submission: This is an addendum to the original Biopharmaceutics review for NDA 203-
`752 for Minivelle (estradiol) Transdennal System (see Biopharmaceutics review by Dr.
`Tapash Ghosh dated August 20, 2012, in DARRTS).
`
`The following comments were included in that original review and were discussed
`subsequently with the Applicant in a tele-conference held on September 11, 2012. This
`addendum captures the Applicant’s acknowledgment and agreement on these issues as
`submitted officially under SDN-012 on September 17, 2012.
`
`1.
`
`In Vitro Drug Release Method and Acceptance Criteria
`. The following drug release method and acceptance criteria are acceptable on an
`interim basis.
`
`Acceptance Criteria
`Apparatus
`
`
`Ll/L2/L2 testing
`
`USP
`
`Apparatus 6
`
`2 hr: W"
`
`MM)
`6 hr:
`18 hr: TBD (report value)
`24 hr: W"
`900 ml: 0.05 mg/24 hr and
`0.075 my24 hr, 0.1 mg/24 hr 36 hr: TBD (report Value)
`
`Refer to USP <724> for
`
`. The Applicant will also collect drug release profile data for the additional 18 and
`36 hours time-points for the registration batches starting at the next scheduled
`stability time-point and for the upcoming validation batches. The extension of the
`
`Reference ID: 31 90608
`
`

`

` of drug can be consistently
`
` will
`
`collection period to 36 hrs will ensure that
`achieved.
`(cid:131) The Applicant will also investigate whether an
`result in a higher release rate with
`of drug being released in a shorter
`sampling period, without loosing the discriminating ability.
`(cid:131) The drug release data collected during the first year from approval date will be
`used for the setting of the final acceptance criteria.
`(cid:131) The collected data and a proposal for the final drug release method and acceptance
`criteria should be submitted to FDA within fifteen months from approval date, under
`a prior approval supplement (PAS) to the NDA.
`(cid:131) Upon review of the data provided in the PAS, the drug release methodology and
`acceptance criteria for Minivelle TDS will be finalized,
`
`
`
`Review: In the official submission SDN-012 dated September 17, 2012, the Applicant
`confirmed the following commitments:
`
`
`(cid:190) In the IR Response dated 31-Jul-2012 Noven agreed “to add drug release
`sampling timepoints at 18 and 36 hours.” “We agree to collect 18 and 36 hour
`data starting at the next stability timepoint and for the upcoming validation
`batches.” Noven further agrees to collect dissolution data including the 18 and 36
`hr timepoints for 12 months. By the end of 15 months, Noven will submit the
`dissolution data, proposed acceptance criteria, and justification as a
`postapproval supplement.
`
`
`
`(cid:190) Noven commits to evaluating the release rate method suggestion provided by the
`
`Agency in the IR dated 13-Jul-2012. This consists of
`The results of this evaluation will also be included
`in the post approval supplement planned for submission in 15 months.
`
`
`Reviewer’s Comment: The above agreements are acknowledged by the reviewer and are
`acceptable.
`
`Recommendation: The Applicant’s commitments described above will be revisited upon
`submission of their responses 15 months from the time of approval. Overall, from the
`Biopharmaceutics perspective, NDA 203-752 for
` different strengths of Minivelle
`(estradiol) Transdermal System is recommended for APPROVAL.
`
`
`------------------------------------------------------
`Tapash K. Ghosh, Ph. D.
`Primary Biopharmaceutics Reviewer
`Office of New Drug Quality Assessment
`
`
`
` --------------------------------------------------
`Angelica Dorantes, Ph. D.
`Biopharmaceutics Team Leader
`Office of New Drug Quality Assessment
`
`
`
`
`
`
`Reference ID: 3190608
`
`2
`
`(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/
`----------------------------------------------------
`
`TAPASH K GHOSH
`09/18/2012
`
`ANGELICA DORANTES
`09/18/2012
`
`Reference ID: 3190608
`
`

