*5243107*
`
`Ax
`
`9243107
`
`A
`
`{Part of Complete Approval Document 5204906A} Climara 0.025mg
`Transdermal System (Berlex Laboratories) 04/05/2001
`Supplemental Approval [Severe Vasomotor Symptoms and Vulvar
`and Vaginal Atrophy]: S16 ApprovalLetter; Final Labeling
`
`This document was provided by:
`
`FOI Services, Inc
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`301-975-0702
`Email:
`infofoi@foiservices.com
`
`
`
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`
`MYLAN- EXHIBIT 1015
`0001
`
` 
`

 
`
`
`

`

`gaylray.
`
`”
`
`%,LC DEPARTMENTOFHEALTII&ITUMANSERVICES
`PublicHeaithService
`caTHALTa
`ot
`Food and Drug Administration
`
`Rackville MD 20857
`
`NDA 20-375/S-016
`
`Berlex Laboratories, Inc.
`Attention: Geoffrey Millington
`Manager, Drug Regulatory Affairs
`340 Changebridge Road
`P.O, Box 1000
`Montville, NJ_ 07450-1000
`
`Dear Mr. Millington
`
`Please refer to your supplemental new drug application dated June 2, 2000, reccived June 5, 2000,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Climara® (Estradiol!
`transdermal System) 0.025, 0.05, 0.075, 0.1! mg/day.
`
`Weacknowledge receipt of your submissions dated July 31, August 4, 10, 17, 18, and September 15,
`2000, January 5, February 13 and March 19, 21, 27, April 3 and April 4, 200).
`
`This supplemental new drug application provides for the use of the 0.025 mg/day Climara® (Estradiol
`transdermal System) for the treatment of moderate to severe vasomotor symptomsand vulvar and
`vaginal atrophy associated with the menopause.
`
`We have completed the review ofthis supplemental application, as amended, and have concluded that
`adequate information has been presented to demonstrate that the drug productis safe and effective for
`use as recommended in the agreed uponlabeling text. Accordingly, the supplemental application is
`approved effective on the date ofthis letter.
`
`Thefinal printed labeling (FPL) must be identical to the enclosed labeling (package insert submitted
`April 4, 2001 and patient package insert submitted April 4, 2001).
`
`Please submit the copies offinal printed labeling (FPL) electronically according to the guidance for
`industry titled Providing Regulatory Submissions in Electronic Format - NDA (January 1999).
`Alternatively, you may submit 20 paper copies of the FPLas soonasit is available but no more than 30
`daysafterit is printed. Please individually mount ten of the copies on heavy-weight paper or similar
`matenal, For administrative purposes,this submission should be designated "FPL for approved
`supplement NDA 20-375/S-016." Approvalofthis submission by FDAis not required before the
`labeling is used.
`
`Be advised that, as of Apri! 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
`assessmentofthe 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.
`
`
`
`0002
`
`
`
`
`

`

`NDA20-375/S-016
`Pape 2
`
`In addition, please submit three copies of the introductory promotional materials that you propose to
`use for this product. All proposed materials should be submitted in draft or mock-up form,not final
`print. Please submit one copyto this Division and two copies ofboth the promotional materials and
`the package insert directly to:
`
`Division of Drug Marketing, Advertising, and Communications, HFD-42
`Food and Ding Administration
`5600 Fishers Lane
`Rockville, Maryland 20857
`
`If a letter communicating important information about this drug product (i.c.. a "Dear Health Care
`Professional”Jeter) is issued to physicians and others responsible for patient care, we request that you
`submit a copy ofthe Ictter to this NDA and a copyto the following address:
`
`MEDWATCH,HF-2
`FDA
`5600 Fishers Lane
`Rockville, MD 20857
`
`Please submit one market package ofthe drug product whenit is available.
`
`We remind you that you must comply with the requirements for an approved NDAset forth under
`21 CFR 314.80 and 314.81.
`
`If you have any questions,call Diane Moore, BS, Regulatory Project Manager, at (301) 827-4260.
`
`Sincerely,
`
`jdee appended electronic signature page;
`
`Susan Allen, M.D.
`Director
`Division of Reproductive and Urologic Drug Products
`Office of Drug Evaluation UI
`Center for Drug Evaluation and Research
`
`
`
`0003
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:20-375/S-016
`
`FINAL PRINTED LABELING
`
`
`
`0004
`
`

