Vivelle-Dot: Package Insert and Label Information

VIVELLE-DOT- estradiol patch, extended release
Novartis Pharmaceuticals Corporation

WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, and BREAST CANCER

Estrogen-Alone Therapy

Endometrial Cancer

There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestogen to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.2)].

Cardiovascular Disorders and Probable Dementia

The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone, relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.3)].

The WHI Memory Study (WHIMS) estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.4)].

Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.3, 14.4)].

Only daily oral 0.625 mg CE was studied in the estrogen-alone substudy of WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen-alone products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen-alone therapy, taking into account her individual risk profile.

Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

Estrogen Plus Progestin Therapy

Cardiovascular Disorders and Probable Dementia

The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.3)].

The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.4)].

Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.3, 14.4)].

Breast Cancer

The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.2), and Clinical Studies (14.3)].

Only daily oral 0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events, dementia and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestogen products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen plus progestogen therapy, taking into account her individual risk profile.

Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

1 INDICATIONS AND USAGE

Vivelle-Dot is indicated for:

1.1 Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause

1.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy Due to Menopause

Limitations of Use: When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy, first consider the use of topical vaginal products.

1.3 Treatment of Hypoestrogenism Due to Hypogonadism, Castration, or Primary Ovarian Failure

1.4 Prevention of Postmenopausal Osteoporosis

Limitations of Use: When prescribing solely for the prevention of postmenopausal osteoporosis, first consider the use of non-estrogen medications. Consider estrogen therapy only for women at significant risk of osteoporosis.

2 DOSAGE AND ADMINISTRATION

Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, consider addition of a progestogen to reduce the risk of endometrial cancer. Generally, a woman without a uterus does not need to use a progestogen in addition to her estrogen therapy. In some cases, however, hysterectomized women who have a history of endometriosis may need a progestogen [see Warnings and Precautions (5.2, 5.14)].

Use estrogen-alone or in combination with a progestogen at the lowest effective dose and the shortest duration consistent with treatment goals and risks for the individual woman. Reevaluate postmenopausal women periodically as clinically appropriate to determine whether treatment is still necessary.

2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause

Start therapy with Vivelle-Dot 0.0375 mg per day applied to the skin twice weekly. Make dosage adjustments based on the clinical response. Initiate Vivelle-Dot at once in a woman not currently taking oral estrogens or in a woman switching from another estradiol transdermal therapy. In women who are currently taking oral estrogens, initiate treatment with Vivelle-Dot 1 week after withdrawal of oral hormone therapy, or sooner if menopausal symptoms reappear in less than 1 week. Attempts to taper or discontinue Vivelle-Dot at 3 to 6-month intervals.

Give Vivelle-Dot continuously in a woman who does not have an intact uterus. In a woman with an intact uterus, give Vivelle-Dot on a cyclic schedule (for example, 3 weeks on Vivelle-Dot followed by 1 week off Vivelle-Dot).

2.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause

Start therapy with Vivelle-Dot 0.0375 mg per day applied to the skin twice weekly. Dosage adjustment should be guided by the clinical response. Attempts to taper or discontinue Vivelle-Dot at 3 to 6-month intervals.

In women not currently taking oral estrogens or in women switching from another estradiol transdermal therapy, treatment with Vivelle-Dot may be initiated at once. In women who are currently taking oral estrogens, initiate treatment with Vivelle-Dot 1 week after withdrawal of oral hormone therapy, or sooner if menopausal symptoms reappear in less than 1 week.

Give Vivelle-Dot continuously in a woman who does not have an intact uterus. In a woman with an intact uterus, give Vivelle-Dot on a cyclic schedule (for example, 3 weeks on Vivelle-Dot followed by 1 week off Vivelle-Dot).

2.3 Hypoestrogenism Due to Hypogonadism, Castration, or Primary Ovarian Failure

2.4 Prevention of Postmenopausal Osteoporosis

Start therapy with Vivelle-Dot 0.025 mg per day applied to the skin twice weekly.

In women not currently taking oral estrogens or in women switching from another estradiol transdermal therapy, treatment with Vivelle-Dot may be initiated at once. In women who are currently taking oral estrogens, initiate treatment with Vivelle-Dot 1 week after withdrawal of oral hormone therapy, or sooner if menopausal symptoms reappear in less than 1 week.

Vivelle-Dot may be given continuously in a woman who does not have an intact uterus. In a woman with an intact uterus, Vivelle-Dot may be given on a cyclic schedule (for example, 3 weeks on Vivelle-Dot followed by 1 week off Vivelle-Dot).

2.5 Application Instructions

Place the adhesive side of Vivelle-Dot on a clean, dry area of the trunk of the body (including the abdomen or buttocks). Do not apply Vivelle-Dot to the breasts.

