Vivelle-Dot

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.

In a multiple-dose study consisting of three 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/day and 0.1 mg/day were applied to abdominal application sites while the 0.1 mg/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 four different dosages.

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

The corresponding pharmacokinetic parameters are summarized in the table below.

Table 1: Steady-State Estradiol Pharmacokinetic Parameters for Systems Applied to the Abdomen (mean ±standard deviation) Nonbaseline-corrected data*

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.

No specific investigation of the tissue distribution of estradiol absorbed from Vivelle-Dot (estradiol transdermal system) in humans has been conducted. 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.

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. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the 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 gut 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.

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 (estradiol transdermal system) 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.

Special Populations

Vivelle-Dot (estradiol transdermal system) was only investigated in postmenopausal women.

Drug Interactions

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 preparations (Hypericum perforatum), 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 side effects.

Adhesion

Based on combined data from three short-term clinical trials consisting of 471 observations, 85% of Vivelle-Dot (estradiol transdermal system) adhered completely to the skin over the 3.5-day wear period. Three (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 (estradiol transdermal system) 0.05 mg/day.

Clinical Studies

In a pharmacokinetic study, Vivelle-Dot (estradiol transdermal system) was shown to be bioequivalent to Vivelle. In two controlled clinical trials with Vivelle, of 356 subjects, 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 patients 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 patients was 11.5. Results at Weeks 4, 8, and 12 of treatment are shown in the figure below. (See 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.

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., ≥0.827 g/cm²) were enrolled in this study; 194 patients were randomized to one of the four 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 52.0 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 subjects (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. Patients 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 three lower doses. There were no statistically significant differences in pairwise comparisons among the three 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

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 non-significant results were obtained for the lower dose groups at earlier time points. The highest Vivelle dose was superior to the three lower doses, and there were no significant differences among the three 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

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 Women's Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of the use of oral 0.625 mg conjugated estrogens (CE) per day alone or the use of oral 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (non-fatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.

The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index”. Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79, 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 2 below.

Table 2: Relative and Absolute Risk Seen in the CE/MPA Substudy of WHIa

For those outcomes included in the “global index”, absolute excess risks per 10,000 women-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)

The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and WARNINGS, Dementia.)

Vivelle-Dot®
(estradiol transdermal system)

Read this PATIENT INFORMATION before you start using Vivelle-Dot® (estradiol transdermal system) (estradiol transdermal system) and read all the information that you get each time you refill Vivelle-Dot (estradiol transdermal system) . 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 (estradiol transdermal system) . Vivelle-Dot (estradiol transdermal system) 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 (estradiol transdermal system) (AN ESTROGEN HORMONE)?

• Estrogens increase the chances of getting cancer of the uterus.
  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.
• Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or strokes.
  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 (estradiol transdermal system) .

What is Vivelle-Dot® (estradiol transdermal system) ?

Vivelle-Dot (estradiol transdermal system) is a patch that contains the estrogen hormone, estradiol. When applied to the skin as directed below, Vivelle-Dot (estradiol transdermal system) releases estrogen through the skin into the bloodstream.

What is Vivelle-Dot (estradiol transdermal system) used for?

Vivelle-Dot (estradiol transdermal system) 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 (estradiol transdermal system) .

• 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 (estradiol transdermal system) to control these problems. If you use Vivelle-Dot (estradiol transdermal system) 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 (estradiol transdermal system) 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 (estradiol transdermal system) .

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 (estradiol transdermal system) ?

Do not start taking Vivelle-Dot (estradiol transdermal system) 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 (estradiol transdermal system) .
• 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 (estradiol transdermal system) or any of its ingredients.
  See the end of this leaflet for a list of ingredients in Vivelle-Dot (estradiol transdermal system) .
• think you may be, or know that you are, pregnant.

Tell your healthcare provider:

if you are breast-feeding.The hormone in Vivelle-Dot (estradiol transdermal system) 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 (estradiol transdermal system) works. Vivelle-Dot (estradiol transdermal system) 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 (estradiol transdermal system) ?

1. Start at the lowest dose and talk to your healthcare provider about how well that dose is working for you.
2. Estrogens should be used at the lowest dose possible for your treatment, only as long as needed. The lowest effective dose of Vivelle-Dot (estradiol transdermal system) 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 (estradiol transdermal system) .

Application Instructions for Vivelle-Dot (estradiol transdermal system)

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

• Decide upon which two 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 two-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® (estradiol transdermal system)

• Apply patch to lower abdomen, below the waistline. 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 one week.