`

`NDA20-375/S-016
`Page 3
`
`Rx Only
`
`PRESCRIBING INFORMATION
`
`Climara® estradiol transdermal system
`
`
`
` 4. ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER.Closeclinical surveillance of
`ail women taking estrogensis important. Adequate diagnostic measures, including endometnal
`sampling whenindicated, should be undertakento rule out malignancyin all cases of undiagnosed
`
`persistent or recurring abnormalvaginal 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 doses.
`
`
`
`
`. There is no indication for estrogen therapy during pregnancyor during the immediate postpartum
`
`period. Estrogensare ineffective for the prevention or treatment of threatened or habitual abortion.
`
`
`Estrogensare notindicated for the prevention of postpartum breast engorgement.
`
`
`
`
`DESCRIPTION
`Climara®, estradiol transdermal system, is designed to release 17f-estradiol continuously upon
`application to intact skin. Four (6.5, 12.5, 18.75 and 25.0 cm*) systems are available to provide
`nominalin vivo delivery of 0.025, 0.05, 0.075 or 0.1 mg respectively of estradiol per day. The period of
`use is 7 days. Each system has a contact surface areaof either 6.5, 12.5, 18.75 or 25.0 cm*, and
`contains 2.0, 3.8, 5.7 or 7.6 mgof estradiol USP respectively. The composition of the systems perunit
`area is identical.
`
`Estradiol USP (17-estradiol) is a white, crystalline powder, chemically described as
`estra-1,3,5(10}triene-3,17B-diol. {thas an empirical formula of C1sH24O2 and molecular weightof
`272.37. The structural formula is:
`
`
`
`The Climara® system comprises two layers. Proceedingfrom thevisible surface toward the surface
`attached to the skin, these layers are (1) a translucent polyethylene film, and (2} an acrylate adhesive
`matrix containing estradiol USP. A protective liner (3) of siliconized or fluoropolymer-coated polyester
`film is attached to the adhesive surface and must be removed before the system can be used,
`
`(1) Film Backinganigntun
`
`(3) Protective Uner
`
`
`
`0005
`
`

`

`NDA20-375/5-016
`Page 4
`
`The active componentof the system is 17$-estradiol. The remaining componentsof the system
`(acrylate copolymer adhesive,fatty acid esters, and polyethylene backing) are pharmacologically
`inactive.
`
`CLINICAL PHARMACOLOGY
`
`The Climara® system provides systernic estrogen replacement therapy by releasing 17}-estradiol, the
`major estrogenic harmone secreted by the human ovary.
`
`Estrogensare 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, estradiolis the principalintracellular 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 womenis the ovarianfollicle, which secretes 70 to 500 pg
`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 adrenalcortex, to estrone by
`peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most
`abundantcirculating estrogens in postmenopausal women.
`
`Estrogens act through binding to nuclear receptors in estrogen-responsivetissues. To date, two
`estrogen receptors have been identified. These vary in proportion from tissueto tissue.
`
`Circulating estrogens modulate the pituitary secretion of the gonadotropinsluteininizing hormone (LH)
`and follicle stimulating hormone (FSH) through a negative feedback mechanism and estrogen
`replacement therapy acts to reduce the elevated levels of these hormones seenin postmenopausal
`women.
`
`A two-yearclinicaltrial enrolled a total of 175 healthy, hysterectomized, postmenopausal, non-
`osteoporotic (i.e., lumbar spine bone mineral density > 0.9 gm/cm?) womenat 10 study centers in the
`United States. 129 subjects were allocated to receive active treatment with 4 different doses of 17 B-
`estradiol patches (6.5, 12.5, 15, 25 cm) and 46 subjects were allocated to receive placebo patches.
`77% of the randomized subjects (100 an active drug and 34 on placebo) contributed data to the
`analysis of percent change of A-P spine bone mineral density (BMD), the primary efficacy variable
`(see Figure 1). A statistically significant overall treatmenteffect at each timepoint was noted,implying
`bone preservation forall active treatment groupsatall timepoints, as opposed to bone loss for placebo
`at all timepoints.
`
`
`
`0006
`
`

