IIIIII IIIIIIIII
`
`*5210490*
`
`IIIIII
`* A *l
`
`5210490
`
`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
`1‘1 Firstfield Road
`
`Gaithersburg MD 20878-1704 USA
`Phone: 301-975-9400
`Fax:
`301 -975-0702
`
`Email:
`
`Infofoi@foiservices.com
`
`Do you need additional U.S. Government information?
`
`Since 1975. FOI Services. Inc has specialized in acquiring government files using the Freedom of
`Information Act. We have millions of pages of unpublished documentation already on file and available for
`immediate delivery.
`
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`www.foiserw'ces.com
`
`any of the Information in these documents; the documents will be faithful copies of the information supplied to FOI Services. Inc.
`
`Unless specified otherwise, all of FOI Services' documents have been released by the US. Government under the provisions of the
`Freedom of Information Act and are therefore available to the general public. FOI Services. Inc. does not guarantee the accuracy of
`
` 
`

 
`
`
`MYLAN - EXHIBIT 1016
`
`0001
`
`

`

`«1:- -.
`
`
`
`0002
`
`

`

`ann.‘
`
`aflh.
`
`“a...
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`Public Health Service
`
`
`—
`
`$5 , .
`
`Food and Drug Administration
`Roch“. MD 20857
`
`NDA 21-310
`
`'
`
`'-
`
`Watson Laboratories. Inc.
`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 (NBA) dated January 12, 2001, received Ianuary 16, 2001,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Alora (estradiol
`u‘ansdertual system) 0.025 rug/day, 0.05 mglday, 0.075 rug/day. and 0.! 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 rag/day strength product and 2) addition
`of an indication for the prevention of postmenopausal osteoporosis for all strengths.
`
`We have completed the review ofthis application, as amended, and have concluded that adequate
`infomfionhas been presented to dermnstrate “testbedrugproductis safe andefiective 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 theymdyet misbranded and an unapproved new drug.
`
`Please submit the copies of final printed labeling (FPL) electronically according to the guidance for
`industry titled Providingiegularoov Submissions in Electronic Format - NDA (January 1999).
`Alternatively, mysubmit 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, I999, 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
`
`t‘lw a
`In addition, please submit three copies ofthe introductory promotional materials that you propose to
`use for this product. Allproposed materials should be submitted in 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, RFD—42
`Food and Drug Administration
`5600 Fishers Lane
`
`Rockville, Maryland 20857
`
`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). All 15~day alert reports, periodic (including quarterly) adverse drug eitperience
`reports, field alerts, annual reports. supplements. and other submissions should be addressed to the
`original NDA, NDA 20655, for this drug product, not to this NDA. In the firm, do not make
`submissions to this NDA except for the final printed labeling requested above.
`
`Ifyou have any questions, call Samuel Y. Wu, Phann.D., Regulatory Project Manager, at
`301-827-6416.
`
`- .
`
`Sincerely.
`
`{See uppemfed electronic .t'igflttmre page.”
`
`David G. Orlofi'. MD.
`Director
`
`Division of Metabolic and Endocrine Drug Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`Enclosure
`
`APPEARS THIS WAY
`Oll ORIGINM.
`
`
`
`0004
`
`

`

`
`
`This Is a rspmsi
`this page Is the
`
`on of an electronic record that was signed electronically and
`substation of the electronlc slgnaturs.
`
` h
`
`ls/
`
`-
`
`David Orloff
`4/5/02 01:11:46 PM
`
`APPEARSTHISWAY
`
`0" ORIGINAL
`
`E
`
`
`
`0005
`
`

