*5243107*
`
`*A*
`
`5243107
`
`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 Approval Letter; Final Labeling
`
`This document was provided by:
`
`FOI Services, Inc
`704 Quince Orchard Road - Suite 275
`
`Gaithersburg MD 20878-1751 USA
`Phone:
`301-975—9400
`Fax:
`301-975-0702
`
`Email:
`
`infofoi@foiservices.com
`
`
`
`
`any of the information in these documents; the documents will be faithful copies of the information supplied to FOI Services, Inc.
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`
`0001
`
`MYLAN - EXHIBIT 1015
`
` 
`

 
`
`
`

`

`'IVK‘fit
`
`a,
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`
`
`
` g DEPARTMENTOFHEALTH&HUMANSERVICES PublicHealthService
`
`"m
`
`Food and Drug Administration
`Rockville MD 20857
`
`NDA 20-375/8-016
`
`Berlex Laboratories, Inc.
`Attention: Geoffrey Millington
`Manager, Drug Regulatory Affairs
`340 Changebridge Road
`PO. Box l000
`
`Montville. NJ 074504000
`
`Dear Mr. Millington
`
`Please refer to your supplemental new drug application dated June 2, 2000, received June 5, 2000,
`submitted under section 505(b) of the Federal Food, Dnlg, and Cosmetic Act for Climara® (l-lstradiol
`transdcrmal System) 0.025, 0.05, 0.075, 0.! mg/day.
`
`We acknowledge receipt of your submissions dated July 3 I, August 4, 10, 17, 18, and September 15,
`2000. January 5, February l3 and March 19,21,27, April 3 and April 4. 2001.
`
`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 symptoms and vulvar and
`vaginal atrophy associated with the menopause.
`
`We have completed the review of this supplemental application. as amended. and have concluded that
`adequate infomation has been presented to demonstrate that the drug product is safe and effective for
`use as recommended in the agreed upon labeling text. Accordingly, the supplemental application is
`approved effective on the date of this letter.
`
`The final 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 of final 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 FPL as soon as it is available but no more than 30
`days afler 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
`supplement NDA 20-375/3-016." Approval of this submission by FDA is not required before the
`labeling is used.
`
`Be advised that, as of April l, 1999. all applications for new active ingredients. new dosage forms, new
`indications, new routes of administration, and new dosing regimens are required to contain an
`assessment of the safety and effectiveness of the product in pediatric patients unless this requirement is
`waived or deferred (63 FR 66632). We are waiving the pediatric study requirement for this action on
`this application.
`
`
`
` 0002
`
`
`
`

`

`NDA 20-37518-016
`
`Page 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 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. MED-42
`Food and Drug Administration
`5600 Fishers Lane
`
`Rockville, Maryland 20857
`
`If a letter communicating important information about this drug product (i.e.r a " Dear Health Care
`Professional" letter) is issued to physicians and others responsible for patient care, we request that you
`submit a copy of the letter to this NDA and a copy to the following address:
`
`MEDWATCH, HF-2
`FDA
`
`5600 Fishers Lane
`
`Roekville, MD 20857
`
`Please submit one market package of the drug product when it is available.
`
`We remind you that you must comply with the requirements for an approved NDA set forth under
`21 CFR 3 [4.80 and 314.81.
`
`If you have any questions, call Diane Moore, BS, Regulatory Project Manager. at (301) 827-4260.
`
`Sincerely,
`
`{See “I‘llg'fldfi'd cir'err‘um‘c signature page:
`
`Susan Allen, MD.
`Director
`
`Division of Reproductive and Urologic Drug Products
`Office of Drug Evaluation [II
`Center for Drug Evaluation and Research
`
`
`
`0003
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER: 20-375/8-016
`
`FINAL PRINTED LABELING
`
`
`
`0004
`
`