`

`NDA 20-375/8-016
`Page 5
`
`Figure 1. Mean Percent Change from Baseline in Lumbar Spine
`{A-P View) Bone Mineral Density
`By Treatment and Time
`last observation carried forward**
`
`%CHANGE
`
`16-00
`
`20-0
`
`BASEUNE
`
`TREATMERT
`
`6-40
`
`
`12-Mi)
`visit
`PLAGE BO — —- — 65am
`ee + 125em? + 15cm
`—~—- Bor
`
`Percent change in BMDofthetotal hip (see Figure 2). was alsostatistically significantly different from
`placebo forall active treatment groups. The results of the measurements of biachemical markers
`supported the finding of efficacy for all doses of transdermalestradiol. Serum osteocaicin levels
`decreased, indicative of a decrease in bone formation,atall timepoints forall active treatment doses,
`statistically significantly different from placebo (which generally rose). Urinary deoxypyridinoline and
`pyridinoline changes also suggested a decrease in bone tumoverforall active treatment groups.
`
`
`
`0007
`
`

`

`NDA 20-375/8-016
`Page 6
`
`Figure 2. Mean Percent Change
`from Baseline in Total Hip
`by Treatment and Time*
`last observation caried forward**
`
`gs CELLeh
`— wi
`6
`~— “5 —-— +85
`an = OMe eo
`
`end
`
`wi
`
`2
`4
`a
`=z
`x °
`
`2 “
`
`dl
`
`
`
`
`
`12M0
`VEIT
`
`TREATMENT PLACEBQ«=—-— ~~ + Sem?
`——— - t28 em" ——--+— Sc?
`—— — -— Bem
`
`
`
`18-M0
`
`24-0
`
`6-40
`
`4S
`
`ASELINE
`
`Footnote: This figure is based on 74% of the randomized subjects (95 on active drug
`and 34 on placebo}.
`
`PHARMACOKINETICS
`
`Transdermal administration of Climara® produces mean serum concentrations of estradiol comparable
`to those produced by premenopausal womenin the early follicularf phase of the ovulatory cycle. The
`pharmacokinetics of estradiol following application of the Climara® system were investigated in 197
`healthy postmenopausal womenin six studies.In five of the studies Climara® system was applied to
`the abdomen and in a sixth study application to the buttocks and abdomen were compared.
`
`Absorption: The Climara® transdermal delivery system continuously releases estradiol which is
`transported acrossintact skin leading to sustained circulating levels of estradiol during a 7 day
`treatment period. The systemic availability of estradiol after transdermal administration is about 20
`times higher than thatafter oral administration. This difference is due to the absenceoffirst pass
`metabolism when estradiol is given by the transdermalroute.
`
`
`
`0008
`
`
`
`

`

`NDA20-375/S-016
`Page 7
`
`in a bioavailability study, the Climara® 6.5 cm” was studied with the Climara® 12.5 cm’ as reference.
`The mean estradiol levels in serum from the two sizes are shownin Figure 3.
`
`Figure 3
`Mean Serum 17B-Estradiol Concentrations vs. Time Profile following Application of a 6.5 cm’
`Transdermal Patch and Application of a 12.5 cm?Climara®patch.
`
`(pg/mL)
`CONCENTRATIONS
`
`0
`30
`60
`legend: © 6.5 em? Climara patch
`012.5 cm? Climara patch
`
`80
`TIME (HOURS)
`
`120
`
`150
`
`160
`
`
`
`Dose proportionality was demonstrated for the Climara® 6.5 cm? transdermal system as compared to
`the Climara® 12.5 cm? transdermal system in a 2-week crossoverstudy with a 1-week washout period
`betweenthe two transderma! systems in 24 postmenopausal women.
`
`0009
`
`
`
`

