HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not includeall the information needed to use
`MINIVELLEsafely and effectively. See full prescribing information for
`MINIVELLE.
`
`MINIVELLE® (estradiol transdermal system)
`Initial U.S. Approval: 1975
`
`WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR
`DISORDERS, BREAST CANCER, and PROBABLE DEMENTIA
`Seefullprescribing information for complete boxed warning.
`
`Estrogen-Alone Therapy
`© There is an increased risk of endometrial cancer in a woman with a
`uterus who uses unopposed estrogens (5.2)
`« Estrogen-alone therapyshould not be used for the prevention of
`cardiovascular disease or dementia (5.1, 5.3)
`« The Women’s Health Initiative (WHI) estrogen-alone substudy
`reported increased risks of stroke and deep vein thrombosis (DVT)(5.1)
`* The WHI MemoryStudy (WHIMS)estrogen-alone ancillary study of
`WHI reported an increased risk of probable dementia in
`postmenopausal women 65 years of age and older (5.3)
`Estrogen Plus Progestin Therapy
`« Estrogen plus progestin therapy should not be used for the prevention
`of cardiovascular disease or dementia (5.1, 5.3)
`« The WHI estrogen plus progestin substudy reported increased risks of
`DVT, pulmonary embolism (PE), stroke, and myocardial infarction
`(MI)(5.1)
`« The WHI estrogen plus progestin substudy reported increased risks of
`invasive breast cancer(5.2)
`« The WHIMSestrogen plus progestin ancillary study of WHI reported
`an increased risk of probable dementia in postmenopausal women 65
`
`years of age and older(5.3)
`
`—_i@—_— RECENT MAJOR CHANGES
`Indications and Usage (1.2)
`Dosage and Administration (2.2)
`Warnings and Precautions (5.15)
`
`9/2014
`9/2014
`9/2014
`
`———————_ INDICATIONSANDUSAGE
`MINIVELLE® is an estrogen indicated for:
`« Treatment of moderate to severe vasomotor symptoms due to menopause
`(1.1)
`* Prevention of postmenopausal osteoporosis (1.2)
`
`DOSAGE AND ADMINISTRATION
`* For Vasomotor Symptoms: Start therapy with MINIVELLE®0.0375 mg
`per day applied to the skin twice weekly. Dosage adjustment should be
`guided bythe clinical response (2.1)
`
`e For Postmenopausal Osteoporosis Prevention: Start therapy with
`MINIVELLE 0.025 mgper day applied to the skin twice weekly. The dose
`may be adjusted as necessary (2.2)
`
`MINIVELLEshould be placed on a clean, dryarea on the lower abdomen
`(belowthe umbilicus) or buttocks. MINIVELLE should not be applied to
`the breasts (2.3)
`
`DOSAGE FORMS AND STRENGTHS
`Transdermal system: 0.025 mg/day, 0.0375 mg/day, 0.05 mg/day, 0.075
`mg/day, and 0.1 mg/day (3)
`
`CONTRAINDICATIONS
`Undiagnosed abnormal genital bleeding (4)
`Known,suspected, or history of breast cancer (4, 5.2)
`Knownor suspected estrogen-dependent neoplasia (4, 5.2)
`Active DVT, PE, ora history of these conditions (4, 5.1)
`Active arterial thromboembolic disease (for example, stroke and M1), or a