`

`NDA 20-375lS-016
`
`Page 3
`
`Rx Only
`
`PRESCRBBING INFORMATION
`
`Climara‘D estradiol transden'nal system
`
`1.
`
`
` ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER. Close clinical surveillance of
`all women taking estrogens is important. Adequate diagnostic measures. including endometrial
`sampling when indicated. should be undertaken to rule out malignancy in all cases of undiagnosed
`persistent or recurring abnormal vaginal bleeding. There is currently no evidence that the use of
`natural estrogens results in a different endometrial risk profile than synthetic estrogens of
`
`
`equivalent estrogen doses.
`
`
`
`
`. There is no indication for estrogen therapy during pregnancy or during the immediate postpartum
`
`period. Estrogens are ineffective for the prevention or treatment of threatened or habituai abortion.
`
`
`Estrogens are not indicated for the prevention of postpartum breast engorgement.
`
`
`
`
`,
`DESCRIPTION
`Climara°. estradiol transdermal system, is designed to release 17fl-estradiol continuously upon
`application to intact skin. Four (6.5. 12.5. 18.75 and 25.0 cm2} systems are available to provide
`nominal in 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 area of either 6.5. 12.5. 18.75 or 25.0 cm2. and
`contains 2.0. 3.8. 5.7 or 7.6 mg of estradiol USP respectively. The composition of the systems per unit
`area is identical.
`
`Estradiol USP (17B-estradiol) is a white. crystalline powder, chemically described as
`estra-‘l.3.5(10)—lriene-3.17B-diol. It has an empirical formula of C13H2402 and molecular weight of
`272.37. The structural formula is:
`
`
`
`The ClimaraO system comprises two layers. Proceeding from the visible 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—coaled polyester
`film is attached to the adhesive surface and must be removed before the system can be used.
`
`firzrnwmmm{3) Protective [their
`
`(11 Fill! Mm
`
`
`
`0005
`
`

`

`NDA 20-37513-016
`
`Page 4
`
`The active component of the system is 1TB-estradiol. The remaining components of the system
`(acrytate copolymer adhesive. fatty acid esters. and polyethylene backing) are pharmacologically
`inactive.
`
`CLINICAL PHARMACOLOGY
`
`The Climara‘” system provides systemic estrogen replacement therapy by releasing 17B—estradiol, the
`major estrogenic hormone secreted by the human ovary.
`
`Estrogens are largely responsible for the development and maintenance of the female reproductive
`system and secondary sexual characteristics Although circulating estrogens exist'in a dynamic
`equilibrium of metabolic interconversions. estradiol'is the principal intracellular human estrogen andis
`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 TO 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 adrenal cortex. to estrone by
`peripheral tissues. Thus. estrone and the sulfate conjugated form. estrone sulfate. are the most
`abundant circulating estrogens in postmenopausal women.
`
`Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date. two
`estrogen receptors have been identified. These vary in proportion from tissue to tissue.
`
`Circulating estrogens modulate the pituitary secretion of the gonadotrcpins luteininizing 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 seen in postmenopausal
`women.
`
`A two-year clinical trial enrolled a total of 175 healthy. hysterectomized. postmenopausal. non-
`osteoporotic (i.e.. lumbar spine bone mineral density > 0.9 gmfcm’3)women at 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 on 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 treatment effect at each timepoint was noted. implying
`bone preservation for all active treatment groups at all timepoints. as opposed to bone loss for placebo
`at all timepoints.
`
`
`
`0006
`
`

`

`NDA Ell-375134)! 6
`
`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 fonward“
`
`'5CHANGE
`
`Percent change in BMD of the total hip (see Figure 2). was also statistically significantly different from
`placebo for all active treatment groups. The results of the measurements of biochemical markers
`supported the finding of efficacy for all doses of transdermal estradiel. Serum osteocalcin levels
`decreased. indicative of a decrease in bone formation. at all timepoints for all active treatment doses.
`statistically significantly different from placebo (which generally rose). Urinary deoxypyridinoline and
`pyridinoline changes also suggested a decrease in bone turnover for all active treatment groups.
`
`
`
`0007
`
`

