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`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
`Fax:
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`Email:
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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
`
` 
`

 
`
`
`MYLAN- EXHIBIT 1016
`0001
`
`

`

`a "2
`
`
`
`0002
`
`

`

`aor”
`;
`*
`“Nene
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`Public Health Service
`
`oo.
`Food and Drug Administration
`*...
`Rockvile MO 20857
`
`NDA 21-310 oo
`
`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 (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
`transdermal system) 0.025 mg/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 f.
`letter.
`
`This new drug application provides for 1) addition of a 0.025 mg/day strength product and 2) addition
`of an indication for the prevention ofpostmenopausal osteoporosis for all strengths.
`
`Wehave completed the review ofthis application, as amended, and have concluded that adequate
`information has been presented to demonstrate that the drug product is safe and effective for use as
`recommended in the agreed upon enclosed labeling text. Accordingly, the application is approved
`effective on the date ofthis 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 the.produet misbranded and an unapproved new drug.
`
`Please submit the copies offinal printed labeling (FPL) electronically according to the guidance for
`industry titled Providing@egulatory Submissions in Electronic Format - NDA (January 1999).
`Alternatively, youcmay-submit 20 paper copies of the FPL as soon as it is available but no more than 30
`days afterit is printed. - Please individually mount ten ofthe copies on heavy-weightpaper or similar
`material. For administrative purposes, this submission should be designated "FPL for approved NDA
`21-310." Approvalofthis submission by FDAis not required before the labeling is used.
`
`Be advised that, as ofApril 1, 1999, all applications for new active ingredients, new dosage forms, new
`indications, new routes ofadministration, and new dosing regimens are required to contain an
`assessmentofthe safety and effectiveness of the product in pediatric patients unless this requirementis
`waived or deferred (63 FR 66632). We are waiving the pediatric study requirement forthis action on
`this application.
`
`
`
`0003
`
`

`

`NDA 21-310
`Page 2
`
`+...
`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, HFD-42
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, Maryland 20857
`
`Please submit one market package of the drug product when it is available.
`
`Weremind 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 experience
`reports, field alerts, annual reports, supplements, and other submissions should be addressed to the
`original NDA, NDA 20-655,for this drug product, not to this NDA. In the future, do not make
`submissions to this NDA except for the final printed labeling requested above.
`
`Ifyou have any questions, call Samuel Y. Wu, Pharm.D., Regulatory Project Manager,at
`301-827-6416.
`
`2
`
`Sincerely,
`
`{See appended electronic signature page!
`
`David G. Orloff, 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 electronic record that was signed electronically and
`this page is the
`rganifestation of the electronic signature.
`/s/
`
`:
`ad
`
`David Orlott
`4/5/02 01:11:46 PM
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`
`
`0005
`
`

`

`ve
`
`re
`
`
`
`0006
`
`

`

`en
`
`See
`
` C. DEPARTMENTOFHEALTH&HUMANSERVICES PublicHealthService
`
`.*
`Food and Drug Administration
`
`Rockville MD 20857
`
`NDA21-310
`
`Watson Laboratories, Inc.
`Attention: Dorothy A. Frank, M.S., R.A.C.
`Director, Regulatory Affairs
`Research Park
`417 Wakara Way
`Salt Lake City, UT 84108
`
`Dear Ms. Frank:
`
`NOV 16 2001
`
`Please refer to your new drug application (NDA)dated January 12, 2001, received January 16, 2001,
`submitted under section 505(b) ofthe Federal Food, Drug, and Cosmetic Act for Alora (estradiol
`transdermal 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.
`
`We have completed the review ofthis application, as amended, andit 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 copy of your proposed container and
`pouch Jabel.
`
`H additional information relating to the safety or effectiveness of this drug becomesavailable, revision
`of the labeling may be required.
`Under 21 CFR 314,50(8\'5)(viX0), we request that you update yourNDA by submitting all safety
`information you now have regarding your new drug. The safety update should include data from al]
`nonclinical and clinicalZyudies ofthe 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
`
`