`history ofthese conditions (4, 5.1)
`« Known anaphylactic reaction or angioedema or hypersensitivity with
`MINIVELLE (4)
`* Known liver impairmentor disease (4, 5.10)
`* Knownprotein C, protein S, or antithrombin deficiency, or other known
`thrombophilic disorders (4)
`* Knownor suspected pregnancy (4, 8.1)
`
`WARNINGS AND PRECAUTIONS
`e Estrogens increase the risk ofgallbladder disease (5.4)
`« Discontinue estrogen if severe hypercalcemia, loss ofvision, severe
`hypertriglyceridemia or cholestatic jaundice occurs (5.5, 5.6, 5.9, 5.10)
`« Monitor thyroid function in women on thyroid replacement therapy (5.11,
`5.18)
`
`ADVERSE REACTIONS
`Most commonadverse reactions (greater than or equal to 5 percent) with
`Vivelle are: headache, breast tenderness, back pain, pain in limb, and
`nasopharyngitis, dyspepsia, nausea, sinusitis, and intermenstrual bleeding
`(6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Noven at 1-
`800-455-8070 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
`
`—— DRUG INTERACTIONS
`Inducers and/or inhibitors of CYP3A4 mayaffect estrogen drug metabolism
`(7.1)
`
`USEIN SPECIFIC POPULATIONS
`e Nursing Mothers: Estrogen administration to nursing women has been
`shown to decrease the quantity and quality of breast milk. Detectable
`amounts of estrogens have been identified in the breast milk of women
`receiving estrogens. (8.3)
`© Geriatric Use: Anincreased risk of probable dementia in women over 65
`years of age wasreported in the WHIMSancillary studies of the WHI(5.3,
`8.5)
`
`See 17 for PATIENT COUNSELING INFORMATIONand FDA-
`approved patientlabeling
`
`Revised: 9/2014
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR
`DISORDERS, BREAST CANCER,and PROBABLE DEMENTIA
`
`1
`
`2
`
`he
`
`INDICATIONS AND USAGE
`1.1
`Treatment of Moderate to Severe Vasomotor Symptoms
`1.2
`Prevention of Postmenopausal Osteoporosis
`DOSAGE AND ADMINISTRATION
`2.1
`Treatment of Moderate to Severe Vasomotor Symptoms
`2.2.
`Prevention of Postmenopausal Osteoporosis
`2.3.
`Patch Application Instructions
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1
`Cardiovascular Disorders
`5.2. Malignant Neoplasms
`5.3.
`Probable Dementia
`
`Reference ID: 3632965
`
`4
`5
`.6
`7
`
`Gallbladder Disease
`Hypercalcemia
`Visual Abnomnalities
`Addition of a Progestin When a Woman Has Not Had a
`Hysterectomy
`Elevated Blood Pressure
`5.8
`Hypertriglyceridemia
`5.9
`5.10 Hepatic Impairment and/or Past History of Cholestatic Jaundice
`$.11 Hypothyroidism
`5.12 Fluid Retention
`5.13. Hypocalcemia
`§.14 Exacerbation of Endometriosis
`5.15
`Severe Anaphylactic/Anaphylactoid Reactions and Angioedema
`5.16 Exacerbation of Other Conditions
`5.17. Laboratory Tests
`5.18 Drug-Laboratory Test Interactions
`ADVERSE REACTIONS
`6.1
`Clinical Trials Experience Nqyen Pharmaceuticals, Inc.
`EX2003
`Mylan Tech., Inc. v. Noven Pharma., Inc.
`IPR2018-00173
`
`6
`
`

