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Vivelle-Dot
T2004-65/T2004-66
100922-6
Vivelle-Dot®
(estradiol transdermal system)
Continuous delivery for twice-weekly application
Rx only
Prescribing Information
ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER
Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of “natural” estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses. (See WARNINGS, Malignant Neoplasms, Endometrial Cancer.)
CARDIOVASCULAR AND OTHER RISKS
Estrogens with or without progestins should not be used for the prevention of cardiovascular disease. (See WARNINGS, Cardiovascular Disorders.)
The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age), during 5 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo (see CLINICAL PHARMACOLOGY, Clinical Studies).
The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative to placebo. It is unknown whether this finding applies to younger postmenopausal women or to women taking estrogen alone therapy. (See CLINICAL PHARMACOLOGY, Clinical Studies.)
Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
DESCRIPTION
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
The molecular formula of estradiol is C18H2402. The molecular weight is 272.39.
Vivelle-Dot is comprised of three 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.
| ----- (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.
CLINICAL PHARMACOLOGY
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 by 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, two 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.
Pharmacokinetics
The skin metabolizes estradiol only to a small extent. In contrast, orally administered estradiol is rapidly metabolized by the liver to estrone and its conjugates, giving rise to higher circulating levels of estrone than estradiol. Therefore, transdermal administration produces therapeutic plasma levels of estradiol with lower circulating levels of estrone and estrone conjugates and requires smaller total doses than does oral therapy.
Clinical Studies
INDICATIONS AND USAGE
Vivelle-Dot® (estradiol transdermal system) is indicated in:
- Treatment of moderate to severe vasomotor symptoms associated with the menopause.
- Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.
- Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.
- Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered.
The mainstays for decreasing the risk of postmenopausal osteoporosis are weight-bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400-800 IU/day may also be required to ensure adequate daily intake in postmenopausal women.
CONTRAINDICATIONS
Vivelle-Dot® (estradiol transdermal system) should not be used in women with any of the following conditions:
- Undiagnosed abnormal genital bleeding.
- Known, suspected or history of cancer of the breast.
- Known or suspected estrogen-dependent neoplasia.
- Active deep vein thrombosis, pulmonary embolism or a history of these conditions.
- Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction).
- Liver dysfunction or disease.
- Vivelle-Dotshould not be used in patients with known hypersensitivity to its ingredients.
- Known or suspected pregnancy. There is no indication for Vivelle-Dot in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy (see PRECAUTIONS).
WARNINGS
See BOXED WARNINGS.
The use of unopposed estrogens in women who have a uterus is associated with an increased risk of endometrial cancer.
1. Cardiovascular Disorders
Estrogen and estrogen/progestin therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogens should be discontinued immediately.
Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.
2. Malignant Neoplasms
3. Dementia
In the Women’s Health Initiative Memory Study (WHIMS), 4,532 generally healthy postmenopausal women 65 years of age and older were studied, of whom 35% were 70 to 74 years of age and 18% were 75 or older. After an average follow-up of 4 years, 40 women being treated with CE/MPA (1.8%, n = 2,229) and 21 women in the placebo group (0.9%, n = 2,303) received diagnoses of probable dementia. The relative risk for CE/MPA vs placebo was 2.05 (95% confidence interval 1.21 – 3.48), and was similar for women with and without histories of menopausal hormone use before WHIMS. The absolute risk of probable dementia for CE/MPA vs placebo was 45 vs 22 cases per 10,000 women-years, and the absolute excess risk for CE/MPA was 23 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use.) It is unknown whether these findings apply to estrogen alone therapy.
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. Hypercalcemia
Administration of estrogen may lead to severe hypercalcemia in patients 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.
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.
PRECAUTIONS
A. General
1. Addition of a progestinwhen 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 a possible increased risk of breast cancer.
2. 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. Blood pressure should be monitored at regular intervals with estrogen use.
