`
`5243107
`
`A
`
`* 5 2 4 3 1 0 7 *
`
`* 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
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`Email:
`infofoi@foiservices.com
`
`.
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`
`
`
`0001
`
`MYLAN - EXHIBIT 1015
`
`
`
`i4 DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`
`Food and Drug Administration
`Rockville WD 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, received June 5, 2000,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Climara® (Hstradiol
`transdermal System) 0.025, 0.05,0.075,0.1 mg/day.
`
`We acknowledge receipt of your submissions dated July 31, August 4,10, 17, 18, and September 15,
`2000, January 5, February I3and 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 information 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 after it is printed. Please individually mount ten of the copies on heavy-weight paper or similar
`material. For administrative purposes, this submission should be designated "FPL for approved
`supplement NDA 20-375/S-016." Approval of this submission by FDA is not required before the
`labeling is used.
`
`Be advised that, as of April 1, 1999. all applications for new active ingredients, new dosage forms, new
`indications, new routes of administration, and new dosing regimens are required to contain an
`assessment of the safety and effectiveness of the product in pediatric patients unless this requirement is
`waived or deferred (63 FR 66632). We are waiving the pediatric study requirement for this action on
`this application.
`
`0002
`
`
`
`NDA 20-375/S-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 Dmg Marketing, Advertising, and Communications, IIFD-42
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, Maryland 20857
`
`If a letter communicating important information about this drug product (i.e., 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
`Rockville, 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 314.80 and 314.81.
`
`If you have any questions, call Diane Moore, BS, Regulatory Project Manager, at (301) 827-4260.
`
`Sincerely,
`
`jScc apjti'ndcd clmronic si^naturi' piigci
`
`Susan Allen, M.D.
`Director
`Division of Reproductive and Urologic Drug Products
`Office of Drug Evaluation III
`Center for Drug Hvaluation and Research
`
`0003
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER: 20-375/S-016
`
`FINAL PRINTED LABELING
`
`0004
`
`
`
`NDA 20-375/S-016
`Page 3
`
`RxOnly
`
`PRESCRIBING INFORMATION
`
`Climara® estradiol transdermal 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 ciirrently no evidence that the use of
`natural estrogens results in a different endometrial risk profile than synthetic estrogens of
`equivalent estrogen doses.
`
`2. 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 habitual abortion.
`Estrogens are not indicated for the prevention of postpartum breast engorgement.
`
`DESCRIPTION
`Climara®, estradiol transdermal system, is designed to release 17p-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 (17[i-estradiol) is a white, crystalline powder, chemically described as
`estra-l.a.SnOHriene^.lTp-diol. It has an empirical formula of CiaHa-A and molecular weight of
`272.37. The structural formula is:
`
`...H
`
`HjC
`
`or R
`
`Hi
`
`The Climara® 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-coated polyester
`film is attached to the adhesive surface and must be removed before the system can be used.
`
`(1J Film Backing
`(2) Dntf Adhesive Layer
`(3) Prulectlvt Uner
`
`0005
`
`
`
`NDA 20-575/S-016
`Page 4
`
`I
`
`The active component of the system is 17p-estradiol. The remaining components of the system
`(acrylate copolymer adhesive, fatty acid esters, and polyethylene backing) are pharmacologically
`inactive,
`
`CLINICAL PHARMACOLOGY
`
`The Climara® system provides systemic estrogen replacement therapy by releasing 17p-eslradiol, 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 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 fig
`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 (issues. 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 gonadotropins 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 gm/cmz) women at 10 study centers in the
`United States. 129 subjects were allocated to receive active treatment with 4 different doses of 17 p-
`estradiol patches (6.5,12.5,15,25 cm2) 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 20-375/S-0I6
`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**
`
`ti
`
`«ti
`S 2-
`<
`X o
`^ a
`
`— JS-SIZS' "'' — ——.115. .