`

`NDA 20-375/S-016
`Page &
`
`Dose proportionality was also demonstratedfor the Climara® system (12.5 cm? and 25 cm2 yin a 1-
`week study conducted in 54 postmenopausal women. The mean steady stale levels (Cavg) of the
`estradiol during the application of Climara® 25 cm? and 12.5 cm? on the abdomen were about 80 and
`40 pa/mL, respectively.
`
`In a 3-week multiple application study in 24 postmenopausal women,the 25.0 cm? Glimara® system
`produced average peakestradiol concentrations (Cmax) of approximately 100 pg/mL. Trough values
`at the end of each wearinterval (Cmin) were approximately 35 pg/mL. Nearly identical serum curves
`were seen each week,indicatinglittle or no accumulation of estradiolin the body. Serum estrone peak
`and trough levels were 60 and 40 pg/mL, respectively.
`
`In a single-dose, randomized, crossover study conducted to comparethe effectof site of application,
`38 postmenopausal women wore a single Climara® 25 cm? system for one week on the abdomen and
`butfocks. The estradiol serum concentration profiles are shownin Figure 4. Cmax and Cavg values
`were, respectively, 25% and 17% higher with the buttock application than with the abdomen
`application.
`
`Figure 4.
`Observed Mean (+ S.E.) Estradiol Serum Concentrations for a One Week Application of the Climara®
`system (25 cm’) to the abdomen and buttocks of 38 postmencpausal women.
`
`OOOw2pmez
`FE.89
`
`o
`
`tft
`
`4M
`
`BM & 0 72 MB RS 1 me Ms
`SAMPLING TIME - HOURS AFTER PATCH APPLICATION
`
`TREATMENT=|~—— BUTTOCK —- AGDOMEN
`
`tH 1 Oe
`
`
`
`0010
`
`

`

`Climara®|Surface|Application|No.of Cmin|CavgCmax
`
`
`
`Delivery|Area (pg/mL}|(pg/mL)|(pg/mL)Site Subdjects
`
`
`Rate
`cm
`16.5|Abdomen[24 |S
`(0.05|12.5|Abdomen|102
`[O41 [25|Abdomen[139
`[O4125|Buttock=[38|Single
`
`
`
`
`
`
`NDA20-375/S-016
`Page 9
`
`Table 4 Provides a summary of estradiol pharmacokinetic parameters determined during evaluation of
`Climara”.
`
`Table 1
`Pharmacokinetic Summary
`{Mean Estradiol Values)
`
`Therelative standard deviation of each pharmacokinetic parameter after application to the abdomen
`averaged 50%, which is indicative of the considerable intersubject variability associated with
`transdermal drug delivery. The relative standard deviation of each pharmacokinetic parameter after
`application to the buttock was lower than that after application to the abdomen (e.g., for Cmax 39% vs
`62%, and for Cavg 35% vs 48%).
`
`Distribution: The distribution of exogenous estrogensis similar to that of endogenous estrogens.
`Estrogens are widelydistributed in the body and are generally found in higher concentrations in the
`sex hormonetarget organs. Estradiol and other naturally occurring estrogens are bound mainly to sex
`hormone binding globulin (SHBG), and to lesser degree to albumin.
`
`Metabolism: Exogenous estrogens are metabolized in the same manner as endogenousestrogens.
`Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These
`transformations take place mainly in the fiver. 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 theliver, biliary secretion of
`conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal
`women a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone
`sulfate, which serves as a 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. After removal of the Climara® system, serum estradiol levels decline in about 12 hours to
`preapplication levels with an apparenthalf-life of approximately 4 hours.
`
`Special poputatians:
`
`Genatric: There have not been sufficient numbers ofgeriatric patients involved in clinical studies
`utilizing Climara® to determine whether those over 65 years of agediffer from younger subjects in their
`response to Climara®.
`
`Pediatric: No pharmacokinetic study for Climara® has been conducted in a pediatric population.
`
`Gender: Climara® is indicated for use in womenonly.
`
`Race: No studies were doneto determinethe effect of race on the pharmacokinetics of Climara®.
`
`0011
`
`
`
`