3. Before You Apply Vivelle-Dot® (estradiol transdermal system)

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

4. How to Apply Vivelle-Dot® (estradiol transdermal system)

• Each patch is individually sealed in a protective pouch.
• Tear open the pouch at the tear notch (do not use scissors).
• Remove the patch.

• Apply the patch immediately after removing from pouch.
• Holding the patch with the rigid protective liner facing you, remove half of the liner, which covers the sticky surface of the patch.

• 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.

• 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.

• Grasp an edge of the remaining protective liner and gently pull it off.
• AVOID TOUCHING THE STICKY SIDE OF THE PATCH WITH YOUR FINGERS.

• 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.

• 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.

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® (estradiol transdermal system)

• 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 (estradiol transdermal system) 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 (estradiol transdermal system) ?

• Talk with your healthcare provider regularly about whether you should continue taking Vivelle-Dot (estradiol transdermal system) .
• 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 (estradiol transdermal system) .
• 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 for getting heart disease. Ask your healthcare provider for ways to lower your chances for getting heart disease.

General information about safe and effective use of Vivelle-Dot (estradiol transdermal system)

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take Vivelle-Dot (estradiol transdermal system) for conditions for which it was not prescribed. Do not give Vivelle-Dot (estradiol transdermal system) to other people, even if they have the same symptoms you have. It may harm them.

Keep Vivelle-Dot (estradiol transdermal system) out of the reach of children.

This leaflet provides a summary of the most important information about Vivelle-Dot (estradiol transdermal system) . If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Vivelle-Dot (estradiol transdermal system) 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 (estradiol transdermal system) ?

Vivelle-Dot (estradiol transdermal system) 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 25°C (77°F). Do not store outside of their pouches. Apply immediately upon removal from the protective pouch.

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Vivelle-Dot® (estradiol transdermal system) (estradiol transdermal system) for conditions for which it was not prescribed.

Do not give Vivelle-Dot (estradiol transdermal system) to other people, even if they have the same symptoms you have. It may harm them.

Keep this and all drugs out of the reach of children. In case of overdose, remove the system and call your doctor, hospital, or poison control center immediately.

This leaflet summarizes the most important information about Vivelle-Dot (estradiol transdermal system) . If you would like more information, talk to your healthcare provider. You can ask for information about Vivelle-Dot (estradiol transdermal system) that is written for health professionals.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on the following:

• the condition being treated
• other medical conditions you have
• other medications you are taking
• how you respond to this medication

The recommended starting dose of Vivelle-Dot (estradiol) transdermal patches for the treatment of menopause symptoms is 0.0375 mg per day applied to the skin twice weekly. 

The recommended starting dose of Vivelle-Dot (estradiol) transdermal patches for the prevention of osetoprosis in women after menopause is 0.025 mg per day applied to the skin twice weekly.

You should not use this medicine if you are allergic to estradiol, if you are pregnant, or if you have:

• unusual vaginal bleeding that a doctor has not checked;

• liver disease;

• a bleeding or blood-clotting disorder;

• a recent history of heart attack or stroke;

• a history of hormone-dependent cancer (such as breast, uterine, ovarian, or thyroid cancer); or

• if you have ever had a blood clot (especially in your lung or your lower body).

Estradiol should not be used to prevent heart disease, stroke, or dementia, because this medicine may actually increase your risk of developing these conditions.

To make sure estradiol is safe for you, tell your doctor if you have:

• heart disease;

• risk factors for coronary artery disease (such as diabetes, lupus, smoking, being overweight, having high blood pressure or high cholesterol, having a family history of coronary artery disease, or if you have had a hysterectomy);

• a history of jaundice caused by pregnancy or birth control pills;

• hereditary angioedema (an immune system disorder);

• a thyroid disorder;

• kidney disease;

• asthma;

• epilepsy or other seizure disorder;

• migraines;

• lupus;

• porphyria (a genetic enzyme disorder that causes symptoms affecting the skin or nervous system);

• endometriosis or uterine fibroid tumors;

• gallbladder disease;

• high or low levels of calcium in your blood; or

• if you have had your uterus removed (hysterectomy).

Long-term use of estradiol may increase your risk of breast cancer, heart attack, stroke, or blood clot. Talk with your doctor about your individual risks before using estradiol transdermal long term.

FDA pregnancy category X. Do not use estradiol if you are pregnant. Tell your doctor right away if you become pregnant during treatment. Use effective birth control while you are using this medicine.

Estradiol can pass into breast milk. This medicine may slow breast milk production. Do not use if you are breast-feeding a baby.

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Estradiol may increase your risk of developing a condition that may lead to uterine cancer. Your doctor may prescribe a progestin to help lower this risk. Report any unusual vaginal bleeding right away.

This medication comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions.