`

`—_
`
`NDA21-310 ..
`Alora (estradiol tranfdermal system)
`Page 2
`—
`
`2. When assembling the sections describing discontinuations due to adverse events, serious
`adverse events, and common adverse events, incorporate new safety data as follows:
`
`*
`
`e
`
`©
`
`¢
`
`Present new safety data from the studies for the proposed indication using the same format
`as the original NDA submission.
`
`Present tabulations of the new safety data combined with the original NDA data.
`
`Include tables that compare frequencies of adverse events in the original NDA with the
`retabulated frequencies described in the bullet above.
`
`For indications other than the proposed indication, provide separate tables for the
`frequencies ofadverse events occurring in clinical trials.
`
`3. Present a retabulation ofthe 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 ofan adverse event. In addition, provide
`hatrative summaries for serious adverse events.
`
`5. Describe any information that suggests a substantial change in the incidence ofcommon, but
`less serious, adverse events between the new data and the original NDA data.
`
`6. Provide a summary ofworldwide experience on the safety ofthis drug. Include an updated
`estimate ofuse for drug marketed in other countries.
`
`7. Provide English translations ofcurrent approved foreign labeling not previously submitted.
`
`Within 10 days after thedate ofthis letter, you are required to amend the application, notify us ofyour
`intent to file an amendment, or follow one ofyour other options under 21 CFR 314.110. In the absence
`ofany such action FDA miay proceed to withdraw the spplication. Any amendment should respond to
`all the deficiencies listgd. We will not process a partial reply as a major amendment nor will the
`review clock bereactiVured until all deficiencies have been addressed.
`The drugproduct maynotbe legallymarieted until you have beennotified in writing that the
`application is approved.
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`
`
`0008
`
`

`

`$ “
`NDA 21-310
`Alora (estradiol transdermal system)
`Page 3 =
`
`Ifyou have any questions, call Samuel Y. Wu, Pharm.D., Regulatory Project Manager,at
`301-827-6416.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`David G. Orloff, M.D.
`Director -
`Division ofMetabolic and Endocrine Drug Products
`Office ofDrug Evaluation Ll
`Center for Drug Evaluation and Research
`
`Enclosure
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`
`
`0009
`
`

`

` WITHHOLD_3(0 pace (S) -
`
`Draft
`Ca bé | IN9
`
`
`
`

`

`$...
`rT
`
`This Is a representation of an electronic record that was signed electronically and
`this page is themanifestation of the electronic signature.
`
`ame eee eee Fe ee ew eZee ee
`
`David Orloff
`11/16/01 12:21:21 PM
`
`ppreans THISSRY
`
`APPEARSTHIS Wa
`
`
`
`0011
`
`

`

`aenun,
`
`-
`.
`
`~& DEPARTMENTOFHEALTH&HUMANSERVICES
`
`PublicHealthService
`
`Food and Drug Administration
`Rockville MD 20857
`
`mle,
`
`*
`
`-
`
`-
`
`NDA 23-310
`
`_
`
`~
`
`Watson Laboratories,Inc.
`
`Attention: DorothyFrank, M.S.,R.A.C.
`
`Director, Regulatory Affairs
`Research Park
`4)7 Wakara Way
`Salt Lake City, UT 84108
`
`JAN 1 8 ane
`
`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 transdermal system)
`0.02 Smg/day, 0.05 mg/day, and 0.075 mg/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 ofthis application, as amended, and it is approvable. Before this application
`may be approved, however,it will be necessary for you to address the following Isbeling issues:
`
`1, 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 Alora Compared to Placebo,”
`submit the efficacy data from 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 Agency in figure 3 is an example ofthe 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. 0.05 and 0.075 mg/day.” A 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 labeling (text for the package insert, text for the patient package insert). Additions
`have been noted with indesiining, deletions have been noted as etikeeute. Additional comments requiring
`response are in 14 pt bold face type.
`
`Ifadditional information refitting to the safety or effectiveness ofthis drug becomes available, revision ofthe
`labeling may be
`7
`
`Within 10 days after the date ofthis letter, you are required to arnend the supplemental application, notify us of
`ycur intentto file an amendment, or follow one ofyour other options under 2] CFR 314.110. In the absence of
`any such action FDA may proceed to withdraw the application. Any amendment should respondtoall 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
`
`

