Estraderm

See BOXED WARNINGS.

The use of unopposed estrogens in women who have a uterus is associated with an increased risk of endometrial cancer.

Cardiovascular disorders

Estrogen and estrogen/progestin therapy have 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.

In the Women's Health Initiative study (WHI), an increase in the number of myocardial infarctions and strokes has been observed in women receiving CE compared to placebo.

In the CE/MPA substudy of WHI an increased risk of coronary heart disease (CHD) events (defined as non-fatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs 30 per 10,000 women years). The increase in risk was observed in year one and persisted.

In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 woman-years). The increase in risk was observed after the first year and persisted.

In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with CE/MPA-0.625 mg/ 2.5 mg per day demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and in the placebo group in HERS, HERS II, and overall.

Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.

In the Women's Health Initiative study (WHI), an increase in VTE has been observed in women receiving CE compared to placebo. In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 woman-years in the CE/MPA group compared to 16 per 10,000 woman-years in the placebo group. The increase in VTE risk was observed during the first year and persisted.

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

Malignant Neoplasms

The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold 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 associated with prolonged use with increased risks of 15- to 24-fold for five to ten years or more, and this risk has been shown to persist for at least 8 to15 years after estrogen therapy is discontinued.

Clinical surveillance of all women taking estrogen/progestin combinations 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 of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women's Health Initiative (WHI) substudy of CE/MPA (see CLINICAL PHARMACOLOGY, Clinical Studies). The results from observational studies are generally consistent with those of the WHI clinical trial and report no significant variation in the risk of breast cancer among different estrogens or progestins, doses, or routes of administration.

The CE/MPA substudy of WHI reported an increased risk of breast cancer in women who took CE/MPA for a mean follow-up of 5.6 years. Observational studies have also reported an increased risk for estrogen/progestin combination therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. In the WHI trial and from observational studies, the excess risk increased with duration of use. From observational studies, the risk appeared to return to baseline in about five years after stopping treatment. In addition, observational studies suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen/progestin combination therapy as compared to estrogen alone therapy.

In the CE/MPA substudy, 26% of the women reported prior use of estrogen alone and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01-1.54), and the overall absolute risk was 41 vs 33 cases per 10,000 woman-years, for CE/MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs 25 cases per 10,000 woman-years, for CE/MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs 36 cases per 10,000 woman-years for CE/MPA compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups.

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

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 versus 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 versus placebo was 45 versus 22 cases per 10,000 woman-years, and the absolute excess risk for CE/MPA was 23 cases per 10,000 woman-years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use.)

Gallbladder Disease

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

Hypercalcemia

Administration of estrogen may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If this occurs, the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

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.

• Novartis Pharmaceuticals Corporation

Serious side effects have been reported with Estraderm. See the “Estraderm Precautions” section.

Common side effects of Estraderm include the following:

• Redness and irritation at the application site
• Headache
• Breast Pain
• Irregular Vaginal Bleeding or Spotting
• Stomach/Abdominal Cramps, Bloating
• Nausea and Vomiting
• Hair Loss

This is not a complete list of Estraderm side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Tell your doctor if you are pregnant or plan to become pregnant.

Estraderm should not be used during pregnancy. There appears to be little or no increased risk of birth defects in children born to women who inadvertently used estrogens during early pregnancy. Talk to your doctor right away if you become pregnant while taking Estraderm.

Apply a skin patch as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra patches to make up the missed dose.

This section provides information on the proper use of a number of products that contain estrogen. It may not be specific to Estraderm. Please read with care.

Take this medicine only as directed by your doctor. Do not take more of it and do not take or use it for a longer time than your doctor ordered. For patients taking any of the estrogens by mouth, try to take the medicine at the same time each day to reduce the possibility of side effects and to allow it to work better.

This medicine usually comes with patient information or directions. Read and follow the instructions in the insert carefully. Ask your doctor if you have any questions.

For patients taking any of the estrogens by mouth or by injection:

• Nausea may occur during the first few weeks after you start taking estrogens. This effect usually disappears with continued use. If the nausea is bothersome, it can usually be prevented or reduced by taking each dose with food or immediately after food.

