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`Menostar (Berlex) 06/08/2004 Approval [Postmenopausal
`Osteoporosis]: Approval Letter; Final Labeling
`
`This document was provided by:
`
`FOI Services, Inc
`704 Quince Orchard Road * Suite 275
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`
`MYLAN- EXHIBIT 1017
`0001
`
`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Packagefor:
`
`APPLICATION NUMBER:
`
`21-674
`
`Trade Name:
`
`Menostar
`
`Generic Name:
`
`Sponsor:
`
`Berlex Laboratories
`
`Approval Date:
`
`_ June 8, 2004
`
`Indications:
`
`Provides for the use of Menostar for the prevention of
`postmenopausal osteoporosis
`
`
`
`0002
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`21-674
`
`CONTENTS
`
`
`
`
`Reviews / Information Included in this NDA Review.
`
`Approval Letter
`Approvable Letter 1
`Approvable Letter 2
`Final Printed Labeling
`Medical Review(s
`Chemistry Review(s
`EA/FONSI
`
`|
`
`
`
`0003
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`21-674
`
`APPROVAL LETTER
`
`
`
`0004
`
`
`
`-pester,%,
`
`wHALTy%
`
`(__ DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`e10
`
`Public Health Service
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 21-674
`
`Berlex Laboratories Inc.
`Attention: Geoffrey Millington
`Manager, Drug Regulatory Affairs
`340 Changebridge Road; P.O. Box 1000
`Montville, NJ 07045-1000
`
`Dear Mr. Millington:
`
`Please refer to your new drug application (NDA) dated August 7, 2003, received August 8, 2003,
`submitted under section 505b of the Federal Food, Drug, and Cosmetic Act for Menostar (estradiol
`transdermal system).
`
`We acknowledge receipt of your submissions dated October 7, November 14, December17, 2003 and
`March 15, May 4, 12, 14, and June 2, and 8 (2 submissions), 2004.
`
`This new drug application provides for the use of Menostar (estradiol transdermal system) for prevention
`of postmenopausal osteoporosis.
`
`Wehave completed our review ofthis application andit is approved, effective on the date ofthisletter,
`for use as recommended in the agreed-uponlabeling text and with the minor editorial changesto the foil
`pouches, containers and cartons listed below. The changes to the foil pouches must.be implemented
`before manufacture of batch no. 2.
`
`General Revisions to foil pouches, containers and cartons:
`
`1. Relocate the graphic that covers the beginning letter ‘M’of the proprietary nameso that it does
`not interfere with the readability of the proprietary name.
`
`2.
`
`Increase.the prominenceofthe established nameand strength, so that they are at least one-half
`the size of the proprietary name.
`
`3. Eliminate the terminal zeroslisted throughout the container labels and carton labeling since thcy
`could be misinterpreted (e.g., 1.0 as 10).
`
`Specific Revision to the foil pouches (sample and trade):
`
`1.
`
`Inciude the route of administration on the principal display panel (e.g., For Transdermal Use).
`
`
`
`0005
`
`
`
`NDA 21-674
`Page 2
`
`Specific Revisions to Menostar Carton Labeling (4 systems, 6 x 4 systems, sample card):
`
`{.
`
`Increase the prominence ofthe route of administration statement on the principal display panel.
`
`2. Revise the net quantity statement to read ‘4 Transdermal Systems’, ‘6 Patient Packs each
`containing ‘4 Transdermal Systems’ or ‘1 Transdermal System’, as appropriate.
`
`The final printed labeling (FPL) must be identical to the enclosed labeling for the package imsert and the
`patient packageinsert and include the minoreditorial revisions to the submitted labeling (foil pouch,
`containers and cartons, submitted May 14, 2004). We remind you of your agreement to make the
`labeling changesto the foil pouches before production of batch no. 2. These changes can be submitted
`as 2 CBE-O labeling supplement, which must contain final printed labeling.
`
`These revisions are terms of the NDA approval. Marketing the product before makingtherevisions,
`exactly as stated, in the product’s labeling may render the product misbranded and an unapproved new
`drug.