3. Hypertriglyceridemia. In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.
4. Impaired Liver Function and past history of cholestatic jaundice. Although transdermally administered estrogen therapy avoids first-pass hepatic metabolism, estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued.
5. Hypothyroidism. Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients 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. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.
6. Fluid Retention. Because estrogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.
7. Hypocalcemia. Estrogens should be used with caution in individuals with severe hypocalcemia.
8. Ovarian Cancer. The CE/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 ovarian cancer for CE/MPA vs placebo was 1.58 (95% confidence interval 0.77 – 3.24) but was not statistically significant. The absolute risk for CE/MPA vs placebo was 4.2 vs 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen alone, in particular for ten or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations.
9. Exacerbation of Endometriosis. Endometriosis may be exacerbated with administration of estrogens. A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.
10. Exacerbation of Other Conditions. Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraines or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.
B. Patient Information.
Physicians are advised to discuss the Patient Information leaflet with patients for whom they prescribe Vivelle-Dot® (estradiol transdermal system).
C. Laboratory Tests.
Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response, rather than by serum hormone levels (e.g., estradiol, FSH).
D. Drug/Laboratory Test Interactions.
- 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. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.
- Other binding proteins may be elevated in serum (i.e., corticosteroid-binding globulin [CBG], sex hormone-binding globulin [SHBG]), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
- Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.
- Impaired glucose tolerance.
- Reduced response to metyrapone test.
E. Carcinogenesis, Mutagenesis, Impairment of Fertility.
Long-term, continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
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.
F. Pregnancy.
Vivelle-Dot should not be used during pregnancy. (See CONTRAINDICATIONS.)
G. Nursing Mothers.
Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when Vivelle-Dot is administered to a nursing woman.
H. Pediatric Use.
Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay. Safety and effectiveness in pediatric patients have not otherwise been established.
Large and repeated doses of estrogen over an extended time period have been shown to accelerate epiphyseal closure, which could result in short adult stature if treatment is initiated before the completion of physiologic puberty in normally developing children. 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.
Estrogen treatment of prepubertal girls also induces premature breast development and vaginal cornification, and may induce vaginal bleeding. (See INDICATIONS and DOSAGE AND ADMINISTRATION.)
I. Geriatric Use.
The safety and effectiveness in geriatric patients have not been established.
In the Women’s Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n = 3,729) were 65 to 74 while 18% (n = 803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Alzheimer’s disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of women that were older than 70. (See WARNINGS, Dementia.) It is unknown whether these findings apply to estrogen alone therapy.
ADVERSE REACTIONS
See BOXED WARNINGS, WARNINGS and PRECAUTIONS.
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. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