`

`Postmarketing Experience
`6.2
`DRUG INTERACTIONS
`7.1 Metabolic Interactions
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3.
`Nursing Mothers
`8.4
`Pediatric Use
`8.5
`Genatne Use
`8.6
`Renal Impairment
`8.7
`Hepatic Impairment
`OVERDOSAGE
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3. Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`13,1 Carcinogenesis, Mutagenesis, Impairment ofFertility
`
`10
`
`12
`
`13
`
`14
`
`CLINICAL STUDIES
`14.1 Effects on Vasomotor Symptoms
`14.2 Effects on Bone Mineral Density
`14.3 Women’s HealthInitiative Studies
`14.4 Women’s Health Initiative Memory Study
`REFERENCES
`HOWSUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2
`Storage and Handling
`PATIENT COUNSELING INFORMATION
`17.1 Vaginal Bleeding
`17.2. Possible Serious Adverse Reactions with Estrogen-Alone
`Therapy
`17.3. Possible Less Serious but Common Adverse Reactions with
`Estrogen-Alone Therapy
`*Sections or subsections omitted from the full prescribing information
`are notlisted.
`
`Reference ID: 3632965
`
`0002
`
`

`

`FULL PRESCRIBING INFORMATION
`
`WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST
`CANCER, and PROBABLE DEMENTIA
`
`Estrogen-Alone Therapy
`
`Endometrial Cancer
`
`Thereis an increased risk of endometrial cancer in a woman with a uterus who uses
`unopposed estrogens. Adding a progestin to estrogen therapy has been shownto reducethe
`risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
`Adequate diagnostic measures, including directed or random endometrial sampling when
`indicated, should be undertaken to rule out malignancy in postmenopausal women with
`undiagnosedpersistent or recurring abnormal genital bleeding /see Warnings and
`Precautions(5.2)].
`
`|
`
`Cardiovascular Disorders and Probable Dementia
`
`Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or
`dementia /see Warningsand Precautions(5.1, 5.3), and Clinical Studies (14.3, 14.4)].
`
`The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of
`stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age)
`during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone,
`relative to placebo /see Warnings and Precautions(5.1), and Clinical Studies (14.3)].
`
`The WHI Memory Study (WHIMS) estrogen-aloneancillary study of WHI reported an
`increasedrisk of developing probable dementia in postmenopausal women65yearsof age
`or older during 5.2 years of treatment with daily CE (0.625 mg)-alone,relative to placebo.
`It is unknown whetherthis finding applies to younger postmenopausal women/see
`Warnings and Precautions (5.3), Use in Specific Populations (8.5), and Clinical Studies
`(14.4)].
`
`In the absence of comparable data, these risks should be assumedto be similar for other
`doses of CE and other dosage formsof estrogens.
`
`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.
`
`Estrogen Plus Progestin Therapy
`
`Cardiovascular Disorders and Probable Dementia
`
`Estrogen plus progestin therapy should not be used for the prevention of cardiovascular
`disease or dementia /see Warnings and Precautions(5.1, 5.3), and Clinical Studies (14.3,
`14.4].
`
`The WHI estrogenplus progestin substudy reported increased risks of DVT, pulmonary
`embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women(50 to 79
`years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with
`medroxyprogesterone acetate
`
`Reference ID: 3632965
`
`O003
`
`

`

`
`
`Precautions (5.1), and Clinical Studies (14.3)].
`
`The WHIMSestrogen plus progestin ancillary study of the WHI, reported an increased
`risk of developing probable dementia in postmenopausal women65yearsof age or older
`during 4 yearsof treatment with daily CE (0.625 mg) combined with MPA(2.5 mg),
`relative to placebo. It is unknown whetherthis finding applies to younger postmenopausal
`women/see Warnings and Precautions (5.3), Use in Specific Populations (8.5), and Clinical
`Studies (14.4)].
`
`Breast Cancer
`
`The WHI estrogen plus progestin substudy also demonstrated an increased risk of
`invasive breast cancer /see Warnings and Precautions (5.2), and Clinical Studies (14.3)].
`
`In the absence of comparable data, these risks should be assumedto be similar for other
`doses of CE and MPA,and other combinations and dosage forms of estrogens and
`progestins.
`
`Estrogens with or without progestins should be prescribed at the lowest effective doses and
`for the shortest duration consistent with treatmentgoals andrisks for the individual
`woman.
`
`
`
`1
`
`1.1
`
`INDICATIONS AND USAGE
`
`Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause
`
`MINIVELLEisindicated for the treatment of moderate to severe vasomotor symptomsdue to
`menopause.
`
`1.2
`
`Prevention of Postmenopausal Osteoporosis
`
`MINIVELLEis indicated for the prevention of postmenopausal osteoporosis.
`
`Limitation of Use
`
`Whenprescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be
`considered for womenatsignificant risk of osteoporosis and non-estrogen medications should be
`carefully considered.
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`Generally, when estrogenis prescribed for a postmenopausal womanwith a uterus, a progestin should be
`considered to reduce the risk of endometrial cancer. A woman without a uterus does not need a progestin.
`In somecases, however, hysterectomized women with a history of endometriosis may need a progestin
`[see Warnings and Precautions(5.2, 5.14)].
`
`Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective dose and
`for the shortest duration consistent with treatment goals and risks for the individual woman.
`4
`
`Reference ID: 3632965
`
`Ob04
`
`