`

`NDA 20—375I'S—016
`
`Page 6
`
`Figure 2. Mean Percent Change
`from Baseline in Total Hip
`by Treatment and Time’
`last observation carried forward”
`
`,J Its-rm first”?
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`
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`
`Footnote: This figure is based on 74% of the randomized subjects (95 on active drug
`and 34 on placebo}.
`
`PHARMACOKINETICS
`
`Transdermal administration of Ciimara” produces mean serum concentrations of estradiol comparable
`to those produced by premenopausal women in the early follicularphase of the ovulatory cycle. The
`phan’nacokinetics of estradiol following application of the Ciimara" system were investigated in 197
`healthy postmenopausal women in 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 across intact 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 that after oral administration. This difference is due to the absence of first pass
`metabolism when estradiol is given by the transdermal route.
`
`
`
`
`
`
`
`0008
`
`

`

`NDA 20-375/8-016
`
`Page 7
`
`ln a bioavailability study. the Climara‘D 6.5 cm2 was studied with the Climara" 12.5 cm2 as reference.
`The mean estradiol levels in 5mm from the two sizes are shown in Figure 3.
`
`Figure 3
`Mean Serum 175-Estradiol Concentrations vs. Time Profile following Application of a 6.5 cm2
`Transdermal Patch and Application of a 12.5 cmzClimara‘D patch.
`
`(:39!le
`CONCENTRATIONS
`
`0
`
`30
`
`EU
`
`90
`
`120
`
`150
`
`130
`
`team 0 6.5 cm? cllmara pawn
`D125 cma Chara patch
`
`TIME MRS}
`
`Dose proportionality was demonstrated for the Climara” 6.5 cm2 transderrnal system as compared to
`the Climate” 12.5 cm2 transden'nal system in a 2-week crossover study with a 1-week washout period
`between the two transdermai systems in 24 postmenopausal women.
`
`
`
`0009
`
`
`
`

`

`NDA 20-375/3—016
`
`Page 8
`
`Dose proportionality was also demonstrated for the Climara" system (12.5 cm2 and 25 cm2)in a 1-
`week study conducted in 54 postmenopausal women. The mean steady state levels (Cavg) of the
`estradiol during the application of Climara” 25 cm2and 12.5 cm2 on the abdomen were about 80 and
`40 pglmL respectively.
`
`In a 3-week multiple application study in 24 postmenopausal women, the 25.0 cm2 Ciimara" system
`produced average peak estradiol concentrations (Cmax) of approximately 100 pgimL. Trough values
`at the end of each wear interval (Cmin) were approximately 35 pgimL. Nearty identical serum curves
`were seen each week. indicating little or no accumulation of estradiol in the body. Serum estrone peak
`and trough levels were 60 and 40 pgimL. respectively.
`
`In a single-dose. randomized crossover study conducted to compare the effect of site of application,
`38 postmenopausal women wore a single Climara“ 25 cm2 system for one week on the abdomen and
`buttocks. 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 (1 S.E. ) Estradiol Semm Concentrations for a One Week Application of the Climara”
`system (25 cm2)to the abdomen and buttocks of 38 postmenopausal women.
`
`aha-g
`
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`
`ouunuwnuammmmmmmm
`WM-Hflflfiflflfllflflmflfl
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`
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`
`