`
`The electronic labeling rule published December 11, 2003, (68 FR 69009) requires submission of
`labeling content in electronic format effective June 8, 2004. For additional information, consult the
`following guidances for industry regarding electronic submissions: Providing Regulatory Submissions in
`Electronic Format — NDAs (January, 1999) and draft guidance Providing Regulatory Submissions in
`Electronic Format — Content ofLabeling (February 2004). The guidances specify labeling to be
`submitted in pdfformat. To assist in our review, we request that labeling also be submitted in MS Word
`format. If formatted copies of all labeling pieces (i.e., package insert, patient package insert, container
`labels, and carton labels} are submitted electronically, labeling does not need to be submitted in paper.
`For administrative purposes, designate this submission “FPL for approved NDA 21-674.” Approval of
`this submission by FDAis not required before the labeling is used.
`
`All applications for new active ingredients, new dosage forms, new indications, new routes of
`administration, and new dosing regimens are required to contain an assessmentof the safety and
`effectiveness of the productin pediatric patients unless this requirementis waived or deferred. We are
`waiving the pediatric study requirementfor this application.
`
`In addition, submit three copies ofthe introductory promotional materials that you proposeto use forthis
`product, Submit all proposed materials in draft or mock-up form, not final print. Send one copyto this
`division and two copies of both the promotional materials and the package insert directly to:
`
`Division of Drug Marketing, Advertising,
`and Communications, HFD-42
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, MD 20857
`
`Weremind you that you must comply with reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81).
`
`
`
`0006
`
`
`
`NDA 21-674
`Page 3
`
`All 15-day alert reports, periodic (including quarterly) adverse drug experience reports, field
`alerts, annual reports, supplements, and other submissions should be addressed to the original
`NDA 20-375 for this drug product, not to this NDA. In the future, do not make submissions to
`this NDA except for the final printed labeling requested above.
`
`If you have any questions, call Pat Madara, Regulatory Project Manager, at (301) 827-6416.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`David G. Orioff, M.D.
`Director
`Division of Metabolic and Endocrine Drug Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`Enclosure:
`
`packageinsert
`patient packageinsert
`
`
`
`0007
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`21-674
`
`APPROVED LABELING
`
`
`
`0008
`
`
`
`Rx only
`___Menostar™(estradiol transdermal system)
`PRESCRIBING INFORMATION
`
`ESTROGENS INCREASE THERISK OF ENDOMETRIAL CANCER
`
`
`Closeclinical surveillance of all women taking estrogens is important. Adequate
`diagnostic measures, including endometrial sampling when indicated, should be
`undertaken to rule out malignancyin all cases of undiagnosed persistent or recurring
`abnormal vaginal bleeding. There is no evidence that the use of “natural” estrogens
`results in a different endometrial risk profile than synthetic estrogens at equivalent
`estrogen doses. (See WARNINGS,Malignant neoplasms, Endometrial cancer.)
`
`
`
`
`
`
`
`
`
`
`CARDIOVASCULAR AND OTHER RISKS
`
`Estrogens with and without progestins should not be used for the prevention of
`cardiovascular disease, (See WARNINGS, Cardiovascular disorders.)
`
`The Women’s Health Initiative (WHI) study reported increased risks of myocardial
`infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in
`postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral
`conjugated estrogens (CE 0.625mg) combined with medroxyprogesterone acetate (MPA
`2.5mg) relative to placebo (see CLINICAL PHARMACOLOGY,Clinical Studies.)
`
`
`
`
`
`
`
`
`
`
`The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, reported
`increased risk of developing probable dementia in postmenopausal women 65 years of
`age or older during 4 years of treatment with oral conjugated estrogens plus
`medroxyprogesterone acetate relative to placebo.It is unknown whether this finding
`applies to younger postmenopausal women or to women taking estrogen alone therapy.
`(See CLINICAL PHARMACOLOGY,Clinical Studies.)
`
`
`
`
`
`
`
`
`
`
`
`Other doses of oral conjugated estrogens with medroxyprogesteronc acetate, and other
`combinations and dosage forms of estrogens and progestins were not studied in the WHI
`clinical trials and, in the absence of comparable data, these risks should be assumedto be
`similar. Because of these risks, estrogens with or without progestins should be prescribed
`at the lowest effective doses and for the shortest duration consistent with treatment goals
`and risks for the individual woman.
