loi
`
`5210490 A
`
`:
`ill
`
`* 5 2 1 0 4 9 0 *
`
`* A *
`
`Alora 0.025mg, 0.05mg, 0.075mg, 0.1mg
`Transdermal System (Watson Laboratories)
`04/05/2002 Approval [Postmenopausal
`Osteoporosis]: Approval Letter; Approvable Letter;
`Final Labeling
`
`This document was provided by: FOI Services, Inc
`"11 Firstfield Road
`Gaithersburg MD 20878-1704 USA
`Phone: 301-975-9400
`301-975-0702
`Fax:
`Email:
`infofoi@foiservices.com
`
`Do you need additional U.S. Government information?
`
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`Information Act. We have millions of pages of unpublished documentation already on file and available for
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`
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`
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`Freedom of Information Act and are therefore available to the general public. FOI Services, Inc. does not guarantee the accuracy of
`any of the information in these documents; the documents will be faithful copies of the information supplied to FOI Services, Inc.
`
` 
`

 
`0001
`
`MYLAN - EXHIBIT 1016
`
`

`

`CFNTRR FOR nRTTf? KVAT.TTATTON AND RRSF.ARfTH
`
`AppHcatioP NninW fylTW o?l--3'0
`
`APPROVAI. I.RTTRP
`
`t
`
`0002 
`
`

`

`'(4 DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`t - .
`
`Public Health Service
`
`Food and Drug Administration
`RodcvffleMD 20857
`
`NDA 21-310
`
`Watson Laboratories, be.
`Attention: Dorothy A. Frank, M.S., R.A.C.
`Executive Director, Proprietary Regulatory Affairs
`417 Wakara Way
`Salt Lake City, UT 84108
`
`Dear Ms. Frank:
`
`Please refer to your new drug application (NDA) dated January 12,2001, received 5anuary 16,2001,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Alora (estradiol
`transdermal system) 0.025 rag/day, 0.05 mg/day, 0.075 mg/day, and 0.1 mg/day.
`
`Your submission of February 5,2002, constituted a complete response to our January 18,2002, action
`letter.
`
`This new drug application provides for 1) addition of a 0.025 mg/day strength product and 2) addition
`of an indication for die prevention of postmenopausal osteoporosis for all strengths.
`
`We have completed the review of this application, as amended, and have concluded that adequate
`infonnatioa has been presented to demonstrate that the drug product is safe rod effective for use as
`recommended in the agreed upon enclosed labeling text Accordingly, the application is approved
`effective on the date of this letter.
`
`The final printed labeling (FPL) must be identical to the enclosed labeling (text for the package insert,
`text for the patient package insert) and submitted draft labeling (pouch and carton labels submitted on
`November 15,2001). Marketing the product with FPL that is not identical to the approved labeling
`text may render tbc; product misbranded and an unapproved new drug.
`
`Please submit the copies of final printed labeling (FPL) electronically according to the guidance for
`industry titled Providingitegulatory Submissions in Electronic Format - NDA (January 1999).
`Alternatively, youanay-submit 20 paper copies of the FPL as soon as it is available but no more than 30
`days after it is printed. • Please individually mount ten of the copies on heavy-weight paper or similar
`material. For administrative purposes, this submission should be designated "FPL for approved NDA
`21-310." Approval of this submission by FDA is not required before the labeling is used.
`
`Be advised that, as of April 1,1999, all applications for new active ingredients, new dosage forms, new
`indications, new routes of administration, and new dosing regimens are required to contain an
`assessment of the safety and effectiveness of the product in pediatric patients unless this requirement is
`waived or deferred (63 FR 66632). We are waiving the pediatric study requirement for this action on
`this application.
`
`0003 
`
`