`

`NDA 20-375/S-016
`Page 10
`
`Patients with Renal (mpairment: Total estradiol serum levels are higher in postmenopausal women
`with end stage renal cisease (ESRD)receiving maintenance hemodialysis than in normal subjects at
`baseline and following oral doses of estradiol. Therefore, conventional transdermal estradiol doses
`usedin individuals with normal renal function may be excessive for postmenopausal women with
`ESRDreceiving maintenance hemodialysis.
`
`Patients with Hepatic Impairment: Estragens may be poorly metabolized in patients with impairedliver
`function and should be administered with caution.
`
`Drug Interactions: No drug interaction studies have been conducted.
`
`Adhesion
`
`An open-label study of adhesion potentials of placebo transdermal systems that correspond to the 6.5
`cm? and 12.5 cm’sizes of Climara® was conducted in 112 healthy women of 45-75 years of age. Each
`woman applied both transdermal systems weekly, on the upper outer abdomen,for three consecutive
`weeks.
`{t should be noted that lower abdomen and upper quadrantof the buttock are the approved
`sites of application for Climara®.
`
`The adhesion assessment was donevisually on Days 2, 4, 5, 6, 7 of each week of transdermal system
`wear. A total of 1654 adhesion observations were conducted for 333 transdermal systems of each
`size.
`
`Of these observations, approximately 90% showed essentially nolift for both the 6.5 cm’ and 12.5 cm?
`transdermal systems. Of the tota! numberof transdermal systems applied, approximately 5% showed
`complete detachmentfor eachsize.
`Adhesion potentials of the 18.75 cm? and 25.0 cm?sizes of transdermal systems (0.075 mg/day and
`0.1 mg/day) have not been studied.
`
`Clinical Studies
`
`Climara®is effective in reducing moderate to severe vasomotor symptoms in postmenopausal women.
`
`A total of 214 patients were enrolled in a study, to determinethe efficacy of Climara® 0.05 mg/day and
`0.1 mg/day compared to placebo and an active comparator. Women took drugin a cyclical fashion
`(three weeks on and one weekoff).
`
`A study of 214 women 25 to 74 years old met the qualification criteria and were randomly assigned to
`one of the three treatment groups: 72 to the 0.05 mg estradiol patch, 70 to the 0.1 mg estradiol patch,
`and 72 to placebo, Potential subjects were postmenopausal women in good general health who
`experienced vasomotor symptoms. Natural menopause patients had not menstruatedfor at least 12
`months and surgical menopause patients had undergonebilateral oophorectomyat Jeast four weeks
`before evaluation for study entry.
`In order to enter the 11-week treatment phase of the study, potential
`subjects must have experienced a minimum offive moderate to severe hat flushes per week, or a
`minimum of 15 hot flushes of any severity per week, for two consecutive weeks. Women wore the
`patchesin a cyclical fashion (three weeks on and one weekoff).
`
`During treatment, all subjects used diaries to record the numberand severity of hot flushes. Subjects
`were monitored byclinic visits at the end of Weeks 1, 3, 7, and 11 and by telephone at the end of
`Weeks 4, 5, 8, and 9.
`
` 
`
`0012
`
`

`

`NDA 20-375/S-016
`Page t1
`
`Adequate data for the analysis of efficacy was available from 191 subjects. The results are presented
`as the mean + SD numberofflushes in each of the three treatment weeks of each 4-week cycle.
`In
`the 0.05 mg estradiot group, the mean weekly hotflush rate acrossall treatment cycles decreased
`from 46 + 6.5 at baseline to 20 + 3.0 (-67.0%). The 0.1 mg estradiol group had a declinein the mean
`weekly hot flush rate from 52 + 4.4 at baseline to 16 + 2.4 (-72.0%).
`In the placebo group, the mean
`weekly hot flush rate declined from 53 + 4.5 at baseline to 46 + 6.5 (-18.1%). Compared with placebo,
`the 0.05 mg and 0.1 mg estradiol groups showeda statistically significantly larger mean decrease in
`hot flushes acrossall treatment cycles (P< 0.05). When the response to treatment was analyzed for
`eachof the three cycles of therapy, similarstatistically significant differences were observed between
`both estradiol treatment groups and the placebo group duringall treatment cycles.
`
`In a double-blind, placebo-controlled, randomized study of 187 women receiving Climara®
`0.025 mg/day or placebo continuously for up to three 28-day cyctes, the Climara® 0.025 mg/day
`dosage was shownto be statistically better than placebo at Weeks 4 and 12 forrelief of both the
`frequency (see Table 3) and severity of moderate-to-severe vasomotor symptoms.
`
`Table 3
`Mean Changefrom Baseline in the Number of Moderate-to-Severe Vasomotor Symptoms ({TT)
`
`E,TDS sts
`
`Week 4
`82
`-6.45
`4.65
`
`Week 12
`
` Treatment Group|Statistics
`
`fe 5.14
`
`pC SO oe vce|743
`[s«s pValue
`<0.002
`
`A second active-controltrial of 193 randomized subjects was supportive of the placebo-controlledtrial.
`
`INDICATIONS AND USAGE
`
`Climara®is indicatedin the:
`
`1. Treatment of moderate to severe vasomotor symptoms associated with the menopause.
`
`2. Treatmentof vulvar and vaginal atrophy.
`
`3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarianfailure.
`
`4. Prevention of postmenopausal osteoporosis(loss of bone mass). The mainstays of prevention of
`postmenopausal osteoporosis are weight bearing exercise, an adequate calcium and vitaminDintake,
`and whenindicated, estrogen. Postmenopausal women absorb dietary calcium lessefficiently than
`premenopausal women and require an average of 1500mg/dayof elemental calcium to remainin
`neutral calcium balance. The average calcium intake in the USA is 400-600 mg/day. Therefore, when
`not contraindicated, calcium supplementation may be helpful for women with suboptimaldietary intake.
`
`Estrogen replacementtherapy reduces bone resorption andretards or halts postmenopausal bone
`loss. Studies have shown an approximately 60% reduction in hip and wrist fractures in women whose
`
`0013
`
` 
`
`