`

`r-'
`
`«Ea-—
`
`
`
`0006
`
`

`

`a DEPARTMEN'LOFHEALTH & HUMAN SERVICES Public Health Service
`
`T
`Food and Drug Administration
`Wolf) 2035?
`c.-
`
`N'DA 21-310
`
`Watson laboratories. Inc.
`Attention: Dorothy A. Frank. M.S., RAE.
`Director, Regulatory Affairs
`Research Park
`
`417 Wuhan Way
`Salt Lake City. UT 84108
`
`DearMs. Frank:
`
`NOV 162001
`
`Please refer to your new drug application (NDA) dated January 12, 2001, received January 16. 2001.
`submitted under section 505(1)) ofthe Federal Food. Drug. and Cosmetic Act for Alora (estradiol
`transdennal system) 0.025 ins/day, 0.05 rug/day, and 0.075 mg/day.
`
`We acknowledge receipt of your submissions dated February 14, May ll, September 26, October 16
`and 19, and November 7, 2001.
`
`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 the patient package insert). In addition, submit a cepy of your proposed container and
`pouch label.
`
`11' additional information relating to the safety or effectiveness of this drug becomes available. revision
`of the labeling may be required.
`
`Under 21 CFR 312.50(fl_)(5)(vi)(b). we request that you update your NDA by submitting all safety
`information you now have regarding your new drug. The safety update should include data fi'orn nu
`nonciinical and clinicalyudies of the drug trader consideration regardless of indication, dosage form,
`u-‘II
`'
`..,
`or dose level.
`___-_
`-
`
`1. Describe in detail any significant changes or findings in the safety profile.
`
`
`
`0007
`
`

`

`—-
`
`5t. , .
`Hour-310
`Alan (estradiol :mfienml system)
`.—
`Page 2
`
`2. When assembling the sections describing discontinrntions due to adverse events, serious
`adverse events. and common adverse events, incorporate new safety data as follows:
`
`. Presenrnewufmydmfiomnremdiufmtbepmpmedindicsfionuinstbemefom
`estheoriginslNDAsubrnission.
`
`- PresemtebulnfionsofdrenewufetydltecombinedwiththeoriginalNDA data.
`
`-
`
`lneludetsblesthetconrperefi'equeneiesofldveneeventsintheoriginslNDAwiththe
`retebulatedfiequenciesflcribedinthebulletebm.
`
`- Forindimfionlothathanthepropooedindicnfimpmvidemteublcsforfire
`fi-equeneieeofedwrseeventsocernfingincliniceluisls.
`
`3. Present a reubulntion ofthe moons 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 mummies for each patient who died dining a clinical
`study or who did not complete a snrdybweuse ofen adverse event. In addition, provide
`narrative slimmer-ice for serious adverse events.
`
`5. Deeeribeenyinforrnntionthateuggeetusubmntisl chengeintheineidence ofcornrncn. but
`lussefiomadverseevenrsbetweenthenewrhusndrheofigimlNDAdsrs.
`
`6. Provide a unwary ofworldwide experience ontbessfety ofrhis drug. Include an updated
`estinmeofuse fordrusmarketedinothercounniee.
`
`7. Provide English correlations of cur-en approved foreign labeling not previomly submitted.
`
`Within lOdaynflerth‘edlteofthis leflcr,youmtequiredtommdtheapplicotion,nofifyusofyour
`mwmmfihmhemmwfouowoneofyowotboropfionsrmderZICFR 314.110. lntheabsence
`ofsnysuehection FDAmsyproceedtcwithdr-awtheepplicstion. Any amendment should respondto
`nllthedefieienciesliswd. Wewillnotpmceuspmielreplyuamajoramendmentnorwillthe
`reviewelockbemcfiueduntilslldeficieneieehavebeenoddressed.
`“tau-l
`—
`
`Thedmsproduet nrlynotbe leglllymnrkered until youhsve beennotificd in wdtingtbsttbe
`application is approved
`
`APPEARS THl-S WM
`0" ORIGINAL
`
`
`
`0008
`
`