`

`
`
`
`
`NDA 20—375/8-01 6
`
`Page 9
`
`Table 1 (provides a summary of estradiol pharmacokinetic parameters determined during evaluation of
`Climara .
`
`Table 1
`
`Pharrnacokinetic Summary
`{Mean Estradiol Values)
`
`Climara'
`Delivery
`Rate
`
`
`
`
`
`
`Surface Application
`Area
`Site
`cm2
`I“ Sinle E_-_
`“WE-II-
`
`fl-E-__—m_fi-—
`
`
`
`art-mm
`
`No. of
`Subjects
`
`
`Cmax
`Cmin
`(091ij
`(pglmL)
`(pglmL)
`
`
`
`The relative standard deviation of each pharrnacokinetic parameter after application to the abdomen
`averaged 50%, which is indicative of the considerable intersubject variability associated with
`transderrnal dmg delivery. The relative standard deviation of each pharmacokinelic 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 estrogens is similar to that of endogenous estrogens.
`Estrogens are widely distributed in the body and are generally found in higher concentrations in the
`sex hormone target organs. Estradiol and other naturally occum'ng estrogens are bound mainly to sex
`hormone binding globulin (SHBGL and to lesser degree to 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. Estradiol is converted reversibty 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 postmenopausat
`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 Climarao System, serum estradiol levels decline in about 12 hours to
`preapplication levels with an apparent half-life of approximately 4 hours.
`
`Special populations:
`
`Geriatric: There have not been sufficient numbers of geriatric patients involved in clinical studies
`utilizing Ctimara8 to determine whether those over 65 years of age differ from younger subjects in their
`response to Climaras.
`
`Pediatric: No phan‘naookinetic study for Climara° has been conducted in a pediatric population.
`
`Gender: Climara” is indicated for use in women only.
`
`Race: No studies were done to determine the effect of race on the pharmacokinetics of Climara“.
`
` 0011
`
`
`
`

`

`NDA 20-375/5-016
`
`Page to
`
`Patients with Renal impairment: Total estradiol serum levels are higher in postmenopausal women
`vvith end stage renal disease (ESRD) receiving maintenance hemodialysis than in normal subjects at
`baseline and following oral doses of estradiol. Therefore. conventional transdermal estradiol doses
`used in individuals with normal renal function may be excessive for postmenopausal women with
`ESRD receiving maintenance hemodialysis.
`
`Patients with Hepatic impairment: Estrogens may be peony metabolized in patients with impaired liver
`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
`cm2 and 12.5 cm2 sizes of Climara” was conducted in 112 healthy women of 45-75 years of age. Each
`woman applied both transderrnal systems weekly. on the upper outer abdomen. for three consecutive
`weeks.
`it should be noted that lower abdomen and upper quadrant of the buttock are the approved
`sites of application for Climaras‘.
`
`The adhesion assessment was done visually 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 no lift for both the 6.5 cm’and 12.5 cm2
`transdermal systems. 0f the total number of transdermal systems applied. approximately 5% showed
`complete detachment for each size.
`
`Adhesion potentials of the 18.75 cm2 and 25.0 cm: sizes of transdennal systems (0.075 mglday and
`0.1 mglday) 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 enrotled in a study. to determine the efficacy of Climate” 0.05 mgldey and
`0.1 mglday compared to placebo and an active comparator. Women took drug in a cyclical fashion
