.
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`||||
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`I*52
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`
`|| |||||||
`
`*A*
`
`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:
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`
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`
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`Freedom of Information Act and are therefore available to the general public. FOI Services. Inc. does not guarantee the accuracy of
`
` 
`

 
`
`
`MYLAN - EXHIBIT 1017
`
`0001
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICA TION NUMBER:
`
`2 1-674
`
`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
`
`APPLICA TION NUMBER:
`
`2 1 -674
`
`CONTENTS
`
`
`
`Reviews / Information Included in thlS NAD Review.
`
`
`
`A roval Letter
`A. '. rovable Letter 1
`A rovable Letter 2
`Final Printed Labelin_
`
`Medical Review 5
`
`Chemistr Review s
`
`EA/FONSI
`
`fl_ _
`_________
`X
`
`__I_=X
`
`
`
`0003
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 1 -674
`
`APPROVAL LETTER
`
`
`
`0004
`
`

`

`L“ 5!lug-L
`
`5'
`.
`= C DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`a.“
`
`Public Health Service
`
`Food and Drug Administration
`Rockvillo, MD 20857
`
`NDA 2l-674
`
`Berlex Laboratories Inc.
`
`Attention: Geoffrey Millington
`Manager, Drug Regulatory Affairs
`340 Changebridge Road; PO. 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, December 17, 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 (cstradiol transdermal system) for prevention
`of postmenopausal osteoporosis.
`
`We have completed our review of this application and it is approved, effective on the date of this letter,
`for use as recommended in the agreed—upon labeling text and with the minor editorial changes to the foil
`pouches, containers and cartons listed below. The changes to the foil pouches mustbe 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 name so that it does
`not interfere with the readability of the proprietary name.
`
`2.
`
`Increasethe prominence of the established name and strength, so that they are at least one-half
`the size of the proprietary name.
`
`3. Eliminate the terminal Zeros listed throughout the container labels and carton labeling since they
`could be misinterpreted (e.g., 1.0 as 10).
`
`Specific Revision to the foil pouches (sample and trade):
`
`1.
`
`Include 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):
`
`1.
`
`Increase the prominence of the 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 insert and the
`patient package insert and include the minor editorial revisions to the submitted labeling (foil pouch,
`containers and cartons, submitted May 14, 2004). We remind you of your agreement to make the
`labeling changes to the foil pouches before production of batch no. 2. These changes can be submitted
`as a CBE-O labeling supplement, which must contain final printed labeling.
`
`These revisions are terms of the NDA approval. Marketing the product before making the revisions,
`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 drafi 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 FDA is 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 assessment of the safety and
`effectiveness of the product in pediatric patients unless this requirement is waived or deferred. We are
`waiving the pediatric study requirement for this application.
`
`In addition, submit three copies of the introductory promotional materials that you propose to use for this
`product. Submit all proposed materials in draft or mock-up form, not final print. Send one copy to this
`division and two copies of both the promotional materials and the package insert directly to:
`
`Division of Drug Marketing, Advertising,
`and Communications, RFD-42
`Food and Drug Administration
`5600 Fishers Lane
`
`Rockville, MD 20857
`
`Werernind 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. Orloff, MD.
`Director
`
`Division of Metabolic and Endocrine Drug Products
`Office of Drug Evaluation 11
`Center for Drug Evaluation and Research
`
`Enclosure:
`
`package insert
`patient package insert
`
`
`
`0007
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-674
`
`APPROVED LABELING
`
`
`
`0008
`
`