`

`Biopharmaceutics Review
`Office of New Drug Quality Assessment
`
`'
`
`Strength(s), and Dosing Regimen:
`
`0.1, 0.075, 0.05, 0.03 75,
`twice weekl
`
`mg/day;
`
`
`
`Indication: Treatment of moderate to severe vasomotor
`
`symptoms (VMS) associated with
`meno o ause
`
`0ND Division: Division of Reproductlve and Urologic
`Products (DRUP)
`
`Reviewer Ta ash Ghosh, Ph.D.
`
`SYNOPSIS
`
`Submission: On 12/29/2011, Noven Pharmaceuticals submitted NDA 203—752 seeking
`approval of Minivelle (17B-estradiol [E2]) Transdermal System for the treatment of
`moderate to severe vasomotor symptoms (VMS) associated with menopause with a right
`of cross—reference to NDA 20-323 Vivelle (approved on 10/28/1994) and NDA 20-538
`for Vivelle—Dot (approved on 7/31/1996) from Novartis. Vivelle and Vivelle-Dot are E2
`transdermal systems manufactured by Noven Pharmaceuticals Inc. and marketed by
`Novartis. Minivelle is a revised formulation with a smaller active surface area compared
`to the approved products Vivelle and Vivelle-Dot.
`
`M“) dosing strengths of Minivelle are proposed to provide nominal doses of mu),
`0.0375, 0.05, 0.075, or 0.1 mg of E2 per day via the skin. Each corresponding system has
`an active Sluface area of mm), 2.48, 3.30, 4.95, or 6.6 cm2 and contains mu), 0.62, 0.83,
`1.24, or 1.65 mg of E2 USP, respectively.
`
`Review: The Biopharmaceutics review is focused on the evaluation and acceptability of the
`data supporting: (l) the proposed in vitro drug release methodology and acceptance criteria,
`and (2) the biowaiver request for the lower strengths of Minivelle Transdermal System.
`
`SUNIMARY OF FINDINGS AND CONCLUSIONS
`
`The safety and efficacy of Minivelle was bridged from Vivelle via a bioequivalence (BE)
`study using the highest strength of the proposed Minivelle and the approved Vivelle
`transdermal systems (Study N28-004: Single-dose, 2-way crossover BE study in 100
`healthy, nonsmokingpostmenopausal women).
`
`Reference ID: 31 76963
`
`

`

`Excerpts from Clinical Pharmacology review by Chongwoo Yu, Ph. D. is described
`below:
`
`Dr. Yu’s BE analysis results are summarized in Table 1 below:
`
`Table l: Reviewer 5 Baseline Couected E2 BE Anal sis Results (N:96)
`
`
` 30.791. 7%
`108.8%
`84.5%
`84.5‘3";
`86.1‘30
`9Ratio ofLSMal
`
`102-4 115 6°
`
`794.290 3%
`
`79.-.290 3%
`0) (4)
`A) “van: (Bl) X 100.
`
`Caloulated using least-«wanes means according to the formula: e[
`b
`90% Geometric Confidence [men's] using ln-tmnsfmmed data.
`
`For baseline corrected E2, the 90% geometric confidence intervals (CI) are within the BE
`acceptance range (i.e., 80.00-125.00%) for AUCg4 and Cmax but not for AUClzo and
`AUC”. There is a shifi towards slightly lower exposure from Minivelle (Test) compared
`to Vivelle (Reference) for AUC120 and AUCinf. Considering that the patch was applied for
`the duration for 84 hours in this study, this reviewer finds the BE assessment based on
`AUCg4 rather than AUC120 or AUC“ to be more clinically relevant as AUC120 or AUCinf
`include time points that belong to the post-removal period.
`
`Overall, Dr. Yu concludes that BE between Minivelle (1.65 mg E2/6.6 cm2) and
`Vivelle® (8.66 mg E2/29 cm2) has been established regarding Cmax and AUC following
`a single dose administration for 84 hours to the lower abdomen in postmenopausal
`women.
`
`The applicant also conducted a dose proportionality study to support their biowaiver
`request for doses lower than 0.1 mg/day. Baseline corrected AUC84 and Cmax increased
`linearly and E2 were found to be dose proportional among the 3 nominal doses of 0.025
`mg/day, 0.05 mg/day, and 0.1 mg/day following a single dose of Minivelle in a three-way
`crossover study in postmenopausal women (see Clinical Pharmacology review).
`
`To support the approval of the biowaiver request for the proposed mu) lower strengths of
`Minivelle, the Applicant submitted the following information:
`
`(1) Establishment of BE to Vivelle at the highest strength of 0.1 mg/day;
`(2) Establishment of dose proportionality over the dose range of 0.025 - 0.1 mg/day;
`(3) Proportional composition of the formulations for the different doses of Minivelle; and
`(4) Comparable in vitro dissolution profiles for all the strengths of Minivelle (12 > 50).
`
`RECOMMENDATION:
`
`ONDQA-Biopharmaceutics has evaluated the information provided in NDA 203-3 72 for
`Minivelle (estradiol) Transdennal System and has the following cements:
`
`1. Biowaiver Request
`I The in vitro drug release profile of each one of the lower strengths of Minivelle
`TDS was compared vs. the drug release profile of the highest strength (6.6 cm2 vs.
`
`Reference ID: 31 76963
`
`

