HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`MINIVELLE safely and effectively. See full prescribing information for
`MINIVELLE.
`
`MINIVELLE1i (estradiol trausdermal system)
`Initial [1.5. Approval: 1915
`
`WARNING: ENDOMETRIAL CANCER. CARDIOVASCULAR
`DISORDERS, BREAST CANCER, and PROBABLE DEMEN'I‘IA
`Seefullprescribing harm-motion for complete boxed warning.
`
`Estrogen-Alone Therapv
`I There is an increased risk of endometrial cancer in a woman with a
`uterus who uses unopposed estrogeus (5.2)
`I Estrogen—alone therapy should not be used for the prevention of
`cardiovascular disease or dementia (5.], 5.3)
`I The Women’s Health lnitiafive (WHI) estrogen—alone suhstudy
`reported increased risks of stroke and deep vein thrombosis (DVT) (5.1)
`I The WIII Memory Study (WI-HMS) estrogen-alone ancillary study of
`Will reported an increased risk of probable dementia in
`postmenopausal women 65 years of age and older (5.3)
`Estrogen Plus Plggestin Therapv
`I Estrogen plus progestin therapy should not be used for the prevention
`of cardiovascular disease or dementia (5.1, 5.3)
`I The W'HI estrogen plus progestin substudy reported increased risks of
`DVT, pulmonary embolism (PE), stroke, and myocardial infarction
`(MI) (5-1)
`I The WHI estrogen plus progestin snbstudy reported increased risks of
`invasive breast cancer (5.2)
`I The WHIMS estrogen plus progestin ancillary study of Wl-II reported
`an increased risk of probable dementia in postmenopausal women 65
`
`years of age and older (5.3)
`
`— RECENT MAJOR CHANGES—
`Indications and Usage (1.2]
`9(2014
`Dosage and Administration (2.2]
`932014
`Warnings and Precautions (5.15}
`9/2014
`
`—INDI(JA'I‘IDNS AND USAGE
`MINWELLE® is an estrogen indicated for:
`I Treatment ot‘moderate to severe vasomotor symptoms due to menopause
`(171)
`I Prevention of postmenopausal osteopm‘osis (1.2)
`
`DOSAGE AND ADMINISTRATION
`
`I For Vasomotor Smptoms: Start therapy with MlNlVl-llJJ—I" 0.03"}5 mg
`per day applied to the skin twice weekly. Dosage adjustment should he
`guided by the clinical response (2.1)
`
`I For Postmenopausal Osteoporosis Prevention: Start therapy with
`MINIVELLE 0.025 mg per day applied to the skin twice ueekly. The dose
`may be adjusted as necessary (2.2)
`
`MINlVl-ILiJ-L should he placed on a clean. dry area on the lower abdomen
`(below the umbilicus) or buttocks. MINIVELLE should not be applied to
`the breasts (2.3)
`
`— DOSAGE FORMS AND STRENGTHS
`Transdermal system: 0.025 mgiday. 0.0375 mgfday. 0.05 mgx‘day. 0.0?5
`mgfday, and 0.1 mgiday (3)
`
`CONTRAINDICATIONS
`Undiagnoscd abnormal genital bleeding (4)
`Known. suspected. or history of breast cancer (4, 5.2)
`Known or suspected estrogen-dependent neoplasia (4. 5.2)
`Active DVI', PE, or a history of these conditions (4, 5.1}
`Active arterial thromboembolie disease (for example, stroke and MI), or a
`history ot‘thcse conditions (4. 5.] )
`I Known anaphylactic reaction or angioederna or hypersensitivity with
`MTNWEIII: (4)
`I Known liver impairment or disease (4, 5.10)
`I Known protein C. protein S, or antithrombin deficiency. or other known
`thrombophilic disorders (4)
`I Known or suspected pregnancy (4. 8.1)
`
`\VARNINGS AND PRECAUTIONS
`I Estrogens increase the risk 01‘ gallbladder disease (5.4)
`I Discontinue estrogen ifsevcre hypercalcemia, loss of vision, severe
`hypertriglyceridemia or cholestatie jaundice occurs (5.5, 5.6, 5.9. 5.10)
`I Monitor thyroid function in women on thyroid replacement therapy (5.| I,
`5.18)
`
`ADVERSE REACTIONS
`Most colrunon adverse 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 intmnenstrual bleeding
`(6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Noven at 1—
`800—455—8070 or FDA at 1—8tlt’l—FDA—1088 or amtfdagovflnedwatdr
`
`DRUG iNTERACTIONS—
`[nducers andfor inhibitors ofCYP3A4 may afl'ect estrogen dug metabolism
`(7.1)
`
`USE IN SPE(.‘.IFIC POPULATIUNS
`I 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 estrogcns. (8.3)
`I Geriatric Use: An increased risk of probable dementia in women over 65
`years of age was reported in the WIllMS ancillary studies of the W111 (5.5,
`3.5)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling
`
`Revised: 9i2lll4
`
`FULL PRESCRIBING INFORMATION: CON'I'EN'I‘S*
`
`WARNING: ENDOME'I‘RIAI. CANCER, CARDIOVASCULAR
`DISORDERS, BREAST CANCER, and PROBABLE DEMIENTIA
`
`l
`
`2
`
`'JI-li-b-I
`
`INDICATIONS AND USAGE
`1.]
`Treatment ol'Moderate to Severe Vasomotor Symptoms
`l .2
`Prevention of Postmenopausal Osteoporosis
`DOSAGE AND ADMINISTRATION
`2.1
`Treatment ol‘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
`
`5.4
`5.5
`5.6
`5.?
`
`Gallbladder Disease
`I Iypercalc elnia
`Visual Abnormalities
`Addition ofa Progestiu When a Woman Has Not [lad a
`Hysterectomy
`Elevated Blood Pressure
`5.8
`I-Iypertriglyceridernia
`5.9
`[Iepatic Impaimlcnt andtor Past llislory ol‘Cholestatic Jaundice
`5.10
`5.1 l Hypothyroidism
`5.12 Fluid Retention
`5.13
`I--lypocalcemia
`5.14 Exacerbation ot‘l—anonictriosis
`5.15
`Severe Anaphylacticr‘Anaphylactoid Reactions and Angioedema
`5.16 Exacerbation ol'Otlter Conditions
`5.1 7 Laboratory 'l'ests
`5.18 Drug-Laboratory Test lnteractions
`ADVERSE REACTIONS
`
`6-1
`
`Clinical Trials Brunettes Noven Pharmaceuticals. Inc.
`EX2003
`
`Mylan TECH, "10. V. NOVBFI Pharma., ll'lC.
`IPR2018-00174
`
`6
`
`0001
`
`