For patients using the transdermal (skin patch):

• Wash and dry your hands thoroughly before and after handling the patch.
• Apply the patch to a clean, dry, non-oily skin area of your lower abdomen, hips below the waist, or buttocks that has little or no hair and is free of cuts or irritation. The manufacturer of the 0.025-mg patch recommends that its patch be applied to the buttocks only. Furthermore, each new patch should be applied to a new site of application. For instance, if the old patch is taken off the left buttock, then apply the new patch to the right buttock.
• Do not apply to the breasts. Also, do not apply to the waistline or anywhere else where tight clothes may rub the patch loose.
• Press the patch firmly in place with the palm of your hand for about 10 seconds. Make sure there is good contact, especially around the edges.
• If a patch becomes loose or falls off, you may reapply it or discard it and apply a new patch.
• Each dose is best applied to a different area of skin on your lower abdomen, hips below the waist, or buttocks so that at least 1 week goes by before the same area is used again. This will help prevent skin irritation.

For patients using the topical emulsion (skin lotion):

• Washing and drying hands thoroughly before each application.
• Apply while you are sitting comfortably. Apply one pouch to each leg every morning.
• Apply the entire contents of one pouch to clean, dry skin on the left thigh. Rub the emulsion into the entire thigh and calf for 3 minutes until thoroughly absorbed.
• Apply entire contents of the second pouch to clean, dry skin on the right thigh. Rub the emulsion into the entire thigh and calf for 3 minutes until thoroughly absorbed.
• Rub any remaining emulsion on both hands on the buttocks.
• Washing and drying hands thoroughly after application.
• To avoid transfer to other individuals, allow the application areas to dry completely before covering with clothing.

If you are using the Evamist® transdermal spray:

• Spray the medicine on your skin on the inside of your forearm, between the elbow and the wrist.
• Do not allow your child to touch the area of the arm where the medicine was sprayed. If you cannot avoid to come nearer with your child, wear clothes with long sleeves to cover the application site.
• If your child comes in direct contact with the arm where the medicine was sprayed, wash your child's skin right away with soap and water.
• Do not allow your pets to lick or touch the arm where the medicine was sprayed.

Dosing

The dose medicines in this class will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of these medicines. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For conjugated estrogens
• For oral dosage form (tablets):
  • For treating breast cancer in women after menopause and in men:
    • Adults—10 milligrams (mg) three times a day for at least 3 months.
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), or symptoms of menopause:
    • Adults—0.3 milligram (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month. Your doctor may change the dose based on how your body responds to the medication.
  • To prevent loss of bone (osteoporosis):
    • Adults—0.3 milligram (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month. Your doctor may change the dose based on how your body responds to the medication.
  • For treating ovary problems (female hypogonadism or for starting puberty):
    • Adults and teenagers—0.3 to 0.625 milligram (mg) a day. Your doctor may want you to take the medicine only on certain days of the month.
  • For treating ovary problems (failure or removal of both ovaries):
    • Adults—1.25 milligram (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
  • For treating prostate cancer:
    • Adults—1.25 to 2.5 milligram (mg) three times a day.
• For injection dosage form:
  • For controlling abnormal bleeding of the uterus:
    • Adults—25 milligrams (mg) injected into a muscle or vein. This may be repeated in six to twelve hours if needed.

For esterified estrogens
• For oral dosage form (tablets):
  • For treating breast cancer in women after menopause and in men:
    • Adults—10 milligrams (mg) three times a day for at least three months.
  • For treating a genital skin condition (vulvar atrophy) or inflammation of the vagina (atrophic vaginitis), or to prevent loss of bone (osteoporosis):
    • Adults—0.3 to 1.25 mg a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
  • For treating ovary problems (failure or removal of both ovaries):
    • Adults—1.25 mg a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
  • For treating ovary problems (female hypogonadism):
    • Adults—2.5 to 7.5 mg a day. This dose may be divided up and taken in smaller doses. Your doctor may want you to take the medicine each day or only on certain days of the month.
  • For treating symptoms of menopause:
    • Adults—0.625 to 1.25 mg a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
  • For treating prostate cancer:
    • Adults—1.25 to 2.5 mg three times a day.