Apply the skin patch to clean, dry skin on your stomach or buttocks. Choose a different spot within these skin areas each time you apply a new patch. Avoid skin that is oily, irritated, or damaged.

Do not apply a skin patch to your breasts. Do not apply a patch where it might be rubbed off by tight clothing, such as under an elastic waistband.

If a patch falls off, try sticking it back into place. If it does not stick well, put on a new patch on a different skin area and leave it on only for the rest of your wearing time. Do not change your patch removal schedule.

Some transdermal patches contain aluminum that may burn your skin if you wear the patch during an MRI (magnetic resonance imaging). Remove the patch before undergoing such a test.

If you need surgery or medical tests or if you will be on bed rest, you may need to stop using this medicine for a short time. Any doctor or surgeon who treats you should know that you are using estradiol.

Your doctor should check your progress on a regular basis (every 3 to 6 months) to determine whether you should continue this treatment. Self-examine your breasts for lumps on a monthly basis, and have regular mammograms while using estradiol transdermal.

Store at room temperature away from moisture and heat. Keep each patch in its pouch until you are ready to use it.

After removing a skin patch, fold it in half so it sticks together. Discard the folded patch in a place children and pets cannot get to.

Grapefruit and grapefruit juice may interact with estradiol and lead to unwanted side effects. Discuss the use of grapefruit products with your doctor.

Other drugs may interact with estradiol, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

No drug interaction studies have been conducted with Vivelle-Dot.

     Metabolic Interactions

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 side effects.

     Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

See FDA-approved patient labeling (Patient Information and Instructions for Use)

Advise patients to read the Patient Information and Instructions for Use. The complete text of the Patient Information and Instructions for Use is reprinted at the end of this document.

Vaginal Bleeding

Inform postmenopausal women of the importance of reporting unusual 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 [see Warnings and Precautions (5.1, 5.2, and 5.3)].

Possible Less Serious but 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.

T2017-86
August 2017

PATIENT INFORMATION

Vivelle-Dot® (vī-VEL-dot)

(estradiol transdermal system)

Read this Patient Information 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 medical condition or your treatment.

What is Vivelle-Dot?

Vivelle-Dot is a prescription medicine patch (Transdermal System) that contains estradiol (an estrogen hormone). 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.
• Treat moderate to severe menopausal changes in and 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 menopausal changes 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 women before menopause if their 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 treatment with Vivelle-Dot.

Who should not use Vivelle-Dot?

Do not start using Vivelle-Dot if you:

• have unusual vaginal bleeding
  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.
• 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 use Vivelle-Dot.
• had a stroke or heart attack
• currently have or have had blood clots
• currently have or have had liver problems
• have been diagnosed with a bleeding disorder
• are allergic to Vivelle-Dot or any of its ingredients
  See the list of ingredients in Vivelle-Dot at the end of this leaflet.
• think you may be pregnant
  Vivelle-Dot is not for pregnant women. If you think you may be pregnant, you should have a pregnancy test and know the results. Do not use Vivelle-Dot if the test is positive and talk to your healthcare provider.

What should I tell my healthcare provider before I use Vivelle-Dot?

Before you use Vivelle-Dot, tell your healthcare provider if you:

• have any unusual vaginal bleeding
  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.
• have any other medical conditions
  Your healthcare provider may need to check you more carefully if you have certain conditions such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, angioedema (swelling of face and tongue), or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.
• are going to have surgery or will be on bed rest
  Your healthcare provider will let you know if you need to stop using Vivelle-Dot.
• are breastfeeding
  The hormone in Vivelle-Dot can pass into your breast milk.

Tell your healthcare provider 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.

How should I use Vivelle-Dot?

For detailed instructions, see the step-by-step instructions for using Vivelle-Dot at the end of this Patient Information.

• Use Vivelle-Dot exactly as your healthcare provider tells you to use it.
• Vivelle-Dot is for skin use only.
• Change your Vivelle-Dot patch 2 times a week or every 3 to 4 days.
• Apply your Vivelle-Dot patch to a clean, dry area of your lower abdomen. This area must be clean, dry, and free of powder, oil or lotion for your patch to stick to your skin.
• Apply your Vivelle-Dot patch to a different area of your abdomen each time. Do not use the same application site 2 times in the same week.
• Do not apply Vivelle-Dot to your breasts.
• If you forget to apply a new Vivelle-Dot patch, you should apply a new patch as soon as possible.
• You and your healthcare provider should talk regularly (every 3 to 6 months) about your dose and whether you still need treatment with Vivelle-Dot.