`

`NDA 21-310
`Page 2
`
`*
`
`In addition, please submit three copies of the introductory promotional materials that you propose to
`use for this product AlljJroposed materials should be submitted m draft or mock-up form, not final
`print. Please submit one copy to this Division and two copies of both the promotional materials and
`the package insert directly to:
`
`Division of Drug Marketing, Advertising, and Communications, HFD-42
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, Maryland 208S7
`
`Please submit one market package of the drug product when it is available.
`
`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81). Ail 15-day alert reports, periodic (including quarterly) adverse drug experience
`reports, field alerts, annual reports, supplements, and other submissions should be addressed to the
`original NDA, NDA 20-655, for this dnig product, not to this NDA. In the future, do not make
`submissions to this NDA except for the final printed labeling requested above.
`
`If you have any questions, call Samuel Y. Wu, Pharm.D., Regulatory Project Manager, at
`301-827-6416.
`
`I
`
`Sincerely,
`
`{See app&Khd electronic xigntunre page!
`
`David G. OrlofT, M.D.
`Director
`Division of Metabolic and Endocrine Drug Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`Enclosure
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`0004 
`
`

`

`This is a representation of an olectronic record that was signed electronically and
`this paga is the rjpfttfestatlon of the electronic signature.
`
`/ s /
`
`David Orloff
`4 / 5 / 0 2 0 1 : 1 1 : 4 6 PM
`
`MPEMIS xms WM
`ON ORIGINAL
`
`«
`
`i
`
`0005 
`
`

`

`rENTFJR FOR MMIfi KVAT.TTATfON ANI> RKSEARCH
`ApplicaHnnNiynher MbA"
`
`APPROV ART ,F. T
`
`£S
`
`I
`
`0006 
`
`

`

`\
`
`DEPARTMENT OF HEALTH A HUMAN SERVICES
`
`Public Health Servica
`
`Food and Drug Adminiatrstion
`RockvMaMD 20857
`
`NOV 1 6 2001
`
`NDA 21-310
`
`Watson Laboratories, Inc.
`Attention: Dorothy A. Frank, MS., R-A.C.
`Director, Regulatory Affairs
`Research Park
`417 Wakaia Way
`Salt Lake City, UT 84108
`
`Dear Ms. Frank:
`
`Please refer to your new drug application (NDA) dated January 12,2001, received January 16,2001,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Alora (estradiol
`transdeimal system) 0.025 mg/day, 0.05 mg/day, and 0.075 mg/day.
`
`We acknowledge receipt of your submissions dated February 14, May 11, September 26, October 16
`and 19, and November 7,2001.
`
`i
`
`We have completed the review of this application, as amended, and it is approvable. Before this
`application may be approved, however, it will be necessary for you to submit revised draft labeling for
`the drug. The labeling should be identical in content to the enclosed labeling (text for the package
`insert, text for die patient package insert). In addition, submit a copy of your proposed container and
`pouch label.
`
`If additional infoimation relating to the safety or effectiveness of this drug becomes available, revision
`of the labeling may be required.
`
`Under 21 CFR 314.50(flXSXviX^)>
`request that you update your NDA by submitting all safety
`information you now have regarding your new drug. The safety update should include data from all
`nonclinical and clinical yudies of die drug under consideration regardless of indication, dosage form,
`or dose level.
`
`1. Describe in detail any significant changes or findings in the safety profile.
`
`0007 
`
`

`

`V , .
`NDA.21-JIG
`Alora (estradiol truXkronl system)
`Page 2
`~.
`
`2. When assembling the sections describing discontinuations due to adverse events, serious
`adverse events, and common advene events, incorporate new safety data as follows:
`
`• Present new safety data from the studies for the proposed indication using foe same format
`as the original NDA submission.
`
`• Present tabulations of die new safety data combined with the original NDA data.
`
`• Include tables that compare frequencies of advene events in the original NDA with die
`retabulated frequencies described in the bullet above.
`
`• For indications other than the proposed indication, provide sepamte tables for the
`frequencies of adverse events occurring in clinical trials.
`
`3. Present a retabulation of the reasons for premature study discontinuation by incorporating the
`drop-outs from the newly completed studies. Describe any new trends or patterns identified.
`
`4. Provide case report forms and narrative summaries for each patient who died during a clinical
`study or who did not complete a study because of an adverse event. In addition, provide
`narrative summaries for serious adverse events.
`
`5. Describe any information that suggests a substantial change in the incidence of common, but
`less serious, adverse events between the new data and the original NDA data.
`
`6. Provide a summary of worldwide experience on the safety of this drug. Include an updated
`estimate of use for drug marketed in other countries.
`
`7. Provide F.ngiuii translations of current approved foreign Labeling not previously submitted
`
`Within 10 days after the^date of this letter, you are required to amend the application, notify us of your
`intent to file an amendment, or follow one of your other options under 21 CFR 314.110. in the absence
`of any such action FDA may proceed to withdraw die application. Any amendment should respond to
`all the deficiencies lisfpd. We will not process a partial reply as a major amendment nor will the
`review clock be reactfated until all deficiencies have been addressed.
`
`The drug product mfey not be legally marketed until you have been notified in writing that the
`application is approved.
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`#
`
`0008 
`
`