`

`Postmenopausal womenshould be re-evaluated periodically as clinically appropriate to determineif
`treatmentis still necessary.
`
`2.1
`
`Treatment of Moderate to Severe Vasomotor Symptoms
`
`Start therapy with MINIVELLE 0.0375 mg per day applied to the skin twice weekly. Dosage adjustment
`should be guided bythe clinical response.
`
`Therapy should be started at the lowest effective dose and the shortest duration consistent with the
`treatment goals. Attempts to taper or discontinue the medication should be madeat 3 to 6 monthintervals.
`
`Zin
`
`Prevention of Postmenopausal Osteoporosis
`
`Start therapy with MINIVELLE0.025 mgper day applied to the skin twice weekly. The dose may be
`adjusted as necessary.
`
`2.3
`
`Patch Application Instructions
`
`The adhesive side of MINIVELLEshouldbe placed on a clean, dry area on the lower abdomen (below
`the umbilicus) or buttocks. MINIVELLEshould notbe appliedto the breasts.
`
`MINIVELLEshould be replaced twice weekly (every 3-4 days).
`
`The sites of application mustbe rotated, with an interval of at least | week allowed between applications
`to a particularsite.
`
`The area selected should not be oily, damaged,orirritated. The waistline should be avoided, since tight
`clothing may rub the system off. The system should be applied immediately after opening the pouch and
`removing the protective liner. The system should be pressed firmly in place with the palmof the hand for
`about 10 seconds, makingsure there is good contact with the skin, especially around the edges. In the
`event that a system should fall off, the same system may be reapplied. If the same system cannot be
`reapplied, a new system should be applied to another location. If a woman has forgotten to apply a patch,
`she should apply a new patch as soon as possible. In either case, the original treatment schedule should be
`continued. The interruption of treatment in women taking MINIVELLEmightincrease the likelihood of
`breakthrough bleeding, spotting and recurrence of symptoms.
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`Transdermal system: 0.025 mg/day, 0.0375 mg/day, 0.05 mg/day, 0.075 mg/day, and 0.1 mg/day.
`
`4
`
`CONTRAINDICATIONS
`
`MINIVELLEis contraindicated in womenwith any of the following conditions:
`
`e Undiagnosed abnormalgenital bleeding
`
`e Known,suspected or history of breast cancer
`
`e Known orsuspected estrogen-dependent neoplasia
`
`e Active DVT, PE,or a history of these conditions
`5
`
`Reference ID: 3632965
`
`8005
`
`

`

`e Active arterial thromboembolic disease (for example, stroke and MI), or a history of these
`conditions
`
`e
`
`e
`
`e
`
`e
`
`Knownanaphylactic reaction or angioedema or hypeersensitivity with MINIVELLE
`
`Knownliver impairment or disease
`
`Knownprotein C, protein S, or antithrombin deficiency, or other known thrombophilic
`disorders
`
`Knownor suspected pregnancy
`
`5
`
`5.1
`
`WARNINGS AND PRECAUTIONS
`
`Cardiovascular Disorders
`
`An increased risk of stroke and DVT has been reported with estrogen-alone therapy. An increasedrisk of
`PE, DVT, stroke and MIhas beenreported with estrogen plus progestin therapy. Should any of these
`occuror be suspected, estrogen with or without progestin therapy should be discontinued immediately.
`
`Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use,
`hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE)(for example, personal
`history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed
`appropriately.
`
`Stroke
`
`In the WHI estrogen-alone substudy,a statistically significant increased risk of stroke was reported in
`women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to womenin the same age
`group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated
`in year | and persisted /see Clinical Studies (14.3)]. Should a stroke occuror be suspected, estrogen-
`alone therapy should be discontinued immediately.
`
`Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women
`receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years).’
`
`In the WHIestrogen plus progestin substudy, a statistically significant increased risk of stroke was
`reported in women 50 to 79 years of age recciving CE (0.625 mg) plus MPA (2.5 mg) compared to
`womenin the same age group receiving placebo (33 versus 25 per 10,000 women-years) /see Clinical
`Studies, 14.3)]. The increase in risk was demonstratedafter the first year and persisted.' Should a stroke
`occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.
`
`Coronary Heart Disease
`
`In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as
`nonfatal MI, silent MI, or CHD death) was reported in womenreceiving estrogen-alone comparedto
`placebo” [see Clinical Studies (14.3)/.
`
`Subgroup analyses of women 50 to 59 years of age suggesta statistically non-significant reduction in
`CHDevents (CE [0.625 mg]-alone compared to placebo) in womenwith less than 10 years since
`menopause(8 versus 16 per 10,000 women-years).'
`
`Reference ID: 3632965
`
`8006
`
`