`
`
`
`
`
`
`
`
`
`0009
`
`
`
`DESCRIPTION
`
`Menostar™,estradiol transdermai system, is designed to provide nominalin vivo delivery
`of 14 mcg 17f-estradiol per day continuously upon application to intact skin, The period
`of use is 7 days. The transdermal system has a contact surface area of 3.25 cm2, and
`contains 1.0 mg ofestradiol USP.
`
`Estradiol USP (17f-estradiol) is a white, crystalline powder, chemically described as
`estra-1,3,5(10)-triene-3, 17B-diol.
`It has an empirical formula of Cjg H24 O2 and
`molecular weight of 272.39. The structural formulais:
`
`
`
`The Menostar™ transdermal system comprises three layers. Proceeding from the visible
`surface toward the surface attachedto 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 transdermal system can be used.
`
`(1) Flm BaokingaSee(3)Protective Lingr
`
`The active component ofthe transdermal system is 17B-estradiol. The remaining
`components of the transdermal system (acrylate copolymer adhesive, fatty acid esters,
`and polyethylene backing) are pharmacologically inactive.
`
`CLINICAL PHARMACOLOGY
`
`The Menostar™ transdermal system provides systemic estrogen therapy by releasing
`178-estradiol, the major estrogenic hormone secreted by the human ovary.
`|
`
`Endogenousestrogensare 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 receptorlevel.
`
`
`
`0010
`
`
`
`The primary source of estrogen in normally cycling adult womenis the ovarian follicle,
`which secretes 70 to 500 meg ofestradiol daily, depending on the phase of the menstrual
`cycle, After menopause, most endogenousestrogen 1s 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 abundantcirculating
`estrogens in postmenopausal women.
`
`Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To
`date, two estrogen receptors have been identified. These vary in proportion from tissue to
`tissue.
`
`Circulating estrogens modulate the pituitary secretion of the gonadotropins,luteinizing
`hormone (LH)andfollicle stimulating hormone (FSH), through a negative feedback
`mechanism. Estrogens act to reduce the elevated levels of these hormonesseen in
`postmenopausal women.
`
`The decline of ovarian estrogen production that accompanies menopause or
`oophorectomyresults in the acceleration of bone loss and bone resorption. Bone
`resorption is increased more than bone formation especially in the early years of
`menopause where bonelossis the greatest. In some women,these changeswill
`eventually lead to decreased bone mass, osteoporosis and increased risk for fractures,
`particularly that of the spine, hip, and wrist. Vertebral fractures are the most common
`type of osteoporotic fracture in postmenopausal women.
`Postmenopausal women with low scrum estradiol concentrations and high serum
`concentrations of sex hormone-binding globulin (SHBG) have an increased risk of hip
`and vertebral fractures. Postmenopausal estrogen therapy decreases bone resorption,
`helping to reestablish balance between resorption and formation. This effect appears to be
`effective for as long as treatmentis continued.
`
`PHARMACOKINETICS
`
`The bioavailability of estradiol following application of a Menostar™transdermal
`system, relative to that of a transdermal system delivering 25 mcg/day, was investigated
`in 18 healthy postmenopausal women mean age 66 years(range 60-80 years). The mean
`serum estradiol concentrations. upon administration of the two patches to the lower
`abdomen are shown in Figure 1. Transdermal administration of Menostar" produced
`geometric mean serum concentration (Cavg) of estradiol of 13.7 pg/mL. No patches
`failed to adhere during the one week application period of both transdermal systems.
`- Following application of the Menostar™ transdermal system to the abdomen,it is
`estimated to provide an average nominalin-vivo daily delivery of 14 mcg estradiol/day.
`
`Absorption
`The Menostar™ transdermal delivery system continuously releases estradiol whichis
`transported across intact skin leading to sustained circulating levels of estradiol during a
`7-day treatment period. The systemic availability of estradiol after transdermal
`
`
`
`0011
`
`
`
`administration is about 20 times higher than thatafter oral administration. This difference is
`due to the absence offirst pass metabolism, whenestradiolis given by the transdermalroute.