`

`(am)
`4.95 cmz, 6.6 cm2 vs. 3.3 cm2, 6.6 cm2 vs. 2.475 cm2, and 6.6 cm2 vs.
`The release profiles are similar in shape and met the criteria for similarity (f 1 and
`f2 factors).
`
`I The results from the BE study and similarity 12 test support the Applicant’s
`request for a BA/BE waiver for the proposed lower strengths of Minivelle
`transdermal and the biowaiver is granted.
`
`2.
`
`In Vitro Drug Release Method and Acceptance Criteria
`I The following drug release method and acceptance criteria are acceptable on an
`interim basis.
`
`Apparatus
`
`Cylinhnder Medium
`
`Acceptance Criteria
`
`Volume USP
`
`Apparatus 6
`
`Water at
`32°C
`
`(b) (4)
`M“)
`6 hr:
`18 hr: TBD (report value)
`24 hr:
`0”“)
`9—00ml: 0.05 mg/24 hr and
`0.075 mg/24 hr, 0.1 mg/24 hr 36 hr: TBD (report Value)
`
`Refer to USP <724> for
`L1/L2/L2 testin
`
`I The Applicant will also collect drug release profile data for the additional 18 and
`36 hours time-points for the registration batches starting at the next scheduled
`stability time-point and for the upcoming validation batches. The extension of the
`m4) of drug can be consistently
`collection period to 36 hrs will ensure that
`achieved.
`
`.
`4
`DH ) W111
`I The Applicant will also investigate whether an
`result in a higher release rate with M“) of drug being released in a shorter
`sampling period, without loosing the discriminating ability.
`I The drug release data collected during the first year from approval date will be
`used for the setting of the final acceptance criteria.
`I The collected data and a proposal for the final drug release method and acceptance
`criteria should be submitted to FDA within fifteen months from approval date, under
`a prior approval supplement (PAS) to the NDA.
`I Upon review of the data provided in the PAS, the drug release methodology and
`acceptance criteria for Minivelle TDS will be finalized,
`
`The specific language/details for the Post Marketing Commitment (PMC) to collect and
`submit the additional information needs to be agreed upon with the Applicant before the
`action letter for this NDA is issued.
`
`Reference ID: 31 76963
`
`

`

` different
`Overall, from the Biopharmaceutics perspective, NDA 203-752 for
`strengths of Minivelle (estradiol) Transdermal System is recommended for APPROVAL.
`
`
`
`Tapash K. Ghosh, Ph. D.
`Primary Biopharmaceutics Reviewer
`Office of New Drug Quality Assessment
`---------------------------------------------------
`
`
`Angelica Dorantes, Ph. D.
`Biopharmaceutics Team Leader
`Office of New Drug Quality Assessment
`
`-----------------------------------------------------------
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3176963
`
`4
`
`(b) (4)
`
`

`

`BIOPHARMACEUTICS ASSESSMENT
`
`Product Descrintion & Formulation:
`
`Minivelle is comprised of three layers: (1) a translucent- film (2) an adhesive
`formulation containing E2, acrylic adhesive, silicone adhesive, oleyl alcohol, NF,
`povidone, USP and dipropylene glycol, and (3) a polyester release liner which is attached
`to the adhesive surface and must be removed before the system can be used.
`
`are l: 'I'he3 La ersofMinidot
`
`7////////////////////////////////////////////////
`.
`:‘
`
`----- (3) Protective Liner
`
`""‘l’B‘w‘dng
`----- (2) Adhesive Containing E2
`
`Table 1: Patch Sizes and E2 . :- Unit for Vivelle, Vivelle Dot, and Mnivelle
`
`
`
`Reference ID: 3176963
`
`

