Vivelle-dot Patch, Extended Release
FDA Label NDC 66758-147

• There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestogen to estrogen-only 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 menopausal women with abnormal genital bleeding of unknown etiology [see Warnings and Precautions (5.2)].

VIVELLE-DOT is indicated for:

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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.

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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.

The timing of VIVELLE-DOT initiation can affect the overall benefit-risk profile. Consider initiating VIVELLE-DOT in women < 60 years old or < 10 years since menopause onset [see Warnings and Precautions (5), Use in Specific Populations (8.5) and Clinical Studies (14)].

When estrogen is prescribed for a menopausal woman with a uterus, the addition of a progestogen has been shown to reduce the risk of endometrial cancer. There are possible risks associated with the use of progestogens plus estrogens that differ from those of estrogen-alone regimens. See prescribing information for progestogens indicated for the prevention of endometrial hyperplasia in non-hysterectomized menopausal women receiving estrogens [see Warnings and Precautions (5.2, 5.3)].

Generally, a woman without a uterus does not need to use a progestogen with estrogen therapy. In some cases, however, hysterectomized women with a history of endometriosis may benefit from the addition of a progestogen [see Warnings and Precautions (5.13)].

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.

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).

Make dosage adjustment based on the clinical response. Reevaluate postmenopausal women periodically as clinically appropriate to determine if treatment is still necessary.

Start therapy with VIVELLE-DOT 0.0375 mg per day applied to the skin twice weekly.

Start therapy with VIVELLE-DOT 0.0375 mg per day applied to the skin twice weekly.

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Start therapy with VIVELLE-DOT 0.025 mg per day applied to the skin twice weekly.

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.

Transdermal system: 0.025 mg/day, 0.0375 mg/day, 0.05 mg/day, 0.075 mg/day, and 0.1 mg/day.

VIVELLE-DOT is contraindicated in women with any of the following conditions:

• Abnormal genital bleeding of unknown etiology [see Warnings and Precautions (5.2)].
• Current or 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, angioedema, or hypersensitivity to VIVELLE-DOT [see Warnings and Precautions (5.14)].
• Hepatic impairment or disease [see Warnings and Precautions (5.9)].
• Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders.

VIVELLE-DOT is contraindicated in women with active DVT, PE, stroke, or a history of these conditions [see Contraindications (4)]. Immediately discontinue VIVELLE-DOT if a PE, DVT, or stroke, occurs or is suspected. If feasible, discontinue VIVELLE-DOT at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

The safety and efficacy of VIVELLE-DOT for the prevention of cardiovascular disorders have not been established.

The Women’s Health Initiative (WHI) estrogen-alone trial reported increased risks of pulmonary embolism (PE), deep vein thrombosis (DVT), and stroke, in postmenopausal women (50 to 79 years of age, average age 63.6 years) during 7.2 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] relative to placebo. Analyses were also conducted in women aged 50-59 years, a group of women more likely to present with new onset of moderate to severe VMS compared to women of other age groups in the trial.

Only daily oral 0.625 mg CE was studied in the WHI estrogen-alone trial. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events to lower CE doses, other routes of administration, or other estrogen 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 [see Clinical Studies (14.3)].

Venous Thromboembolism

In women aged 50-59 years, the WHI estrogen-alone trial reported a relative risk for PE of 1.53 (95% confidence interval [CI], 0.63, 3.75) for CE compared to placebo, with an absolute risk difference of 4 per 10,000 women-years (WYs; 10 versus 6). The relative risk for DVT was 1.66 (95% CI, 0.75, 3.67) for CE compared to placebo, with a risk difference of 5 per 10,000 WYs (13 versus 8).

In the overall study population of women aged 50-79 years, the WHI estrogen-alone trial reported a relative risk of PE of 1.35 (95% CI, 0.89, 2.05) for CE compared to placebo, with a risk difference of 4 per 10,000 WYs (14 versus 10). The relative risk for DVT was 1.48 (95% CI, 1.06, 2.07) for CE compared to placebo, with a risk difference of 7 per 10,000 WYs (23 versus 15) [see Clinical Studies (14.3)].