`

`In the WHI estrogen plus progestin substudy, there wasa statistically non-significant increased risk of
`CHDevents reported in womenreceiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women
`receiving placebo (41 versus 34 per 10,000 womenyears).' An increasein relative risk was demonstrated
`in year |, and a trend toward decreasingrelative risk was reported in years 2 through 5 /see Clinical
`Studies (14.3)].
`
`In postmenopausal women with documented heart disease (n = 2,763, average 66.7 years of age), ina
`controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin
`Replacement Study; [HERS]), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no
`cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPAdid not
`reduce the overall rate of CHD events in postmenopausal women with established CHD. There were more
`CHDevents in the CE plus MPA-treated group than in the placebo group in year |, but not during the
`subsequent years. Two thousand, three hundred and twenty-one (2,321) women from the original HERS
`trial agreed to participate in an open-label extension of HERS, HERSII. 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 plus MPA group and the placebo group in the HERS, HERSII, and overall.
`
`Venous Thromboembolism
`
`In the WHI estrogen-alone substudy,the risk of VTE (DVT and PE), was increased for women receiving
`daily CE (0.625 mg)-alone comparedto placebo (30 versus 22 per 10,000 women-years), although only
`the increased risk of DVT reachedstatistical significance (23 versus 15 per 10,000 womenyears). The
`increase in VTE risk was demonstrated duringthefirst 2 years: [see Clinical Studies (14.3)]. Should a
`VTEoccuror be suspected, estrogen-alone therapy should be discontinued immediately.
`
`In the WHIestrogen plus progestin substudy,a statistically significant 2-fold greater rate of VTE was
`reported in womenreceiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to womenreceiving
`placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT
`(26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also
`demonstrated. The increase in VTE risk was demonstrated duringthefirst year and persisted’ /see
`Clinical Studies (14.3)]. Should a VTE occuror be suspected, estrogen plus progestin therapy should be
`discontinued immediately.
`
`If feasible, estrogens should be discontinuedat least 4 to 6 weeks before surgery of the type associated
`with an increased risk of thromboembolism,or during periods of prolonged immobilization.
`
`5.2
`
`Malignant Neoplasms
`
`Endometrial cancer
`
`Anincreased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in
`womenwith a uterus. The reported endometrial cancer risk among unopposedestrogen usersis about 2 to
`12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose.
`Moststudies show nosignificant increased risk associated with the use of estrogens for less than | year.
`Thegreatest risk appears to be associated with prolonged use, with increased risks of 15- to 24-fold for 5
`to 10 years or more. This risk has been shownto persist for at least 8 to 15 years after estrogen therapy is
`discontinued.
`
`Reference ID: 3632965
`
`Og07
`
`

`

`Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important.
`Adequate diagnostic measures, including directed or random endometrial sampling when indicated,
`should be undertaken to rule out malignancy in postmenopausal womenwith undiagnosedpersistent or
`recurring abnormal genital bleeding.
`
`There is no evidencethat the use of natural estrogensresults in a different endometrial risk profile than
`synthetic estrogens of equivalent estrogen dose. Adding a progestin to postmenopausalestrogen therapy
`has been shownto reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial
`cancer.
`
`Breast Cancer
`
`The mostimportant randomizedclinicaltrial providing information about breast cancerin estrogen-alone
`users is the WHI substudy of daily CE (0.625 mg)-alone.
`In the WHI estrogen-alone substudy, after an
`average follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive
`breast cancer(relative risk [RR] 0.80)° [see Clinical Studies (14.3)].
`
`The most important randomizedclinicaltrial providing information about breast cancerin estrogen plus
`progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up
`of 5.6 years, the estrogen plus progestin substudy reported an increasedrisk of invasive breast cancerin
`women whotook daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus
`progestin therapy was reported by 26 percent of the women.Therelative risk of invasive breast cancer
`was |.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA
`compared with placebo. Among women whoreported prior use of hormonetherapy, the relative risk of
`invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years,
`for CE plus MPA compared with placebo. Among women whoreported no prior use of hormonetherapy,
`the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per
`10,000 women-years for CE plus MPA comparedwith placebo. In the same substudy, invasive breast
`cancers werelarger, were morelikely to be node positive, and were diagnosed at a more advancedstage
`in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was
`rare, with no apparent difference between the two groups. Other prognostic factors, such as histologic
`subtype, grade and hormonereceptorstatus did not differ between the groups® /see Clinical Studies
`(14.3)].
`
`Consistent with the WHI clinicaltrial, observational studies have also reported an increasedrisk of breast
`cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy,after
`several years of use. The risk increased with duration of use, and appeared to return to baseline over about
`5 years after stopping treatment (only the observational studies have substantial data on risk after
`stopping). Observational studies also suggest that the risk of breast cancer was greater, and became
`apparentearlier, with estrogen plus progestin therapy as comparedto estrogen-alone therapy. However,
`these studies have not found significant variation in the risk of breast cancer among different estrogen
`plus progestin combinations, doses, or routes of administration.
`
`The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in
`abnormal mammogramsrequiring further evaluation.
`
`All womenshould receive yearly breast examinations by a healthcare provider and perform monthly
`breast self-examinations. In addition, mammography examinations should be scheduled based on patient
`age, risk factors, and prior mammogram results.
`
`Reference ID: 3632965
`
`O008
`
`