`

`
`Biopharmaceutics Information:
`
`
` dosing strengths of Minivelle (estradiol) transdermal system are proposed to provide
`nominal doses of
`, 0.0375, 0.05, 0.075, or 0.1 mg of E2 per day via the skin. Each
` 2.48, 3.30, 4.95, or 6.6 cm2 and
`corresponding system has an active surface area of
`contains
`, 0.62, 0.83, 1.24, or 1.65 mg of E2 USP, respectively.
`
`The safety and efficacy of Minivelle is being leveraged/established via a bridging
`bioequivalence (BE) study between the highest strengths of the proposed Minivelle and
`the approved Vivelle transdermal systems (BE study N28-004; a single-dose, 2-way
`crossover BE study in 100 healthy, nonsmoking postmenopausal women). A dose
`proportionality study to support the biowaiver request for the doses lower than 0.1
`mg/day was also conducted. Baseline corrected AUC84 and Cmax increased linearly and
`E2 were found to be dose proportional among the 3 nominal doses of
` mg/day, 0.05
`mg/day, and 0.1 mg/day following a single dose of Minivelle in a three-way crossover
`study in postmenopausal women (see Clinical Pharmacology review).
`
`additional lower strengths of Minivelle, a biowaiver
`To support the approval of the
`request was submitted based on: (1) the establishment of BE to Vivelle’s highest strength
`of 0.1 mg/day; (2) establishment of dose proportionality over the dose range of 0.025 -
`0.1 mg/day; (3) the fact that different doses of Minivelle are compositionally
`proportional; and (4) comparable in vitro dissolution profiles of all strengths of Minivelle
`(f2 > 50).
`
`Reviewer’s Comment: Qualitatively Minivelle is much similar to Vivelle-Dot than
`Vivelle; however, as efficacy and safety information is available for the original Vivelle,
`the Applicant rightfully bridged the proposed Minivelle with Vivelle via a BE study.
`
`
`Proposed In Vitro Drug Release Methodology and Acceptance Criteria
`
`Method Development: The in vitro drug release method for Minivelle system is similar
`to the method used for the Vivelle Dot (NDA 20-538) transdermal system and it employs
`the methodology for estradiol transdermal systems in the OGD’s database.
`
`Apparatus: The drug release method for the estradiol transdermal system uses Apparatus
`6, the cylinder apparatus as it has the advantage of avoiding a screen that can occlude the
`patch or retain bubbles and are easier to set up and start.
`
`Dissolution Conditions: Water was chosen as the dissolution medium, because it is
`readily available and maintains the sink condition with adequate solubility for the
`estradiol in the transdermal system. Buffer solutions are not necessary since the solubility
`of estradiol is not greatly affected by small changes in pH, as the molecule contains no
`strong acid or basic functionality.
`
`
`
`
`Reference ID: 3176963
`
`6
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`In addition to water, dissolution rofiles were enerated for the Estradiol TDS using three
`other dissolution media
`Results are shown in
`
`Fig 2. Mediawith
`
`
`
`
`
`Estradiol TDS Dissolution Profiles in Different Media
`
`
`
`Speed: Common cylinder speeds areHThe— speed was
`
`e disso utlon profile. 32°C is
`selected to give additional resolution in e ear y part 0
`the dissolution temperature designed to be the temperature of skin.
`
`Based on the above, the following conditions were adopted as the final release testing
`condition by the Applicant:
`
`Apparatus:
`Speed:
`
`USP A aratus 6
`Hp
`
`Medium:
`Water at 32 : 05°C
`Volume: —
`900 mL for 0.05 m I24hr, 0.075 mg/24hr, 0.1 mg/24hr
`Sampling Times:
`*recommended);
`Additionally a 24 hr sampling point is included.
`
`Drag Release Acceptance Criteria: Using the above method, and the release profile in
`water, the Applicant proposed the following criteria for product release and during shelf-
`life testing. Drug release testing limits were established with sample times of 2, 4, 6 and
`24 hours with the following acceptance criteria:
`
`Sample Time
`2 hours
`
`24 hours
`
`%Label Claim
`
`4 hours 6 hours
`
`Reference ID: 3176963
`
`