`

`a
`
`™
`
`NDA21-310
`Page 2
`
`o.
`rT
`This product may be considered to be misbranded under the Federal Food, Drug, and Cosmetic Actifit is
`marketed with these changes prior to approval of this supplemental application.
`
`Ifyou have any questions, call Samuel Y. Wu, Pharm.D., Regulatory Project Manager, at 301-827-6416.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`David G. Orloff, M.D.
`Director
`Division of Metabolic and Endocrine Drug Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`__*
`ee
`
`APPEARS THIS WAY
`ON ORICINAL
`
` 
`
`0013
`
`

`

`Oe) ’
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`sane ee ew eee aeee
`
`Mary Parks
`1/18/02 04:41:09 PM
`for Dr. Orloff
`
`ag THIS WAY
`RTORIGINAL
`
` 
`
`0014
`
`

`

`WITHHOLD.pace (sy,
`
`Uratk
`Labe lanq
`
` 
`
`

`

`
`
`ApplicationNumberNIDA21-310
`
` 
`
`0016
`
`

`

`NDA21-310
`Page 3
`
`TO
`
`Estradiol Matrix
`Transdermal Delivery System
`NDA 21-310
`
`Package Insert
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`27
`;
`
`Watson Laboratories Inc.
`Research Park
`417 Wakare Way
`Salt Lake City, UT 84108 USA
`
` 
`
`0017
`
`

`

`NDA21-310
`Page 4
`
`+...
`Alora®
`(estradiol transdermal system)
`Continuous Delivery for Twice Weekly Dosing
`
`PRESCRIBING INFORMATION
`
`ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER,
`
`estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose.
`
`Close clinical surveillance ofali women taking estrogens is important. Adequate diagnostic measures, including
`endometrial sampling when indicated, should be undertaken to nile out malignancy in all cases of undiagnosed
`persistent or recurring abnormal vaginal bleeding. There is currently no evidence that the use of “natural”
`
`DESCRIPTION
`
`Alora (estradiol transdermal system) is designed to deliver estradiol continuously and consistently over a 3 of 4-
`day interval upon application to intact skin. Four strengths of Alora are available, having nominal in vivo
`delivery rates of 0.025, 0.05, 0,075, and 0.1 mg estradiol per day through skin of average permeability (inter-
`individual variation in skin permeability is approximately 20%). Alora has contact surface areas of 9, 18, 27, an
`36 cm’ and contains 0.75, 1.5, 2.3, and 3.0 mg ofestradiol, USP, respectively. The composition ofthe estradiol
`transdermal systems per unit area is identical. Estradiol, USP is a white, crystalline powder that is chemically
`described as estra-),3,5(10)-triene-3, !7B-diol, has an empirical formula of C;,H24Q, and has molecular weight of
`272.39. The structural formulais:
`
`|
`
`
`
`Alora consists of three layers. Proceeding from the polyethylene backing film as shown in the cross-sectional
`view below, the adhesive matrix drug reservoir that is in contact with the skin consists ofestradiol, USP and
`sorbitan monooleatedissolved in an acrylic adhesive matrix. The polyester overlapped release liner protects the
`adhesive matrix diting storage and is removed priorto application ofthe system to the skin.
`
`1. Polyethytene Becking Fim
`
`2. Adiheeive Matrix Drug Reservoir
`
`3. Gverlapped Aelease Liner Stripe, Peel Tab
`
` 
`
`0018
`
`

