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.
`
`
`MINIVELLE® (estradiol transdermal system)
`
`Initial U.S. Approval: 1975
`
`
`
`
`WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR
`
`
`DISORDERS, PROBABLE DEMENTIA, and BREST CANCER
`
`
`
`
`
`See full prescribing 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)
`
`• The Women’s Health Initiative (WHI) estrogen-
`
`
`alone substudy reported increased risks of stroke
`and deep vein thrombosis (DVT) (5.1)
`
`• The WHI Memory Study (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)
`
`• Do not use estrogen-alone therapy for the
`
`
`
`prevention of cardiovascular disease or dementia
`
`(5.1, 5.3)
`
`
`Estrogen Plus Progestin Therapy
`
`
`
`
`• 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 WHIMS estrogen plus progestin ancillary
`
`
`
`study of WHI reported an increased risk of
`
`probable dementia in postmenopausal women 65
`
`
`
`years of age and older (5.3)
`• Do not use estrogen plus progestogen therapy for
`
`the prevention of cardiovascular disease or
`
`dementia (5.1, 5.3)
`
`
` _________________
`
` _________________ RECENT MAJOR CHANGES
` Boxed Warning 10/2021
`
`
`
`
`
` __________________INDICATIONS AND USAGE _________________
`
`
` MINIVELLE® is an estrogen indicated for:
`
`
`
`
`
`
`
`
` • Treatment of moderate to severe vasomotor symptoms due to
`
` menopause (1.1)
` Prevention of postmenopausal osteoporosis (1.2)
`Limitations of Use
`
`
`
`•
`
`
`
`medications. Consider estrogen therapy only for women at
`
`significant risk of osteoporosis.
`
`DOSAGE AND ADMINISTRATION_______________
` ______________
`
` Start therapy with MINIVELLE® 0.0375 mg per day applied to
`
`the skin twice weekly for the treatment of moderate to severe
`
` vasomotor symptoms due to menopause. Dosage adjustment
`
` should be guided by the clinical response (2.1)
`
`
`Start therapy with MINIVELLE 0.025 mg per day applied to the
`
`skin twice weekly for the prevention of postmenopausal
`
`
`osteoporosis. The dose may be adjusted as necessary (2.2)
`Place MINIVELLE on a clean, dry area on the lower abdomen
`
`(below the umbilicus) or buttocks. Do not apply MINIVELLE 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, 5.2)
`
`
`• Breast cancer or a history of breast cancer (4, 5.2)
`
`
`
`
`• Estrogen-dependent neoplasia (4, 5.2)
`
`
`
`• Active DVT, PE, or a history of these conditions (4, 5.1)
`
`
`
`• Active arterial thromboembolic disease (for example,
`
`
`stroke or MI), or a history of these conditions (4, 5.1)
`
`
`
`
`• Known anaphylactic reaction, angioedema, or
`
`
`hypersensitivity to MINIVELLE (4)
`
`
`
`• Hepatic impairment or disease (4, 5.10)
`
`
`
`Protein C, protein S, or antithrombin deficiency, or
`
`
`
`
`
`•
`other known thrombophilic disorders (4)
`
` _______________WARNINGS AND PRECAUTIONS _______________
`
`
`
` Estrogens increase the risk of gallbladder disease (5.4)
`
`
`
`
`
`
`
`Discontinue estrogen if severe hypercalcemia, loss of vision,
`
`
`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 ___________________
`
` The most common adverse reactions (greater than or equal to 5
`
`
`
` percent) with MINIVELLE are: headache, breast tenderness, back
`
` pain, pain in limb, 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 may affect estrogen drug
`
` metabolism and decrease or increase the estrogen plasma
`
`
` concentration. (7)
`
` See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`
` approved patient labeling.
`
`
`
`
`
` Revised: 10/2021
`
`
`When prescribing solely for the treatment of postmenopausal
`
`
`osteoporosis, first consider the use of non-estrogen
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4874681
`
`

