CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`203752Orig1s000
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`LABELING
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`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
`stroke, DVT, pulmonary embolism (PE), 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)
`__________________ INDICATIONS AND USAGE _________________
` MINIVELLE is an estrogen indicated for the treatment of
`moderate to severe vasomotor symptoms due to menopause (1 1)
`_______________ DOSAGE AND ADMINISTRATION ______________
`
`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)
` 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 (2.1).
`______________ DOSAGE FORMS AND STRENGTHS _____________
`
`Transdermal system 0.0375 mg/day, 0.05 mg/day, 0.075 mg/day,
`and 0.1 mg/day (3).
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR
`DISORDERS, BREAST CANCER AND PROBABLE DEMENTIA 
`INDICATIONS AND USAGE 
`1. 
`DOSAGE AND ADMINISTRATION 
`2. 
`2.1  Treatment of Moderate to Severe Vasomotor Symptoms 
`DOSAGE FORMS AND STRENGTHS 
`3. 
`CONTRAINDICATIONS 
`4. 
`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 
`
`Reference ID: 3209795
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`___________________ 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 with MINIVELLE
`(4)
`Known liver impairment (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 (≥5 percent) with Vivelle are: headache,
`breast tenderness, back pain, pain in limb, and nasopharyngitis, dyspepsia,
`nausea, sinusitis, intermenstrual bleeding. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Noven at 1-
`800-445-8070 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
`(8.3)
`Geriatric Use: An increased risk of probable dementia in women
`over 65 years of age was reported in the Women’s Health Initiative
`Memory ancillary studies of the Women’s Health Initiative (5.3,
`8.5).
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling
`
`Revised: 10/2012
`
`6. 
`7. 
`8. 
`
`5.15  Hereditary Angioedema 
`5.16  Exacerbation of Other Conditions 
`5.17   Laboratory Tests 
`5.18  Drug-Laboratory Test Interactions 
`ADVERSE REACTIONS 
`6.1  Clinical Trials Experience 
`DRUG INTERACTIONS 
`7.1  Metabolic Interactions 
`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 
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`1
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`14.2  Women’s Health Initiative Studies 
`14.3  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.
`
`
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`Reference ID: 3209795
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`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 (14.2, 14.3)].
`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 (14.2)].
`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
`(14.3)].
`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 (14.2,
`14.3].
`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
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`Reference ID: 3209795
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`Precautions (5.1), and Clinical Studies (14.2)].
`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 (14.3)].
`
`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 (14.2)].
`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.
`
`INDICATIONS AND USAGE
`1.
`MINIVELLE is indicated for treatment of moderate to severe vasomotor symptoms due to menopause.
`
`DOSAGE AND ADMINISTRATION
`2.
`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.
`
`Treatment of Moderate to Severe Vasomotor Symptoms
`2.1
`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.
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`Reference ID: 3209795
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`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 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.
`
`DOSAGE FORMS AND STRENGTHS
`3.
`Transdermal system 0.0375 mg/day, 0.05 mg/day, 0.075 mg/day, and 0.1 mg/day.
`
`CONTRAINDICATIONS
`4.
`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 with MINIVELLE
` Known liver impairment
` Known protein C, protein S, or antithrombin deficiency, or other known
`thrombophilic disorders
` Known or suspected pregnancy
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`Reference ID: 3209795
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`5.
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`WARNINGS AND PRECAUTIONS
`
`Cardiovascular Disorders
`5.1
`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 (14.2)]. 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).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, 14.2)]. 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 (14.2)].
`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 (14.2)].
`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
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`Reference ID: 3209795
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`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 (14.2)] 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 was demonstrated during the first year and persisted4 [see
`Clinical Studies (14.2)]. 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 of thromboembolism, or during periods of prolonged immobilization.
`
`Malignant Neoplasms
`5.2
`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 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 (relative risk [RR] 0.80]5 [see Clinical Studies (14.2)].
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`Reference ID: 3209795
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`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
`(14.2)].
`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
`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.7 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.
`
`Probable Dementia
`5.3
`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-
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`Reference ID: 3209795
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`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 (14.3)].
`In the WHIMS estrogen plus progestin ancillary study, 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 (14.3)].
`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 (14.3)].
`
`Gallbladder Disease
`5.4
`A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women
`receiving estrogens has been reported.
`
`Hypercalcemia
`5.5
`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.
`
`Visual Abnormalities
`5.6
`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.
`
`Addition of a Progestin When a Woman Has Not Had a Hysterectomy
`5.7
`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.
`
`Elevated Blood Pressure
`5.8
`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.
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`Reference ID: 3209795
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`Hypertriglyceridemia
`5.9
`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.
`
`Hepatic Impairment and/or Past History of Cholestatic Jaundice
`5.10
`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.
`
`Hypothyroidism
`5.11
`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.
`
`Fluid Retention
`5.12
`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.
`
`Hypocalcemia
`5.13
`Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced
`hypocalcemia may occur.
`
`Exacerbation of Endometriosis
`5.14
`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.
`
`Hereditary Angioedema
`5.15
`Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.
`
`Exacerbation of Other Conditions
`5.16
`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.
`Laboratory Tests
`5.17
`Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the
`management of moderate to severe vasomotor symptoms.
`
`Reference ID: 3209795
`
`10
`
`
`

`

`Drug-Laboratory Test Interactions
`5.18
`Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased
`platelet count; increased factors II, VII antigen, VIII 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 III activity; increased levels of fibrinogen and fibrinogen
`activity; increased plasminogen antigen and activity.
`Increased TBG leading to increased circulating total thyroid hormone levels, as measured by protein-
`bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 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.
`Other binding proteins may be elevated in serum, for example, corticosteroid-binding globulin (CBG),
`sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex
`steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased.
`Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin,
`ceruloplasmin).
`Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations,
`reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglycerides levels.
`Impaired glucose tolerance.
`
`ADVERSE REACTIONS
`6.
`The following serious adverse reactions are discussed elsewhere in labeling:
` Cardiovascular Disorders [see Boxed Warning, Warning and Precaution, (5.1)]
` Endometrial Cancer [see Boxed Warning, Warnings and Precautions (5.2)]
`
`
`
`Clinical Trials Experience
`6.1
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in
`the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and
`may not reflect the rates observed in practice.
`There were no clinical trials conducted with MINIVELLE. MINIVELLE is bioequivalent to Vivelle®.
`The following adverse reactions are reported with Vivelle:
`Table 1:
`Summary of Most Frequently Reported Adverse Reactions (Vivelle versus
`Placebo) Regardless of Relationship Reported at a Frequency > 5 Percent
`Vivelle
`Vivelle
`Vivelle
`Vivelle
`Placebo
`0.0375 mg/day†
`0.05 mg/day†
`0.075 mg/day†
`0.1 mg/day†
`
`(N=130)
`(N=103)
`(N=46)
`(N=132)
`(N=157)
`N (%)
`N (%)
`N (%)
`N (%)
`N (%)
`Gastrointestinal disorders
`Constipation
`5 (3.8)
`Dyspepsia
`12 (9.2)
`Nausea
`8 (6