`
`Figure 1
`
`Mean Uncorrected Serum 17 B-Estradiol Concentrations vs. Time Profile Following
`Application of Menostar™ and Climara® 6.5 cm’ Transdermal System
`
`TM
`
`—_ -+
`
`Menostar
`14 meg/day
`®
`Climara 6. 5 cm? 25 mceg/day
`
`12
`
`24
`
`36
`
`48
`
`GO
`
`72
`
`84
`
`S96
`
`108 120 132 144 155 168 180
`
`
`
`0012
`
`_ §c@ocQO
`
`o 38saL
`
`u E3=aa
`
`Time (h)
`
`—_~
`am)
`E=
`
`Daa c 2—
`
`
`
`Table 1 provides a summary ofestradiol pharmacokinetic parameters determined during
`evaluation of Menostar™ using baseline uncorrected serum concentrations.
`
`Table 1. Summary of Estradiol Pharmacokinetic Parameters (Abdomen Application)
`
`Product
`
`Estradiol
`
`Daily
`Delivery
`Rate,
`mceg/day
`
`(0-tlast)
`
`pg.b/mL.
`
`
`
`Menostar™
`
`/
`
`2296
`
`Pharmacokinetic parameters are expressed in geometeric means except for the tmax which represents the
`median estimate and the Cmin which is expressed as the arithmetic mean,
`
`Theestimated estradiol daily delivery rate for Climara® 6.5 cm’ is quoted from the
`Climara® labeling.
`
`Distribution
`The distribution of exogenousestrogens is similar to that of endogenous estrogens.
`Estrogens are widely distributed in the body and are generally found in higher
`concentrations in the sex hormonetarget organs. Estrogens circulate in the blood largely
`bound to sex hormonebinding globulin (SHBG) and albumin. In the clinical study with
`208 patients on Menostar™, SHBG concentration (mean + SD) remained essentially
`unchanged over the 2 year period (baseline 45.1 + 20.1 nmol/L, 24 month visit 46.4 +
`20.9 nmol/L).
`
`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 mctabolite.
`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 postmenopausal women, a significant proportion
`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 estrio] are excreted in the urine along with glucuronide and sulfate
`conjugates.
`
`Special Populations:
`
`
`
`0013
`
`
`
`Geriatric: The efficacy and safety of Menostar™has been studied in women between 60
`and 80 years of age, with approximately half over 65 years old.
`
`Pediatric: No pharmacokinetic study for Menostar™has been conducted in a pediatric
`population.
`
`Gender: Menostar™is indicated for use in postmenopausal women only.
`
`Race: Nostudies were done to determine the effect of racc on the pharmacokinetics of
`Menostar™.
`
`Patients with Renal Impairment: Totalestradiol 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 transdermalestradiol doses used in individuals with normalrenal
`function may be excessive for postmenopausal women with ESRD receiving maintenance
`hemodialysis.
`
`Patients with Hepatic Impairment: Estrogens may be poorly metabolized in patients with
`impaired liver function and should be administered with caution.
`
`Drug Interactions
`in vitro and in vivo studies have shown that estrogens are metabolized partially by
`cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may
`affect estrogen drug metabolism. Inducers of CYP3A4 suchas St, John’s Wort
`preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may
`reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic
`effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as
`erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice
`may increase plasma concentrations of estrogens and mayresult in side effects.
`
`Adhesion
`In a Menostar pharmacokinetic study with 18 postmenopausal women,no patches failed
`to adhere during the one week application period
`
`Clinical Studies
`The efficacy of Menostar™in the prevention ofpostmenopausal osteoporosis was
`investigated in a 2-year double blind, placebo-controlled, multicenter study in the United
`States. A total of 417 postmenopausal women, 60 to 80 years old, with an intact uterus
`were enrolled in the study. All patients receivedsupplemental calcium and vitamin D.
`
`Menostar™ produced larger increases in bone mass than placebo as reflected by dual-
`energy x-ray absorptiometric (DEXA) measurements of hip and lumbar spine BMD.The
`changes in BMDfrom baseline werestatistically significantly (p <0.001) greater during
`
`
`
`0014
`
`
`
`treatment with Mcnostar™ than during treatment with placebo for hip and spineafter ]
`and 2 years.