`

`3' " '
`NDA 21-310
`Alon (catndiol transact-mu system)
`Page 3
`_
`...'
`
`Ifyou have any questions, call Samuel Y. Wu, PharmD.. Regulatory Project Manager, at
`301-821-6416.
`
`Sincerely,
`
`{SN appendd eta-Ironic signature past}
`
`David G. Orlofi‘, MD.
`Director -
`
`Division ofMetabolic and Endocrinc Drug Products
`Office of Drug Evnlunn'on ll
`Center for Drug Evaluation and Research
`
`Enclume
`
`APPEARS nus mm
`on ORIGINAL
`
`
`
`0009
`
`

`

`WITHHOLD 3‘0 PAGE (3)
`
`DPAF‘F
`
`
`
`

`

`is.r
`
`
`This Is I ropmontnflon of an electronic moon! that was slgncd olectronlcaily and
`thll pay. I: mu'l'nanlfutlflon of tho Iloctronlc sign-turn.
`
`
`---—---u-p-----------—
`
`David Orloff
`11/16/01 12:21:21 PM
`
`up“! ‘3‘ 1““
`
`3 ‘51?”
`
`
`
`0011
`
`

`

`3.
`
`i" /? DEPARTMENTOFHEALTH&HUMANSERVICES
`
`
`
`NDA 23-310
`
`._
`
`-
`
`Watson Laboratories. Inc.
`
`Attention: Dorothy Frank. M.S.. R.A.C.
`
`Director, Regulatory Affairs
`Research Park
`
`41? won Way
`Salt Lake City, UT 84108
`
`Dear Ms. Frank:
`
`PublicHealthService
`
`Food and Darn Administration
`Roeltvile MD 20857
`
`JAN 1 8 m2
`
`Please refer to yournew drug application (NDA) dated January 12, 2001. received January 16. 2001. submitted
`under section 505(b) ofthe Federal Food, Drug. and Cosmetic Act for Mora (estradiol transdennal system)
`0.02 Sing/day. 0.05 rug/day, and 0.015 tug/day.
`
`We acknowledge receipt ofyour 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:
`
`I. The table regarding vasomotor symptoms cannot be verified. To support Table 3, “Mean Change from
`Baseline in Frequency of Moderate-to-Severe Vasornotor. Symptoms for Mora Compared to Placebo.”
`submit the efficacy data floor the placebo-controlled clinical trial (E94001). These data should be provided
`in SAS transport format according to the Guidance for Industry, entitled. “Providing Regulatory
`Submissions in Electronic Format-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 Annoy in figure 3 is an example of the presentation requested for that figure,
`“Mean % change in BMD from baseline at l and 2 years after initiation of therapy with placebo and Alon
`0.025. 0.05 and 0.015 mglday." A new graph using the corrected numbers in the completer and HT
`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 labpjing (text for the package'insert, text for the patient package insert). Additions
`have been noted with Wining. deletions have been noted asm. Additional comments requiring
`reSponse are in 14 pt bold face type.
`
`Ifadditional information reliting to the safety or effectiveness ofthis drug becomes available. revision ofthe
`labeling may be rectified.“
`
`Within 10 days after the date of this letter. you are required to amend the supplemental application. notify us of
`your intent to file an amendment, or follow one ofyour 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
`reacrivated until all deficiencies have been addressed.
`
` 
`
`0012
`
`

`

`NDA 21-310
`Page 2
`
`-_
`
`6..
`r
`
`This pmduct may be considaed to be misbnnded under the Federli Food, Drug. and Cosmetic Act if it is
`marketed with these changes prior to lpproval of this supple—ta] application.
`
`If you have my questions. call Slmuel Y. Wu, Hamil. Regulatory Project Manager. at 301-827-6416.
`
`Sincerely.
`
`{See appended electronic signature page}
`
`David G. Orioff. MD.
`Director
`
`Division of Metabolic and Endocrine Drug Products
`Office of Drug Evaluation 11
`Center for Drug Evaluation and Research
`
`Enclosure
`
`-
`"h
`
`'1
`
`APPEARS 1m: m
`on ORIGENAL
`
` 
`
`0013
`
`