For estradiol
• For oral dosage form:
  • For treating breast cancer in women after menopause and in men:
    • Adults—10 milligrams (mg) three times a day for at least 3 months.
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), ovary problems (female hypogonadism or failure or removal of both ovaries), or symptoms of menopause:
    • Adults—At first, 1 to 2 milligrams (mg) one time per day for at least 3 months. Your doctor may want you to take the medicine each day or only on certain days of the month. Your doctor may also need to change the dose based on how your body responds to the medication.
  • For treating prostate cancer:
    • Adults—1 to 2 milligrams (mg) three times a day.
  • To prevent loss of bone (osteoporosis):
    • Adults—0.5 milligram (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
• For topical emulsion dosage form (skin lotion):
  • For treating symptoms of menopause:
    • Adults—1.74 grams (one pouch) applied to the skin of each leg (thigh and calf) once a day in the morning.
• For transdermal dosage form (skin patches):
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), symptoms of menopause, ovary problems (female hypogonadism or failure or removal of both ovaries), or to prevent loss of bone (osteoporosis):
    For the Climara patches
    • Adults—0.025 to 0.1 milligram (mg) (one patch) applied to the skin and worn for one week. Then, remove that patch and apply a new one. A new patch should be applied once a week for three weeks. During the fourth week, you may or may not wear a patch. Your health care professional will tell you what you should do for this fourth week. After the fourth week, you will repeat the cycle.
    For the Alora, Estraderm, Estradot, Vivelle, or Vivelle-Dot patches
    • Adults—0.025 to 0.1 mg (one patch) applied to the skin and worn for one half of a week. Then, remove that patch and apply and wear a new patch for the rest of the week. A new patch should be applied two times a week for three weeks. During the fourth week, you may or may not apply new patches. Your health care professional will tell you what you should do for this fourth week. After the fourth week, you will repeat the cycle.

For estradiol cypionate
• For injection dosage form:
  • For treating ovary problems (female hypogonadism):
    • Adults—1.5 to 2 milligrams (mg) injected into a muscle once a month.
  • For treating symptoms of menopause:
    • Adults—1 to 5 milligrams (mg) injected into a muscle every 3 to 4 weeks.

For estradiol valerate
• For injection dosage form:
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), symptoms of menopause, or ovary problems (female hypogonadism or failure or removal of both ovaries):
    • Adults—10 to 20 milligrams (mg) injected into a muscle every 4 weeks as needed.
  • For treating prostate cancer:
    • Adults—30 milligrams (mg) injected into a muscle every 1 or 2 weeks.

For estrone
• For injection dosage form:
  • For controlling abnormal bleeding of the uterus:
    • Adults—2 to 5 milligrams (mg) a day, injected into a muscle for several days.
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), or symptoms of menopause:
    • Adults—0.1 to 0.5 milligram (mg) injected into a muscle 2 or 3 times a week. Your doctor may want you to receive the medicine each week or only during certain weeks of the month.
  • For treating ovary problems (female hypogonadism or failure or removal of both ovaries):
    • Adults—0.1 to 1 milligram (mg) a week. This is injected into a muscle as a single dose or divided into more than one dose. Your doctor may want you to receive the medicine each week or only during certain weeks of the month.
  • For treating prostate cancer:
    • Adults—2 to 4 milligrams (mg) injected into a muscle 2 or 3 times a week.

For estropipate
• For oral dosage form (tablets):
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), or symptoms of menopause:
    • Adults—0.75 to 6 milligrams (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
  • For treating ovary problems (female hypogonadism or failure or removal of both ovaries):
    • Adults—1.5 to 9 milligrams (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
  • To prevent loss of bone (osteoporosis):
    • Adults—0.75 milligram (mg) a day. Your doctor may want you to take the medicine each day for twenty-five days of a thirty-one–day cycle.