`

`Estradiol TDS
`
`Estradiol TDS
`Estradiol TDS
`
`Estradiol TDS
`
`
`
`
`
`3 3
`4.95
`
`50857
`RN059-1—P4.95
`__— 50850
`29.0 __— 44189
`
`
`
`The sample times were established to provide an early point at 2 hours to preclude too
`rapid drug release, two points (4 and 6 hours) in the middle of the dissolution profile, and
`a later point at 24 hours to ensure that the majority of the drug substance has been
`released. Testing results from the Bio-lots 50850, 50855, 50857, 50857 and RN059-I—
`P4.95 were averaged to set the mid-points of the specifications. Results from 114 patches
`covering time of release and through six months stability were used to set the mid points.
`
`Product
`
`
`
`____,_._
`__L9t_1_‘.1umbers of Transslsrma! ,Systems .Tssted
`
`Lot number
`
`
`Estradiol TDS
`___
`50855
`
`
`2.475
`50856
`0 0375
`30024-08
`
`
`
`Vivelle
`
`
`
`Reviewer’s Comments:
`
`Upon review of the results, the following cements were sent to the Applicant in an IR
`letter dated 7/13/12.
`
`)‘v Based on the release data/profiles submitted earlier, it appears that me) drug
`release for your proposed product in water can be achieved at 36 hours using your
`proposed method. Therefore, it is recommend that you establish sample points
`and acceptance ranges at 2, 6, 18 and 36 hours for your proposed patch which is
`to be worn for 84 hours.
`
`> It appears that you may be able to achieve a higher release rate of the drug by (hm)
`
`without loosing the discriminatory ability, which may reduce the total
`sampling period.
`
`On July 31, 2012, the Applicant responded as follows:
`
`Noven agrees to add drug release sampling time points at I8 and 36 hours. However, at
`this time Noven has very limited results at these time points and is not able to set
`acceptance ranges based on these data. Further, the validation data currently available
`for the drug release method does not include the 18 and 36 hour time points, and that
`study also needs to be performed. We agree to collect I8 and 36 hour data starting at the
`next stability time point andfor the upcoming validation batches. We will also evaluate
`the entire release profile to ensure that “mean be consistently achieved The
`specification has been updated to include the new sampling times, as described below:
`
`Reference ID: 31 76963
`
`

`

`Test
`
`Acceptance Criteria
`
`Method
`
`Release Rate
`
`Refer to USP <1 724> for individual unit acceptance criteria.
`
`
`
`6 hour
`
`18 hour
`
`24 hour
`
`3 6 hour
`
`Report Value
`
`(b) (4)
`
`Report Value
`
`Dissolution
`
`(him Noven appreciates the
`Regarding the observation on
`suggestion and will take it under consideration. Any changes in
`m“) will be
`submitted as a post-approval supplement.
`
`Reviewer ’s Comments:
`
`1. The drug release test and acceptance criteria are acceptable on an interim basis.
`2. The Applicant will collect drug release profile data at 2, 6, 18, 24, and 36 hourfor
`
`the registration batches starting at the nact stability timepoint andfor the upcoming
`validation batches. The atension of the collection period to 36 hrs will ensure that
`M“) ofdrug can be consistently achieved.
`3. The drug release data collected during thefirst yearfrom approval date will be used
`for the setting of thefinal acceptance criteria.
`(him will
`4. The Applicant will also investigate whether an
`result in a higher release rate with
`one) ofdrug being released in a shorter
`sampling period, without loosing the discriminating ability.
`5. The collected data and a proposalfor thefinal drug release method and acceptance
`criteria should be submitted to FDA within fifteen months from approval date, under a
`prior approval supplement (PAS) to the NBA.
`
`6. Upon review ofthe data provided in the PAS, the drug release methodology and
`acceptance criteria for Minivelle will befinalized,
`
`Biowaiver Reguest
`
`The Applicant proposed to market Minivelle in gldifferent dosage strengths and requested
`a biowaiver for the lower dosage strengths of
`M“) 0.0375 mg/day, 0.05
`mg/day, and 0.075 mg/day with the following justifications per 21 CFR §314.90:
`
`‘7
`
`P The patches for the lower strengths have the same formulations as the highest
`strength used in the BE study. All of them are from the same sheet of the
`fonnulation and the only difference is the size (surface area) of the patches.
`Establishment of BE between Nlinivelle and Vivelle at the highest strength of 0.1
`mg/day.
`Establishment of dose proportionality over the dose range of 0025—01 mg/day.
`In vitro dissolution profiles for all strengths of Minivelle are comparable (12 > 50)
`
`VV
`
`Reference ID: 31 76963
`
`