The following adverse events have been reported with Vivelle-Dot® (estradiol transdermal system) therapy:
| Vivelle 0.025 mg/day† (N=47) N (%) | Vivelle 0.0375 mg/day† (N=130) N (%) | Vivelle 0.05 mg/day† (N=103) N (%) | Vivelle 0.075 mg/day† (N=46) N (%) | Vivelle 0.1 mg/day† (N=132) N (%) | Placebo (N=157) N (%) | |
| Gastrointestinal disorders | ||||||
| Constipation | 2 (4.3) | 5 (3.8) | 4 (3.9) | 3 (6.5) | 2 (1.5) | 4 (2.5) |
| Dyspepsia | 4 (8.5) | 12 (9.2) | 3 (2.9) | 2 (4.3) | 0 | 10 (6.4) |
| Nausea | 2 (4.3) | 8 (6.2) | 4 (3.9) | 0 | 7 (5.3) | 5 (3.2) |
| General disorders and administration site conditions*** | ||||||
| Influenza-like illness | 3 (6.4) | 6 (4.6) | 8 (7.8) | 0 | 3 (2.3) | 10 (6.4) |
| Pain NOS* | 0 | 8 (6.2) | 0 | 2 (4.3) | 7 (5.3) | 7 (4.5) |
| Infections and infestations | ||||||
| Influenza | 4 (8.5) | 4 (3.1) | 6 (5.8) | 0 | 10 (7.6) | 14 (8.9) |
| Nasopharyngitis | 3 (6.4) | 16 (12.3) | 10 (9.7) | 9 (19.6) | 11 (8.3) | 24 (15.3) |
| Sinusitis NOS* | 4 (8.5) | 17 (13.1) | 13 (12.6) | 3 (6.5) | 7 (5.3) | 16 (10.2) |
| Upper respiratory tract infection NOS* | 3 (6.4) | 8 (6.2) | 11 (10.7) | 4 (8.7) | 6 (4.5) | 9 (5.7) |
| Investigations | ||||||
| Weight increased | 4 (8.5) | 5 (3.8) | 2 (1.9) | 2 (4.3) | 0 | 3 (1.9) |
| Musculoskeletal and connective tissue disorders | ||||||
| Arthralgia | 0 | 11 (8.5) | 4 (3.9) | 2 (4.3) | 5 (3.8) | 9 (5.7) |
| Back pain | 4 (8.5) | 10 (7.7) | 9 (8.7) | 4 (8.7) | 14 (10.6) | 10 (6.4) |
| Neck pain | 3 (6.4) | 4 (3.1) | 4 (3.9) | 0 | 6 (4.5) | 2 (1.3) |
| Pain in limb | 0 | 10 (7.7) | 7 (6.8) | 2 (4.3) | 6 (4.5) | 9 (5.7) |
| Nervous system disorders | ||||||
| Headache NOS* | 7 (14.9) | 35 (26.9) | 32 (31.1) | 23 (50.0) | 34 (25.8) | 37 (23.6) |
| Sinus headache | 0 | 12 (9.2) | 5 (4.9) | 5 (10.9) | 2 (1.5) | 8 (5.1) |
| Psychiatric disorders | ||||||
| Anxiety NEC** | 3 (6.4) | 5 (3.8) | 0 | 0 | 2 (1.5) | 4 (2.5) |
| Depression | 5 (10.6) | 4 (3.1) | 7 (6.8) | 0 | 4 (3.0) | 6 (3.8) |
| Insomnia | 3 (6.4) | 6 (4.6) | 4 (3.9) | 2 (4.3) | 2 (1.5) | 9 (5.7) |
| Reproductive system and breast disorders | ||||||
| Breast tenderness | 8 (17.0) | 10 (7.7) | 8 (7.8) | 3 (6.5) | 17 (12.9) | 0 |
| Dysmenorrhea | 0 | 0 | 0 | 3 (6.5) | 0 | 0 |
| Intermenstrual bleeding | 3 (6.4) | 9 (6.9) | 6 (5.8) | 0 | 14 (10.6) | 7 (4.5) |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Sinus congestion | 0 | 4 (3.1) | 3 (2.9) | 3 (6.5) | 6 (4.5) | 7 (4.5) |
| Vascular disorders | ||||||
| Hot flushes NOS* | 3 (6.4) | 0 | 3 (2.9) | 0 | 0 | 6 (3.8) |
| Hypertension NOS* | 2 (4.3) | 0 | 3 (2.9) | 0 | 0 | 2 (1.3) |
† Represents milligrams of estradiol delivered daily by each system
* NOS represents not otherwise specified
** NEC represents not elsewhere classified
*** Application site erythema and application site irritation were observed in a small number of patients (3.2% or less of patients across treatment groups.)
The following additional adverse reactions have been reported with estrogen and/or progestin therapy:
1. Genitourinary system. Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; dysmenorrhea, increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer.
2. Breasts. Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer.
3. Cardiovascular. Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure.
4. Gastrointestinal. Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis, enlargement of hepatic hemangiomas.
5. Skin. Chloasma or melasma, which may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash.
6. Eyes. Retinal vascular thrombosis; intolerance to contact lenses.
7. Central nervous system. Headache; migraine; dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia.
8. Miscellaneous. Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthralgias; leg cramps; changes in libido; anaphylactoid/anaphylactic reactions including urticaria and angioedema; hypocalcemia; exacerbation of asthma; increased triglycerides.