How to Change Vivelle-Dot

• When changing the patch, peel off the used patch slowly from the skin.
• After removal of Vivelle-Dot, patients usually have either no adhesive residue or light adhesive residue. 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 lower abdomen. This area must be clean, dry, cool and free of powder, oil, or lotion.

What are the possible side effects of Vivelle-Dot?

Side effects are grouped by how serious they are and how often they happen when you are treated.

Serious, but less common side effects include:

• heart attack
• stroke
• blood clots
• dementia
• breast cancer
• cancer of the lining of the uterus (womb)
• cancer of the ovary
• high blood pressure
• high blood sugar
• gallbladder disease
• liver problems
• changes in your thyroid hormone levels
• enlargement of benign tumors (“fibroids”)

Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:

• new breast lumps
• nipple discharge
• unusual vaginal bleeding
• changes in vision or speech
• sudden new severe headaches
• severe pains in your chest or legs with or without shortness of breath, weakness and fatigue
• swelling
• rash

Less serious, but common side effects include:

• headache
• breast pain
• irregular vaginal bleeding or spotting
• painful periods
• stomach or abdominal cramps, bloating
• nausea and vomiting
• hair loss
• fluid retention
• vaginal yeast infection
• redness and/or irritation at patch placement site

These are not all the possible side effects of Vivelle-Dot. For more information, ask your healthcare provider or pharmacist for advice about side effects. Tell your healthcare provider if you have any side effect that bothers you or does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may report side effects to Novartis Pharmaceuticals Corporation (1-888-NOW-NOVA or 1-888-669-6682).

What can I do to lower my chances of getting a serious side effect with Vivelle-Dot?

• Talk with your healthcare provider regularly about whether you should continue using Vivelle-Dot.
• If you have a uterus, talk to your healthcare provider about whether the addition of a progestin is right for you.
  The addition of a progestin is generally recommended for a woman with a uterus to reduce the chance of getting cancer of the uterus (womb).
• See your healthcare provider right away if you get vaginal bleeding while using Vivelle-Dot.
• Have a pelvic exam, 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 for getting heart disease.
  Ask your healthcare provider for ways to lower your chances for getting heart disease.

How should I store and throw away used Vivelle-Dot patches?

• Store at room temperature 68°F to 77°F (20°C to 25°C)
• Do not store Vivelle-Dot patches outside of their pouches. Apply immediately upon removal from the protective pouch.
• Used patches still contain estrogen. To throw away the patch, fold the sticky side of the patch together, place it in a sturdy child-proof container, and place this container in the trash. Used patches should not be flushed in the toilet.

Keep Vivelle-Dot and all medicines out of the reach of children.

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 use 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.

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 your healthcare provider or pharmacist for information about Vivelle-Dot that is written for health professionals. For more information, call the toll-free number Novartis Pharmaceuticals Corporation (1-888-NOW-NOVA or 1-888-669-6682).

What are the ingredients in Vivelle-Dot?

Active ingredient: estradiol

Inactive ingredients: a translucent polyolefin film, acrylic and silicone adhesives, oleyl alcohol, NF, povidone, USP, dipropylene glycol and a polyester release liner.

T2017-36
March 2017

INSTRUCTIONS FOR USE

Vivelle-Dot® (vī-VEL-dot)

(estradiol transdermal system)

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

2.       Where to Apply Vivelle-Dot

3.       Before You Apply Vivelle-Dot

4.       How to Apply Vivelle-Dot

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.

Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, NJ 07936

© Novartis

T2014-78
July 2014

PRINCIPAL DISPLAY PANEL

Package Label – 0.025 mg

Rx Only             NDC 0078-0365-42

Vivelle-Dot® (estradiol transdermal system)

Delivers 0.025 mg/day

Includes 8 Systems

PRINCIPAL DISPLAY PANEL

Package Label – 0.0375 mg

Rx Only             NDC 0078-0343-42

Vivelle-Dot® (estradiol transdermal system)

Delivers 0.0375 mg/day

Includes 8 Systems

PRINCIPAL DISPLAY PANEL

Package Label – 0.05 mg

Rx Only             NDC 0078-0344-42

Vivelle-Dot® (estradiol transdermal system)

Delivers 0.05 mg/day

Includes 8 Systems

PRINCIPAL DISPLAY PANEL

Package Label – 0.075 mg

Rx Only             NDC 0078-0345-42

Vivelle-Dot® (estradiol transdermal system)

Delivers 0.075 mg/day

Includes 8 Systems

PRINCIPAL DISPLAY PANEL

Package Label – 0.1 mg

Rx Only             NDC 0078-0346-42

Vivelle-Dot® (estradiol transdermal system)

Delivers 0.1 mg/day

Includes 8 Systems