`

`Ovarian Cancer
`
`The WHIestrogen plus progestin substudy reported a statistically non-significant increased risk of
`ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus
`MPAversusplacebo was1.58 (95 percent CI, 0.77-3.24). The absolute risk for CE plus MPA versus
`placebo was 4 versus 3 cases per 10,000 women-years.’ In some epidemiologicstudies, the use of
`estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated
`with an increased risk of ovarian cancer. However, the duration of exposure associated with increasedrisk
`is not consistent acrossall epidemiologic studies, and some report no association.
`
`5.3
`
`Probable Dementia
`
`In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65
`to 79 years of age was randomizedto daily CE (0.625 mg)-alone or placebo.
`
`After an average follow-up of 5.2 years, 28 womenin the estrogen-alone group and 19 womenin the
`placebo group were diagnosed with probable dementia. Therelative risk of probable dementia for CE-
`alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-
`alone versus placebo was37 versus 25 cases per 10,000 women-years* /see Use in Specific Populations
`(8.5), and Clinical Studies (14.4)].
`
`In the WHIMSestrogen plus progestin ancillary study of WHI, a population of 4,532 postmenopausal
`women 65 to 79 years of age was randomizedto daily CE (0.625 mg) plus MPA (2.5 mg)or placebo.
`
`After an average follow-up of 4 years, 40 womenin the CE plus MPA group and 21 womenin the
`placebo group were diagnosed with probable dementia. Therelative risk of probable dementia for CE plus
`MPAversus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE
`plus MPAversus placebo was 45 versus 22 cases per 10,000 women-years* /see Use in Specific
`Populations (8.5), and Clinical Studies (14.4)].
`
`Whendata from the two populations in the WHIMSestrogen-alone and estrogen plus progestin ancillary
`studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable
`dementia was 1.76 (95 percent CI, 1.19-2.60). Since both ancillary studies were conducted in women 65
`to 79 yearsof age, it is unknown whetherthese findings apply to younger postmenopausal women‘ /see
`Use in Specific Populations(8.5), and Clinical Studies (14.4)]/.
`
`5.4
`
`Gallbladder Disease
`
`A 2- to 4-fold increase in therisk of gallbladder disease requiring surgery in postmenopausal women
`receiving estrogens has been reported.
`
`So
`
`Hypercalcemia
`
`Estrogen administration may lead to severe hypercalcemia in womenwith breast cancer and bone
`metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to
`reduce the serum calcium level.
`
`Reference ID: 3632965
`
`8009
`
`