OVERDOSAGE
Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing drug products by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females.
DOSAGE AND ADMINISTRATION
The adhesive side of Vivelle-Dot® (estradiol transdermal system) should be placed on a clean, dry area of the abdomen. Vivelle-Dot should not be applied to the breasts. Vivelle-Dot should be replaced twice weekly. 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, 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. In either case, the original treatment schedule should be continued. If a woman has forgotten to apply a patch, she should apply a new patch as soon as possible. The new patch should be applied 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.
Initiation of Therapy
When estrogen is prescribed for a postmenopausal woman with a uterus, progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen alone or in combination with a progestin, should be with the lowest effective dose and the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be reevaluated periodically as clinically appropriate (e.g., 3-month to 6-month intervals) to determine whether treatment is still necessary (see BOXED WARNINGS and WARNINGS). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
Patients should be started at the lowest dose. The lowest effective dose of Vivelle-Dot has not been determined for any indication. For treatment of moderate to severe vasomotor symptoms and vulvar and vaginal atrophy associated with the menopause, start therapy with Vivelle-Dot 0.0375 mg/day applied to the skin twice weekly. For the prevention of postmenopausal osteoporosis, start therapy with Vivelle-Dot 0.025 mg/day applied to the skin twice weekly. The dosage may be adjusted as necessary. Reproductive system-associated adverse events were encountered more frequently in the highest dose group (0.1 mg/day) than in other active treatment groups or in placebo-treated patients.
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, treatment with Vivelle-Dot should be initiated 1 week after withdrawal of oral hormone therapy, or sooner if menopausal symptoms reappear in less than 1 week.
Therapeutic Regimen
Vivelle-Dot may be given continuously in patients who do not have an intact uterus. In those patients with an intact uterus, Vivelle-Dot may be given on a cyclic schedule (e.g., three weeks on drug followed by one week off drug).
HOW SUPPLIED
Vivelle-Dot® (estradiol transdermal system), 0.025 mg/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 0078-0365-42
Carton of 3 Patient Calendar Packs of 8 Systems…………………………NDC 0078-0365-45
Vivelle-Dot® (estradiol transdermal system), 0.0375 mg/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 0078-0343-42
Carton of 3 Patient Calendar Packs of 8 Systems…………………………NDC 0078-0343-45
Vivelle-Dot® (estradiol transdermal system), 0.05 mg/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 0078-0344-42
Carton of 3 Patient Calendar Packs of 8 Systems…………………………NDC 0078-0344-45
Vivelle-Dot® (estradiol transdermal system), 0.075 mg/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 0078-0345-42
Carton of 3 Patient Calendar Packs of 8 Systems…………………………NDC 0078-0345-45
Vivelle-Dot® (estradiol transdermal system), 0.1 mg/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 0078-0346-42
Carton of 3 Patient Calendar Packs of 8 Systems…………………………NDC 0078-0346-45
________________________________________
*See DESCRIPTION.
Store at controlled room temperature at 25ºC (77°F).
Do not store unpouched. Apply immediately upon removal from the protective pouch.
REV: AUGUST 2004 T2004-65
PATIENT INFORMATION
Vivelle-Dot®
(estradiol transdermal system)
Read this PATIENT INFORMATION before you start using Vivelle-Dot® (estradiol transdermal system) and read all the information that you get each time you refill Vivelle-Dot. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
The Vivelle-Dot® (estradiol transdermal system) patch that your healthcare provider has prescribed for you releases small amounts of an estrogen hormone through the skin.