`(three weeks on and one week off).
`
`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 postmenopausai women in good general health who
`experienced vasomotor symptoms. Natural menopause patients had not menstruated for at least 12
`months and surgical menopause patients had undergone bilateral oophorectomy at least 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 of five moderate to severe hot flushes per week. or a
`minimum of 15 hot flushes of any severity per week. for two consecutive weeks. Women wore the
`patches in a cyclical fashion (three weeks on and one week off).
`
`During treatment. all subjects used diaries to record the number and severity of hot flushes. Subjects
`were monitored by clinic 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 20~37SlS~0l6
`
`Page 1 l
`
`Adequate data for the analysis of efficacy was available from 191 subjects. The results are presented
`as the mean 3 SD number oi flushes in each of the three treatment weeks of each 4—week cycle.
`In
`the 0.05 mg estradiol group. the mean weekly hotflush rate across all treatment cycles decreased
`from 46 i 6.5 at baseline to 20 i 3.0 (67.0%). The 0.1 mg estradiol group had a decline in the mean
`weekly hot flush rate from 52 :t 4.4 at baseline to 16 i 2.4 (-72.0%).
`In the placebo group, the mean
`weekly hot flush rate declined from 53 $4.5 at baseline to 46 i 5.5 (—18.1 ”/o). Compared with placebo.
`the 0.05 mg and 0.1 mg estradiol groups showed a statistically significantly larger mean decrease in
`hot flushes across all treatment cycles (P< 0.05). When the response to treatment was analyzed for
`each of the three cycles of therapy. similar statistically significant differences were observed between
`both estradiol treatment groups and the placebo group during all treatment cycles.
`
`In a double—blind. placebo—controlled. randomized study of 187 women receiving Climarata
`0.025 mgl'day or placebo continuously for up to three 28-day cycles. the Climara" 0.025 mglday
`dosage was shown to be statistically better than placebo at Weeks 4 and 12 for relief of both the
`frequency (see Table 3) and severity of moderate-to—severe vasomotor symptoms.
`
`Table 3
`Mean Change from Baseline in the Number of Moderate-to—Severe Vasomotor Symptoms (lTT)
`
`Treatment Group
`-
`
`Statistics
`~
`
`Week4
`I
`
`82
`-e.45
`
`Week 12
`-.._
`. 84____ 68
`_
`
`_____ _
`
` Enos“ __
`
`'
`
`"
`“—
`_ __‘
`
`g3
`Placebo
`— -5.11
`— 7.43
`— 5.0.002
`
`_
`
`A second active—control trial of 193 randomized subjects was supportive of the placebo-controlled trial.
`
`INDICATIONS AND USAGE
`
`Climara" is indicated in the:
`
`1. Treatment of moderate to severe vasomotor symptoms associated with the menopause.
`
`2. Treatment of vulvar and vaginal atrophy.
`
`3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian Iailure.
`
`4. Prevention of postmenopausal osteoporosis (loss of bone mass). The mainstays of prevention of
`postmenopausal osteoporosis are weight bearing exercise. an 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 1500mglday of elemental calcium to remain in
`neutral calcium balance. The average calcium intake in the USA is 400-600 mglday. Therefore. when
`not contraindicated. calcium supplementation may be helpful for women with suboptimal dietary intake.
`
`Estrogen replacement therapy reduces bone resorption and retards or halts postmenopausal bone
`loss. Studies have shown an approximately 60% reduction in hip and wrist fractures in women whose
`
` 0013
`
` 
`
`