`—. t.-IS—
`-
`
`- -
`
`<&5
`
`p
`
`P'
`
`p
`
`-25
`125
`- •»
`
`p
`
`•€
`BAStUKE
`
`6-MO
`
`TREATMENT
`
`12-MO
`visn
`PIA&BO
`— - men1
`asm8
`
`1(410
`
`244(0
`
`Won'
`• • "• ISM1
`
`Percent change in BMD of the total hip (see Figure 2), was also statistically significantly different from
`placebo for atl active treatment groups. The results of the measurements of biochemical markers
`supported the finding of efficacy for all doses of transdermal estradiol. Serum osteocalcin levels
`decreased, indicative of a decrease in bone forntation, at all tirnepoints 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 20-375/S-016
`Page 6
`
`Figure 2. Mean Percent Change
`from Baseline in Total Hip
`by Treatment and Time*
`last observation carried forward"
`6
`
`ul
`S 2
`<
`x
`o
`it
`
`-2
`
`-is
`U5_
`W SZTLT-Jg
`" B
`43
`
`85
`
`P
`
`P'
`
`P
`
`•6
`SASEUDE
`
`euo
`
`TRMMENI
`
`12-MO
`VISIT
`— cucieo
`tfitm*
`- -2Scffl»
`
`24-MO
`
`1«-M0
`
`Mem1
`1380*
`
`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 women in the early follicular phase of the ovulatory cycle. The
`pharmacokinetics of estradiol following application of the Climara* 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 Climara9 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/S-016
`Page 7
`
`In a bioavailability study, the Climara®6.5 cm2 was studied with the Climara® 12.5 cm2 as reference.
`The mean estradiol levels in serum from the two sizes are shown in Figure 3.
`
`Figure 3
`Mean Semm 17|}-Estradiol Concentrations vs. Time Profile following Application of a 6.5 cm2
`Transdermal Patch and Application of a 12.5 cm2Climara® patch.
`
`60-.
`
`IT 60-
`£
`at a. 40-
`v>
`o 30-
`
`t-
`«£
`£ 20-
`z
`tu
`^ 10-
`o
`
`o 1
`
`0
`
`T
`
`30
`
`legend: o 6,5 cm2 Climara patch
`• 12.5 cm5 CEmara patch
`
`T
`90
`TIME (HOURS)
`
`T
`120
`
`ISO
`
`1
`160
`
`Dose proportionality was demonstrated for the Climara® 6.5 cm2 transdermal system as compared to
`the Climara® 12.5 cm2 transdermal system in a 2-week crossover study with a 1 -week washout period
`between the two transdermal systems in 24 postmenopausal women.
`
`0009
`
`
`
`NDA 20-375/S-016
`PageS
`
`Dose pToportionality 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 cm2 and 12.5 cm2 on the abdomen were about 80 and
`40 pg/mL, respectively.
`
`In a 3-week multiple application study In 24 postmenopausal women, the 25.0 cm2 Climara® system
`produced average peak estradiol concentrations (Cmax) of approximately 100 pg/mL. Trough values
`at the end of each wear interval (Cmin) were approximately 35 pg/mL Nearly 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 pg/mL, 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 shown in 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 cm2) to the abdomen and buttocks of 38 postmenopausal women.
`
`200
`
`ISO
`M E
`A
`N „
`190
`e o
`N
`c
`f so
`G
`/
`M
`L
`
`1^.
`
`Ot
`0 t t M» 4 S e O 7 2 W« l l» l l D 1 J! U 4 t» 1 l M t J 0 « I
`MMPtmG TIME-HOURS AFHA MICHJWLICHlQtl
`— BUTTOCK
`-- AStttUEH
`
`TREATMENT
`
`0010
`
`
`
`NDA 20-375/S-016
`Page 9
`
`Table 1 provides a summary of estradiol pharmacokinetic parameters determined during evaluation of
`Climara .