`

`o‘I-n J
`
`Thls Is a npuuntctlon of an oloctronlc ncord that was slgnod electronically and
`this pay. is th. mymmflon of tho aloctronlc slgnlluro.
`
`—————————————————————
`
`Mary Parks
`1/18/02 04:41:09 PM
`for Dr. Orloff.
`
` 
`
`0014
`
`

`

`WITHHOLD a3 PAGE (S)
`
`-
`
`"-
`
` 
`
`

`

` 0016
`
`

`

`NDA 21-310
`
`Page 3
`
`Esmdiol Matrix
`
`Transdennal Delivery System
`NDA 21-310
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`Wanna [abet-mien Inc.
`Ranch Put
`
`4!? Wlklll le
`511th City. UT 84108 USA
`
` 
`
`0017
`
`

`

`NDA 21-310
`
`Page4
`
`'5- .- ,
`Mono
`(estr-adiol ttansda'mal sygm)
`Continuous Delivery for Twice Weekly Dosing
`
`PRESCRIBING INFORMATION
`
`ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER.
`
`estrogens mults in a different aadomen-ial risk profile than synthetic eetrogens of equivalent estrogen dose.
`
`Close clinical surveillance ofall women taking estrogen: is important. Adequate diagnostic measures. including
`endometrial satnpling when indie-ad. should be undertaken to rule out malignancy in all cases of undiagnosed
`persistent or recurring abnormal vaginal bleeding. There is ctn'rently no evidence that the use of “neutral”
`
`DESCRIPTION
`
`Alon (esu‘adiol tt'ansdertnal swtetn) is designed to deliver estradiol continuously and consistently over a 3 out-
`day interval upon application to intact skin. Four strengths of Alon are available. having nominal in viva
`-
`delivery rates of 0.025, 0.05, 0.075. and 0.1 mg estndiol perday through skin of average permeability (inter-
`individual variation in skin permeability is approximately 20%). Mon has contact surface areas of 9, 18. 27. an
`36 cm:I and contains 0.75. 1.5, 2.3. and 3.0 mg of estradiol. USP, respectively. The composition of the estradiol
`transdemal systems per unit area is identical. Estradiol, US? is a white. crystalline powder that is chemically
`described as estra-lJJ(lO)-lriene—3, l‘JB-diol. has an empirical formula of C..H;401 and has molecular weight of
`272.39. The structural formula is:
`
`7
`
`
`
`Alora consists of three layeia. Proceeding Earn the polyethylate hacking film as shown in the cross-sectional
`view below. the adhesive Elfin: drug reservoir that is in contact with the skin consists ofcstradiol, USP and
`sorbitan monooleatgdissolved in an acrylic adhesive matrix. The polyester overlapped release liner protects the
`adhesive matrix dfifig storage and is removed prior to application ofthe system to the skin.
`
`amt-man
`
`#7
`
`3. WMWWP‘T‘:
`
` 
`
`0018
`
`