`

`Comparative Dissolution in Water Medium: Comparative dissolution profile testing
`was performed for the proposed highest strength of the Minivelle transdermal system vs.
`the highest Vivelle Transdermal System. To support the biowaiver request, each one of
`the proposed lower strengths of Estradiol TDS was compared vs. the highest strength
`(tested in the BE study). The results are described below:
`
`Figure 1:
`
`Vivelle 29.0 sq. cm TDS vs. Estradiol 6.6 sq. cm TDS
`
`10
`
`Table 2:
`
`Comparison of Vivelle 29.0sq. cm TDS and Estradiol 6.6 sq. cm TDS
`
`
`
`%labelClaimReleased
`
`II
`
`1
`
`
`
`
`Time (hr)
`
`Average %Labet Claim
`Vivelle 29.0 cm2 TDS
`
`Average %Label Claim
`Estradiol 6.6 cm2 TDS
`
`Difference
`Factor f1
`
`
`
`Similarity
`Factor 12
`
`
`
`Reference ID: 3176963
`
`10
`
`

`

`Figure 2:
`
`Estradiol 6.6 sq. cm TDS vs. Estradiol 4. 95 sq. cm TDS
`
`Estradiol 6.6 cm2 TDS vs. Estradiol 4.95 cm2 TDS
`
`ggu 3.
`
`fl
`
`5b
`
`e
`Factor f2
`
`Table 3:
`
`Comparison of Estradiol 6.6 sq. cm TDS and Estradiol 4.95sq. cm TDS
`
`Time (hr)
`
`Average %Label Claim
`Estradiol 6.6 cm2 TDS
`
`Average %Label Claim
`Estradiol 4.95 cm2 TDS
`
`Difference
`Factor f1
`
`Similarity
`
`Reference ID: 3176963
`
`11
`
`

`

`Fi; ure 3:
`
`Estradi016.6 s. cm TDS vs. Estradiol 3.3 .5". cm TDS
`
`Claim
`
`10
`
`15
`
`Time (hr)
`
`Estradiol 6.6 sq. cm TDS vs. Estradiol 3.3 sq. cm TDS %lahel
`Factor f2
`
`Table 4:
`
`Comparison ofEstradiol 6.6 sq. cm TDS and Estradiol 3.3 sq. cm TDS
`
`Average %Label Claim
`(Estradiol 6.6 cm2 TDS)
`
`Average %Label Claim
`(Estradiol 3.3 cm2 TDS)
`
`Difference
`Factor f1
`
`Similarity
`
`Reference ID: 3176963
`
`12
`
`

`

`Figure 4:
`
`Estradiol 6.6 sq. cm TDS vs. Estradi012.475 sq. cm TDS
`
`Estradiol 6.6 cm2 TDS vs. Estradiol 2.475 cm2 TDS
`
`.E
`
`Time (hr)
`Factor #2
`
`100
`90
`80
`70
`60
`50
`4O
`30
`20
`10
`
`10
`
`15
`
`aU a.
`
`D B3
`
`2
`
`Table5
`
`Comparison of Estradtol 6. 6 sq. cm TDS and Estradiol 2. 475 sq. cm TDS
`
`Time (hr)
`
`Average %Label Claim
`(Estradiol 6.6 cm2 TDS)
`
`Average %Label Claim
`(Estradiol 2.475 cm2 TDS)
`
`Difference
`Factor f1
`
`Similarity
`
`Reference ID: 3176963
`
`13
`
`