`

`Rx only
`Menostar'rM gestradiol transdermal gstem)
`PRESCRIBING INFORMATION
`
`
`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 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 (WI-II) 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 (MFA
`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 pestmenopausal 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 medroxyprogesterone acetate, and other
`combinations and dosage forms of estrogens and progestins were not studied in the Will
`clinical trials and, in the absence of comparable data, these risks should be assumed to 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
`
`MenostarTM, estradiol transdermal system, is designed to provide nominal in viva delivery
`of 14 meg HIS—estradiol per day continuously upon application to intact skin. The period
`of use is 7 days. The transdcrmal system has a contact surface area of 3.25 cm2, and
`contains 1.0 mg of estradiol USP.
`
`Estradiol USP (NB-estradiol) is a white, crystalline powder, chemically described as
`estra-1,3,S(10)-triene—3, ITB-diol.
`It has an empirical formula of C13 H24 02 and
`molecular weight of 272.39. The structural formula is:
`
`
`
`The MenostarTM transdermal system comprises three 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 poiyester film is attached to
`the adhesive surface and must be removed before the transdermal system can be used.
`
`(15mm Backing
`% a WWW Law
`
`nwmmMumm
`
`The active component ofthe transdermal system is FIB—estradiol. The remaining
`components of the transdennal system (acrylate copolymer adhesive, fatty acid esters,
`and polyethylene backing) are pharmacologically inactive.
`
`CLINICAL PHARMACOLOGY
`
`The Ivlenostar'l'M transdermai system provides systemic estrogen therapy by releasing
`WEI-estradiol, the major estrogenic hormone secreted by the human ovary.
`_
`
`Endogenous 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.
`
`
`
`0010
`
`

`

`The primary source of estrogen in normally cycling adult women is the ovarian follicle,
`which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual
`cycle. After menopause, most endogenous estrogen is produced by conversion of
`androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus,
`estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating
`estrogens in postmenopausal women.
`
`Estrogcns 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) and follicle stimulating hormone (FSH), through a negative feedback
`mechanism. Estrogens act to reduce the elevated levels of these hormones seen in
`postmenopausal women.
`
`The decline of ovarian estrogen production that accompanies menopause or
`oophorectomy results 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 bone loss is the greatest. In some women, these changes will
`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 serum 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 treatment is continued.
`
`PHARMACOKINETICS
`
`The bioavailability of estradiol following application of a MenostarTM transdcrmal
`system, relative to that of a transdermal system delivering 25 mcglday, 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 transdennal systems.
`- Following application of the lvienosta.r"l'M ttansdermal system to the abdomen, it is
`estimated to provide an average nominal in-vivo daily delivery of 14 mcg estradiol/day.
`
`Absorption
`The Menostar'l‘M 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
`
`
`
`0011
`
`

`

`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.
`
`Figure 1
`
`Mean Uncorrected Serum 1'7 B—Estradiol Concentrations vs. Time Profile Following
`Application of Menostarm and Climara‘D 6.5 cm2 Transdermal System
`
`TM
`
`Menostar
`o
`
`l4 meg/day
`
`cum” 6. s cm1 25 mayday
`
`12
`
`24
`
`36
`
`48
`
`60
`
`72
`
`84
`
`96 108120132144155168180
`
`Time(h)
`
` 
`
`0012
`
`J E
`
`.._.
`U)
`o.v
`i:
`.9in,
`
`
`
`A.
`
`.3;r:
`a:
`
`ocoO E Ebt
`
`o
`DJ
`E:1I.
`a)
`(D
`
`

`

`Table 1 provides a summary of estradiol phannacokinetic parameters determined during
`evaluation of MenostarTM using baseline uncorrected serum concentratious.
`
`Table 1. Summary or Estradiol Pharmacoldnetic Parameters (Abdomfi Application)
`
`Estradiol
`
`
`
`Daily
`Delivery
`Rate,
`
`meg/day
`
`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.
`
`The estimated estradiol daily delivery rate for Climara® 6.5 cm2 is quoted from the
`Climaram labeling.
`
`Distribution
`
`The distribution of exogenous estrogens is similar to that of endogenous estrogens.
`Estrogens are widely distributed in the body and are generally found in higher
`concentrations in the sex hormone target organs. Estrogens circulate in the blood largely
`bound to sex hormone binding globulin (SHBG) and albumin. In the clinical study with
`208 patients on MenostarT”, SHBG concentration (mean .+. SD) remained essentially
`unchanged over the 2 year period (baseline 45.] :I: 20.1 nmolfL, 24 month visit 46.4 :t
`20.9 nrnol/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 estn'ol, which is the major urinary metabolite.
`Estrogens also undergo cnterohepatic 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 estriol are excreted in the urine along with glucuronide and sulfate
`conjugates.
`
`Special Populations.-
`
` 
`
`0013
`
`