Replace Vivelle-Dot twice weekly. Rotate the sites of application, with an interval of at least 1 week allowed between applications to a particular site. Select an area that is not oily, damaged, or irritated. Avoid the waistline, since tight clothing may rub the system off. Apply the system immediately after opening the pouch and removing the protective liner. Press the system firmly in place with the palm of the hand for about 10 seconds, making sure there is good contact, especially around the edges.

In the event that a system falls off, reapply the same system or apply a new system to another location. In either case, continue the original treatment schedule. If a woman has forgotten to apply Vivelle-Dot, have her apply a new system as soon as possible. Apply the new system on the original treatment schedule. The interruption of treatment in women taking Vivelle-Dot 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

Vivelle-Dot is contraindicated in women with any of the following conditions:

  • Undiagnosed abnormal genital bleeding [see Warnings and Precautions (5.2)].
  • Breast cancer or a history of breast cancer [see Warnings and Precautions (5.2)].
  • Estrogen-dependent neoplasia [see Warnings and Precautions (5.2)].
  • Active DVT, PE, or a history of these conditions [see Warnings and Precautions (5.1)].
  • Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions [see Warnings and Precautions (5.1)].
  • Known anaphylactic reaction, or angioedema, or hypersensitivity to Vivelle-Dot
  • Hepatic impairment or disease
  • Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders

5 WARNINGS AND PRECAUTIONS

5.1 Cardiovascular Disorders

Increased risks of stroke and DVT are reported with estrogen-alone therapy. Increased risks of PE, DVT, stroke, and MI are reported with estrogen plus progestin therapy. Immediately discontinue estrogen with or without progestogen therapy if any of these occur or are suspected.

Manage appropriately any risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus).

Stroke

The WHI estrogen-alone substudy reported a statistically significant increased risk of stroke in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 strokes per 10,000 women-years, respectively). The increase in risk was demonstrated in year 1 and persisted [see Clinical Studies (14.3)]. Immediately discontinue estrogen-alone therapy if a stroke occurs or is suspected.

Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years).1

The WHI estrogen plus progestin substudy reported a statistically significant increased risk of stroke in women 50 to 79 years of age receiving CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 stokes per 10,000 women-years) [see Clinical Studies (14.3)]. The increase in risk was demonstrated after the first year and persisted.1 Immediately discontinue estrogen plus progestogen therapy if a stroke occurs or is suspected.

Coronary Heart Disease

The WHI estrogen-alone substudy reported no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) in women receiving estrogen-alone compared to placebo2 [see Clinical Studies (14.3)].

Subgroup analyses of women 50 to 59 years of age, who were less than 10 years since menopause, suggest a reduction (not statistically significant) in CHD events in those women receiving daily CE (0.625 mg)–alone compared to placebo (8 versus 16 per 10,000 women-years).1

The WHI estrogen plus progestin substudy reported an increased risk (not statistically significant) in CHD events in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years).1 An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 [see Clinical Studies (14.3)].

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 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, the HERS II, and overall.

Venous Thromboembolism

In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years3 [see Clinical Studies (14.3)]. Immediately discontinue estrogen-alone therapy if a VTE occurs or is suspected.

The WHI estrogen plus progestin substudy reported a statistically significant 2-fold greater rate of VTE in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted4 [see Clinical Studies (14.3)]. Immediately discontinue estrogen plus progestogen therapy if a VTE occurs or is suspected.

If feasible, discontinue estrogens at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

5.2 Malignant Neoplasms

Endometrial Cancer

An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman 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, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women using estrogen-alone or estrogen plus progestogen therapy is important. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding with unknown etiology.

There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestogen to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

Breast Cancer

The WHI substudy of daily CE (0.625 mg)-alone provided information about breast cancer in estrogen-alone users. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE (0.625 mg)-alone was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80)5 [see Clinical Studies (14.3)].

After a mean follow-up of 5.6 years, the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg) reported an increased risk of invasive breast cancer in women who took daily CE plus MPA compared to placebo.

In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26% of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared with placebo.6 Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the two groups. Other prognostic factors, such as histologic subtype, grade, and hormone receptor status did not differ between the groups6 [see Clinical Studies (14.3)].

Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer with estrogen plus progestin therapy, and a smaller increase in the risk for breast cancer with estrogen-alone therapy, after several years of use. The risk increased with duration of use and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. These studies have not generally found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.

The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.

Ovarian Cancer

The CE plus MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for CE plus MPA versus placebo was 1.58 (95% CI, 0.77-3.24), but it was not statistically significant. The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years7.

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.

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