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

`

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`14 CLINICAL STUDIES
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`14.1 Effects on Vasomotor Symptoms
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`14.2 Effects on Bone Mineral Density
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`14.3 Women’s Health Initiative Studies
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`14.4 Women’s Health Initiative Memory Study
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`15 REFERENCES
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`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
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`16.2 Storage and Handling
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`PATIENT COUNSELING INFORMATION
`17.1 Vaginal Bleeding
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`17.2 Possible Serious Adverse Reactions with Estrogen-Alone
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`Therapy
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`17.3 Possible Less Serious but Common Adverse Reactions with
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`Estrogen-Alone Therapy
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`*Sections or subsections omitted from the full prescribing information
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`are not listed.
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`17
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`7
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`8
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`Postmarketing Experience
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`6.2
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` DRUG INTERACTIONS
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`7.1 Metabolic Interactions
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` USE IN SPECIFIC POPULATIONS
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`Pregnancy
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`8.1
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`8.3 Nursing Mothers
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`8.4
`Pediatric Use
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`8.5 Geriatric Use
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`8.6 Renal Impairment
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`8.7 Hepatic Impairment
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` 10 OVERDOSAGE
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` 11 DESCRIPTION
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` 12 CLINICAL PHARMACOLOGY
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`12.1 Mechanism of Action
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`12.2 Pharmacodynamics
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`12.3 Pharmacokinetics
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`13 NONCLINICAL TOXICOLOGY
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`Reference ID: 3632965
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`2
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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
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` undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and
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`
`
` Precautions (5.2)].
`
`
`
` Cardiovascular Disorders and Probable Dementia
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` Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or
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`
`
`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
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`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,
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`
` 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
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`or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo.
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`
` 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
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`(14.4)].
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`
` In the absence of comparable data, these risks should be assumed to be similar for other
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`doses of CE and other dosage forms of estrogens.
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` Estrogens with or without progestins should be prescribed at the lowest effective doses and
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`for the shortest duration consistent with treatment goals and risks for the individual
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`woman.
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`Estrogen Plus Progestin Therapy
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`Cardiovascular Disorders and Probable Dementia
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`
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` Estrogen plus progestin therapy should not be used for the prevention of cardiovascular
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`disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.3,
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` 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
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` medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and
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` 3
`
`Reference ID: 3632965
`
`
`
`

`

`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
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` women [see Warnings and Precautions (5.3), Use in Specific Populations (8.5), and Clinical
`
`Studies (14.4)].
`
`
`
` Breast Cancer
`
` The WHI estrogen plus progestin substudy also demonstrated an increased risk of
`
`
` invasive breast cancer [see Warnings and Precautions (5.2), and Clinical Studies (14.3)].
`
`
`
`
` In the absence of comparable data, these risks should be assumed to be similar for other
` doses of CE and MPA, and other combinations and dosage forms of estrogens and
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`
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`progestins.
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`
`
` 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
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` woman.
`
`
`
`
`
` INDICATIONS AND USAGE
`
`
`
` 1
`
`
`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.
`
`
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`
`
` 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.
`
`
`
`
`Reference ID: 3632965
`
`
`
` 4
`
`
`
`

`

`
`
` Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if
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`
` 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.
`
`
`
`
`
`
`
`
` 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
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`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:
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`
`
`
`
`
`
` 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
`
`
`
`
`5
`
`
`
`
`
`Reference ID: 3632965
`
`

`

` Active arterial thromboembolic disease (for example, stroke and MI), or a history of these
`
`
`
`
` conditions
`
` Known anaphylactic reaction or angioedema or hypeersensitivity with MINIVELLE
`
`
`
`
` Known liver impairment or disease
`
`
`
`
`
` Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic
`
`
`disorders
`
` Known or suspected pregnancy
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`
`
`
`
` 5
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`
`
` 5.1
`
`
`
` WARNINGS AND PRECAUTIONS
`
`
`
` Cardiovascular Disorders
`
` An increased risk of stroke and DVT has been reported with estrogen-alone therapy. An increased risk of
`
`
`PE, DVT, stroke and MI has been reported with estrogen plus progestin therapy. Should any of these
`
`occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately.
`
`
`
`
`
`Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use,
`
`
`hypercholesterolemia, and obesity) 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.
`
`
`
`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
`
`Reference ID: 3632965
`
`6
`
`
`
`
`
`

`

`
`
`
`
`
`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 was demonstrated during the first year and persisted4 [see
`
`Clinical Studies (14.3)]. Should a VTE occur or be suspected, estrogen plus progestin therapy should be
`
`discontinued immediately.
`
`
`If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated
`
`
`with an increased risk 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.
`
`Reference ID: 3632965
`
`7
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`
`
`
`
`

`

`
`
`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 (14.3)].
`
`
`
`
`
`
`
`
`
`
`
`
`The most important randomized clinical trial providing information about breast cancer in estrogen plus
`
`
`
`progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up
`
`
`of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in
`
`women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus
`
`
`progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer
`
`
`
`
`was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA
`
`compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of
`
`
`
`invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years,
`
`
`
`
`for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy,
`
`
`
`the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per
`
`
`
`
`10,000 women-years for CE plus MPA compared with placebo. In the same substudy, invasive breast
`
`
`cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage
`
`
`
`in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was
`rare, with no apparent difference between the two groups. Other prognostic factors, such as histologic
`subtype, grade and hormone receptor status did not differ between the 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.
`
`
`
`Reference ID: 3632965
`
`
`
` 8
`
`
`
`

`

`
`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.
`
`
`
`
`
`
`
`
` 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 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. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to
`
`reduce the serum calcium level.
`
`Reference ID: 3632965
`
`9
`
`
`
`
`
`

`

`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 rec