`

`(
`
`NDA 21-310
`Alois (estradiol transdermal system)
`Page 3
`
`If you have any questions, call Samuel Y. Wu, PharmD., Regulatory Project Manager, at
`301-827-6416.
`
`Sincerely,
`
`/See appemitd tlectromc ugnaturt puge}
`
`David G. Orioff, MX>.
`Director -
`Division of Metabolic and Endocrine Drug Products
`Office of Drag Evaluation 11
`Center for Drug Evaluation and Research
`
`Enclosure
`
`APPEARS THIS WAY
`OH ORIGINAL
`
`0009 
`
`

`

`WITHHOLD 3(o PAGE (S)
` WITHHOLD_3(0 pace (S) -
`
`Dr-ft-f +
`Draft
`Ca bé | IN9
`0
`
`0010
`
`

`

`\
`
`** •
`
`This ft a raprMantatlofi of an alactronic record that was algnad •lectronlcaJly and
`this paga la thsThantftstatton of tha alactronfc aignatur*.
`/•/
`David OrlofC
`11/16/01 12:21:21 PM
`
`Ap«?!s THIS wr
`0" ORIGINAL
`
`/
`
`0011
`
`

`

`4 •VMV
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`NDA 21-310
`
`Watson UbofBtories, be.
`Attention: Dorothy Frank, M.S., R.A.C.
`Director, Rcgu]*tory AfF»irj
`Research Park
`417 Wakara Way
`Salt Lake City, UT 84108
`
`Public Health Service
`
`Pood ftnd Drug Admtnfouation
`RockvfNe MD 20857
`
`m is a®
`
`Dear Ms. Fnmk:
`Please refer to your new drug application (NDA) dated January 12,2001, received January 16,2001, submitted
`under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Aloni (estradiol transdermal system)
`0.02 Smg/day, 0.05 mg/day, and 0.075 mg/day.
`We acknowledge receipt of your submissions dated January 14 and 16,2002. Your submission of
`November 19,2001, constituted a complete response to our November 16,2001, action letter.
`
`We have completed the review of this application, as amended, and it is approvable. Before this application
`may be approved, however, it will be necessary for you to address the following labeling issues:
`
`1. The table regarding vasomotor symptoms cannot be verified. To support Table 3, "Mean Change from
`Baseline in Frequency of Moderate-to-Severe Vasomotor Symptoms for Alora Compared to Placebo,"
`submit the efficacy data from die placebo-controlled clinical trial (E9400I). These data should be provided
`in SAS transport formal according to the Guidance for Industry, entitled, "Providing Regulatory
`Submissions in Electronic Fonnat-NDAs." Data should include values at baseline and weeks 4,8 and 12,
`utilizing the last observation carried forward (LOCF) data imputation method. A data flag should be used to
`indicate any imputed value.
`
`2. The graph provided by the Agency in figure 3 is an example of the presentation requested for that figure,
`"Mean % change in BMD from baseline at 1 and 2 years after initiation of therapy with placebo and Alora
`0.025.0.0S and 0.075 mg/dayA new graph using the corrected numbers in the completer and ITT
`populations should be generated.
`In addition, it will be necessary for you to submit draft labeling for the drug. Revisions have been incorporated
`directly into the enclosed labfjtng (text for the package insert, text for the patient package insert). Additions
`have been noted with 'TTHl^iltinff deletions have been noted as aitiisems. Additional comments requiring
`response are in 14 pt bold fftCC type.
`If additional information reeling to the safety or effectiveness of this drug becomes available, revision of the
`labeling may be teqoSfeiT'
`
`Within 10 days after the date of this letter, you are required to amend the supplemental application, notify us of
`year intent to file an amendnxnt, or follow one of your other options under 21 CFR 314.110. In the absence of
`any such action FDA may proceed to withdraw the application. Any amendment should respond to all the
`deficiencies listed. We will not process a partial reply as a major amendment nor will the review clock be
`reactivated until all deficiencies have been addressed.
`
`0012 
`
`