`

`NDA 21-310
`
`Page 5
`
`a. , _
`CLINICAL rmruvutELocv
`
`Estrogens are largely responsible for the development and maintenance of the female reproductive system and
`secondary sexual characteristics. Although circulating estrogen: exist in a dynamic equilibrium of metabolic
`interconversions. estndiol 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 estrogut in normally cycling adult
`women is the ovarian follicle, which secretes 70 to 500 ug of estradiol daily. depending on the phase of the
`menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstcnedione.
`secreted bytheadrenal cortex, to estrone by peripheral tissues. Thus. ecu-one and the sulfate conjugated form,
`esu-one sulfide. are the most abundant circulating estrogcns in postmenopausal women.
`
`Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date. two esu‘ogen
`receptors have been identified. These vary in proportion fi'onr tissue to tissue. Circulating estrogens modulate the
`pituitary secretion of the gonadotropins, luteinizin; hormone (Ll-I) and follicle stimulating hormone (FSH)
`through a negative feedback mechanism. Estrogen replacemart therapy acts to reduce the elevated levels of these
`hormones seen in postmenopausal women.
`
`Pharmacokhreflca
`
`The skin metabolizes estradiol only to a small extent. in contrast, orally administered estradiol is rapidly
`metabolized bythe liver to ecu-one and its conjugates. giving rise to higher circulating levels of estrnne than
`eatradiol. Therefore, tranadermal 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 suatuut corneum being the principal factor. Mora presents sufficient concentration of
`estradiol to the surface of the skin to maintain continuous transport over the 3 to 4 day dosing interval.
`
`Direct measurement of total absorbed dose ot'esuadiol through analysis ofresidual :3on content or systems
`worn over
`continuous four day interval during 25! separate occasions in 123 postmenopausal women
`demonstrated that the avenge daily dose absorbed fi'om Alora was 0.003 i 0.001 mg esnadiol per cm2 active
`surface area. The nominal mean in viva daily delivery rates of esu'adiol calculated from these data are 0.021
`mglday. 0.054 mglday, 0.081 trig/day, and 0.1 l rug/day for the 9 en’, 13 an”. 27 m2, and 36 cm: Aim.
`respectively.
`
`In another study, 20 women'also were treated with three consecutive doses ofAlora 0.05 rug/day, Alon 0.075
`rug/day and Mora 0.1 mgfdsy on abdominal application sites. Mean steady state estradiol serum concentrations
`observed over the dosing intervalare shown in Figure l.
`L
`
`..-":—'a-
`
`‘
`
`APPEARS THIS WAY
`0N ORIGINM.
`
` 
`
`0019
`
`

`

`NDA21-310
`
`P3306
`
`i;
`r u-
`
`.
`
`-
`Figure 1
`
`Mean ate-dystete estndiol serum concentration during the third twice weekly
`dose’EfAlon 0.1 rug/day, Alon 0.07s ins/day. and Alon 0.05 nag/day in 20
`
`[III/III
`Inn-Wm"
`
`O
`
`25
`
`50
`
`75
`
`100
`
`125
`
`In I singledose mndomizedctouoverstudyconduoted to compete the effect ofsite ot'Alore application, 31
`posmienopeusel women wote single Alon 0.05 mg/dey for four day periods on the lower abdomen. upper
`quadrant of the buttocks. and outside aspect of the hip. The estndiol serum concentration profiles are shown in
`Figure 2.
`
`Figure 2
`
`Mean eetndiol serum concentrations during I single 4-day wearing of Alon 0.05
`maid-y applied by 31 poeunenopeusel women to the lower abdomen. upper quednnt of
`the buttocks or outer aspect of the hip.
`
` 0
`
`25
`
`75
`50
`Flats-IMAM
`
`100
`
`125
`
`‘C... and C... statistically difl'etent from abdomen
`
`
`
`0020
`
`