`
`Atlumbar spine Menostar™ increased BMD by 2.3% after 1 year and 3.0% after 2 years
`compared with a 0.5% increase after 1 and 2 years of treatment with placebo. Atthe hip
`Menostar™ increased BMD by 0.90%after one year and 0.84% after two years
`compared with a mean decrease of 0.22% after 1 year and 0.71% after 2 years of placebo
`treatment (see Table 2 below).
`
`(Full Analysis Set)
`
`Table 2. Mean Percent BMD Change from Baseline in I.umbar Spine and Total Hip
`
`
`
`
`
`Total hip
`Lumbarspine
`
`
`
`Time points Menostar™ Piacebo p-value|Time points Mencstar™ Placebo p-value
`N = 209
`N = 208
`N = 209
`N=208 .
`
`
`
`n= 189
`n= 186
`
`
`< 0.001
`+0.51
`
`
`
`
`n= 189
`n= 186
`= 185
`
`-0.71 +0.84
`
`24-month
`< 0.001
`< 0.001
`
`Endpoint
`N = total number ofpatients; n= numberof patients with data available for each variable
`
`+2.99
`
`+0.54
`
`The BMD data ofthe study were analyzed according to bascline estradiol levels of the
`patients. Overall, estimated treatment cffects on lumbar spine and total hip BMDafter 2
`years were approximately twice as large in the subgroup with baseline estradiol levels < 5
`pg/mL than in the subgroup with baseline estradiol levels > 5.0 pg/mL [Table 3].
`
`Table 3. Mean percent change in Jumbar spine and total hip BMD at 24 months by subgroups of
`baseline estradiollevel (< 45 pg/mL, > § pg/mL)
`
`Total hip
`"Lumbar spine
`Baseline Treatment|Menostar™ PlaceboMenostar™ Placebo Treatment
`
`
`
`
`estradiol
`difference
`difference
`levels
`
`n= 97
`
`+0.29
`
`‘n= 8&9
`
`+0.31
`
`3.21
`
`(p< 0.001)"
`
`1.59
`
`2.13
`
`(p < 0.001}
`
`
`
`(p = 0.002)
`n= numberofpatients with data available for each variable
`Menostar™ therapy also resulted in consistent, statistically Significant suppression of
`bone turnover, as reflected by changes in serum and urine markers of bone formation
`(osteocaicin and bone-specific alkaline phosphatase) and bone resorption
`
`
`
`0015
`
`
`
`(carboxyterminal telopeptide of type 1 collagen (ICTP) and the urinary deoxypryridoline/
`creatinine ratio).
`
`Women's Health Initiative Studies
`The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy
`postmenopausal womento assessthe risks and benefits of either the use of 0.625 mg
`conjugated estrogens (CE) per day alone or the use of 0.625 mg conjugated estrogens
`plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the
`prevention of certain chronic diseases. The primary endpoint was the incidence of
`coronary heart disease (CHD)(nonfatal myocardial infarction and CHD death), with
`invasive breast cancer as the primary adverse outcome studied. A “global index” included
`the earliest occurrence of CHD,invasive breast cancer, stroke, pulmonary embolism
`(PB), endometrial! cancer, colorectal cancer, hip fixture, or death due to other cause. The
`study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.
`
`The CE/MPAsubstudy was stopped early because, according to the predefined stopping
`mule, the increased risk of breast cancer and cardiovascular events exceeded the specified
`benefits included in the “global! index.” Results of the CE/MPA substudy, which included
`16,608 women {average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5%
`Hispanic), after an average follow-up of 5.2 years are presented in Table 5 below:
`
`Table 5 RELATIVE AND ABSOLUTE RISK SEEN IN THE CE/MPA SUBSTUDY OF
`war
`
`Relative Risk
`CE/MPAvsplacebo
`at 5.2 Years
`(95% CI*)
`
`
`
`1.29 (1,02-1.63)
`CHDevents
`1.32 (1,02-1.72)
`Non-fatal MI
`.