`

`
`
`
`
`1
`
`|
`
`NDA20-375/S-016
`Page ]2
`
`estrogen replacement was begun within a few years of menopause.Studies also suggest that
`estrogen reduces the rate of vertebrat fractures. Even whenstarted aslate as 6 years after
`menopause, estrogen prevents further loss of bone massfor as long as treatmentis continued. When
`estrogen therapyis discontinued, bone mass declines at a rate comparable to the immediate
`postmenopausalperiod.
`
`Eany menopauseis one of the strangest predictors for the development of osteoporosis in all women.
`Other factors associated with osteoporosis include genetic factors,lifestyle and nutrition.
`
`CONTRAINDICATIONS
`
`Estrogens should not be usedin individuals with anyof the fallowing 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 cancerof the breast except in appropriately selected patients being treated for
`metastatic disease.
`
`4. Known or suspected estrogen-dependent neoplasia.
`
`5. Active thrombophlebitis or thromboembolic disorders.
`
`6. Climara® should not be used in patients hypersensitive to its ingredients.
`
`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 appears dependent on durationof treatment and on estrogen dose. Most
`studies show nosignificant 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 forfive to
`ten years or mora, and this risk has been shownto persist for at least 8-15 years after estrogen
`therapyis discontinued.
`
`b.. Breast Cancer.
`
`While some epidemiologic studies suggest a very modest increase in breast cancerrisk for estragen
`alone users versus non-users, other studies have not shown anyincreased risk. The addition of
`progestin to estrogen mayincrease the risk for breast cancer over that noted in non-hormoneusers
`mare significantly (by about 24-40%), althoughthis is based solely on epidemiologic studies, and
`definitive conclusions await prospective, controlledclinicaltrials.
`
`Womenwithout a uterus 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 relief of vasomotor symptoms) are notfelt to be
`at a substantially increased risk for breast cancer. Womenwith a uterus who are candidates for fong-
`
`
`
` 
`
`0014
`
`