`

`
`1
`
`
`2
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR
`
`DISORDERS, PROBABLE DEMENTIA, AND BREAST
`
`
`
`CANCER
`
`INDICATIONS AND USAGE
`
`1.1 Treatment of Moderate to Severe Vasomotor Symptoms Due to
`
`
`
`
`
`Menopause
`
`
`
`
`1.2
`Prevention of Postmenopausal Osteoporosis
`
`
`DOSAGE AND ADMINISTRATION
`2.1
` Treatment of Moderate to Severe Vasomotor Symptoms due to
`
`
`
`
`
`
`Menopause
`
`
`
`
`2.2
`
`
`
`Prevention of Postmenopausal Osteoporosis due to Menopause
`
`
`
`2.3 Application Instructions
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`CONTRAINDICATIONS
`4
`
`
`5 WARNINGS AND PRECAUTIONS
`
` Cardiovascular Disorder
`
`5.1
`
`
`
`5.2 Malignant Neoplasms
`
`
`
`5.3
`Probable Dementia
`
`
`
`5.4 Gallbladder Disease
`
`
`
`5.5 Hypercalcemia
`
`
`5.6 Visual Abnormalities
`
`
`5.7
` Addition of a Progestogen When a Woman Has Not Had a
`
`
`
`
`
`Hysterectomy
`
`
`5.8
` Elevated Blood Pressure
`
`
`
`5.9
` Exacerbation of Hypertriglyceridemia
`
`
`
`
`5.10
` Hepatic Impairment and/or Past History of Cholestatic Jaundice
`
`
`
`
`5.11
` Exacerbation of Hypothyroidism
`
`
`
`
`5.12
` Fluid Retention
`
`
`
`
`5.13
` Hypocalcemia
`
`
`
`5.14
` Exacerbation of Endometriosis
`
`
`
`
`5.15
` Severe Anaphylactic/Anaphylactoid Reactions and Hereditary
`
`
`
`
`Angioedema
`
`
`5.16
` Exacerbation of Other Conditions
`
`
`
`
`
`
`6
`
`
`7
`
`8
`
`5.17
` Laboratory Tests
`
`
`
`5.18 Drug-Laboratory Test Interactions
`
`
`ADVERSE REACTIONS
`
` Clinical Trials Experience
`
`6.1
`
`
` Postmarketing Experience
`
`6.2
`
`
`
`DRUG INTERACTIONS
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`
`8.2 Lactation
`
`
`
`8.4
`Pediatric Use
`
`
`
`8.5 Geriatric Use
`
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`
`12.2 Pharmacodynamics
`
`
`
`12.3 Pharmacokinetics
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`14 CLINICAL STUDIES
`
`14.1
` Effects on Vasomotor Symptoms in Postmenopausal Women
`
`
`
`
` Effects on Bone Mineral Density in Postmenopausal Women
`
`14.2
`
`
`
`
`
`
`14.3 Women’s Health Initiative Studies
`
`
`
`14.4 Women’s Health Initiative Memory Study
`
`
`
`
`15 REFERENCES
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`16.1 How Supplied
`
`
`
`16.2 Storage and Handling
`
`
`
`PATIENT COUNSELING INFORMATION
`17
`
`*Sections or subsections omitted from the full prescribing information
`
`are not listed.
`
`
`
`
`
`
`
`Reference ID: 4874681
`
`
`
`
`
`
`
`

`

`
`
` WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE
`
`
` DEMENTIA, and BREAST CANCER
`
`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 progestogen to estrogen therapy has been shown to reduce the risk of
`
`
`
`endometrial hyperplasia, which may be a precursor to endometrial cancer. Perform adequate
`
`
`diagnostic measures, including directed or random endometrial sampling when indicated, 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
`
`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 and 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)].
`
`
`
`Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia [see
`Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.3, 14.4)].
`
`
`
`
`
`
`Only daily oral 0.625 mg CE was studied in the estrogen-alone substudy of the WHI. Therefore,
`
`the relevance of the WHI findings regarding adverse cardiovascular events and dementia to
`
`
`lower CE doses, other route of administration, or other estrogen-alone products is not known.
`
`
`
`Without such data, it is not possible to definitively exclude these risks or determine the extent of
`
`these risks for other products. Discuss with your patient the benefits and risks of estrogen-alone
`
`
`
`therapy, taking into account her individual risk profile.
`
`
`Prescribe estrogens with or without progestogens 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
`
`
`
`
`
`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
`
`
`medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions
`
`
`(5.1), and Clinical Studies (14.3)].
`
`
`
`
`
`
`Reference ID: 4874681
`
`
`
`
`
`
`
`