`

`NDA2|~310
`
`Page?
`
`'p.
`
`Table 1 provides a Waffle estradiol pharmaooh'netic parameters studied during biopharmaceutic
`evaluation of More.
`
`Table 1
`
`Mean (SD) Pharmacokinetic Profile of Alan Over an 84-Hour Dosing Interval
`
`
`-------fl
`
`flJh)
`flmflm)
`(pymn
`(mwflb
`fiw
`ammo»
`m—mmmmmm
`“Hmmmlmm
`mm—Mflnmmmmm
`
`
`
`
`
`
`
`n—“mm—mm
`
`—m-1m: 67 45 —IHEJIKHEEI
`
`. C... and C... statistically different torn fidomen
`
`Steady state eeu'adiol serum concentrations were measured in two well-controlled clinical trials in the u'eaunentof
`menopausal symptoms of3 month duration (Studies I and 2). and one trial in the prevention of postmenopausaF
`osteoporosis of 2 year duration (Study 3). Table 2 provides a summary of these data.
`
`Table 2
`
`Mean (SD) steady-state cstradiol serum concentrations (pg/ml) in clinical trials of 3 month
`(Studies 1 and 2) and 2 year (Study 3) duration
`
`
`
`
`46.9 (38.5)
`
`38.8 (38.0)
`
`42.6 (23.7)
`
`24.5 02.4)
`
`0.075
`55.7 (36.8)
`m-__—
`
`
`
`
`
`
`
`
`In a 2-year. randomized, double-blind, placebo-controlled, prevention ofpostmenopausal osteoporosis study in
`355 hysterectornized women, the average baseline-adjusted steady-state estradiol serum conomu'ations were l8.6
`pg/ml (45 patients) fin-“the9.1725 mglday dose. 35.9 ngml (47 patients) for the 0.05 mgr/day dose and 50.1 pg/tnl
`(46 patients) for the 0.075 rug/day dose. These values were linearly related and dose proportional.
`
`;
`Distribution
`No specific investiggdon pfthe tissue distribution of emadiol absorbed fi'om Mora in humans has been
`conducted. The distribution of exogenous eatrogena is similar to that ofendogenous astrogeus. Estrogens are
`widely distributed in the body and are generally found in 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 transformations take place mainly in the liver.
`Esn-adiol is convened 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 the gut followed by reabsorption. in
`
`
`
`0021
`
`