Stroke

In women aged 50-59 years, the WHI estrogen-alone trial reported a relative risk for stroke of 0.99 (95% CI, 0.53, 1.85) for CE compared to placebo, with a risk difference of -1 per 10,000 WYs (16 versus 17).

In the overall study population of women aged 50-79 years, the WHI estrogen-alone trial reported a relative risk for stroke of 1.35 (95% CI, 1.07, 1.70) for CE compared to placebo, with a risk difference of 11 per 10,000 WYs (45 versus 34) [see Clinical Studies (14.3)].¹

Endometrial Cancer

In VIVELLE-DOT treated menopausal women with a uterus with persistent or recurring abnormal genital bleeding of unknown etiology, perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to assess for 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. 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-alone therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. There are, however, possible risks associated with the use of progestogens plus estrogens that differ from those of estrogen-alone regimens [see Warnings and Precautions (5.3)].

Breast Cancer

Assess risk and provide surveillance measures for breast cancer, such as breast examinations and mammography. The use of estrogen-alone therapy has been reported to result in an increase in abnormal mammograms requiring further evaluation.

In the WHI estrogen-alone trial, after a median follow-up of 7.2 years, daily CE-alone was not associated with an increased risk of invasive breast cancer. Among women 50- 59 years old, the relative risk was 0.82 (95% CI, 0.50, 1.34) for CE compared to placebo, with a risk difference of -5 per 10,000 WYs (24 versus 29). In the overall study population of women aged 50-79 years (average age 63.6 years), the relative risk was 0.79 (95% CI, 0.61, 1.02), with a risk difference of -7 per 10,000 WYs (28 versus 35) [see Clinical Studies (14.3)]. However, a large meta-analysis including 24 prospective studies of postmenopausal women comparing current use of estrogen-only products with use duration of 5 to 14 years (average of 9 years) versus never use reported a relative risk for breast cancer of 1.33 (95% CI, 1.28 to 1.38).²

Ovarian Cancer

A large meta-analysis including 17 prospective studies of postmenopausal women compared current use of estrogen-only products versus never use and reported a relative risk for ovarian cancer of 1.37 (95% CI, 1.26 to 1.50). The duration of hormone therapy use that was associated with an increased risk of ovarian cancer is unknown.³

If VIVELLE-DOT is administered with a progestogen, there are possible risks associated with the use of progestogens plus estrogens that differ from those of estrogen-alone regimens. Refer to prescribing information for progestogens indicated for the prevention of endometrial hyperplasia in non-hysterectomized menopausal women receiving estrogens.

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. Discontinue estrogens, including VIVELLE-DOT, if hypercalcemia occurs, and take appropriate measures to reduce the serum calcium level.

Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue VIVELLE-DOT pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. Permanently discontinue estrogens, including VIVELLE-DOT, if examination reveals papilledema or retinal vascular lesions.

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.

In women with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Discontinue VIVELLE-DOT if pancreatitis occurs.

Estrogens may be poorly metabolized in women with hepatic impairment. Exercise caution in any woman with a history of cholestatic jaundice associated with past estrogen use or with pregnancy. In the case of recurrence of cholestatic jaundice, discontinue VIVELLE-DOT.

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. Monitor thyroid function in these women during treatment with VIVELLE-DOT to maintain their free thyroid hormone levels in an acceptable range.

Estrogens may cause some degree of fluid retention. Monitor any woman with a condition(s) that might predispose her to fluid retention, such as cardiac or renal impairment. Discontinue estrogen-alone therapy, including VIVELLE-DOT, with evidence of medically concerning fluid retention.

Estrogen-induced hypocalcemia may occur in women with hypoparathyroidism. Consider whether the benefits of estrogen therapy, including VIVELLE-DOT, outweigh the risks in such women.