`

`Geriatric: The efficacy and safety of MenostarTM has been studied in women between 60
`and 80 years of age, with approximately half over 65 years old.
`
`Pediatric: No pharmacokinetic study for MenostarTM has been conducted in a pediatric
`population.
`
`Gender: MenostarTM is indicated for use in postmenopausal women only.
`
`Race: No studies were done to determine the effect of race on the pharmacokinetics of
`Menostarm.
`
`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 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 such as 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 may result in side effects.
`
`Adhesion
`In a Menostar phannacokinetic study with 18 postmenopausal women, no patches failed
`to adhere during the one week application period
`
`Clinical Studies
`
`The efficacy of MenostarTM 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 receivedlsupplemental calcium and vitamin D.
`
`MenostarTM 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 BMD from baseline were statistically significantly (p <0.001) greater during
`
` 
`
`0014
`
`

`

`treatment with Menostar'l'M than during treatment with placebo for hip and spine aflcr l
`and 2 years.
`
`At'lumbar Spine MenostarTM increased BMD by 2.3% afier 1 year and 3.0% afler 2 years
`compared with a 0.5% increase after 1 and 2 years of treatment with placebo. At the hip
`N‘ienostarTM increased BMD by 0.90% after one year and 0.84% afier 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).
`
`Table 2. Mean PercentABMD Change from Baseline in Lumbar Spine and Total Hip
`(Full Analysis Set)
`
`Lumbar spine
`
`Time points Menostarm Placebo
`N=208|
`N=209
`
`12-month
`
`Endpoint
`
`24-month
`
`'
`
`n = 186
`+0.5 1
`
`n =
`
`+0.54
`
`.
`
`Placebo
`N=209
`
`
`
`Endpoint
`Endpoint
`N = total number of patients; n = number of patients with data available for each variable
`
`
`
`
`
`The BMD data of the study were analyzed according to baseline estradiol levels of the
`patients. Overall, estimated treatment effects on lumbar spine and total hip BMD after 2
`years were approximately twice as large in the subgroup with baseline estradiol levels < S
`pg/mL than in the subgroup with baseline estradiol levels 2 5.0 pg/mL [Table 3].
`
`Table 3. Mean percent change in lumbar spine and total hip BMD at 24 months by subgroups of
`baseline estradiel level (< 5 pglmL, 2 5 pglmL)
`
`I
`
`Lumbar spine
`
`Menostarm
`
`Placebo
`
`Treatment Menostarm
`difference
`
`Total hip
`
`Placebo
`
`Baseline
`estradiol
`levels
`
`+0.81
`
`Treatment
`difference
`
`2.13
`
`(p<0.001)
`
`n=97
`
`+0.29
`
`-n=89
`
`3.21
`
`(p<0.001)'
`
`n = number of patients with data available for each variable
`
`Menostar'l'M therapy also resulted-in consistent, statistically significant suppression of
`bone turnover, as reflected by changes in serum and urine markers of bone formation
`(osteocalcin and bone-specific alkaline phosphatase) and bone resorption
`
` 
`
`0015
`
`

`

`(carboxyterminal telopeptide of type I collagen (ICTP) and the urinary deoxypryridoline/
`creatinine ratio).
`
`Women ’s Health Initiative Studies
`
`The Women’s Health Initiative (WI-II) enrolled a total of 27,000 predominantly healthy
`postmenopausal women to assess the 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 CEIMPA on menopausal symptoms.
`
`The CE/MPA substudy was stopped early because, according to the predefmed stopping
`rule, 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), afier an average follow-up of 5.2 years are presented in Table 5 below:
`
`Table 5 RELATIVE AND ABSOLUTE RISK SEEN IN THE CEIMPA SUBSTUDY OF
`
`WHI'
`
`Relative Risk
`
`CB/MPA vs placebo
`at 5.2 Years
`
`(95% CI*)
`
`1.29 (1 .02-l .63)
`1.32 (1.02-1. 72)
`1.13 0.70-1.97
`1.26 1.00-1.59
`1.41 1.07-1.85
`2.13 1.39-3.25
`
`15
`
`1 '
`
`CHI) events
`NonJatal M
`CHD death
`
`Pulmo-
`
`embohsm
`
`events above
`
`' ' v- vein fluombosw'
`
`Vertebral fiacarres '
`
`0.66 0.44-0.98 _
`0.77 0.69-0.86
`
`' adapted from JAMA. 2002; 288:321-333
`5 includes metastatic and non-metastatic breast cancer with the exception of in 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
`I’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 PBS, and 8 more invasive breast cancers, while absolute risk reductions
`per 10,000 women-years were 6 fewer colorectal cancers and S 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 terms of all-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 women in 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. (See BOXED WARNINGS and
`WARNINGS, Dementia.)
`
`INDICATIONS AND USAGE
`
`MenostarTM is indicated for the prevention of postmenopausal osteoporosis. Therapy
`should be considered only for women at significant risk of osteoporosis. Non-estrogen
`medications should be carefirlly 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 helpfiil
`for women with subOptimal dietary intake. Vitamin D supplementation of 400-800
`IU/day may also be required to ensure adequate daily intake in postmenopausal women.
`
`Risk factors for osteoporosis include low bone mineral density, low estrogen levels,
`family history of osteoporosis, previous fracture, small frame (low BMJ), light skin color,
`smoking, and ”alcohol intake. Response to therapy can be predicted by pre-treaunent
`serum estradiol (see Table 3), and can be assessed during treatment by measuring
`biochemical markers of bone formationfresorption, and/or bone mineral density.
`
`Estrogen therapy reduces bone resorption and retards or halts postmenopausal bone loss.
`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 women taking
`
` 
`
`0017
`
`