`CHD death
`1.26 (1.00-1.59
`Invasive breast cancer’
`1.41 (1.07-1.85
`Stroke
`
`
`Pulmonary 2.13 (1.39-3.258s.ti—‘isSSCS@Yembolism
`Colorectal cancer
`0.63(0.43-0.92)16d
`Endometrial cancer
`0.83(0.47-147)16s
`Hip fracture
`Death due to causes other than the
`
`GlobalIndex °
`2.07 (1.49-2.87
`Deep vein thrombosis °
`Vertebral fractures °|0.66(0.44-0.98)TIS
`Other osteoporotic fractures “
`"adapted from JAMA, 2002; 288:321-333
`* includes metastatic and non-metastatic breast cancer with the exception ofin situ breast cancer
`*a subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events,
`invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or
`death due to other causes
`“not included in Global Index.
`* nominal confidence intervals unadjusted for multiple looks and multiple comparisons
`
`
`
`0016
`
`
`
`For those outcomes included in the “global index,” the absolute excess risks per 10,000
`women-years in the group treated with CE/MPA were 7 more CHD events, 8 more
`strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions
`per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The
`absolute excess risk of events included in the “global index” was 19 per 10,000 women-
`years. There was no difference between the groups in termsofall-cause mortality. (See
`BOXED WARNINGS, WARNINGS,and PRECAUTIONS.)
`
`Women’s Health Initiative Memory Study
`The Women’s Health Initiative Memory Study (WHIMS),a substudy of WHI, enrolled
`4,532 predominantly postmenopausal women 65 years of age and older (47% were age
`65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to
`evaluate the effects of CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg
`medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome)
`compared with placebo.
`
`After an average follow-up of 4 years, 40 womenin the estrogen/progestin group (45 per
`10, 000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were
`diagnosed with probable dementia. The relative risk of probable dementia in the hormone
`therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between
`groups became apparent in the first year of treatment. It is unknown whether these
`findings apply to younger postmenopausal women. (Sec BOXED WARNINGSand
`WARNINGS,Dementia.)
`
`INDICATIONS AND USAGE
`
`Menostar™is indicated for the prevention of postmenopausal osteoporosis. Therapy
`should be considered only for womenat significant risk of osteoporosis. Non-estrogen
`medications should be carefully considered.
`
`The mainstays for decreasing the risk of postmenopausal osteoporosis are weight bearing
`exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic
`therapy. Postmenopausal women require an average of 1500mg/day of elemental
`calcium. Therefore, when not contraindicated, calcium supplementation may be helpful
`for women with suboptimal dietary intake. Vitamin D supplementation of 400-800
`TU/day may also be required to ensure adequate daily intake in postmenopausal women.
`
`Risk factors for osteoporosis include [ow bone mineral density, low estrogen levels,
`family history of osteoporosis, previous fracture, small frame (low BMD), light skin color,
`smoking, and alcohol intake. Response to therapy can be predicted by pre-treatment
`serum estradiol (see Table 3), and can be assessed during treatment by measuring
`biochemical markers of bone formation/resorption, and/or bone mineral density.
`
`Estrogen therapy reduces bone resorption and retards or halts postmenopausal boneloss.
`Studies have shown a risk ratio of about 0.4 for hip and wrist fractures in women whose
`estrogen therapy was begun within a few years of menopause, compared to womentaking
`
`
`
`0017
`
`
`
`10
`
`calcium and vitamin D alone. Studies also suggest that estrogen reduces the rate of
`vertebral fractures. Even whenstarted as late as 6 years after menopause, estrogen
`reduces further loss of bone massfor as long astreatment is continued. When estrogen
`therapy is discontinued, bone mass declines at a rate comparable to the immediate
`postmenopausalperiod.
`
`Data from the Women’s Health Initiative study showed that use of estrogen (dose
`equivalent to 0.625 CE) resulted in about 6 less hip fractures per 10,000 women/years,
`compared to use ofplacebo(risk ratio about 0.6).
`
`CONTRAINDICATIONS
`
`WiWohm
`
`Menostar™ should not be used in women with any of the following conditions:
`Undiagnosed abnormalgenital bleeding.
`Known, suspected, or history of cancerofthe breast.
`Known or suspected estrogen-dependent neoplasia.