`
`Table 1
`Pharmacokinetic Summary
`{Mean Estradiol Values)
`
`Climara®
`Delivery
`Rate
`0.025
`0.05
`0.1
`0.1
`
`Surface
`Area
`(cm2)
`6.5
`12.5
`25
`25
`
`Application
`Site
`
`No. of
`Subjects
`
`Dosing
`
`Cmax
`(pg/mL)
`
`Cmin
`(pgMiL)
`
`Cavg
`(pg/mL)
`
`Abdomen
`Abdomen
`Abdomen
`Buttock
`
`24
`102
`139
`38
`
`Single
`Single
`Single
`Single
`
`32
`71
`147
`174
`
`17
`29
`60
`71
`
`22
`41
`87
`106
`
`The relative 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 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 homnone target organs. Estradiol and other naturally occuning 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 endogenous estrogens.
`Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These
`transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both
`can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo
`enterohepatic recirculation via sulfate and glucuranide conjugation in the liver, 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 apparent half-life of approximately 4 hours.
`
`Specia/ popufaftons:
`
`Geriatric: There have not been sufficient numbers of geriatric patients involved in clinical studies
`utilizing Climara® to determine whether those over 65 years of age differ 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 women only.
`
`Race: No studies were done to determine the effect of race on the pharmacokinetics of Climara®.
`
`0011
`
`
`
`NDA 20-375/S-016
`Page 10
`
`I
`
`Patients with Renal Impairment: Total estradiol serum levels are higher in postmenopausal women
`with 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 impainvent: Estrogens may be poorly metabolized in patients with impaired liver
`function and should be administered with caution.
`
`Dnjg 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 transdermal 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 Climara®.
`
`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 cm2and 12.5 cm2
`transdermal systems. Of 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 cm2 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 determine the efficacy of Climara® 0.05 mg/day and
`0.1 mg/day 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 postmenopausal 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
`
`J
`
`I
`
`i
`
`i
`
`i
`
`
`
`NDA 20-375/S-016
`Page 11
`
`Adequate data for the analysis of efficacy was available from 191 subjects. The results are presented
`as the mean + SD number of flushes in each of the three treatment weeks of each 4-week cycle. In
`the 0.05 mg estradiol group, the mean weekly hot flush rate across all treatment cycles decreased
`from 46 ± 6.5 at baseline to 20 ± 3.0 (-67.0%). The 0.1 mg estradiol group had a decline in 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 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, simitar 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 Climara0
`0.025 mg/day or placebo continuously for up to three 28-day cycles, the Climara4 0.025 mg/day
`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 moderale-to-severe vasomotor symptoms.
`
`Table 3
`Mean Change from Baseline in the Number of Moderate-to-Severe Vasomotor Symptoms (ITT)
`
`Treatment Group
`EaTDS
`
`Placebo
`
`Statistics
`N
`Mean
`SD
`N
`Mean
`SD
`p-Value
`
`Week 4
`82
`-6.45
`4.65
`83
`-5.11
`7.43
`<0.002
`
`Week 8
`84
`-7.69
`4.76
`71
`-5.98
`8.63
`
`Week 12
`68
`-7.56
`4.64
`65
`-5.98
`9.69
`<0.003
`
`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 failure.
`
`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 1500mg/day of elemental calcium to remain in
`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 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/S-016
`Page 12
`
`estrogen replacement was begun within a few years of menopause. Studies also suggest that
`estrogen reduces the rate of vertebrat 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.
`
`Eariy 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 endometrial 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 for 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-hormone users
`more significantty {by about 24-40%), 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 estrogen/progestin 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 (ong-
`
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`I
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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 and risk factors.
`
`2. Thromboembolic 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 VIE, 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 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-
`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.
`
`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.
`
`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
`HDL and raising LDL) and (b) impairment of glucose tolerance. The choice of progestin, its dose, and
`its regimen may be important in minimizing these adverse effects.
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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 Estrogen/Progestin
`Replacement Study (HERS), a controlled 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 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 hormone treated
`group than in the placebo group in year 1, but fewer events in years 3 through 5.
`
`3. Elevated blood pressure. In a small number of case reports, substantial increases in blood
`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.
`
`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.
`
`6. Hypothyroidism. Estrogen administration leads to increased thyroid-binding globulin (TBG) levels.
`Patients with normai 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 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 SUPPLIED section.
`
`C.