`

`Reviewer’s Comments:
`1. The in vitro drug release profile of each one of the lower strengths of Minivelle
`(estradiol) TDS was compared vs. the release profile of the highest strength (6.6
`cm2 vs. 4.95 cm2, 6.6 cm2 vs. 3.3 cm2, 6.6 cm2 vs. 2.475 cm2, and 6.6 cm2 vs.
`
` The release profiles are similar in shape and met the criteria for similarity (f
`1 and f2 factors).
`2. The results from the BE study and similarity f2 test support the Applicant’s request
`for a BA/BE waiver for the proposed lower strengths of Minivelle transdermal and
`the biowaiver is granted.
`3. Upon review of the in vitro drug release data to be submitted within 15 months
`from the NDA’s action date for this proposed product, the in vitro drug release
`methodology and the acceptance criteria will be finalized.
`
`
`
`
`
`
`Reference ID: 3176963
`
`14
`
`(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/
`----------------------------------------------------
`
`TAPASH K GHOSH
`08/20/2012
`
`ANGELICA DORANTES
`08/20/2012
`
`Reference ID: 3176963
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`
`
`
`NDA: 203752
`
`Sponsor:
`Submission Type:
`Formulation, Strength(s), and Dosing
`Regimen:
`Indication:
`
`Submission Dates:
`4/27/2012
`MINIVELLE
`Brand Name:
`17β-estradiol (E2)
`Generic Name:
`Chongwoo Yu, PhD
`Clinical Pharmacology Primary Reviewer:
`Clinical Pharmacology Secondary Reviewer: Myong-Jin Kim, PharmD
`OCP Division:
`Division of Clinical Pharmacology 3 (DCP-3)
`OND Division:
`Division of Reproductive and Urologic
`Products (DRUP)
`Noven Pharmaceuticals, Inc.
`Original
`Transdermal film; 0.1, 0.075, 0.05, 0.0375,
` mg/day; twice weekly
`Treatment of moderate to severe vasomotor
`symptoms (VMS) associated with menopause
`
`12/29/2011 and
`
`
`
`
`An Optional Inter-Division Clinical Pharmacology Briefing was held on Thursday, July 26, 2012. The attendees were
`as follows: C. Yu, E.D. Bashaw, H.Y. Ahn. M-J Kim, L. Lee, S. Al Habet, P. Price, C. Strasinger, G. Burckart, J. Shon,
`J. Momper, M. Kusama, S.J. Kim, S. Yu, J. Lee, and M. Yamazaki.
`
`Table of Contents
`
`Table of Contents ............................................................................................................................ 1
`1 Executive Summary ................................................................................................................. 2
`1.1
`Recommendation .............................................................................................................. 3
`1.2
`Post-marketing Requirements or Commitments............................................................... 3
`1.3
`Summary of Important Clinical Pharmacology Findings ................................................. 3
`2 Question Based Review ........................................................................................................... 5
`2.1
`General Attributes............................................................................................................. 5
`2.2
`General Clinical Pharmacology ........................................................................................ 6
`2.3
`Intrinsic Factors .............................................................................................................. 13
`2.4
`Extrinsic Factors ............................................................................................................. 14
`2.5
`General Biopharmaceutics.............................................................................................. 14
`2.6
`Bioanalytical Methods .................................................................................................... 15
`3 Detailed Labeling Recommendations .................................................................................... 16
`4 Appendices............................................................................................................................. 21
`4.1
`Individual Study Reviews............................................................................................... 21
`4.2
`Office of Scientific Investigations Consult Report ......................................................... 42
`4.3
`Clinical Pharmacology Filing Memo.............................................................................. 45
`
`
`
`
`
`Reference ID: 3168676
`
`1
`
`(b) (4)
`
`(b) (4)
`
`