`

`5.6
`
`Visual Abnormalities
`
`Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication
`pending examinationif there is sudden partial or complete loss of vision, or a sudden onsetofproptosis,
`diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be
`permanently discontinued.
`
`5.7
`
`Addition of a Progestin When a Woman Has Not Had a Hysterectomy
`
`Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily
`with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than
`would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursorto
`endometrial cancer.
`
`There are, however, possible risks that may be associated with the use of progestins with estrogens
`comparedto estrogen-alone regimens. These include an increasedrisk of breast cancer.
`
`5.8
`
`Elevated Blood Pressure
`
`In a small numberofcase reports, substantial increases in blood pressure have beenattributed to
`idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized
`effect of estrogens on blood pressure wasnotseen.
`
`5.9
`
`Hypertriglyceridemia
`
`In womenwith pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of
`plasmatriglycerides leading to pancreatitis. Consider discontinuation of treatmentif pancreatitis occurs.
`
`5.10
`
`Hepatic Impairment and/or Past History of Cholestatic Jaundice
`
`Estrogens may be poorly metabolized in patients with impaired liver function. For women with a history
`of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised
`andin the case of recurrence, medication should be discontinued.
`
`5.11
`
`Hypothyroidism
`
`Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal
`thyroid function can compensate for the increased TBG by making more thyroid hormone, thus
`maintaining free Ty and T; serum concentrations in the normal range. Women dependenton thyroid
`hormone replacement therapy whoare also receiving estrogens may require increased dosesoftheir
`thyroid replacement therapy. These womenshould havetheir thyroid function monitored in order to
`maintain their free thyroid hormonelevels in an acceptable range.
`
`5.12
`
`Fluid Retention
`
`Estrogens may cause somedegreeoffluid retention. Womenwith conditions that might be influenced by
`this factor, such as cardiac or renal dysfunction, warrant careful observation whenestrogenis prescribed.
`
`Reference ID: 3632965
`
`10
`
`8010
`
`

`

`5.13
`
`Hypocalcemia
`
`Estrogen therapy should be used with caution in womenwith hypoparathyroidism as estrogen-induced
`hypocalcemia may occur.
`
`5.14
`
`Exacerbation of Endometriosis
`
`A few cases of malignant transformation of residual endometrial implants have been reported in women
`treated post-hysterectomy with estrogen-alone therapy. For women known to haveresidual endometriosis
`post-hysterectomy, the addition of progestin should be considered.
`
`5.15
`
`Severe Anaphylactic/Anaphylactoid Reactions and Angioedema
`
`Cases of anaphylactic/anaphylactoid reactions, which developed anytime during the course of Minivelle
`treatment and required emergency medical management, have been reported in the postmarketingsetting.
`Involvementof skin (hives, pruritus, swollen lips-tongue-face) and either respiratory tract (respiratory
`compromise) or gastrointestinal tract (abdominal pain, vomiting) has been noted.
`
`Angioedema involving eye/eyelid, face, larynx, pharynx, tongue and extremity (hands, legs, ankles, and
`fingers) with or without urticaria requiring medical intervention has occurred in the postmarketing
`experience of using Minivelle. If angioedema involves the tongue, glottis, or larynx, airway obstruction
`may occur. Patients who develop angioedemaanytime during the course of treatment with Minivelle
`should notreceive it again.
`
`Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.
`
`5.16
`
`Exacerbation of Other Conditions
`
`Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraines, porphyria,
`systemic lupus erythematosus, and hepatic hemangiomasand should be used with caution in women with
`these conditions.
`
`5.17
`
`Laboratory Tests
`
`Serum follicle stimulating hormone (FSH)andestradiol levels have not been shown to be useful in the
`management of moderate to severe vasomotor symptoms.
`
`5.18
`
`Drug-Laboratory Test Interactions
`
`Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased
`platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulantactivity, IX, X, XII, VII-X
`complex, I-VII-X complex; and beta-thromboglobulin; decreasedlevels of anti-factor Xa and
`antithrombin III; decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen
`activity; increased plasminogen antigen andactivity.
`
`Increased thyroid-binding globulin (TBG)leadingto increased circulating total thyroid hormonelevels, as
`measured by protein-boundiodine (PBI), Ty levels (by column or by radioimmunoassay)or T; levels by
`radioimmunoassay. T; resin uptake is decreased, reflecting the elevated TBG.Free T, and free T;
`concentrations are unaltered. Womenon thyroid replacement therapy may require higher doses of thyroid
`hormone.
`
`Reference ID: 3632965
`
`11
`
`oO11
`
`

`

`Other binding proteins may be elevated in serum, for example, corticosteroid-binding globulin (CBG),
`sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex
`steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased.
`Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin,
`ceruloplasmin).
`
`Increased plasma high-density lipoprotein (HDL) and HDL; cholesterol subfraction concentrations,
`reduced low-density lipoprotein (LDL) cholesterol concentration,