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, BREAST CANCER, and
`
`
` PROBABLE DEMENTIA
`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)
`
`
`
` • Estrogen-alone therapy should 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 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)
`
`
`
`
`
`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 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)
`
`
`
`RECENT MAJOR CHANGES
`
`
`
` Warnings and Precautions, Malignant
`
`
`
`
` Neoplasms
` 11/2017
`
`
`
`
`
`
`
`
`
`
`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)
`
`
`•
`
`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 by the clinical response (2.1)
`
`
`
`Reference ID: 4175283
`
`
` For Postmenopausal Osteoporosis Prevention: Start therapy with
`
` MINIVELLE 0.025 mg per day applied to the skin twice weekly. The
`
`
` dose may be adjusted as necessary (2.2)
`
`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 (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)
`
`
`
`Known or suspected 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 and MI),
`
`
`
`
`or a history of these conditions (4, 5.1)
`
`
`Known anaphylactic reaction or angioedema or hypersensitivity with
`
`
`MINIVELLE (4)
`
`
`
`Known liver impairment or disease (4, 5.10)
`
`
`
`Known protein C, protein S, or antithrombin deficiency, or other
`
`
`
`
`known thrombophilic disorders (4)
`
`
`
`
`
`Known or suspected pregnancy (4, 8.1)
`
`
`
`
`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
`
`Most common adverse reactions (greater than or equal to 5 percent)
`
`with Vivelle 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 (7.1)
`
`
`
`USE IN SPECIFIC POPULATIONS
`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: An increased risk of probable dementia in women over
` 65 years of age was reported in the WHIMS ancillary studies of the
`
`
` WHI (5.3, 8.5)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`approved patient labeling.
`
`
`
`
`Revised: 11/2017
`
`
`

`

`
`
`
` 7 DRUG INTERACTIONS
`
` 7.1 Metabolic Interactions
`
`
` 8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Renal Impairment
`
`
`
`8.7 Hepatic Impairment
`
`
`
`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
`
`
`14.2 Effects on Bone Mineral Density
`
`
`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
`
`
`17 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 not listed.
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION:
`
`
` CONTENTS*
`
` WARNING: ENDOMETRIAL CANCER,
`
`
`CARDIOVASCULAR DISORDERS, BREAST
`
`
`CANCER, and PROBABLE DEMENTIA
`
`
`1 INDICATIONS AND USAGE
`
`
`1.1 Treatment of Moderate to Severe Vasomotor
`
`
`Symptoms Due to Menopause
`
`
`1.2 Prevention of Postmenopausal Osteoporosis
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Treatment of Moderate to Severe Vasomotor
`
`
`Symptoms
`
`
`2.2 Prevention of Postmenopausal Osteoporosis
`
`
`2.3 Patch Application Instructions
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Cardiovascular Disorders
`
`
`
`5.2 Malignant Neoplasms
`
`
`5.3 Probable Dementia
`
`
`5.4 Gallbladder Disease
`
`
`5.5 Hypercalcemia
`
`
`5.6 Visual Abnormalities
`
`
`5.7 Addition of a Progestin When a Woman Has Not
`
`
`Had a Hysterectomy
`
`
`
`5.8 Elevated Blood Pressure
`
`5.9 Hypertriglyceridemia
`
`
`5.10 Hepatic Impairment and/or Past History of
`
`
`
`Cholestatic Jaundice
`
`
`5.11 Hypothyroidism
`
`
`
`5.12 Fluid Retention
`
`5.13 Hypocalcemia
`
`
`5.14 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
`
`
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`
` 6.2 Postmarketing Experience
`
`
`
`
`Reference ID: 4175283
`
`

`

`
`
` 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 (5.1, 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 medroxyprogesterone acetate (MPA) [2.5 mg],
`
`relative to placebo [see Warnings and Precautions (5.1), and Clinical 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 Clinical Studies (14.4)].
`
`
` Breast Cancer
`
`Reference ID: 4175283
`
`

`

`
`
` 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 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.
`
`
`
`
`
`
`1 INDICATIONS AND USAGE
`
`
`1.1 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
`
`
`MINIVELLE is indicated for the prevention of postmenopausal osteoporosis. 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.
`
`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, 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. Postmenopausal women
`should be re-evaluated periodically as clinically appropriate to determine if treatment is 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 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.
`
`
`
`Reference ID: 4175283
`
`

`

`
`
` MINIVELLE should be replaced twice weekly (every 3-4 days).
`
`
` The sites of application must be rotated, with an interval of at least 1 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 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 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
`
`
`
` • Known, suspected or history of breast cancer
`
`
` • Known or suspected estrogen-dependent neoplasia
`
` • Active DVT, PE, or a history of these conditions
`
`
`
`
` • Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions
`
`
` • Known anaphylactic reaction or angioedema or hypersensitivity with MINIVELLE
`
`
` • Known liver impairment or disease
`
`
`
` • Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders
`
` • Known or suspected pregnancy
`
`
`
`
`
`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
` 5.1 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) 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 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 Clinical Studies (14.3)]. Should a stroke occur or be suspected, estrogen-alone therapy should be
`
`
`discontinued immediately.
`
`
`
`
`
`
`
`
`Reference ID: 4175283
`
`

`

` 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
`
`
`
`
`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-years) [see Clinical 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 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 women receiving estrogen-alone compared to
`
`
`placebo² [see Clinical Studies (14.3)].
`
`
`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
`
`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 Clinical Studies (14.3)].
`
`
`
`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)]. Should a VTE occur or be suspected,
`
`estrogen-alone therapy should be discontinued immediately.
`
`In the WHI 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
`
`
`
`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 of thromboembolism, or during periods of prolonged immobilization.
`
`
`was demonstrated during the first year and persisted⁴[see Clinical Studies (14.3)]. Should a VTE occur or be
`
`5.2 Malignant Neoplasms
`
`Endometrial cancer
`
`
`Reference ID: 4175283
`
`

`

`
`
`
`
`(relative risk [RR] 0.80)⁵ [see Clinical Studies (14.3)].
`
` 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 progestin therapy is important.
` 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.
` 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 CE-alone was not associated with an increased risk of invasive breast cancer
`
`
`
`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 groups⁶ [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
`
`
`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. 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.
`
`Ovarian Cancer
`
`
`Reference ID: 4175283
`
`

`

`cases per 10,000 women-years.⁷
`
` 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
`
`
`
`
`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 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 WHIMS estrogen-alone ancillary study of WHI, 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
`is unknown whether these findings apply to younger postmenopausal women⁸ [see Use in Specific Populations
`
`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
`
`
`
`
`
`(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. If
`
`hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum
`
`
`calcium level.
`
`
`Reference ID: 4175283
`
`

`

`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 of estrogens
`
`
`on blood pressure was not seen.
`
`
`5.9 Hypertriglyceridemia
`
`In women with pre-existing hypertriglyceridemia, 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 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 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.
`
`
`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.
`
`Reference ID: 4175283
`
`

`

` 5.15 Severe Anaphylactic/Anaphylactoid Reactions