throbber
.
`
`Hvagie
`"iUiAt
`
`ima
`320*
`
`+52
`
`LARIATURL aH
`
`kA*
`
`5228320
`
`A
`
`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
`Gaithersburg MD 20878-1751 USA
`Phone:
`301-975-9400
`Fax:
`301-975-0702
`Email:
`infofoi@foiservices.com
`
`Do you need additional U.S. Government information?
`
`Since 1975, FOt Services, inc has specialized in acquiring government files using the Freedom ofinformation Act.
`Wehave millions of pages of unpublished documentation already onfile and available for immediate delivery.
`
`Many of the documents you need are available for immediate downloadingat:
`www.foiservices.com
`
`any ofthe information in these documents; the documents will be faithful copies of the information supplied to FOI Services, Inc.
`
`Unless specified otherwise,all of FOl Services' documents have been released by the U.S, Government underthe provisions of the
`Freedom of Information Act and are therefore availabie to the general public. FO! Services, inc. does not guarantee the accuracy of
`
` 
`
 
`
`
`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

This document is available on Docket Alarm but you must sign up to view it.


Or .

Accessing this document will incur an additional charge of $.

After purchase, you can access this document again without charge.

Accept $ Charge
throbber

Still Working On It

This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.

Give it another minute or two to complete, and then try the refresh button.

throbber

A few More Minutes ... Still Working

It can take up to 5 minutes for us to download a document if the court servers are running slowly.

Thank you for your continued patience.

This document could not be displayed.

We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.

Your account does not support viewing this document.

You need a Paid Account to view this document. Click here to change your account type.

Your account does not support viewing this document.

Set your membership status to view this document.

With a Docket Alarm membership, you'll get a whole lot more, including:

  • Up-to-date information for this case.
  • Email alerts whenever there is an update.
  • Full text search for other cases.
  • Get email alerts whenever a new case matches your search.

Become a Member

One Moment Please

The filing “” is large (MB) and is being downloaded.

Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.

Your document is on its way!

If you do not receive the document in five minutes, contact support at support@docketalarm.com.

Sealed Document

We are unable to display this document, it may be under a court ordered seal.

If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.


Access Government Site

We are redirecting you
to a mobile optimized page.





Document Unreadable or Corrupt

Refresh this Document
Go to the Docket

We are unable to display this document.

Refresh this Document
Go to the Docket