`

`15
`16
`
`17
`
`14
`
`CLINICAL STUDIES
`l4.l Effects on Vasomolor Symptoms
`I42 Effects on Bone Mineral Density
`14.3 Women‘s Health Initiative Studies
`14.4 Women’s Health initiative Memory Study
`REFERENCES
`HOW SUPPLIEDISTORAGE AND HANDLING
`16.1 How Supplied
`I62 Storage and Handling
`PATIENT COUNSELING INFORMATION
`l7.l Vaginal Bleeding
`17.2 Possible Serious Adverse Reactions with Eslrogcn—Alonc
`'l‘llerapy
`|?.3 Possible Ems Sm‘ious but Common Adverse Reactions with
`Estrogen—Alone Therapy
`”Sections or subsections omitted from the full prescribing information
`are not listed.
`
`7
`
`8
`
`It}
`11
`'2
`
`13
`
`Postrnarketing Experience
`6.2
`DRUG INTERACTIONS
`1| Metabolic [nteractions
`USE IN SPECIFIC POPULATIONS
`8.]
`Pregnancy
`8.?-
`Nursing Molhers
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`8.6
`Renal Impairment
`8.?
`Hepatic impairment
`OVERDOSAGE
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mcchanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetjcs
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis. Mutagenesis. [mpairment of Fertility
`
`Reference ID: 3632965
`
`0002
`
`

`

`FULL PRESCRIBING INFORMATION
`
`WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST
`
`CANCER, and PROBABLE DEMENTIA
`
`Estrogen-Alone Therapy
`
`Endometrial Cancer
`
`There is an increased risk of endometrial cancer in a woman with a uterus who uses
`
`unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the
`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
`undiagnosed persistent 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 Warnings and 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-alone ancillary study of WHI reported an
`increased risk of developing probable dementia in postmenopausal women 65 years of age
`or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo.
`It is unknown whether this 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 assumed to be similar for other
`doses of CE and other dosage forms of 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. I, 5.3), and Clinical Studies (14.3,
`14.4}.
`
`The WHI estrogen plus 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
`_esterone acetate
`, relative to lacebo see Warnints and
`
`Reference ID: 3632965
`
`0003
`
`