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`NDA20-375/S-016
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`term use of estrogen/progestin therapy should be advised of potential benefits and risks (including the
`potential for an increased risk of breast cancer). All women should receive yearly breast exams by a
`health-care provider and perform monthly self-breast examinations.
`In addition, mammography
`examinations should be scheduled as suggested by providers based on patient age andrisk factors.
`
`2. Thromboembolic disorders. The physician should be aware of the possibility of thrombotic
`disorders (thrombophlebitis, retinal thrombosis, cerebral embolism, and putmonary embolism) during
`estrogen replacement therapy and bealert to their earliest manifestalions. 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 thrombcembolism. Several epidemiologic studies have found an increased risk of
`venous thromboembelism (VTE)in users of estrogen replacement therapy (ERT) who did not
`have predisposing conditions for VTE, such as past history of cardiovascular disease or a recent
`history of pregnancy, surgery, trauma, or seriousillness. The increased risk was found only in
`current ERT users; it did not persist in former users. The risk appeared to be higher in the first
`year of use and decreased thereafter. The findings were similar for ERT alone or with added
`progestin and pertain to commonly used oral and transdermal doses, with a possible dose-
`dependenteffect on risk. The studies found the VTErisk to be about one case per 10,000
`women per year among womennot using ERT and without predisposing conditions. Therisk in
`current ERT usets was increased to 2-3 cases per 10,000 womenperyear.
`
`‘Cerebrovascular disease. Embolic cerebrovascular events have been reported in women
`receiving postmenopausal estrogens.
`
`Cardiovascular disease. Large dosesof estrogen (5 mg conjugated estrogens per day), comparable
`to those usedto treat cancer of the prostate and breast, have been shown in a large prospective
`clinical trial in mento increasethe risks of nonfatal myocardialinfarction, pulmonary embolism, and
`thrombophiebitis.
`
`3. Gallbladder disease. A 2- to 4-fold increasein the risk of gallbladder disease requiting surgery in
`women receiving postmenopausal! estrogens has been reported.
`
`4. Hypercalcemia. Administration of estrogens may lead to severe hypercalcemia in patients with
`breast cancer and bone metastases.If this occurs, the drug should be stopped and appropriate
`measures taken to reduce the serum calcium level.
`
`PRECAUTIONS
`
`A. General
`
`1. Addition of a progestin when a woman has not had a hysterectomy. Studies of the addition of a
`progestin for 10 or more days of a cycle of estrogen administration or daily with estrogen in a
`continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be
`induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial
`cancer.
`
`There are, however, possible risks that may be associated with the use of progestins in estrogen
`replacement regimens. These include: (a) adverse effects on lipoprotein metabolism {e.g., lowering
`HDLandraising LDL) and (b) impairmentof glucose tolerance. The choice of progestin,its dose, and
`its regimen may be important in minimizing these adverseeffects.
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`2. Cardiovascularrisk. The effects of estrogen replacement on the risk of cardiovascular disease
`have not been adequately studied. However, data from the Heart and Estrogen/Progestin
`Replacement Study (HERS), a controlledclinical trial of secondary prevention of 2,763
`postmenopausal women with documented heart disease, cemonstrated no benefit. During an
`average follow-up of 4.1 years, treatment with oral conjugated estrogen plus medroxyprogesterone
`acetate did not reduce the overall rate of coronary heart disease (CHD) events in post-menopausal
`women with established coronary disease. There were more CHD events in the hormonetreated
`group thanin the placebo group in year 1, but fewer events in years 3 through 5.
`
`In a small numberof case reports, substantial increases in blood
`3. Elevated biood pressure.
`pressure during estrogen replacement therapy have been attributed to idiosyncratic reactions to
`estrogens.
`!n a large, randomized, placebo-controlled clinicaltrial, a generalized effect of estrogen
`therapy on blood pressure was not seen.
`
`4. Famllial hyperlipoproteinemia.In patients with familial defects of lipoprotein metabolism, estrogen
`therapy may be associated with elevations of plasma triglycerides leading tc pancreatitis and other
`complications.
`
`5. Impaired liver function Estrogens may be poorly metabolized in patients with impaired liver
`function.
`
`6. Hypothyroidism. Estrogen administration leads to increased thyroid-binding globulin (TBG)levels.
`Patients with normal thyroid function can compensatefor the increased TBG by making more thyroid
`hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients
`dependent on thyroid hormone replacementtherapy, however, may require increased dosesin order
`to maintain their free thyroid hormonelevels in an acceptable range.
`
`7. Fluid retention. Because estrogens may cause some degreeoffluid retention, conditions which
`might be influenced bythis factor, such as asthma, epilepsy, migraine and cardiacorrenal
`dysfunction, warrant careful observatian when estrogens are prescribed.
`
`8. Exacerbation of endometriosis. Endometriosis may be exacerbated with administration of
`estrogen therapy.
`
`9. Hypocalcemia. Estrogens should be used with caution in individuals with severe hypocalcemia.
`
`B. Patient Information. See text of Patient Information after the HOW SUPPLIEDsection.
`
`C. Laboratory Tests. Estrogen administration should generally be quided byclinical response at the
`smallest dose, rather than laboratory monitoring,for relief of symptomsfor those indications in which
`symptoms are observable.
`
`D. Drug/Laboratory Test Interactions.
`
`1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased
`platelet count; increased factors il, Vil antigen, VIII antigen, VII] coagulant activity, IX, X, X!l, VU-X
`complex,II-Vil-X complex, and betathromboglobulin; decreased levels of anti-factor Xa and
`antithrombin Ill, decreased antithrombinfll activity; increased levels of fibrinogen and fibrinogen
`activity; increased plasminogen antigen and activity.
`
`2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as
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`measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels
`by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3
`concentrations are unaltered.
`
`3