`

`1
`
`Executive Summary
`
`to seek approval of
`The Sponsor submitted a 505(b)(1) new drug application (NDA)
`MINIVELLE (17|3-estradiol [E2] transdermal patch) for the treatment of moderate to severe
`vasomotor symptoms (VMS) associated with menopause with a right of cross-reference to NDA
`020323 Vivelle (approved on October 28. 1994) and NDA 020538 Vivelle-Dot (approved on July
`31. 1996) from Novartis. Vivelle and Vivelle-Dot are E2 trasnsdermal patches manufactured by
`Noven Pharmaceuticals Inc. and marketed by Novartis.
`M ’
`
`It is designed to release the active
`MINIVELLE contains E2 in a multi-polymeric adhesive.
`component, E2. continuously upon application to intact skin. The remaining components of the
`system are pharmacologically inactive. “m dosage strengths of MINIVELLE are available to
`provide nominal delivery rates of M“), 0.0375, 0.05, 0.075. or 0.1 mg of E2 per day via the skin.
`Each corres nding system has an active surface area of mm 2.48, 3.30, 4.95, or 6.6 cm2 and
`contains a» ’, 0.62, 0.83, 1.24, or 1.65 mg of E2 USP, respectively.
`
`The recommended starting dose of MINIVELLE is 0.0375 mg/day. The adhesive side of
`MINIVELLE should be placed on a clean, dry skin area of the abdomen (i.e., below the
`umbilicus) or buttocks twice weekly. The sites of application must be rotated (i.e., left vs. right;
`abdomen vs. buttocks), with an interval of at least 1 week allowed between applications to a
`particular site. Dosage adjustment should be evaluated periodically (e.g., 3-6 month intervals)
`and guided by the clinical response (i.e., the frequency and severity of VMS symptoms). Therapy
`should last for the shortest duration consistent with the treatment goals.
`
`“M" to provide
`Vivelle and Vivelle-Dot are available in five dosage strengths
`nominal delivery rates of 0.025, 0.0375, 0.05, 0.075, or 0.1 mg of E2 per day via skin but their
`active surface areas are larger. Vivelle-Dot which has a smaller active surface area compared to
`Vivelle, was approved based on the establishment of bioequivalence (BE) to Vivelle. Vivelle and
`Vivelle-Dot should be applied to the abdomen (i.e., below the umbilicus) or buttocks and should
`be replaced twice weekly.
`
`In this current NDA, the Sponsor submitted 4 Clinical Pharmacology studies including a pivotal
`BE study (Study N28—004) and a dose-proportionality study (Study N28-005) that used the to-be—
`marketed (TBM) formulation. The safety and efiicacy of MINIVELLE is supported via bridging
`to the findings of Vivelle by demonstrating BE. In addition, skin adhesion was evaluated in the
`pivotal BE (Study N28-004) and dose-proportionality (Study N28-005) studies. Out of the 4
`studies submitted, Study N28-004 and Study N28-005 were reviewed. The other 2 studies were
`not reviewed as they were not relevant to the TBM product.
`
`While there are ggdifferent dosage strengths of MINIVELLE developed, the BE study was
`conducted with only the highest strength (i.e., 0.1 mg/day) and a dose proportionality study was
`conducted to support the biowaiver request for dosage strengths lower than 0.1 mg/day. A
`biowaiver request was submitted for the {mower dosage strengths (i.e., M“), 0.0375, 0.05. and
`0.075 mg/day) based on: (1) the establishment of BB to Vivelle at the highest strength of 0.1
`mg/day; (2) the establishment of dose proportionality over the dose range of 0025-01 mg/day;
`(3) the fact that different dosage strengths of MINIVELLE are compositionally proportional; and
`(4) the comparable in vitro dissolution profiles of all strengths of MINIVELLE (f2 > 50).
`
`For the pivotal BE study (Study N28-004), a formal consult
`
`to the Office of Scientific
`
`Reference ID: 31 68676
`
`

`

`Investigations (OSI) was made for clinical and bioanalytical study site inspections.
`
`1.1 Recommendation
`
`The Office of Clinical Pharmacology (OCP)/Division of Clinical Pharmacology 3 (DCP-3) has
`reviewed NDA 203752 submitted on December 29, 2011 and April 27, 2012. The overall
`Clinical Pharmacology information submitted to support this NDA is acceptable provided that a
`satisfactory agreement is reached regarding the labeling language.
`
`1.2 Post-marketing Requirements or Commitments
`
`None
`
`1.3 Summary of Important Clinical Pharmacology Findings
`
`BE Assessment:
`BE between MINIVELLE (1.65 mg E2/6.6 cm2) and Vivelle (8.66 mg E2/29 cm2) at the highest
`strength (i.e., nominal delivery of 0.1 mg/day) was established following a single dose
`administration to the lower abdomen in a 2-way crossover study (Study N28-004) in 100 healthy,
`nonsmoking postmenopausal women.
`
`
`Table 1: Baseline Corrected E2 BE Results (N=96)
`AUC120
`AUCinf
`AUC84
`
`Ratio of LSMa x 100
`86.1%
`84.5%
`84.5%
`90% geometric CIb
`80.7-91.7%
`79.2-90.3%
`79.2-90.3%
`a Calculated using least-squares means (LSM) according to the formula: e(MINIVELLE (A) – Vivelle (B)) x 100
`b 90% Geometric Confidence Interval (CI) using ln-transformed data
`
`Cmax
`108.8%
`102.4-115.6%
`
`
`For baseline corrected E2, the 90% geometric confidence intervals (CI) wer