`

`NDA21-310
`Page 5
`
`o...
`CLINICAL PHARMACOLOGY
`Estrogens are largely respeasibie for the development and maintenance of the fernale 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 adult
`women is the ovarian follicle, which secretes 70 to 500 1g ofestradiol 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. Thus, estrone and the suifate conjugated form,
`estrone sulfate, are the most abundantcirculating 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 gonadotopins,luteinizing 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 estradiolis rapidly
`metabolized by the liver to estrone andits conjugates, giving rise to higher circutating levels of estrone than
`estradiol. Therefore, transdermal administration produces therapeutic plasma levels of estradiol with lower levelsff.
`of estrone and estrone conjugates and requires smaller total doses than does oral therapy.
`
`Absorption
`Estradiol ts transported across intact skin and into the systemic circulation by # passive diffusion process, the rate
`of diffusion across the stratum comeum beingthe principal factor. Alora presents sufficient concentration of
`estradiol to the surface ofthe skin to maintain continuous transport over the 3 to 4 day dosing interval).
`
`Direct measurement oftotal absorbed dose of estradiol through analysis of residual estradiol content of systems
`wom overacontinuous 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 cm’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 em’, 18 cm’, 27 cm’, and 36 cm’ Alora,
`respectively.
`
`In another study, 20 womezralso were treated with three consecutive doses ofAlora 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.
`>
`
`a
`
`APPEARS THIS WAY
`ON ORIGINAL
`
` 
`
`0019
`
`

`

`NDA 21-310
`Page 6
`
`;
`+.
`Figure 1
`wr
`Mean Steadystate estradiol serum concentration during the third twice weekly
`doseofAlora 0.{ mg/day, Alora 0.075 mg/day, and Alora 0.05 mg/dayin 20
`postmenopausal women.
`
`160
`
`F 140
`B 120
`W100
`a0
`
`§ 6040
`j 20
`°
`
`
`
`100
`75
`sO
`25
`Hours Post-Appllostion of Third Cows
`
`125
`
`0
`
`In a single dose randomized crossover study conducted to compare the 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 hip. The estradiol serum concentration profiles are shown in
`Figure 2.
`
`Figure 2
`
`Mean estradiol serum 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 the hip.
`
`
`
`50
`73
`Hours PostApplication
`
`100
`
`125
`
`“Cons and Cyyg Statistically different from abdomen
`
`
`
`0020
`
`

`

`NDA 21-310
`Page 7
`
`-
`
`Table 1 provides a sumumaigyofthe estradiol pharmacokinetic parameters studied during biopharmaceutic
`
`evaluation of Alora.
`
`Table 1
`
`Mean (SD) Pharmacokinetic Profile of Alora Over an §4-Hour Dosing Interval
`
`
`
`» Con ad C,,g Statistically different from abdomen
`
`Steady state estradiol serum concentrations were measured in two well-controlled clinical triais in the treatmentof
`menopausal symptoms of 3 month duration (Studies | and 2), and onetrial in the prevention of postmenopausal’
`osteoporosis of 2 year duration (Study 3). Table 2 provides a summary ofthese data.
`
`Table 2
`
`Mean (SD) steady-state estradiol serum concentrations (pg/m))in clinica] trials of 3 month
`(Studies 1 and 2) and 2 year (Study 3) duration
`
`
`poms[i *dCes ay
`[00s|a6aces)|seacen|26030
`
`
`~oors870858)
`[ot|wamm|moan]-|
`
`
`
`
`In a 2-year, randomized, double-blind, placebo-controlled, prevention ofpostmenopausal osteoporosis study in
`355 hysterectomized women, the average baseline-adjusted steady-state estradiol serum concentrations were 18.6
`pg/ml (45 patients) forthe0:°025 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 lincarly related and dose proportional.
`
`x
`Distribution
`Nospecific investigation ofthe tissue distribution ofestradio! absorbed from Alora in humans has been
`conducted. The distribution of exogenous estrogens is similar to that ofendogenous estrogens. Estrogens are
`widely distributed in the body and are generally found in higher concentrations in the sex hormonetarget organs.
`Estrogens circulate in the blood largely bound to sex hormone binding giobulin (SHBG) and albumin.
`
`Metabolism
`Exogenousestrogens 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 Jiver.
`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 conjugationin the
`liver, biliary secretion of conjugates into theintestine, and hydrolysis in the gut followed by reabsorption. In
`
`
`
`0021
`
`