`

`NDA 21-310
`Page 2
`
`r '
`This product nay be considered to be misbranded under the Federal Food, Drug, and Cosmetic Act if it is
`marketed with these changes prior to approval of this supplemental application.
`
`If you have any questions, call Samuel Y. Wu, Pharm.D., Regulatory Project Manager, at 301-827-6416.
`
`Sincerely,
`
`{Set appended electronic signature page}
`
`David G. Oiioff, M.D.
`Director
`Division of Metabolic and Endocrine Drag Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`Enclosure
`
`appears th!" '.'.'ay
`oh oric'nal
`
`(
`
`*
`
`0013 
`
`

`

`*
`This It a reprtMiutUon of an alactronlc record that was signed alactronically and
`thla paga la tha mantfaatatlon of tha atactronlc algnatura.
`/s/
`Mary Parks
`1/18/02 04:41:09 PM
`for Dr. Orloff
`
`t t
`
`(
`
`WKMSWIS'IIM
`0M
`
`•
`
`0014 
`
`

`

`A3
`WITHHOLD.pace (sy,
`WITHHOLD
`PAGE (S)
`
`Uratk
`Labe lanq
`
`0015 
`
`

`

`CENTER FOR PRTIft FVAT.T7ATTON ANT) RRSFARPH
`
`ApplicatioB Niitnliiar MP A c2\~3lO
`
`t.
`
`PTNA1. PRTMTED T.ABET.fNf?
`
`0016 
`
`

`

`NDA 21-310
`Page 3
`
`Estradiol Matrix
`Transdermal Delivery System
`NDA 21-310
`
`Package Insert
`
`appears this way
`ON ORIGINAL
`
`Wama Labontoriei Inc.
`Reaeaich Puk
`417 Wafcan Way
`Salt Lake City, UTM10S USA
`
`#
`
`0017 
`
`

`

`NDA 21-310
`Page 4
`
`_
`
`.
`
`^ .
`Aloratt
`(estradiol transdermal system)
`Continuous Delivery for Twice Weekly Dosing
`
`PRESCRIBING INFORMATION
`
`ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER.
`
`Close clinical surveillance of all women taking estrogens is important Adequate diagnostic measures, including
`endometrial sampling when indicated, should be undertaken to rale out malignancy in all cases of undiagnosed
`persistent or recurring abnormal vaginal bleeding. There is currently no evidence that the use of "natural"
`estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose.
`
`DESCRIPTION
`
`Aiora (estradiol tnttsdennal system) is designed to deliver estradiol continuously and consistently over a 3 or4-
`day interval upon application to intact skin. Four strengths of Alora are available, having nominal in vivo
`deliveiy rates of0.025,0.05,0.075, and 0.1 mg estradiol per day through skin of average penneability (inter-
`individual variation in skin penneability is approximately 20%). Alora has contact surface areas of 9,18,27, an
`36 cm2 and contains 0.75,1.5,2.3, and 3.0 mg of estradiol, USP, respectively. The composition of the estradiol
`transdermal systems per unit area is identical. Estradiol, USP is a white, crystalline powder that is chemicaUy
`described as estra-lv3^5(10)-triene-3, ITD-diol, has an empirical formula of Ci(H»Oi and has molecular weight of
`272.39. The structural fonnula is:
`
`CM
`
`CH
`
`>
`
`o
`
`HO
`
`Bstracfiof
`
`Alora consists of three layers. Proceeding from the polyethylene backing film as shown in the cross-sectional
`view below, the adhesive cgatrix drug reservoir that is in contact with the skin consists of estradiol, USP and
`sorbitan monooleat^dissolved in an acrylic adhesive matrix. The polyester overlapped release liner protects the
`adhesive matrix during storage and is removed prior to application of the system to the skin.
`
`1. PulyU i|<»i m BajM HJ Fim
`
`2. Aiti—hiM««rhtDruQr>—
`
`X a OMriapp«dB«iMMLJnarSHp*PMiTrt>
`
`0018 
`
`