This leaflet describes the risks and benefits of treatment with Vivelle-Dot. Vivelle-Dot is not for everyone. Talk to your healthcare provider if you have any questions or concerns about this medication.
| WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT VIVELLE-DOT (AN ESTROGEN HORMONE)? |
|
| Report any unusual vaginal bleeding right away while you are taking estrogens. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. |
|
| Using estrogens with or without progestins may increase your chances of getting heart attacks, strokes, breast cancer, and blood clots. Using estrogens may increase your risk of dementia. You and your healthcare provider should talk regularly about whether you still need treatment with Vivelle-Dot. |
What is Vivelle-Dot®?
Vivelle-Dot is a patch that contains the estrogen hormone, estradiol. When applied to the skin as directed below, Vivelle-Dot releases estrogen through the skin into the bloodstream.
What is Vivelle-Dot used for?
Vivelle-Dot is used after menopause to:
| ● | reduce moderate to severe hot flashes. |
Estrogens are hormones made by a woman’s ovaries. The ovaries normally stop making estrogens when a woman is between 45 and 55 years old. This drop in body estrogen levels causes the “change of life” or menopause (the end of monthly menstrual periods). Sometimes, both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes “surgical menopause.”
When the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest or sudden strong feelings of heat and sweating (“hot flashes” or “hot flushes”). In some women, the symptoms are mild and they will not need estrogens. In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether you still need treatment with Vivelle-Dot.
| ● | treat moderate to severe dryness, itching and burning in or around the vagina. |
You and your healthcare provider should talk regularly about whether you still need treatment with Vivelle-Dot to control these problems. If you use Vivelle-Dot only to treat your dryness, itching, and burning in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you.
| ● | treat certain conditions in which a young woman’s ovaries do not produce enough estrogens naturally. |
| ● | help reduce your chances of getting osteoporosis (thin weak bones). |
Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break. If you use Vivelle-Dot only to prevent osteoporosis from menopause, talk with your healthcare provider about whether a different treatment or medicine without estrogens might be better for you. You and your healthcare provider should talk regularly about whether you should continue with Vivelle-Dot.
Weight-bearing exercise, like walking or running, and taking calcium and vitamin D supplements may also lower your chances of getting postmenopausal osteoporosis. It is important to talk about exercise and supplements with your healthcare provider before starting them.
Who should not take Vivelle-Dot?
Do not start taking Vivelle-Dot if you:
| ● | have unusual vaginal bleeding. |
| ● | currently have or have had certain cancers. |
| Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should take Vivelle-Dot. | |
| ● | had a stroke or heart attack in the recent past (for example in the past year). |
| ● | currently have or have had blood clots. |
| ● | currently have or have had liver problems. |
| ● | are allergic to Vivelle-Dot or any of its ingredients. |
| See the end of this leaflet for a ul of ingredients in Vivelle-Dot. | |
| ● | think you may be, or know that you are, pregnant. |
Tell your healthcare provider:
| ● | if you are breast-feeding. The hormone in Vivelle-Dot can pass into your milk. |
| ● | about all of your medical problems. Your healthcare provider may need to check you more carefully if you have certain conditions such as asthma (wheezing), epilepsy (seizures), migraine, endometriosis, lupus, or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. |
| ● | about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how Vivelle-Dot works. Vivelle-Dot may also affect how other medicines work. |
| ● | if you are going to have surgery or will be on bed rest. You may need to stop taking estrogens. |
How should I take Vivelle-Dot?
- Start at the lowest dose and talk to your healthcare provider about how well that dose is working for you.
- Estrogens should be used at the lowest dose possible for your treatment, only as long as needed. The lowest effective dose of Vivelle-Dot has not been determined for any indication. You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about the dose you are taking and whether you still need treatment with Vivelle-Dot.