`

` 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 and 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 Clinical Studies (14.4)].
`
`
`
`Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or
`
`dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.3, 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)].
`
`
`
`
`Only daily oral 0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin
`
`
`
`
`
`substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse
`
`
`cardiovascular events, dementia and breast cancer to lower CE plus other MPA doses, other
`
`
`
`routes of administration, or other estrogen plus progestogen products is not known. Without
`
`such data, it is not possible to definitively exclude these risks or determine the extent of these
`
`
`risks for other products. Discuss with your patient the benefits and risks of estrogen plus
`
`progestogen therapy, taking into account her individual risk profile.
`
`
`
`
`
`Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest
`
`
`
`duration consistent with treatment goals and risks for the individual woman.
`
`
`
`
`
`
` 1 INDICATIONS AND USAGE
`
`
`
` MINIVELLE is indicated for:
`
`
`
` 1.1 Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause
`
`
`
`
`
` 1.2 Prevention of Postmenopausal Osteoporosis
`
`
` Limitation of Use
` When prescribing solely for the prevention of postmenopausal osteoporosis, first consider the
`
`
`
` use of non-estrogen medications. Consider estrogen therapy only for women at significant risk
`
` of osteoporosis.
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
` Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, consider addition of a
`
`
`
`
`
`
` progestogen to reduce the risk of endometrial cancer. Generally, a woman without a uterus, does not need
`
`
`
` to use a progestogen in addition to her estrogen therapy. In some cases, however, hysterectomized women
`
`
`
`
`
` who have a history of endometriosis may need a progestogen [see Warnings and Precautions (5.2, 5.14)].
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4874681
`
`
`
`
`
`
`
`

`

`
`
`Use estrogen-alone, or in combination with a progestogen, at the lowest effective dose and for the shortest
`
`
`
`duration consistent with treatment goals and risks for the individual woman. Reevaluate postmenopausal
`
`
`
`women periodically as clinically appropriate to determine if treatment is still necessary.
`
`
`
` 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause
`
` Start therapy with MINIVELLE 0.0375 mg per day applied to the skin twice weekly. Make dosage
` adjustments based on clinical response. Attempt to taper or discontinue MINIVELLE at 3 to 6 month
`
`
`
` intervals.
`
`
`
` 2.2 Prevention of Postmenopausal Osteoporosis due to Menopause
`
`
`
`
`
`
`
` 2.3 Application Instructions
` Place the adhesive side of MINIVELLE on a clean, dry area on the lower abdomen (below the umbilicus)
`
`
`
` or buttocks. Do not apply MINIVELLE to the breasts.
` Replace MINIVELLE twice weekly (every 3-4 days).
`
` Rotate the sites of application, with an interval of at least 1 week allowed between applications to a
`
`
` particular site.
`
`
`
`
`
` Select an area for application that is not oily, damaged, or irritated. Avoid the waistline, since tight
`
` clothing may rub the system off. Apply the system immediately after opening the pouch and removing the
`
` protective liner. Press the system 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 falls off,
`
`
`
`
`
`
`
` reapply the same system or apply a new system to another location. In either case, continue the original
`
`
`
`
`
`
`
` treatment schedule. If a woman has forgotten to apply MINIVELLE, have her apply a new system as soon
`
`
`
`
` as possible. Apply the new system on the original treatment schedule. The interruption of treatment in
`
`
`
`
`
` women taking MINIVELLE might increase 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
`
` MINIVELLE is contraindicated in women with any of the following conditions:
`
`
`
` • Undiagnosed abnormal genital bleeding [see Warnings and Precautions (5.2)].
`
` • Breast cancer or a history of breast cancer [see Warnings and Precautions (5.2)].
`
`
`
`
`
` • Estrogen-dependent neoplasia [see Warnings and Precautions (5.2)].
`
`
`
`
`
` • Active DVT, PE, or a history of these conditions [see Warnings and Precautions (5.1)].
`
`
`
`
`
` • Active arterial thromboembolic disease (for example, stroke or MI), or a history of these conditions
`
`
`
`
` [see Warnings and Precautions (5.1)].
`
`
` • Known anaphylactic reaction, angioedema, or hypersensitivity to MINIVELLE
`
` • Hepatic impairment or disease
`
`
` • Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4874681
`
`
`
`
`
`
`
`