`

`NDA 21-310
`Page 5
`CLINICAL PHARMASL'OCV
`
`Estrogens are largely responsible for the development and maintenance of the female reproductive system and
`secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic
`interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its
`metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling aduh
`women is the ovarian follicle, which secretes 70 to 500 |*g of estradiol daily, depending on the phase of the
`menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione,
`secreted by the adrenal cortex, to estrone by peripheral tissues. Tims, estrone and the sulfate conjugated form,
`estrone sulfate, an die most abundflM circulating estrogens in postmenopausal women.
`Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen
`receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the
`pituitary secretion of the gonadotropins, hiteinmng hormone (LH) and follicle stimulating hormone (FSH)
`through a negative feedback mechanism. Estrogen replacement therapy acts to reduce the elevated levels of these
`hormones seen in postmenopausal women.
`
`Pharmacokinetics
`
`The skin metabolizes estradiol only to a small extent. In contrast, orally administered estradiol is rapidly
`metabolized by the liver to estrone and its conjugates, giving rise to higher circulating levels of estrone than
`estradiol. Therefore, transdermal administration produces therapeutic plasma levels of estradiol with lower levels
`of estrone and estrone conjugates and requires smaller total doses than does oral therapy.
`
`Absorption
`Estradiol is transported across intact skin and into the systemic circulation by a passive diffusion process, the rate
`of diffusion across the stratum coraeum being the principal factor. Alora presents sufficient concentration of
`estradiol to the surface of the sldn to maintain continuous transport over the 3 to 4 day dosing interval.
`
`Direct measurement of total absorbed dose of estradiol through analysis of residual estradiol content of systems
`worn over a continuous four day interval during 251 separate occasions in 123 postmenopausal women
`demonstrated that the average daily dose absorbed from Alora was 0.003 ± 0 001 mg estradiol per cm2 active
`surface area. The nominal mean in vivo daily delivery rates of estradiol calculated from these data are 0.027
`mg/day, 0.054 mg/day, 0.081 mg/day, and 0.11 mg/day for the 9 cm3,18 cm1,27 cm2, and 36 cm1 Alora,
`respectively.
`
`In another study, 20 womenlso were treated with three consecutive doses of Alora 0.05 mg/day, Alora 0.075
`mg/day and Alora 0.1 mg/day on abdominal application sites. Mean steady state estradiol serum concentrations
`observed over the dosing interval are shown in Figure 1.
`
`appears this way
`on original
`
`0019 
`
`

`

`NDA 21-310
`Page 6
`
`^ •
`
`Figure 1
`
`Mean Steady state estradiol senun coaceatntion during the third twice weekly
`doscof Alora 0.1 mg/diy, Alora0.075 mg/day, and Alora 0.05 mg/day in 20
`postmenopausal women.
`
`160
`
`120 -
`
`I 140 -
`'-vrx
`100 - fA y
`\
`
`O ai
`• aanmt/*m
`A OCBnv**
`
`80 -
`5 eo -
`« 40 -
`i • 20 -
`0
`
`Dodngbterwl
`
`0
`
`SO
`75
`100
`25
`HDM FMtAppaeWon ofTNrd OOM
`
`129
`
`In a single dose randomized crowover study conducted to compare die effect of site of Alora application, 31
`postmenopausal women wore single Alora 0.05 mg/day for four day periods on the lower abdomen, upper
`quadrant of the buttocks, and outside aspect of the bip. The estradjol serum concentration profiles are shown in
`Figure 2.
`
`Figure 2
`
`Mean estradiol senun concentrations during a single 4-day wearing of Alora 0.05
`mg/day applied by 31 postmenopausal women to the lower abdomen, upper quadrant of
`the buttocks or outer aspect of Ac hip.
`
`1
`
`ISO
`f 140 -
`A 120 -
`100 -
`90 -
`& i 'o-
`I » 20 -
`e 40 -
`
`0
`
`O
`
`A HP"
`
`Doting IntarMl
`
`kO1
`
`0
`
`25
`
`i
`73
`90
`Hour* PMt AaMtan
`
`r
`100
`
`125
`
`*CWa and CIVI statistically different from abdomen
`
`0020 
`
`