For ethinyl estradiol
• For oral dosage form (tablets):
  • For treating breast cancer in women after menopause and in men:
    • Adults—1 milligram (mg) three times a day.
  • For treating ovary problems (female hypogonadism or failure or removal of both ovaries):
    • Adults—0.05 milligram (mg) one to three times a day for 3 to 6 months. Your doctor may want you to take the medicine each day or only on certain days of the month.
  • For treating prostate cancer:
    • Adults—0.15 to 3 milligrams (mg) a day.
  • For treating symptoms of menopause:
    • Adults—0.02 to 0.05 milligram (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month.

For ethinyl estradiol and norethindrone
• For oral dosage form (tablets):
  • For treating symptoms of menopause:
    • Adults—1 tablet (5 mcg ethinyl estradiol and 1 mg of norethindrone) each day.
  • To prevent loss of bone (osteoporosis):
    • Adults—1 tablet (5 mcg ethinyl estradiol and 1 mg of norethindrone) each day.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

If you miss a dose of this medicine, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

If you forget to wear or change a patch, put one on as soon as you can. If it is almost time to put on your next patch, wait until then to apply a new patch and skip the one you missed. Do not apply extra patches to make up for a missed dose.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

A.       General

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.

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.

In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.

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.

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.

Because estrogens may cause some degree of fluid retention, conditions which might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.

Estrogens should be used with caution in individuals with severe hypocalcemia.

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 woman-years. In some epidemiologic studies, the use of estrogen-alone, in particular for 10 or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations.

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.

Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine 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 Estraderm® (estradiol transdermal system).

C.       Laboratory Tests

Estrogen administration should be initiated at the lowest dose for the approved indication and then guided by clinical response, rather than by serum hormone levels (e.g., estradiol, FSH).

D.       Drug/Laboratory Test Interactions

1. 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.
   
2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, 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.
   
3. Other binding proteins may be elevated in serum (i.e., corticosteroid-binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased 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).
   
4. Increased plasma HDL and HDL-2 cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.
   
5. Impaired glucose tolerance.
   
6. 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 WARNING, 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

Estrogens 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 Estraderm 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

Clinical studies of Estraderm did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

      In the Women’s Health Initiative Memory Study (WHIMS), 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 2-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.)

The adhesive side of the Estraderm® (estradiol transdermal system) system should be placed on a clean, dry area of the skin on the trunk of the body (including the buttocks and abdomen). The site selected should be one that is not exposed to sunlight. Estraderm should not be applied to the breasts. The Estraderm system 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 unlikely event that a system should fall off, the same system may be reapplied. If necessary, a new system may be applied. In either case, the original treatment schedule should be continued.

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 WARNING 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.

      Estraderm is currently available in two dosage forms – 0.05 mg and 0.1 mg. Patients should be started at the lowest dose. The lowest effective dose of Estraderm has not been determined. 

      For treatment of moderate to severe vasomotor symptoms or moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause, initiate therapy with Estraderm 0.05 applied to the skin twice weekly.

      Prophylactic therapy with Estraderm to prevent postmenopausal bone loss should be initiated with the 0.05 mg/day dosage as soon as possible after menopause. The dosage may be adjusted if necessary. Discontinuation of estrogen therapy may reestablish bone loss at a rate comparable to the immediate postmenopausal period.

      In women not currently taking oral estrogens, treatment with Estraderm may be initiated at once. In women who are currently taking oral estrogen, treatment with Estraderm should be initiated 1 week after withdrawal of oral hormone therapy, or sooner if menopausal symptoms reappear in less than 1 week.

Therapeutic Regimen

Estraderm therapy may be given continuously in patients who do not have an intact uterus. In those patients with an intact uterus, Estraderm may be given on a cyclic schedule (e.g., 3 weeks on drug followed by 1 week off drug).

Package Label – 0.05 mg/day

Rx Only             NDC 0078-0480-42

Estraderm®

estradol transdermal system

Delivers 0.05 mg/day

Package Label – 0.1 mg/day

Rx Only             NDC 0078-0481-42

Estraderm®

estradol transdermal system

Delivers 0.1 mg/day