`

`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
` 5.1 Cardiovascular Disorder
`
`
`
`
`
` Increased risks of stroke and DVT are reported with estrogen-alone therapy. Increased risks of PE, DVT,
` stroke and MI are reported with estrogen plus progestin therapy. Immediately discontinue estrogen with
`
`
`
`
`
`
` or without progestogen therapy if any of these occur or are suspected.
` Manage appropriately any 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).
`
`
`
`
` Stroke
`
`
`The WHI estrogen-alone substudy reported a statistically significant increased risk of stroke in women 50
`
`
`to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group
`
`
`receiving placebo (45 versus 33 strokes per 10,000 women-years, respectively). The increase in risk was
`
`
`demonstrated in year 1 and persisted [see Clinical Studies (14.3)]. Immediately discontinue estrogen-
`
`
`
`alone therapy if a stroke occurs or is suspected.
`
`
`
`
`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).¹
`
`The WHI estrogen plus progestin substudy reported a statistically significant increased risk of stroke 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 strokes per 10,000 women-years, respectively) [see
`
`
`
`Clinical Studies, (14.3)]. The increase in risk was demonstrated after the first year and
`
`
`
`
`
`persisted.¹ Immediately discontinue estrogen plus progestogen therapy if a stroke occurs or is suspected.
`
`
`
`
`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).¹
`
`
`
`
`
`The WHI estrogen plus progestin substudy reported a statistically significant increased risk of stroke 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 strokes per 10,000 women-years) [see Clinical Studies,
`
`
`
`
`
`(14.3)]. The increase in risk was demonstrated after the first year and persisted.¹ Immediately discontinue
`
`
`estrogen plus progestogen therapy if a stroke occurs or is suspected.
`
`Coronary Heart Disease
`
`
`The WHI estrogen-alone substudy reported no overall effect on coronary heart disease (CHD) events
`
`
`
`(defined as nonfatal MI, silent MI, or CHD death) in women receiving estrogen-alone compared to
`
`placebo² [see Clinical Studies (14.3)].
`
`
`
`
`Subgroup analyses of women 50 to 59 years of age, who were less than 10 years since menopause,
`
`
`
`
`
`suggest a reduction (not statistically significant) of CHD events in those women receiving daily CE
`
`
`(0.625 mg)-alone compared to placebo (8 versus 16 per 10,000 women-years).¹
`
`
`The WHI estrogen plus progestin substudy reported an increased risk (not statistically significant) of
`
`
`
`
`
`
`CHD events 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 Clinical Studies (14.3)].
`
`
`
`
`
`Reference ID: 4874681
`
`
`
`
`
`
`
`

`

`
`
`
` In postmenopausal women with documented heart disease (n = 2,763, average 66.7 years of age), in a
` 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 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 MPA-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 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 CE plus MPA group and the placebo group in the HERS, HERS II, 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 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)]. Immediately
`
`
`
`
`discontinue estrogen-alone therapy if a VTE occurs or is suspected.
`
`
`The WHI estrogen plus progestin substudy reported a statistically significant 2-fold greater rate of VTE 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 Clinical Studies (14.3)].
`
`
`
`
`
`Immediately discontinue estrogen plus progestogen therapy if a VTE occurs or is suspected.
`
`
`
`If feasible, discontinue estrogens at 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
`
`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.
`
`Clinical surveillance of all women using estrogen-alone or estrogen plus progestogen therapy is
`
`important. Perform adequate diagnostic measures, including directed or random endometrial sampling
`
`
`
`when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or
`
`
`recurring abnormal genital bleeding with unknown etiology.
`
`
`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 progestogen to estrogen therapy has been
`
`
`
`shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
`
`Breast Cancer
`
`
`
`
`Reference ID: 4874681
`
`
`
`
`
`
`
`