A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. Consider the addition of progestogen therapy for women known to have residual endometriosis post-hysterectomy.

A few cases of anaphylactic/anaphylactoid reactions are reported in the postmarketing use of VIVELLE-DOT. Involvement of skin (hives, pruritus, swollen lips-tongue-face) and either respiratory tract (respiratory compromise) or gastrointestinal tract (abdominal pain, vomiting) are noted.

Angioedema involving eye/eyelid, face, larynx, pharynx, tongue and extremity (hands, legs, ankles, and fingers) with or without urticaria requiring medical intervention are reported in the postmarketing use of VIVELLE-DOT. Angioedema involving the tongue, glottis, or larynx, may result in airway obstruction. Do not give VIVELLE-DOT to any woman who develops angioedema during treatment with VIVELLE-DOT.

Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. Consider whether the benefits of estrogen therapy outweigh the risks in such women.

Estrogen therapy, including VIVELLE-DOT, may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraines, porphyria, systemic lupus erythematosus, and hepatic hemangiomas. Consider whether the benefits of estrogen therapy outweigh the risks in such women.

Serum follicle-stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy.

Laboratory parameters may be useful in guiding dosage for the treatment of hypoestrogenism due to hypogonadism, castration and primary ovarian failure.

• 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 thyroid-binding globulin (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, and increased triglycerides levels.
• Impaired glucose tolerance.

The following serious adverse reactions are discussed elsewhere in labeling:

• Cardiovascular Disorders [see Warnings and Precautions (5.1)]
• Malignant Neoplasms [see Boxed Warning, Warnings and Precautions (5.2)]

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 VIVELLE-DOT. VIVELLE-DOT is bioequivalent to VIVELLE^®. The following adverse reactions have been reported with VIVELLE therapy:

The following additional adverse reactions have been identified during post-approval use of VIVELLE-DOT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Genitourinary System

Vaginal hemorrhage and abnormal withdrawal bleeding or flow, breakthrough bleeding, spotting, uterine leiomyomata, vaginitis, vaginal discharge, ovarian cancer, endometrial hyperplasia, dysmenorrhea.

Breast

Enlargement, pain, nipple discharge, fibrocystic breast changes, breast cancer.

Cardiovascular

Deep venous thrombosis, pulmonary embolism, thrombophlebitis.

Gastrointestinal

Nausea, vomiting, abdominal cramps, bloating, cholelithiasis, liver function tests abnormal, diarrhea.

Skin

Application site reactions include localized bleeding, bruising, burning, discomfort, dryness, eczema, edema, erythema, erythema multiforme, erythema nodosum, inflammation, irritation, pain, papules and vesicles. Other skin reactions include paresthesia, skin discoloration, skin pigmentation, urticaria, swelling, loss of scalp hair, hirsutism, pruritus, and rash.

Eyes

Intolerance to contact lenses.

Central Nervous System

Migraine, dizziness, chorea, nervousness, affect liability, irritability.

Miscellaneous

Decrease in weight, reduced carbohydrate tolerance, edema, arthralgias, leg cramps, changes in libido, purpura, hypersensitivity, anaphylactic reaction, anaphylactoid reaction, angioedema.

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John’s wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, and grapefruit juice may increase plasma concentrations of estrogens and may result in adverse reactions.

Risk Summary

VIVELLE-DOT is not indicated for use in pregnancy. There are no data with the use of VIVELLE-DOT in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogen and progestins) before conception or during early pregnancy.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Risk Summary

Estrogens are present in human milk and can reduce milk production in breast-feeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well-established.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VIVELLE-DOT and any potential adverse effects on the breastfed child from VIVELLE-DOT or from the underlying maternal condition.

VIVELLE-DOT is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population.

If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended during estrogen administration.