`

`NDA 20-375/3-016
`
`Page 12
`
`estrogen replacement was begun within a few years of menopause. Studies also suggest that
`estrogen reduces the rate of vertebral fractures. Even when started as late as 6 years after
`menopause, estrogen prevents further loss of bone mass for as long as treatment is continued. When
`estrogen therapy is discontinued. bone mass declines at a rate comparable to the immediate
`postmenopausal period.
`
`Eady menopause is one of the strongest 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 used in individuals with any of the following conditions:
`
`1. Known or suspected pregnancy (see PRECAUTIONS). Estrogens may cause fetal harm when
`administered to a pregnant woman.
`
`2. Undiagnosed abnormal genital bleeding.
`
`3. Known or suspected cancer of the breast 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 endometriat cancer risk among unopposed estrogen users is about 2 to 12 fold greater
`than in non-users. and appears dependent on duration of treatment and on estrogen dose. Most
`studies show no significant increased risk associated with use of estrogens for less than one year. The
`greatest risk appears associated with prolonged use-. with increased risks of 15- to 24-fold tor five to
`ten years or more. and this risk has been shown to persist for at least 8-15 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-homone users
`more significantly (by about 2440%), although this is based solely on epidemiologic studies. and
`definitive conclusions await prospective, controlled clinical trials.
`
`Women without 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 estrogenfprogestin 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—
`
`
`
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`NDA 20-375/8-016
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`' Page l3
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`term use of estrogeniprogestin 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 and risk factors.
`
`2. Thromboemholic disorders. The physician should be aware of the 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 thromboembolism. Several epidemiologic studies have found an increased risk of
`venous thromboembolism (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 serious illness. The increased risk was found only in
`current ERT users; it did not persist in tumor 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-
`dependent effect on risk. The studies found the VTE risk to be about one case per 10.000
`women per year among women not using ERT and without predisposing conditions. The risk in
`current ERT users was increased to 2-3 cases per 10,000 women per year.
`
`'Cerebrovascular disease. Embolic cerebrovascular events have been reported in women
`receiving postmenopausal estrogens.
`
`Cardiovascular disease. Large doses of estrogen {5 mg conjugated estrogens per day). comparable
`to those used to treat cancer of the prostate and breast, have been shown in a large prospective
`clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and
`thrombophlebitis.
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`3. Gallbladder disease. A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in
`women receiving postmenopausal estrogens has been reported.
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`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 ofa
`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 (9.9.. lowering
`HDL and raising LDL) and (b) impairment of glucose tolerance. The choice of progestin, its close. and
`its regimen may be important in minimizing these adverse effects.
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`NDA 20-37S/S-OI6
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`Page 14
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`2. Cardiovascular risk. The effects of estrogen replacement on the risk of cardiovascular disease
`have not been adequately studied. However. data from the Heart and Estrogeanrogestin
`Replacement Study (HERS). a controtled clinical trial of secondary prevention of 2.763
`postmenopausal women with documented heart disease. demonstrated no benefit. During an
`average follow-up of 4.1 years. treatment with oral conjugated estrogen plus modroxyprogesterone
`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 hormone treated
`group than in the placebo group in year 1. but fewer events in years 3 through 5.
`
`In a small number of case reports. substantial increases in blood
`3. Elevated blood pressure.
`pressure during estrogen replacement therapy have been attributed to idiosyncratic reactions to
`estrogens.
`In a large, randomized. placebo-controlled clinical trial. a generalized effect of estrogen
`therapy on blood pressure was not seen.
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`4. Familial hyperlipoproteinemia. In patients with familial defects of lipoprotein metabolism. estrogen
`therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other
`complications.
`
`5. Impaired liver function Estrogens may be poorly metabolized in patients with impaired liver
`function.
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`6. Hypothyroidism. Estrogen administration leads to increased thyroid-binding globulin (TBG) levels.
`Patients with nonnat thyroid function can compensate for 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 replacement therapy. however. may require increased doses in order
`to maintain their free thyroid hormone levels in an acceptable range.
`
`7. Fluid retention. Because estrogens may cause some degree of fluid retention. conditions which
`might be influenced by this factor. such as asthma. epilepsy. migraine and cardiac or renal
`dysfunction, warrant careful observation when estrogens are prBScn’bed.
`
`8. Exacerbation of endometrlosls. Endornetriosis may be exacerbated with administration of
`estrogen therapy.
`
`9. Hypocalcemia. Estrogens should be used with caution in individuals with severe hypocalcemia.
`
`B. Patient lnfonnation. See text of Patient Information afterthe HOW SUPPLIED section.
`
`0. Laboratory Tests. Estrogen administration should generally be guided by clinical response at the
`smallest dose. rather than laboratory monitoring. for relief of symptoms for those indications in which
`symptoms are observable.
`
`D. DruglLaboratory Test Interactions.
`
`1. Accelerated prothrombin time, partial thromboplastin time. and piatelet aggregation time: increased
`platelet count; increased factors It. VII antigen. VIII antigen, Vlll coagulant activity. IX. X. XII. Vii-X
`complex. Il-Vll-X complex, and betathromboglobulin; decreased levels of anti-factor Xa and
`antithrombin III, decreased antithrombin ill activity: increased levels of fibrinogen and fibrinogen
`activity: increased ptasminogen antigen and activity.
`
`2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone. as
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`NDA 20-37S/S-OI6
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`Page 15
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`measured by protein-bound