`Active deep vein thrombosis, pulmonary embolism or a history of these conditions.
`Active or recent (e.g. within the past year) arterial thromboembolic disease(e.g.,
`stroke, myocardial infarction).
`Liver dysfunction or disease.
`Menostar™ should not be used in patients with known hypersensitivity to its
`ingredients.
`8. Knownor suspected pregnancy. There is no indication for Menostar™ in pregnancy.
`There appears to be little or no increased risk of birth defects in children born to
`women who have used estrogens and progestins from oral contraceptives
`inadvertently during early pregnancy (See PRECAUTIONS.)
`
`mm
`
`WARNINGS
`
`. See BOXED WARNINGS.
`
`Cardiovascular disorders.
`1.
`Estrogen and estrogen/progestin therapy have been associated with an increased risk of
`cardiovascular events such as myocardial infarction and stroke, as well as venous
`thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of
`these occur or be suspected, estrogens should be discontinued immediately.
`
`Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco
`use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal
`history or family history ofVTE, obesity, and systemic lupus erythematosus) should be
`managed appropniately.
`
`a. Coronary heart disease and stroke
`In the Women’s Health Initiative (WHI) study, an increase in the number of myocardial
`infarctions and strokes has been observed in women receiving CE compared to placebo.
`
`
`
`0018
`
`
`
`These observations are preliminary (See CLINICAL PHARMACOLOGY,Clinical
`Studies.)
`
`In the CE/MPAsubstudy of WHI an increased risk of coronary heart disease (CHD)
`events (defined as non-fatal myocardial infarction and CHD death) was observed in
`womenreceiving CE/MPA compared to women receiving placebo (37 vs. 30 per 10,000
`women years). The increase in risk was observed in year one andpersisted.
`
`In the same substudy of WHI, an increased risk of stroke was observed in women
`receiving CE/MPA compared to womenreceiving placebo (29 vs. 21 per 10,000 women-
`years). The increase in risk was observed after the first year and persisted.
`
`In postmenopausal women with documentedheart disease
`(n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of
`cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS)
`treatment with CE/MPA (0.625mg/2.5mg per day) demonstrated no cardiovascular
`benefit. During an average follow-up of 4.1 years, treatment with CE/MPAdid not
`reducethe overall rate of CHD events in postmenopausal women with established
`coronary heart disease. There were more CHD events in the CE/MPA-treated group than
`in the placebo group in year 1, but not during the subsequent years. Two thousand three
`hundred and twenty one women from the original HERStrial agreed to participate in an
`open label extension of HERS, HERS IL. Average follow-up in HERSII was an
`additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were
`comparable among women in the CE/MPA group andthe placebo group in HERS, HERS
`Il, and overall.
`
`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.
`
`b. Venous thromboembolism (VTE)
`In the Women’s Health Initiative (WHI) study, an increase in VTE has been observed in
`women receiving CE compared to placebo. These observations are preliminary. (See
`CLINICAL PHARMACOLOGY,Clinical Studies.)
`
`In the CE/MPAsubstudy of WHI, a 2-fold greater rate of VTE, including deep venous
`thrombosis and pulmonary embolism, was observed in women receiving CE/MPA
`compared to women receiving placebo. The rate of VTE was 34 per 10,000 women -
`years in the CE/MPA group compared to 16 per 10,000 women-yearsin the placebo
`group. The mcrease in VTE risk was observed during thefirst year and persisted.
`
`If feasible, estrogens should be discontinued atleast 4 to 6 weeks before surgery ofthe
`type associated with an increased risk of thromboembolism, or during periods of
`prolonged immobilization.
`
`
`
`0019
`
`
`
`12
`
`2.
`
`Malignant neoplasms
`
`a. Endometrial cancer
`The use of unopposed estrogens in women with intact uteri has been associated with an
`increased risk of 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 dosc. Most studies show no
`significant increased risk associated with use of estrogensfor fess than one year. The
`greatest risk appears associated with prolonged use, with increasedrisks of 15- to 24-fold
`for five to ten years or more andthis risk has been shownto persist for at least 8 to 15
`years after estrogen therapy is discontinued.
`
`Clinical surveillance of ail women taking estrogen/progestin c