There have not been sufficient numbers of geriatric women involved in clinical studies utilizing VIVELLE-DOT to determine whether those over 65 years of age differ from younger subjects in their response to VIVELLE-DOT.

The Women’s Health Initiative Studies

In the WHI estrogen-alone trial (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies (14.3)].

The Women’s Health Initiative Memory Study

In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of probable dementia in women receiving estrogen-alone [see Clinical Studies (14.4)].

Since the trial was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger menopausal women [Clinical Studies (14.3)]. The safety and efficacy of VIVELLE-DOT for the prevention of dementia has not been established.

Overdosage of estrogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of VIVELLE-DOT therapy with institution of appropriate symptomatic care.

VIVELLE-DOT (estradiol transdermal system) contains estradiol in a multipolymeric adhesive. The system is designed to release estradiol continuously upon application to intact skin.

Five dosage strengths of VIVELLE-DOT are available to provide nominal in vivo delivery rates of 0.025, 0.0375, 0.05, 0.075, or 0.1 mg of estradiol per day via the skin. Each corresponding system has an active surface area of 2.5, 3.75, 5.0, 7.5, or 10.0 cm² and contains 0.39, 0.585, 0.78, 1.17, or 1.56 mg of estradiol USP, respectively. The composition of the systems per unit area is identical.

Estradiol USP is a white, crystalline powder, chemically described as estra-1,3,5 (10)- triene-3,17β-diol.

The structural formula is:

Estradiolstructuralformula (Vivelledot01)

The molecular formula of estradiol is C₁₈H₂₄0₂. The molecular weight is 272.39 g/mol.

VIVELLE-DOT is comprised of 3 layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are (1) a translucent polyolefin film (2) an adhesive formulation containing estradiol, acrylic adhesive, silicone adhesive, oleyl alcohol, NF, povidone, USP and dipropylene glycol, and (3) a polyester release liner which is attached to the adhesive surface and must be removed before the system can be used.

Vivelledotlayerimage (Vivelledot02)

----- (1) Backing ----- (2) Adhesive Containing Estradiol ----- (3) Protective Liner

The active component of the system is estradiol. The remaining components of the system are pharmacologically inactive.

Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.

The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, 2 estrogen receptors have been identified. These vary in proportion from tissue to tissue.

Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

Generally, a serum estrogen concentration does not predict an individual woman’s therapeutic response to VIVELLE-DOT nor her risk for adverse outcomes. Likewise, exposure comparisons across different estrogen products to infer efficacy or safety for the individual woman may not be valid.

Absorption

In a multiple-dose study consisting of 3 consecutive system applications of the original formulation [VIVELLE (estradiol transdermal system)] which was conducted in 17 healthy, postmenopausal women, blood levels of estradiol and estrone were compared following application of these units to sites on the abdomen and buttocks in a crossover fashion. Systems that deliver nominal estradiol doses of approximately 0.0375 mg per day and 0.1 mg per day were applied to abdominal application sites while the 0.1 mg per day doses were also applied to sites on the buttocks. These systems increased estradiol levels above baseline within 4 hours and maintained respective mean levels of 25 and 79 pg/mL above baseline following application to the abdomen; slightly higher mean levels of 88 pg/mL above baseline were observed following application to the buttocks. At the same time, increases in estrone plasma concentrations averaged about 12 and 50 pg/mL, respectively, following application to the abdomen and 61 pg/mL for the buttocks. While plasma concentrations of estradiol and estrone remained slightly above baseline at 12 hours following removal of the systems in this study, results from another study show these levels to return to baseline values within 24 hours following removal of the systems.

Figure 1 illustrates the mean plasma concentrations of estradiol at steady-state during application of these patches at 4 different dosages.

Figure 1. Steady-State Estradiol Plasma Concentrations for Systems Applied to the Abdomen Nonbaseline-corrected Levels

Figure1 (Vivelledot03)

The corresponding pharmacokinetic parameters are summarized in Table 2.