`

`
`
`Precautions (5.1), and Ciinical Studies (14.3)].
`
`The WHIMS estrogen plus progestin ancillary study of the WHI, reported an increased
`
`risk of developing probable dementia in postmenopausal women 65 years of age or older
`
`during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg),
`relative to placebo. It is unknown whether this finding applies to younger postmenopausal
`women [see Warnings and Precautions (5. 3), Use in Specific Populations (8. 5), and Ciinicair
`Studies (14.4)].
`
`Breast Cancer
`
`The WHl estrogen plus progestin substudy also demonstrated an increased risk of
`invasive breast cancer [see Warnings andr Precautions (5.2), and Clinical Studies (I4.3)/.
`
`In the absence of comparable data, these risks should be assumed to 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 treatment goals and risks for the individual
`woman.
`
`
`
`I
`
`1.1
`
`INDICATIONS AND USAGE
`
`Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause
`
`MINIVELLE is indicated for the treatment of moderate to severe vasomotor symptoms due to
`menopause.
`
`1.2
`
`Prevention of Postmenopausal Osteoporosis
`
`MlNlVELLE is indicated for the prevention of postmenopausal osteoporosis.
`
`Limitation of Use
`
`When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be
`
`considered for women at significant risk of osteoporosis and non-estrogen medications should be
`
`carefully considered.
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`Generally, when estrogen is prescribed for a postmenopausal woman with 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 some cases, however, hysterectomizcd 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.
`
`Reference ID: 3632965
`
`4
`
`0004
`
`

`

`Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if
`treatment is still necessary.
`
`2.]
`
`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 by the 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 made at 3 to 6 month intervals.
`
`2.2
`
`Prevention of Postmenopausal Osteoporosis
`
`Start therapy with MINIVELLE 0.025 mg per day applied to the skin twice weekly. The dose may be
`adjusted as necessary.
`
`2.3
`
`Patch Application Instructions
`
`The adhesive side of MINIVELLE should be placed on a clean, dry area on the lower abdomen (below
`
`the umbilicus) or buttocks. MINIVELLE should not be applied to the breasts.
`
`MINIVELLE should be replaced twice weekly (every 3-4 days).
`
`The sites of application must be rotated, with an interval of at least I week allowed between applications
`
`to a particular site.
`
`The area selected should not be oily, damaged, or irritated. 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 palm of the hand for
`
`about 10 seconds, making sure there is good contact with the skin, especially around the edges. In the
`
`event that a system should fall OK, 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 MIN IVELLE might increase the likelihood of
`
`breakthrough bleeding, spotting and recurrence of symptoms.
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`Transdermal system: 0.025 mg/day, 0037’5 mg/day, 0.05 mg/day, 0.075 mg/day, and 0.1 mg/day.
`
`4
`
`CONTRAINDICATIONS
`
`MINIVELLE is contraindicated in women with any of the following conditions:
`
`0 Undiagnosed abnormal genital bleeding
`
`0 Known, suspected or history of breast cancer
`
`0 Known or suspected estrogen-dependent neoplasia
`
`0 Active DVT, PE, or a history of these conditions
`5
`
`Reference ID: 3632965
`
`0005
`
`

`

`I Active arterial thromboembolic disease (for example, stroke and M1), or a history ofthese
`conditions
`
`I Known anaphylactic reaction or angiocdcma or hypccrscnsitivity with MINNELLE
`
`I Known liver impairment or disease
`
`I Known protein C, protein S, or antithrombin deficiency, or other known thrombophilie
`disorders
`
`I Known or 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 increased risk of
`
`PE, DVT, stroke and MI has been reported with estrogen plus progestin therapy. Should any of these
`
`occur or 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) andfor 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 ?9 years of age receiving daily CE (0625 mg)-alone compared to women in the same age
`
`group receiving placebo (45 versus 33 per 10,000 women—years). The increase in risk was demonstrated
`
`in year 1 and persisted [see Clinic-a! Studies (14.3)]. Should a stroke occur or 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 WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was
`
`reported in women 50 to 79 years of age receiving CE (0.625 mg) plus MPA (2.5 mg) compared to
`
`women in the same age group receiving placebo (33 versus 25 per 10,000 women -ycars) [see ('iinieai
`Studies, 14.3)]. The increase in risk was demonstrated after the first year and persisted.1 Should a stroke
`occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.
`
`Coronary Heart Disease
`
`In the Wl-ll estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as
`
`nonfatal Ml, silent M1, or CHD death) was reported in women receiving estrogen-alone compared to
`placebo2 [see Cz'iriicaz' Studies 04.3)].
`
`Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in
`
`CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since
`menopause (8 versus 16 per 10,000 women-years).1
`
`Reference ID: 3632965
`
`0006
`
`