`

`NDA 21-310
`Page 7
`
`Table 1 provides a sumirt^ryafAe estradiol phannacokinetic parameters studied during biopharmaceutic
`evaluation of Alon.
`
`Table 1
`
`Mean (SD) Pharmacokinetic Profile of Alon Over an 84-Hour Dosing Interval
`c
`Q*
`w»
`(pg/ml)
`(pg/ml)
`43 (12) 64 (19)
`86 (40)
`53(23)
`58 (20)
`»8 (38)
`11118)
`45121}
`48(17)
`
`Dosing
`Multiple
`Multiple
`Multiple
`Single
`Single
`Single
`
`GM*
`(pgftnl)
`92^3}
`120(60)
`144(57)
`53 (23)
`67(45)
`69(30)
`
`CL
`(Lto)
`54 f 18)
`53(12)
`61 (18)
`69£2j
`66<£232
`62(18)
`
`Atom
`(nag/day)
`0.05
`0.075
`0.1
`
`Application
`N
`Site
`20
`Abdomen
`20
`Abdomen
`42
`Abdomen
`31
`Abdomen
`31
`Buttock
`31
`HiP*
`• CM •od Cptg tudttkally diffenut from ibdotnen
`
`0.05
`
`Steady state estradiol serum concentrations were measured in two well-controlled clinical trials in the trestment of
`menopausal symptoms of 3 month duration (Studies 1 and 2), and one trial in the prevention of postmenopausal-'
`osteoporosis of 2 year duration (Study 3). Table 2 provides a summary of these data.
`
`Table 2
`
`Mean (SD) steady-state estradiol serum coacentrations (pg/ml) in clinical trials of 3 month
`(Studies 1 and 2) and 2 year (Study 3) duration
`
`Alon
`(mg/day)
`0.025
`0.05
`0.075
`0.1
`
`Study 1
`
`Study 2
`
`46.9 (38.5)
`
`38.8 (38.0)
`
`99.2 (77.0)
`
`97.0(87.5)
`
`Study 3
`24.5 (12.4)
`42.6(23.7)
`56.7 (36.8)
`
`In a 2-year, randomized, double-blind, placebo-controlled, prevention of postmenopausal osteoporosis study in
`355 hysterectomized women, the avenge baseline^adjusted steady-state estradiol serum concentrations wen 18.6
`pg/ml (45 patients) for The 0.1725 mg/day dose, 35.9 pg/ml (47 patients) for the 0.05 mg/day dose and 50.1 pg/ml
`(46 patients) for the 0.075 mg/day dose. These values were linearly related and dose proportional.
`
`^
`DistribuUoH
`No specific inveatigation pf the tissue distribution of estradiol absorbed from Alora in humans has been
`conducted. The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are
`widely distributed in the body and are generally found b higher concentrations in the sex hormone target organs.
`Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.
`
`Metabolism
`Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in
`a dynamic equilibrium of metabolic interconversions. These transfonnations take place mainly in the liver.
`Estradiol is converted reversibly to estrone, and both can be converted to estriol. which is the major urinary
`metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the
`liver, biliary secretion of conjugates into the intestine, and hydrolysis in die gut followed by reabsorption. In
`
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`NDA 21-310
`Page 8
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`_
`
`_
`
`portion of die circulating estrogens exist as sulfate conjugates, especially
`postmenopausal women
`estrone sulfate, which serves as ft circulating reservoir for the formation of more active estrogens.
`
`~~
`Excretion
`Estradiol, estrone and estriot are excreted in the urine along with glucuronide and sulfate conjugates. The
`apparent mean (SD) serum half-life of estradiol determined from biopharmaceutic studies conducted with Alora
`is 1.75 ± 2.87 hours.
`
`Special PopulatloDS
`Alora has been studied only in heahhy postmenopausal women (approximately 90% Caucasian). There are no
`long term studies in postmcQopcusal women with an intact uterus. No pharmacokinetic studies were conducted in
`other special populations, inchidiqg patients with icnal or hepatic impairment
`
`Drug luteracttani
`In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P4S0 3A4
`(CYP3A4). Therefore, inducers or inhibitors ofCYP3A4 may affect estrogen drug metabolism. Inducers of
`CYP3A4 such as St John's Wort preparations (Hypericum perfoouum), pbenobarbital, phenytoin,