VIVELLE-DOT (estradiol transdermal system), the revised formulation with smaller system sizes, was shown to be bioequivalent to the original formulation, VIVELLE (estradiol transdermal system), used in the clinical trials.

Distribution

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone-binding globulin (SHBG) and albumin.

Metabolism

Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver by Cytochrome 450 isoforms CYP1A2 and CYP3A4. Estradiol undergoes further metabolism to sulfate and glucuronide conjugates. Estradiol and its metabolites are glucuronidated by UGT1A1 and UGT2B7. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

Excretion

Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The half-life values calculated after dosing with the VIVELLE-DOT ranged from 5.9 to 7.7 hours. After removal of the transdermal systems, serum concentrations of estradiol and estrone returned to baseline levels within 24 hours.

Adhesion

Based on combined data from 3 short-term clinical trials consisting of 471 observations, 85% of VIVELLE-DOT adhered completely to the skin over the 3.5-day wear period. Three percent (3%) of the systems detached and were reapplied or replaced during the 3.5-day wear period. Approximately 80% of the transdermal systems evaluated in these studies were VIVELLE-DOT 0.05 mg per day.

Long-term, continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

In a pharmacokinetic study, VIVELLE-DOT was shown to be bioequivalent to VIVELLE. In 2 controlled clinical trials with VIVELLE, of 356 women, the 0.075 and 0.1 mg doses were superior to placebo in relieving vasomotor symptoms at Week 4, and maintained efficacy through Weeks 8 and 12 of treatment. In this original study, the 0.0375 and 0.05 mg doses, however, did not differ from placebo until approximately Week 6, therefore, an additional 12-week, placebo-controlled study in 255 women was performed with VIVELLE to establish the efficacy of the lowest dose of 0.0375 mg. The baseline mean daily number of hot flushes in these 255 women was 11.5. Results at Weeks 4, 8, and 12 of treatment are shown in Figure 2.

Figure 2. Mean (SD) Change from Baseline in Mean Daily Number of Flushes for VIVELLE 0.0375 mg Versus Placebo in a 12-week Trial

Figure2 (Vivelledot04)

The 0.0375 mg dose was superior to placebo in reducing both the frequency and severity of vasomotor symptoms at Week 4 and maintained efficacy through Weeks 8 and 12 of treatment. All doses of VIVELLE (0.0375 mg, 0.05 mg, 0.075 mg, and 0.1 mg) are effective for the control of vasomotor symptoms.

Efficacy and safety of VIVELLE in the prevention of postmenopausal osteoporosis have been studied in a 2-year, double-blind, randomized, placebo-controlled, parallel-group study. A total of 261 hysterectomized (161) and non-hysterectomized (100), surgically or naturally menopausal women (within 5 years of menopause), with no evidence of osteoporosis (lumbar spine bone mineral density within 2 standard deviations of average peak bone mass, i.e., at least 0.827 g/cm²) were enrolled in this study; 194 women were randomized to 1 of the 4 doses of VIVELLE (0.1, 0.05, 0.0375, or 0.025 mg/day) and 67 patients to placebo. Over 2 years, study systems were applied to the buttock or the abdomen twice a week. Non-hysterectomized women received oral medroxyprogesterone acetate (2.5 mg/day) throughout the study.

The study population comprised naturally (82%) or surgically (18%) menopausal, hysterectomized (61%) or non-hysterectomized (39%) women with a mean age of 52 years (range 27 to 62 years); the mean duration of menopause was 31.7 months (range 2 to 72 months). Two hundred thirty-two (89%) of randomized women (173 on active drug, 59 on placebo) contributed data to the analysis of percent change from baseline in bone mineral density (BMD) of the AP lumbar spine, the primary efficacy variable. Women were given supplemental dietary calcium (1000 mg elemental calcium/day) but no supplemental vitamin D. There was an increase in BMD of the AP lumbar spine in all VIVELLE dose groups; in contrast to this, a decrease in AP lumbar spine BMD was observed in placebo patients. All VIVELLE doses were significantly superior to placebo (p < 0.05) at all time points with the exception of VIVELLE 0.05 mg/day at 6 months. The highest dose of VIVELLE was superior to the 3 lower doses. There were no statistically significant differences in pairwise comparisons among the 3 lower doses (See Figure 3).