`

`In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of
`
`CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women
`receiving placebo (41 versus 34 per 10,000 women years).1 An increase in relative risk was demonstrated
`in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 [see Ciinicai
`
`Studies (14.3)].
`
`In postmenopausal women with documented heart disease (11 = 2,263, average 66.7 years of age), in a
`
`controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogeanrogestin
`
`Replacement Study; [HERSJ), 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 MPA did not
`
`reduce the overall rate of CHD events in postmenopausal women with established CHD. There were more
`
`CHD events in the CE plus MFA-treated group than in the placebo group in year 1, 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 ofHERS, HERS 11. Average follow-up in HERS II
`
`was an additional 2.? 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, HERS II, and overall.
`
`Venous Thromboemboiism
`
`In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE), was increased for women receiving
`
`daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only
`
`the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women years). The
`increase in VTE risk was demonstrated during the first 2 years3 [see Clinical Studies (14.3)]. Should a
`VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately.
`
`In the W’HI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was
`
`reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving
`
`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 during the first year and persisted4 [see
`
`Ciinicai Studies (14.3)]. Should a VTE occur or be suspected, estrogen plus progestin therapy should be
`
`discontinued immediately.
`
`If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated
`
`with an increased risk ofthromboembolism, or during periods of prolonged immobilization.
`
`5.2
`
`Malignant Neoplasms
`
`Endomen'iai cancer
`
`An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in
`
`women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to
`
`12 times 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 the use of estrogens for less than 1 year.
`
`The greatest 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 shown to persist for at least 8 to 15 years after estrogen therapy is
`discontinued.
`
`Reference ID: 3632965
`
`0007
`
`

`

`Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important,
`
`Adequate diagnostic measures, including directed or random cndometrial sampling when indicated,
`
`should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or
`
`recurring abnormal genital bleeding.
`
`There is no evidence that the use of natural estrogens results in a different endometrial risk profile than
`
`synthetic estrogens of equivalent estrogen dose. Adding a progestin to postmenopausal estrogen therapy
`
`has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial
`cancer.
`
`Breast Cancer
`
`The most important randomized clinical trial providing information about breast cancer in 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 C E-alone was not associated with an increased risk of invasive
`breast cancer (relative risk [RRj 0.80)5 [see Clinical Studies (14.3)].
`
`The most important randomized clinical trial providing information about breast cancer in 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 increased risk of invasive breast cancer in
`
`women who took 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. The relative risk of invasive breast cancer
`
`was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA
`
`compared with placebo. Among women who reported prior use of hormone therapy, 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 who reported no prior use of hormone therapy,
`
`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 compared with placebo. In the same substudy, invasive breast
`
`cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage
`
`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 hormone receptor status did not differ between the groups'5 [see Clinical Studies
`(14.3)].
`
`Consistent with the WHI clinical trial, observational studies have also reported an increased risk 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 stoppin g 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
`
`apparent earlier, with estrogen plus progestin therapy as compared to 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 mammograms requiring further evaluation.
`
`All women should 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
`
`0008
`
`