`

`NDA 21-310
`
`Page 8
`
`_
`
`postmenopausal women fipificant portion ofthe circulating eatrogens exist as sulfate conjugates. especially
`estrone sulfate. which serves as a circulating reservoir for the formation of more active estrogens.
`'—
`
`Excretion
`
`Estr'adiol. estrone and atrial are exacted in the urine along with giucuronide and sulfate conjugates. The
`apparent mean (SD) serum half-life ofestradiol determined from biopharrnaceutic studies conducted with Alora
`is 1.15 :h 2.87 hours.
`
`Special Populations
`Alon has been studied only in healthy postmenopausal women (approximately 90% Caucasian). There are no
`long term studies in postmenopausal women with an intact utenrs. No pharmacokinetic snrdiea were conducted in
`other special populations, including patients with rural or hepatic impairment.
`
`Drug Interactions
`In vitro and in vivo studies have shown that estrogena are metabolized partially by cytochrome P450 3A4
`(CYP3A4). Therefore. inducers or inhibitors of CYPSA4 may affect estrogen drug metabolism. Inducers of
`CYP3A4 such as St. John's Wort preparations (Hypericum perforanrm), phenobarbital, phenytoin.
`carbamazepine. rifampin and dexamethasone may reduce plasma comentrations ofeatrogens. possibly resulting
`in a decrease in therapeutic effects andlor changes in the uterine bleeding profile. Inhibitors ofCYP3A4 such as
`cimetidine. crythromycin. clatithromycin. ltetoconaaale. itraconacole. ritonavir. and grapefruit juice may i
`plasma concentrations of estrogens and may result in side effects.
`
`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 cm2 size More. The placebos were
`applied twice weekly for 4 weeks on the lower quadrant of the abdomen. It should be noted that the lower
`abdoman. the upper quadrant ofthe buttocks or outer aspect of the hip are the approved sites of application for
`Mora. Subjects were instructed not to do strenuous activities. take baths, use hot min 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 ofthe 9 cmz. 21 cm: and 35 cm’ sizes of Mora have not been studied.
`
`CLINICAL STUDIES
`
`Efren on vasomotor symptoms
`Efficacy of Alon has been studied in a double blindldouble dummy. randomized. parallel group. placebo-
`controlled u-ial involving {m of268 postmenopausal women over a 12-week dosing period. Only women
`having estradiol and FSH serum concentrations in the postrmnropauaal range and who exhibited a weekly average
`of at least 60 moderate-louver: hot flushes during the screening period were enrolled in the studies.
`as
`
`Patients receivedmos mglday and a placebo system or Alon 0.1 rug/day and a placebo system, or two
`placebo systems dos-ed twice weekly over a 12-week duration. Measures of efi'rcacy included mean reduction in
`weekly number of moderate-tomato vasomotor symptoms when compared to the mean baseline average
`determined during a 2-week pro-dosing screening period. Alon was shown to be statistically better titan placebo
`at Weeks 4 and 12 for relief ofboth the frequency (see Table 3) and Severity of vasomotor syrnptcms.
`
`
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`NDA 21-310
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`
`:5 .-
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`.
`
`Table}
`
`Mean Change from Baseline in Frequency ofModerate-to-Sevcre
`'Vaaornotor Symptoms for Alon Contpared to Placebo (IT?)
`
`
`
`‘lndicates “fluidly significant dillbnneee between both strengths of More and placebo
`using an ANCOVA model adjusting bf baseline.
`
`Eject! on velar and vaginal mphy
`Vaginal cytology was obtained pre-dosing and at last visit in 54 women treated with More 0.05 mg/day, in 45
`women treated with Alon 0.1 nag/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 Alon 0.05 myday, Alon 0.] mg/day. and placebo groupe
`respectively. Corresponding reductions in basal/parabasal and intermediate eells were also observed.
`
`Em on bone mineral husky
`Lumbar spine bone mineral density (BMD) wu measured by DEXA in a two-year. randomized. multi-
`center, double-blind, placebo-controlled. study in 355 hysterectomized. non-osteoporotic women (i.e.. T-
`seores > 4.5). Eighty-six percent of the women were Caucasim, the mean age was 53.2 years (range 26
`to 69). and the average number ofyears since menopause (natural or surgical) was not determined. Three
`More doses (0.025. 0.05 and 0.075 mglday) were compared to placebo in terms of the % change in BMD
`fi-ombaselinetoYear 2. Theme appliedeverya or4daysonaltematesidesofthe 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 96 changes in BMD from baseline are ilhrsnated in
`Figure 3.
`
`0" ORIGINAL
`
`
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`NDA21-310
`
`Page l0
`
`Figure 3
`
`Mean 96 ehaniii in BMD from baseline at l and 2 years aRer initiation of therapy with
`Placebo and Alan 0.025. 0.05 and 0.075 rag/day in the cornpleter and intent-to-treat
`population with last obeuvation carried forward (LOCF)
`
`fidumalnfluoiombaaaina
`
`bannubuoqub
`
`Year I
`
`Yearz
`
`LOOP
`
`Treatment Din-anon (years)
`
`0.075 row
`“5 M
`
`0 025 maid
`
`Pluto
`
`A total of 196 patients (44 - 0.025 meld, 49 -— 0.050 tug/d, 45 - 0.075 lug/d, and 58 — placebo) were included in
`the completer population compared with 258 patients (59 — 0.025 ins/d. 64 - 0.050 mg/d, 63 — 0.075 trig/d, and