Figure 3. Bone Mineral Density-AP Lumbar Spine Least Squares Means of Percentage Change from Baseline All Randomized Patients with at Least One Post-baseline Assessment Available with Last Post-baseline Observation Carried Forward

Figure3 (Vivelledot05)

Analysis of percent change from baseline in femoral neck BMD, a secondary efficacy outcome variable, showed qualitatively similar results; all doses of VIVELLE were significantly superior to placebo (p<0.05) at 24 months. The highest VIVELLE dose was superior to placebo at all time points. A mixture of significant and nonsignificant results were obtained for the lower dose groups at earlier time points. The highest VIVELLE dose was superior to the 3 lower doses, and there were no significant differences among the 3 lower doses at this skeletal site (See Figure 4).

Figure 4. Bone Mineral Density-Femoral Neck Least Squares Means of Percentage Change from Baseline All Randomized Patients with at Least One Post-baseline Assessment Available with Last Post-baseline Observation Carried Forward

Figure4 (Vivelledot06)

The mean serum osteocalcin (a marker of bone formation) and urinary excretion of cross-link N-telopeptides of Type 1 collagen (a marker of bone resorption) decreased numerically in most of the active treatment groups relative to baseline. However, the decreases in both markers were inconsistent across treatment groups and the differences between active treatment groups and placebo were not statistically significant.

The WHI estrogen-alone trial enrolled predominantly healthy postmenopausal women to assess the risks and benefits of daily oral CE (0.625 mg)-alone compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, colorectal cancer, hip fracture, or death due to other cause. This trial did not evaluate the effects of CE-alone on menopausal symptoms.

The WHI estrogen-alone trial was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints. Centrally adjudicated results for stroke events, after a median follow-up of 7.2 years, reported estrogen-alone increased the risk for stroke in overall population compared to placebo, but this excess risk was not present in the 50-59 years subgroup examined.

No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared to placebo was reported in final centrally adjudicated results from the estrogen-alone trial, after a median follow-up of 7.2 years.^4,5

Results of the estrogen-alone trial, which included 10,739 women (average age of 63.6 years, range 50 to 79 years; 75.3% White, 15.1% Black, 6.1% Hispanic, 3.6% Other), after a median follow up of 7.2 years are presented in Table A.

Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The study results for women 50-59 years old in the WHI estrogen-alone trial are shown in Table B.

The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age and older (45% were age 65 to 69 years of age; 36% were 70 to 74 years of age; and 19% were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo. Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD.⁶

Using updated data after a median follow-up of 7.2 years, the relative risk of probable dementia for CE- alone versus placebo was 1.47 (95% CI, 0.85-2.52). The absolute risk of probable dementia for CE-alone versus placebo was 33 versus 22 cases per 10,000 women-years.¹ Since analysis was performed on women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Use in Specific Populations (8.5)].

• 1.Manson, J. E., et al Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA, 310(13): 1353–1368 (2013). https://doi.org/10.1001/jama.2013.278040.
• 2.Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet. 2019 Sep 28;394(10204):1159-1168. doi: 10.1016/S0140-6736(19)31709-X. Epub 2019 Aug 29. PMID: 31474332; PMCID: PMC6891893.
• 3.Collaborative Group On Epidemiological Studies Of Ovarian Cancer; Beral V, Gaitskell K, Hermon C, Moser K, Reeves G, Peto R. Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies. Lancet. 2015 May 9;385(9980):1835-42. doi: 10.1016/S0140-6736(14)61687-1. Epub 2015 Feb 13. PMID: 25684585; PMCID: PMC4427760.
• 4.Anderson GL, et al; Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004 Apr 14;291(14):1701-12. doi: 10.1001/jama.291.14.1701. PMID: 15082697.
• 5.Espeland MA, Rapp SR, Shumaker SA, Brunner R, Manson JE, Sherwin BB, Hsia J, Margolis KL, Hogan PE, Wallace R, Dailey M, Freeman R, Hays J; Women's Health Initiative Memory Study. Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study. JAMA. 2004 Jun 23;291(24):2959-68. doi: 10.1001/jama.291.24.2959. PMID: 15213207.