`

`NDA 21-310
`Page 8
`postmenopausal women Ssignificant portion ofthe circulating estrogens exist as sulfate conjugates, especially
`estrone sulfate, which serves as & circulating reservoir for the formation of more active estrogens.
`
`~
`Excretion
`Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The
`apparent mean (SD) serum half-life ofestradiol determined from biopharmaceutic studies conducted with Alora
`is 1.75 + 2.87 hours.
`
`Special Populations
`Alora has been studied only in healthy postmenopausal women (approximately 90% Caucasian). There are no
`long term studies in postmenopausal women with an intact uterus. No pharmacokinetic studies were conducted in
`other special populations, inchiding patients with renal or hepatic impairment.
`
`Drug Interactions
`In vitro and in vivo studies bave shown that estrogens are metabolized partially by cytochrome P450 3A4
`(CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of
`CYP3A4 such as St. John's Wort preparations (Hypericum perforatum), phenobarbital, phenytoin,
`carbamazepine, 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 ofCYP3A4 such as
`cimetidine, erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, and grapefruit juice may i
`plasma concentrations ofestrogens and mayresult in side effects.
`
`Adhesion
`The adhesion potential of AJora was evaluated in a randomized clinical trial involving 408 healthy
`postmenopausal women who wore placebo systems corresponding to the 18 cm? size Alora. The placebos were
`applied twice weekly for 4 weeks on the lower quadrant ofthe abdomen. It should be noted that the lower
`abdomen, the upper quadrant ofthe buttocks of outer aspect of the hip are the approved sites ofapplication 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 ofthe 9 cm’, 27 cm’ and 36 cm’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, paralie) group, placebo-
`controlied trial involvifig atal of268 postmenopausal women over a 12-week dosing period. Only women
`having estradio] and FSH serum concentrations in the postmenopausal range and who exhibited a weekly average
`of at least 60 moderate-to-severe hot flushes during the screening period were enrolied in the studies.
`=
`Patients received Alera-0,.05 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-to-severe vasomotor symptoms when compared to the mean baseline average
`determined during a 2-week pre-dosing screening period. Alora was shown to be statistically better than placebo
`at Weeks 4 and 12 forrelief ofboth the frequency (see Table 3) and severity of vasomotor symptoms.
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`NDA 21-310
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`Table 3
`£. we.
`Mean Change from Baseline in Frequency ofModerate-to-Severe
`“Vasomotor Symptoms for Alora Compared to Placebo (ITT)
`
`
`
`*Tndicates statistically significant differences between both strengths of Alora and placebo
`using an ANCOVA model adjusting for baseline.
`
`Effects on vulvar and vaginal atrophy
`Vaginal cytology was obtained pre-dosing and atlast visit in 54 women treated with Alora 0.05 mg/day, in 45
`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,
`respectively. Corresponding reductions in basal/parabasal and intermediate cells were also observed.
`
`Effects on bone mineral density
`Lumbar spine bone mineral density (3MD) was measured by DEXA in a two-year, randomized, multi-
`center, double-blind, placebo-controiled, study in 355 hysterectomized, non-osteoporotic women (i.e., T-
`scores > -2.5). Eighty-six percentofthe women were Caucasian, the mean age was 53.2 years (range 26
`to 69), and the average number of years since menopause (natural 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 alternate sides of the lower
`abdomen. All patients received 1000 mg oforal elemental calcium daily. The average baseline lumbar
`spine T-score was -).64 (range -2.7 to 3.8). The % changes in BMD from baseline are j]hustrated in
`Figure 3.
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`APPEARS THIS WA