`

` The WHI substudy of daily CE (0.625 mg)-alone provided information about breast cancer in estrogen-
`
`
`
`
` alone users. 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)⁵ [see Clinical
`
`
`
`
`
`
`
`Studies (14.3)].
`
`
`
`
`
`After a mean follow-up of 5.6 years, the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg)
`
`
`
`
`reported an increased risk of invasive breast cancer in women who took daily CE plus MPA compared to
`
`placebo.
`
`
`
`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.6 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 groups⁶ [see Clinical Studies (14.3)].
`
`
`
`
`
`
`
`
`
`Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast
`
`
`
`
`cancer with estrogen plus progestin therapy, and a smaller increase in the risk for breast cancer with
`
`
`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 apparent earlier, with estrogen plus progestin therapy as compared to estrogen-
`
`
`
`
`
`alone therapy. These studies have not generally 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.
`
`
`Ovarian Cancer
`The CE plus MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian
`
`
`
`
`cancer. After an average follow-up of 5.6 years, the relative risk for CE plus MPA versus placebo was
`
`
`
`1.58 (95 percent CI, 0.77-3.24), but it was not statistically significant. The absolute risk for CE plus MPA
`
`versus placebo was 4 versus 3 cases per 10,000 women-years.7
`
`A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used
`
`hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary
`
`
`
`
`
`analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies.
`
`
`
`The relative risks associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI]
`
`
`
`
`
`1.32 to 1.50); there was no difference in the risk estimates by duration of the exposure (less than 5 years
`
`
`
`
`
`[median of 3 years] vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis). The
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4874681
`
`
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`
`
`
`

`

` relative risk associated with combined current and recent use (discontinued use within 5 years before
`
`
`
`
`
` cancer diagnosis) was 1.37 (95% CI 1.27-1.48), and the elevated risk was significant for both estrogen-
` alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an
`
`
`
`
`
` increased risk of ovarian cancer, however, is unknown.
`
`
`
` 5.3 Probable Dementia
`
`
` In the WHI Memory Study (WHIMS) estrogen-alone ancillary study, a population of 2,947
`
`
` hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone 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 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 was 37 versus 25 cases per 10,000 women-years⁸ [see Use in Specific Populations
`
`
`
`(8.5), and Clinical Studies (14.4)].
`
`
`
`In the WHIMS 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 [see Use in Specific
`
`
`Populations (8.5), and Clinical 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 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 years of age, it is unknown whether these findings apply to younger postmenopausal women⁸ [see
`
`
`Use in Specific Populations (8.5), and Clinical 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 Hypercalcemia
`
`
` Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone
`
`metastases. Discontinue estrogens, including MINIVELLE, if hypercalcemia occurs, and take appropriate
`
` measures to reduce the serum calcium level.
`
` 5.6 Visual Abnormalities
`
`
`
`
`
` Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue MINIVELLE
` pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis,
`
`
`
`
`
` diplopia, or migraine. Permanently discontinue estrogens, including MINIVELLE, if examination reveals
` papilledema or retinal vascular lesions.
`
`
`
`
`
`Reference ID: 4874681
`
`
`
`
`
`
`
`

`

`5.7 Addition of a Progestogen When a Woman Has Not Had a Hysterectomy
`
`
`
`
`Studies of the addition of a progestogen 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
`
`
`
`
`progestogens 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 of estrogens on blood pressure was not seen.
`
`
`
`
`
`5.9 Exacerbation of Hypertriglyceridemia
`
`In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of
`
`plasma triglycerides leading to pancreatitis. Dis