VIVELLE-DOT (estradiol transdermal system), 0.025 mg per day-each 2.5 cm² system contains 0.39 mg of estradiol USP for nominal* delivery of 0.025 mg of estradiol per day.

Patient Calendar Pack of 8 Systems………………………………………NDC 66758-145-83

VIVELLE-DOT (estradiol transdermal system), 0.0375 mg per day-each 3.75 cm² system contains 0.585 mg of estradiol USP for nominal* delivery of 0.0375 mg of estradiol per day.

Patient Calendar Pack of 8 Systems………………………………………NDC 66758-146-83

VIVELLE-DOT (estradiol transdermal system), 0.05 mg per day-each 5.0 cm² system contains 0.78 mg of estradiol USP for nominal* delivery of 0.05 mg of estradiol per day.

Patient Calendar Pack of 8 Systems………………………………………NDC 66758-147-83

VIVELLE-DOT (estradiol transdermal system), 0.075 mg per day-each 7.5 cm² system contains 1.17 mg of estradiol USP for nominal* delivery of 0.075 mg of estradiol per day.

Patient Calendar Pack of 8 Systems………………………………………NDC 66758-148-83

VIVELLE-DOT (estradiol transdermal system), 0.1 mg per day-each 10.0 cm² system contains 1.56 mg of estradiol USP for nominal* delivery of 0.1 mg of estradiol per day.

Patient Calendar Pack of 8 Systems………………………………………NDC 66758-149-83

[*see DESCRIPTION (11)]

Store at 20° to 25°C (68° to 77°F). Excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.]

Do not store unpouched. Apply immediately upon removal from the protective pouch.

Used transdermal systems still contain active hormone. To discard, fold the sticky side of the transdermal system together, place it in a sturdy child-proof container, and place this container in the trash. Used transdermal systems should not be flushed in the toilet.

Advise women to read the FDA-approved patient labeling (Patient Information and Instructions for Use)

Vaginal Bleeding

Inform postmenopausal women to report any vaginal bleeding to their healthcare providers as soon as possible [see Warnings and Precautions (5.2)].

Possible Serious Adverse Reactions with Estrogen-Alone Therapy

Inform postmenopausal women of possible serious adverse reactions of estrogen-alone therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia (for persons age 65 years and older) [see Warnings and Precautions (5.1, 5.2,8.5)].

Possible Common Adverse Reactions with Estrogen-Alone Therapy

Inform postmenopausal women of possible less serious but common adverse reactions of estrogen-alone therapy such as headache, breast pain and tenderness, nausea and vomiting.

INSTRUCTIONS FOR USE

VIVELLE-DOT^® (vī-VEL-dot)

(estradiol transdermal system)

Read this Instructions for Use before you start using VIVELLE-DOT and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment.

• 1.Determine Your Schedule for Your Twice-a-Week Application

Ifuimage1 (Vivelledot07)

Decide upon which 2 days you will change your patch. Your VIVELLE-DOT (estradiol transdermal system) individual carton contains a calendar card printed on its inner flap. Mark the 2-day schedule you plan to follow on your carton’s inner flap. Be consistent. If you forget to change your patch on the correct date, apply a new one as soon as you remember. No matter what day this happens, stick to the schedule you have marked on the inner flap of your carton (your calendar card).