`72 — placebo) in the intent-to-treat, last observation carried forward population.
`
`All Alon doses were statistically superior to placebo for the primary endpoint. percent change in BMD from
`baseline. The mean 2-year (LOCF) percent changes in 13th for 0.025 mg/d. 0.05 myd. 0.075 mg/d. and placebo
`were 1.45%, 3.39%. 4.24%, and 41.80% respectively.
`
`INDICATIONS ”US$611
`Alora'ts indicatedIn:
`
`1. Treatment of moderate-to-severe vasomotor symptoms associated with the menopause.
`2. Treatment of mint anivaginal atrophy.
`3. Treatment ofW due to hypogonadism. castration or primary ovarian failure
`4. Prevention of postmenopausal osteoporosis. Estrogen replacement therapy reduces bone resorption and
`retards postmenopausal bone loss. When estrogen therapy“ll discontinued, bone mass declines at a rate
`comparable to that of the immediate poamtcnopauaal period.
`
`The mainstays of prevention of postmenopausal osteoporosis are weight-bearing exercise, adequate calcium
`and vitamin D intake and. when indicated, estr-ogerr. Postmenopausal women absarb dietary calcium less
`efficiently than pranenopausal women and require an average of UM mglday of elemental calcium to
`remain in neutral calcitun balance. The average calcium inure in the US is 400-600 myday. Therefore. when
`not contraindicated. calcium supplementation may be helpful for women with suboptimal dietary intake.
`Vitamin D supplementation of 400-800 lU/day may also be required to ensure adequate daily intake in
`posnnenopausal women.
`
`.
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`NDA 21-310
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`
`it. ..
`.
`vs"
`Risk factors for momma] osteoporosis include early menopause. moderately low bone mass. thin body
`build. Caucasian or Asian race, family history of osteoporosis, and lifestyle (sedentary exercise habits.
`cigarette smoking and.-alcohol abuse).
`
`CONTRAINDICATIONS
`
`Estrogens should not be used in individuals with any ofthe following conditions:
`. Known or suspected pregnancy; see PRECAUTIONS. Estrogens may cause fetal harm when administered
`to a pregnant woman.
`Undiagnosed abnormal genital bleeding;
`Known or suspected cancer ofthe breast;
`Known or suspected estrogen-dependent neoplasia;
`Active deep vein thrombosiafpulmonary embolism or a history of these conditions.
`Known hypersensitivity to any of the components of Alon.
`
`WARNINGS
`l.
`
`Induction of Malignant Neaplastna.
`a. Emmim 'l'hereported endometrisl cancerriskamongtmopposedestrogen users isaboutz
`to 12-fold greaterthan in non-users, and appears dependentonduration ofueatrnent and on estrogen
`don. Most studies show no significant increased risk associated with use ofastrogens for less titan one
`year. The greatest risk appears associated with prolonged use, with increased risks of [5 to 24-fold for
`five totaiyeamormoreandthis riskhasbeenshowntopersistforat leastBto l5 years afterestrogen
`therapy is discontinued.
`
`b. Breast meet. While some epidemiologic studies suggest a very modest increase in breast cancer risk
`for estrogen-alone users versus non-users. other studies have not shown any increased risk. The addition
`of progatin to estrogen may increase the risk for breast cancer over that noted in non-hormone users
`more significantly (by about 24 to 40%), although this is based solely on epidemiologic studies. and
`definitive conclusions await prospective, controlled clinical trials.
`
`Wom- without a uterus who require hormone replacement should receive estrogen-alone therapy. and
`should not be expo“ unnecessarily to progestins. Women with a uterus who are candidates for short-
`terrn combination eatrogenlprogeatin therapy (for relief of vasomotor symptoms) are not felt to be at a
`substantially increased risk for breast cancer. Women with a uterus who are candidates for long-term use
`of esoogen/progestin therapy should be advhed ofpotattisl benefits and risks (including the potential for
`an increaseda'iak of‘bteaat cancer).
`
`All women should receive yearly breast exams by a health-care provider and perform monthly breast-self
`examinations. In Idition, mammography examinations should be scheduled as suggested by providers
`based on Egon: gge and risk factors.
`
`2.
`
`Thromboenrbolle Disorders
`
`The physician should be aware ofthe possibility of thrombotic disorders (thrombophlebitis. retinal
`thrombosis, cerebral embolism, and pulmonary embolism) during estrogen replacement therapy and be alert
`to their earliest manifestations. Should any of these occur- or be suspected, estrogen replacement therapy
`should be discontinued immediately. Patients who have risk factors for thrombotic disorders should be kept
`under careful observation.
`
`Venous thromboernboilsnr. Several epiderniologic surdiea have found an increased risk of venous
`thrombOembolism (VTE) in users ofestrogen replacement therapy (ERT) who did not have predisposing
`conditions for VTE. such as past history of cardiovascular disease or a recent history of pregnancy,
`
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`NDA 21-310
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`'—
`
`-serious illnes. The increased risk was found only in current ERT users; it did not
`surgery. traiuna.
`Theriskappearedtobehigherintltefirstyearofuseandd