Application Instructions for Vivelle-Dot (estradiol transdermal system)
1. Determine Your Schedule for Your Twice-a-Week Application
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2. Where to Apply Vivelle-Dot®
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3. Before You Apply Vivelle-Dot®
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4. How to Apply Vivelle-Dot®
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PLEASE NOTE:
| ● | Contact with water while bathing, swimming or showering will not affect the patch. |
| ● | In the event that a patch should fall off, AVOID TOUCHING THE STICKY SIDE WITH YOUR FINGERS. Put the same patch back on a different site, making sure to press the patch firmly into place for at least 10 seconds. |
| ● | Continue to follow your original twice-a-week schedule you have marked on the inner flap of your individual carton (your calendar card). |
| ● | If necessary, if the same patch cannot be reapplied, apply a new patch at another location but continue to follow your original schedule. |
5. How to Change and Discard Vivelle-Dot®
| ● | When changing the patch, peel off the used patch slowly. |
| ● | Fold the used patch in half (sticky sides together) and discard appropriately, in the trash. |
| ● | PLEASE KEEP OUT OF THE REACH OF CHILDREN. |
| ● | If any adhesive residue remains on your skin after removing the patch, allow the area to dry for 15 minutes. Then, gently rub the area with oil or lotion to remove the adhesive from your skin. |
| ● | Keep in mind, the new patch must be applied to a different area of your abdomen. This area must be clean, dry, cool and free of powder, oil or lotion. |
What are the possible side effects of estrogens?
Less common but serious side effects include:
| —— | Breast cancer |
| —— | Cancer of the uterus |
| —— | Stroke |
| —— | Heart attack |
| —— | Blood clots |
| —— | Dementia |
| —— | Gallbladder disease |
| —— | Ovarian cancer |
These are some of the warning signs of serious side effects:
| —— | Breast lumps |
| —— | Unusual vaginal bleeding |
| —— | Dizziness and faintness |
| —— | Changes in speech |
| —— | Severe headaches |
| —— | Chest pain |
| —— | Shortness of breath |
| —— | Pains in your legs |
| —— | Changes in vision |
| —— | Vomiting |
Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptom that concerns you.
Common side effects include:
| —— | Headache |
| —— | Breast pain |
| —— | Irregular vaginal bleeding or spotting |
| —— | Stomach/abdominal cramps, bloating |
| —— | Nausea and vomiting |
| —— | Hair loss |
Other side effects include:
| —— | High blood pressure |
| —— | Liver problems |
| —— | High blood sugar |
| —— | Fluid retention |
| —— | Enlargement of benign tumors of the uterus (“fibroids”) |
| —— | Vaginal yeast infection |
Other side effects of Vivelle-Dot may be possible. If you have questions, talk to your healthcare provider or pharmacist.
What can I do to lower my chances of a serious side effect with Vivelle-Dot?
| ● | Talk with your healthcare provider regularly about whether you should continue taking Vivelle-Dot. |
| ● | If you have a uterus, talk to your healthcare provider about whether the addition of a progestin is right for you. |
| ● | See your healthcare provider right away if you get vaginal bleeding while taking Vivelle-Dot. |
| ● | Have a breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often. |
| ● | If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances of getting heart disease. Ask your healthcare provider for ways to lower your chances of getting heart disease. |
General information about safe and effective use of Vivelle-Dot
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take Vivelle-Dot for conditions for which it was not prescribed. Do not give Vivelle-Dot to other people, even if they have the same symptoms you have. It may harm them. Keep Vivelle-Dot out of the reach of children.
This leaflet provides a summary of the most important information about Vivelle-Dot. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Vivelle-Dot that is written for health professionals. You can get more information by calling the toll-free number [(888-NOW-NOVA) (888-669-6682)].
What are the ingredients in Vivelle-Dot?
Vivelle-Dot is comprised of three 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.
The active component of the system is estradiol. The remaining components of the system are pharmacologically inactive.
Other Information
Do not store above 25ºC (77ºF). Do not store outside of their pouches. Apply immediately upon removal from the protective pouch.
T2004-66
REV: AUGUST 2004 T2004-65/T2004-66
100922-6
Manufactured by:
Noven Pharmaceuticals Inc.
Miami, FL 33186
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, NJ 07936
© Novartis