• 2.Where to Apply VIVELLE-DOT

Ifuimage2 (Vivelledot08)

Apply patch to a dry area of the skin of the trunk of the body, including the lower abdomen, or buttocks. Avoid the waistline, since clothing may cause the patch to rub off. Do not apply patch to breasts. When changing your patch, based on your twice-a-week schedule, apply your new patch to a different site. Do not apply a new patch to that same area for at least 1 week.

• 3.Before You Apply VIVELLE-DOT

Ifuimage3 (Vivelledot09)

Make sure your skin is: Clean (freshly washed), dry and cool. Free of any powder, oil, moisturizer or lotion. Free of cuts or irritations (rashes or other skin problems).

• 4.How to Apply VIVELLE-DOT

Ifuimage4 (Vivelledot10)	Each patch is individually sealed in a protective pouch. Tear open the pouch at the tear notch (do not use scissors). Remove the patch.
Ifuimage5 (Vivelledot11)	Apply the patch immediately after removing from the pouch. Holding the patch with the rigid protective liner facing you, remove half of the liner, which covers the sticky surface of the patch.
Ifuimage6 (Vivelledot12)	Avoid touching the sticky side of the patch with your fingers. Using the other half of the rigid protective liner as a handle, apply the sticky side of the patch to the selected area of the abdomen or buttocks.
Ifuimage7 (Vivelledot13)	Press the sticky side of the patch firmly into place. Smooth it down. While still holding the sticky side down, fold back the other half of the patch.
Ifuimage8 (Vivelledot14)	Grasp an edge of the remaining protective liner and gently pull it off. Avoid touching the sticky side of the patch with your fingers.
Ifuimage9 (Vivelledot15)	Press the entire patch firmly into place with the palm of your hand. Continue to apply pressure, with the palm of your hand over the patch, for approximately 10 seconds.
Ifuimage10 (Vivelledot16)	Make sure that the patch is properly adhered to your skin. Go over the edges with your finger to ensure good contact around the patch.

Note:

• Showering will not cause your patch to fall off.
• If your patch falls off reapply it. If you cannot reapply the patch, apply a new patch to another area and continue to follow your original placement schedule.
• If you stop using your VIVELLE-DOT patch or forget to apply a new patch as scheduled, you may have spotting, or bleeding, and recurrence of symptoms.
• 5.Throwing Away Your Used Patch
• When it is time to change your patch, remove the old patch before you apply a new patch.
• To throw away the patch, fold the sticky side of the patch together, place it in a sturdy child-proof container, and place the container in the trash. Used patches should not be flushed in the toilet.

This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.

Mfd. by: Noven Pharmaceuticals, Inc.

Miami, FL 33186 for

Sandoz Inc., Princeton, NJ 08540

Revised: November 2023

100922-16-US

NDC 66758-145-83

0.025

VIVELLE dot^®

(estradiol transdermal system)

Delivers 0.025 mg/day

Rx only

Includes 8 Systems

Twice Weekly

Fb1 (Fb1)

NDC 66758-146-83

0.0375

VIVELLE dot^®

(estradiol transdermal system)

Delivers 0.0375 mg/day

Rx only

Includes 8 Systems

Twice Weekly

Fb2 (Fb2)

NDC 66758-147-83

0.05

VIVELLE dot^®

(estradiol transdermal system)

Delivers 0.05 mg/day

Rx only

Includes 8 Systems

Twice Weekly

Fb3 (Fb3)

NDC 66758-148-83

0.075

VIVELLE dot^®

(estradiol transdermal system)

Delivers 0.075 mg/day

Rx only

Includes 8 Systems

Twice Weekly

Fb4 (Fb)

NDC 66758-149-83

0.1

VIVELLE dot^®

(estradiol transdermal system)

Delivers 0.1 mg/day

Rx only

Includes 8 Systems

Twice Weekly

Fb5 (Fb5)