`caibatnazepine, rifampin and dexamethasone may reduce plasma concentrations of estrogens, possibly resulting
`in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as f
`cimetidine, erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, and grapefruit juice may increased •
`plasma concentrations of estrogens and may result in side effects.
`C
`
`Adhesion
`The adhesion potential of Alora was evaluated in a randomized clinical trial involving 408 healthy
`postmenopausal women who wore placebo systems corresponding to the 18 cm1 size Alora. The placebos were
`applied twice weekly for 4 weeks on the lower quadrant of the abdomen. It should be noted that the lower
`abdomen, the upper quadrant of the buttocks or outer aspect of the hip are the approved sites of application for
`Alora. Subjects were instructed not to do strenuous activities, take baths, use hot tubs or swim. In 968
`observations, there was a partial or complete adhesion rate of approximately 97%. The total detachment rate was
`approximately 3%. Adhesion potentials of the 9 cm2,27 cm2 and 36 cm1 sizes of Alora have not been studied.
`
`CLINICAL STUDIES
`
`Effects on vasomotor symptoms
`Efficacy of Alora has been studied in a double blind/double dummy, randomized, parallel group, placebo-
`controlled trial involviflg atOtal of268 postmenopausal women over a 12-week dosing period. Only women
`having estradiol and FSH scrum concentrations in the postmenopausal range and who exhibited a weekly average
`of at least 60 moderate-to-aevere hot flushes during the screening period were enroled in the studies.
`
`Patients received AljUrMiOS mg/day and a placebo system or Alora 0.1 mg/day and a placebo system, or two
`placebo systems dosed twice weekly over a 12-week duration. Measures of efficacy included mean reduction in
`weekly number of moderate^o-severe vasomotor symptoms when compared to the mean baseline avenge
`determined during a 2-week pre-dosing screening period. Alora was shown to be statistically better than placebo
`at Weeks 4 and 12 for relief of both the frequency (see Table 3) and severity of vasomotor symptoms.
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`NDA 21-310
`Page 9
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`ir #
`
`Table 3
`
`Mean Change from Baseline in Frequency of Moderate-to-Severe
`"Vasomotor Symptoms for Alon Compared to Placebo (TTT)
`
`Week of
`Thcnpy
`
`Mean Change fiom Baseline
`Alon
`Alora
`0.05 mg/day
`Placebo
`0.1 mg/day
`N»87
`N - 90
`N -91
`Baseline - 90
`Baseline - 92
`Baseline "SS
`4 *
`-45
`-70
`-57
`-49
`8
`-77
`-65
`-54
`-79
`-68
`1 2 *
`*lDdjeate> itatiiiicalty liiniScam djlftmices between both ttnngtlit of Alora and placebo
`using •> ANCOVA model adjutting far baietine.
`
`Effects ott vuhnr and vaginat atrophy
`£
`Vaginal cytology was obtained pie-dosing and at last visit in 54 women treated with Alora 0.05 mg/day, in 45 E'
`f_
`women treated with Alora 0.1 mg/day and in 46 women in the placebo group. Superficial cells increased by a
`mean of 18.7%, 23.7% and 8.7*/. for the Alora 0.05 mg/day, Alora 0.1 mg/day, and placebo groups,
`Mr
`respectively. Corresponding reductions in basal/jparabasal and intermediate cells were also observed.
`
`Effects on bone Mineral density
`Lumbar spine bone mineral density (BMD) waa measured by DEXA in a two-year, randomized, multi-
`center, double-blind, placebo^controlled, study in 355 hysterectomized, non-osteoporotic women (1.6., T-
`scores > -2.5). Eighty-six percent of the women were Caucasian, the mean age was 53.2 yean (range 26
`to 69), and the avenge number of years since menopause (natunl or surgical) was not determined. Three
`Alora doses (0.025,0.05 and 0.075 mg/day) were compared to placebo in terms of the % change in BMD
`from baseline to Year 2. The systems were applied every 3 or 4 days on aftemate sides of the lower
`abdomen. All patients received 1000 mg of oral elemental calcium daily. The average baseline lumbar