`ON ORIGINAL
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`Figure 3
`Mean % change in BMD from baseline at ] and 2 years after initiation oftherapy with
`Placebo and Alora 0.025, 0.05 and 0.075 mg/day in the compieter and intent-to-treat
`population with last observation carried forward (LOCF)
`
`
`
`%changeinBMDfrombaseline
`
`2ewwnveuw@4ow& 0.075 myid
`
`0.05 mgid
`
`0.025 mgAd
`
`Placebo
`
`Year?
`
`Year2
`
`LOCF
`
`Treatment Duration (years)
`
`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
`the completer population compared with 258 patients (59 — 0.025 mg/d, 64 - 0.050 mg/d, 63 — 0.075 mg/d, and
`72 — placebo) in the intent-to-treat, last observation carried forward population.
`
`All Alora doses were statistically 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 ANDUSAGE
`Alora is indicated in:
`1. Treatment ofmoderate-to-severe vasomotor symptoms associated with the menopause.
`2. Treatment ofvulvar angvaginal atrophy.
`3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian faiture.
`4. Prevention of postmenopausal osteoporosis. Estrogen replacementtherapy reduces bone resorption 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 postmenopsusal 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 {500 mg/day of elemental calcium to
`remain in neutral calcium balance. The average calcium inteke in the US is 400-600 mg/day. Therefore, when
`not contraindicated, calcium supplementation may be helpful for women with suboptimaldietary intake.
`Vitamin D supplementation of 400-800 [U/day may also be required to ensure adequate daily intake in
`postmenopausal women.
`
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`NDA21-310
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`e.
`7:
`Risk factors for postmenopausal 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 andalcohol 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
`1.
`to a pregnant woman.
`Undiagnosed abnormal genital bleeding;
`Known or suspected cancer of the breast;
`Known or suspected estrogen-dependent neoplasia,
`Active deep vein thrombosis/pulmonary embolism or a history of these conditions.
`Known hypersensitivity to any of the components ofAlora.
`
`AwPwn
`
`WARNINGS
`1.
`Induction of Malignant Neoplasms.
`a. Endometrial cancer, The reported endometrial cancer risk among unopposed estrogen users is about 2
`to 12-fold greater than in non-users, and sppears dependent on duration oftreatment and on estrogen
`dose. Moat studies show no significant increased risk associated with use ofestrogens 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 least 8 to 15 years after estrogen
`therapy is discontinued.
`
`b. Breast cancer. 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 progestin 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.
`
`Women without a utenss who require hormone replacement should receive estrogen-alone therapy, and
`should not be exposed unnecessarily to progestins. Women with a uterus who are candidates for short-
`term combination estrogen/progestin therapy (for reliefof 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 estrogen/progestin therapy should be advised ofpotential benefits and risks (including the potential for
`an increasedsisk ofbreaat cancer),
`All women should receive yearly breast exams by a health-care provider and perform monthly breast-self
`examinations. In ggidition, mammography examinations should be scheduled as suggested by providers
`based on patient age and risk factors.
`
`2. Thromboembelic Disorders
`The physician should be aware ofthe possibility of thrombotic disorders (thrombophlebitis,retina!
`thrombosis, cerebral embolism, and pulmonary embolism) during estrogen replacement therapy andbe alert
`to their carliest manifestations. Should any of these occur or be suspected, estrogen replacementtherapy
`should be discontinued immediately. Patients who have risk factors for thrombotic disorders should be kept
`under careful observation.
`
`Venous thromboentbolism. Severa