`

`OVGI’iflJ? Cancer
`
`The WHI estrogen 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
`
`MPA versus placebo was 1.58 (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 epidemiologic studies, 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 increased risk
`
`is not consistent across all epidemiologic studies, and some report no association.
`
`5.3
`
`Probable Dementia
`
`In the WHIMS estrogen-alone ancillary study ofWHI, a population of 2,947 hysterectomized women 65
`to 79 years of age was randomized to daily CE (0.625 mg)-alonc or placebo.
`
`After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the
`
`placebo group were diagnosed with probable dementia. The relative risk of probable dementia for C E-
`
`alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-
`alone versus placebo was 37 versus 25 cases per 10,000 women-yearsH [588 Use in .S'peeific Popuiaiions
`(8.5), and Ciinicai Studies (14.4)].
`
`In the WHlMS estrogen plus progestin ancillary study of WHI, a population of 4,532 postmenopausal
`
`women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.
`
`After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the
`
`placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus
`
`MPA versus placebo was 2.05 (95 percent CI, 1.21—3.48). The absolute risk of probable dementia for CE
`plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years8 [se 3 Use in Specific
`Populations (8.5), and (‘i'iiiicai Studies (14.4)].
`
`When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary
`
`studies were pooled as planned in the WHTMS protocol, the reported overall relative risk for probable
`
`dementia was 1.76 (95 percent Cl, 1.19-2.60). Since both ancillary studies were conducted in women 65
`to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 [see
`Use in 530619in Populations (8. 5), and Ciinica! Studies (14.4)].
`
`5.4
`
`Gallbladder Disease
`
`A 2— to 4—fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women
`
`receiving estrogens has been reported.
`
`5.5
`
`Hyperealcemia
`
`Estrogen administration may lead to severe hyperealeemia in women with 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
`
`0009
`
`

`

`5.6
`
`Visual Abnormalities
`
`Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication
`
`pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis,
`
`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 precursor to
`endometrial cancer.
`
`There are, however, possible risks that may be associated with the use of progestins with estrogens
`
`compared to estrogen-alone regimens. These include an increased risk of breast cancer.
`
`5.8
`
`Elevated Blood Pressure
`
`In a small number of case reports, substantial increases in blood pressure have been attributed to
`
`idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized
`
`effect ofestrogens on blood pressure was not seen.
`
`5.9
`
`Hypertriglyeeridemia
`
`In women with lire-existing hypertriglyeeridemia, estrogen therapy may be associated with elevations of
`
`plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs.
`
`5.10
`
`Hepatic Impairment and/or Past History of Cholestafie Jaundice
`
`Estrogens may be poorly metabolized in patients with impaired liver function. For women with a history
`
`of eholestatic j aundice associated with past estrogen use or with pregnancy, caution should be exercised
`and in 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 T4 and T3 serum concentrations in the normal range. Women dependent on thyroid
`
`hormone replacement therapy who are also receiving estrogens may require increased doses of their
`
`thyroid replacement therapy. These women should have their thyroid function monitored in order to
`
`maintain their free thyroid hormone levels in an acceptable range.
`
`5.12
`
`Fluid Retention
`
`Estrogens may cause some degree of fluid retention. Women with conditions that might be influenced by
`
`this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogen is prescribed.
`
`Reference ID: 3632965
`
`10
`
`0010
`
`

`

`5.13
`
`Hypocalcemia
`
`Estrogen therapy should be used with caution in women with 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 have residual endometriosis
`
`post-hysterectomy, the addition of progestin should be considered.
`
`5.15
`
`Severe AnaphylacticlAnaphylaetoid Reactions and Angioedema
`
`Cases of anaphylaetici’anaphylactoid reactions, which developed anytime during the course of Minivcllc
`
`treatment and required emergency medical management, have been reported in the postmarkcting setting.
`
`Involvement of skin (hives, pruritus, swollen lips-tonguc-facc) and either respiratory tract (respiratory
`
`compromise) or gastrointestinal tract (abdominal pain, vomiting) has been noted.
`
`Angioedema involving eyeleyelid, 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 Minivclle. If angiocdema involves the tongue, glottis, or larynx, airway obstruction
`
`may occur. Patients who develop angiocdema anytime during the course of treatment with Minivelle
`
`should not receive it again.
`
`Exogenous cstrogens may exacerbate symptoms of angiocdema in women with hereditary angiocdema.
`
`5.16
`
`Exacerbation of Other Conditions
`
`Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraines, porphyria,
`systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with
`these conditions.
`
`5.1?
`
`Laboratory Tests
`
`Serum follicle stimulating hormone (FSH) and estradiol 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 ll, VII antigen, Vlll antigen, VIII coagulant activity, IX, X, XII, VII-X
`
`complex, II-VII-X complex; and beta-thromboglobulin; decreased levels of anti-factor Xa and
`
`antithrombin III; decreased antithrombin [II activity; increased levels of fibrinogen and fibrinogen
`
`activity; increased plasminogen antigen and activity.
`
`Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone levels, as
`
`measured by protein-bound iodine (P Bl), T4 levels (by column or by radioimmunoassay) or T 3 levels by
`
`radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3
`
`concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid
`hormone.
`
`Reference ID: 3632965
`
`11
`
`0011
`
`

`

`Other binding proteins m