`spine T-score was -0.64 (range -2.7 to 3.8). The % changes in BMD from baseline are ilhisiraied in
`Figure 3.
`
`APPEARS THIS WAT
`ON ORIGINAL
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`NDA 21-310
`Page 10
`
`^ *
`
`Figure 3
`
`Mean % change in BMD from baseline at 1 and 2 years after initiation of therapy with
`Placebo and Alora 0.025,0.05 and 0.075 mg/day in the compteter and intent-to-treat
`population with last observation carried forward (LOCF)
`
`i
`1
`1
`1 J*
`
`•fi 1
`
`Comptotra
`
`ITT
`
`0.076 moH
`0.08 rr^/d
`
`0.029 mg/d
`
`-o
`
`YMr2
`VMTt
`Traatment Duration (yaara)
`
`LOCF
`
`A total of 196 patients (44 - 0.025 mg/d, 49 - 0.050 mg/d, 45 - 0.075 mg/d, and 58 - placebo) were included in
`die completer population compated with 258 patients (59 - 0.025 mg/d, 64 - 0.050 mg/d, 63 - 0.075 tag/d, and
`72 - placebo) in the intent-to-treat, last observation carried forward population.
`
`All Alora doses were itf»*ifHically superior to placebo for the primary endpoint, percent change in BMD from
`baseline. The mean 2-year (LOCF) percent changes in BMD for 0.025 mg/d, 0.05 mg/d, 0.075 mg/d, and placebo
`were 1.45%, 3.39%, 4.24%, and -0.80% respectively.
`
`INDICATIONS AND'USAGE
`Alora is indicated in:
`1. Treatment of tnodefate^o-sevece vasomotor symptoms asaociatcd with the menopause.
`2. Treatment of vulvar ao^ vaginal atrophy.
`3. Treatment ofhjjjgestrogeniim due to hypogonadism, castration or primaiy ovarian failure.
`4. Prevention of postmenopausal osteoporosis. Estrogen replacement therapy reduces bone rcsoipuon and
`retards postmenopausal bone loss. When estrogen therapy is discontinued, bone mass declines at a rate
`comparable to that of the immediate postmenopausal period.
`
`The mainstays of prevention of postmenopausal osteoporosis are weight-bearing exercise, adequate calcium
`and vitamin D intake and, when indicated, estrogen. Postmenopausal women absorb dietary calcium less
`efficiently than premenopausal women and require an average of 1500 mg/day of elemental calcium to
`remain in neutral calcium balance. The average calcium intake in the US is 400-600 mg/day. Therefore, when
`not eontramdicated, calcium supplementaiion may be helpful for women with suboplima! dietary intake.
`Vitamin D supplementation of400-800 lU/day may also be required to ensure adequate daily intake in
`postmenopausal women.
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`NDA 21-310
`Page 11
`
`4 •r- " '
`Risk factors for postntfoopausal osteoporosis include early menopause, moderately low bone mass, thin body
`build, Caucasian or Asian nee, faintly history of osteoporosis, and lifestyle (sedentary exercise habits,
`cigarette smoking antfilcofaol abuse).
`
`CONTRAINDICATIONS
`Estrogens should not be used in individuals with any of the following conditions:
`1. Known or suspected pregnancy, see PRECAUTIONS. Estrogens may cause fetal harm when administered
`to a pregnant woman.
`2. Undiagnosed abnormal genital bleeding;
`3. Known or suspected cancer of the breast;
`4. Known or suspected estrogen-dependent neoplasia;
`5. Active deep vein thromboaia/pulmonary embolism or a history of these conditions.
`6. Known bypersensitivity to any of the components of Alorm.
`
`WARNINGS
`1. Induction of Malignant Neopbunu.
`a. Endomitriti cmctr. The reported endometrial cancer risk among unopposed estrogen uscn is about 2
`to 12-fold greater than in non-users, and appears dependent on duration of treatment and on estrogen
`dose. Most studies show no significant increased risk associated with use of estrogens for less than one
`year. The greatest risk appears associated with prolonged use, with increased risks of 15 to 24-fold for
`five to ten years or more, and this risk has been shown to persist for at (east 8 to 15 yean after estrogen
`therapy is discontinued.
`
`b. Breast autcer. While some epidem