`

`10
`
`calcium and vitamin D alone. Studies also suggest that estrogen reduces the rate of
`vertebral fractures. Even when started as late as 6 years after menopause, estrogen
`reduces 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.
`
`Data fi'orn 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 of placebo (risk ratio about 0.6).
`
`CONTRAINDICATIONS
`
`P‘PP’N.‘
`
`MenostarT” should not be used in women with any of the following conditions:
`Undiagnosed abnormal genital bleeding.
`Known, suspected, or history of cancer of the 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 thrombocmbolic disease (e.g.,
`stroke, myocardial infarction).
`Liver dysfunction or disease.
`~19
`. MenostarTM should not be used in patients with known hypersensitivity to its
`ingredients.
`_
`8. Known or suspected pregnancy. There is no indication for MenostarTM 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.)
`
`WARNINGS
`
`. See BOXED WARNINGS.
`
`1.
`
`Cardiovascular disorders.
`
`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 of VTE, obesity, and systemic lupus erythematosus) should be
`managed appropriately.
`
`a. Coronary heart disease and stroke
`In the Women's Health Initiative (WEI) study, an increase in the number of myocardial
`infarctions and strokes has been observed in women receiving CE compared to placebo.
`
` 
`
`0018
`
`

`

`ll
`
`These observations are preliminary (See CLINICAL PHARMACOLOGY, Clinical
`Studies.)
`
`In the CE/Nfl’A substudy of WI-I] an increased risk of coronary heart disease (CHD)
`events (defined as non-fatal myocardial infarction and CHD death) was observed in
`women receiving CE/MPA compared to women receiving placebo (37 vs.'30 per 10,000
`women years). The increase in risk was observed in year one and persisted.
`
`In the same substudy of WHI, an increased risk of stroke was observed in women
`receiving CE/MPA compared to women receiving 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 documented heart 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 CEMA (0.625mg/2.5mg per day) demonstrated no cardiovascular
`benefit. During an average follow—up of 4.1 years, treatment with CEIMPA did not
`reduce the overall rate of CHD events in postmenopausal women with established
`coronary heart disease. There were more CHD events in the CEMA—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 HERS trial agreed to participate in an
`open label extension of HERS, HERS II. Average follow—up in HERS II was an
`additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were
`comparable among women in the CEfMPA group and the placebo group in HERS, HERS
`II, 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 thramboembalism (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 CFJMPA substudy 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 CB/MPA group compared to 16 per 10,000 women—years in the placebo
`group. The increase in VTE risk was observed during the first year and persisted.
`
`If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the
`type associated with an increased risk of thromboembolism, or during periods of
`prolonged immobilization.
`
` 
`
`0019
`
`

`

`l2
`
`2.
`
`Malignant neoplasms
`
`a. Endometrr'al 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 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 to 15
`years after estrogen therapy is discontinued.
`
`Clinical surveillance of all women taking estrogen/progestin combinations is important.
`Adequate diagnostic