Alora

Alora information, interactions and side effects, Alora (estradiol transdermal system) is designed to deliver estradiol continuously and consistently over a 3 or 4-day interval upon application to intact skin. Four strengths of Alora (estradiol transdermal system) are available, having nominal in vivo delivery rates of 0.025, 0.05, 0.075, and 0.1 mg estradiol per day through skin of average permeability (inter-individual variation in skin permeability is approximately 20%). Alora (estradiol transdermal system) has contact surface areas of 9, 18, 27, and 36 cm2 and contains 0.77, 1.5, 2.3, and 3.1 mg of estradiol, USP, respectively. The composition of the estradiol transdermal systems per unit area is identical. Estradiol, USP is a white, crystalline powder that is chemically described as estra-1,3,5(10)-triene-3, 17β-diol, has an empirical formula of C18H24O2 and has molecular weight of 272.39. The structural formula is:

alora

Alora (estradiol transdermal system) consists of three layers. Proceeding from the polyethylene backing film as shown in the cross-sectional view below, the adhesive matrix drug reservoir that is in contact with the skin consists of estradiol, USP and sorbitan monooleate dissolved in an acrylic adhesive matrix. The polyester overlapped release liner protects the adhesive matrix during storage and is removed prior to application of the system to the skin.

alora2

INDICATIONS

Alora (estradiol transdermal system) is indicated in:

  1. Treatment of moderate to severe vasomotor symptoms associated with the menopause.
  2. 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.
  3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
  4. 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 to remain in neutral calcium balance. 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.

DOSAGE AND ADMINISTRATION

Alora (estradiol transdermal system) should be administered twice weekly, as instructed. The adhesive side of the Alora (estradiol transdermal system) system should be placed on a clean, dry area of skin. The recommended application site is the lower abdomen. In addition, the upper quadrant of the buttocks or outer aspect of the hip may be used. Alora (estradiol transdermal system) should not be applied to the breasts. The sites of application should 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 rotective 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 necessary, a new system may be applied to another site. The original treatment schedule should be maintained.

Initiation of Therapy

For treatment of moderate-to-severe vasomotor symptoms, vulvar and vaginal atrophy associated with the menopause, hypogonadism, castration, or primary ovarian failure, treatment is usually initiated with Alora (estradiol transdermal system) 0.05 mg/day applied to the skin twice weekly. The lowest dose and regimen that will control symptoms should be chosen and medication should be discontinued as promptly as possible. Attempts to discontinue or taper medication should be made at 3-month to 6-month intervals.

For the prevention of postmenopausal osteoporosis, the minimum dose of Alora (estradiol transdermal system) that has been studied and shown to be effective is 0.025 mg/day applied to the skin twice weekly. Bone mineral density measurements should be repeated to monitor treatment efficacy. The dosage may be increased as necessary, depending on bone mineral density and adverse events.

In women who are not currently taking oral estrogens or in women switching from topical therapy or another transdermal estradiol therapy, treatment with Alora (estradiol transdermal system) can be initiated at once. In women who are currently taking oral estrogens, treatment with Alora (estradiol transdermal system) should be initiated one week after withdrawal of oral therapy or sooner if menopausal symptoms reappear in less than one week.

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 limited to 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 if treatment is still necessary. 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.

Therapeutic Regimen

Alora (estradiol transdermal system) may be administered in a continuous regimen in patients who do not possess an intact uterus. In those patients with an intact uterus who are not using concomitant progestin therapy, Alora (estradiol transdermal system) can be administered on a cyclic schedule (e.g., three weeks of therapy followed by one week without) for the treatment of postmenopausal symptoms. However, no studies have been conducted using this intermittent regimen for the prevention of postmenopausal osteoporosis.

HOW SUPPLIED

Alora 0.025 mg/day (estradiol transdermal system). Each 9 cm2 system contains 0.77 mg of estradiol, USP for nominal delivery of 0.025 mg of estradiol per day when dosed in a twice weekly regimen.

NDC 52544-884-08 Patient Calendar Box of 8 Systems

Alora 0.05 mg/day (estradiol transdermal system). Each 18 cm2 system contains 1.5 mg of estradiol, USP for nominal delivery of 0.05 mg of estradiol per day when dosed in a twice weekly regimen.

NDC 52544-471-08 Patient Calendar Box of 8 Systems
NDC 52544-471-23 Patient Calendar Box of 24 Systems

Alora 0.075 mg/day (estradiol transdermal system). Each 27 cm2 system contains 2.3 mg of estradiol, USP for nominal delivery of 0.075 mg of estradiol per day when dosed in a twice weekly regimen.

NDC 52544-472-08 Patient Calendar Box of 8 Systems

Alora 0.1 mg/day (estradiol transdermal system). Each 36 cm2 system contains 3.1 mg of estradiol, USP for nominal delivery of 0.1 mg of estradiol per day when dosed in a twice weekly regimen.

NDC 52544-473-08 Patient Calendar Box of 8 Systems

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).

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

Discard used Alora (estradiol transdermal system) in household trash in a manner that prevents accidental application or ingestion by children, pets, or others.

SIDE EFFECTS

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. Incidence of adverse events > 2% of each treatment group is given in Table 5.

Table 5: Incidence of Adverse Events > 2% for Alora (estradiol transdermal system) and Placebo Systems (data are expressed as N and (%) of treatment group)

 

Body System Preferred Term Placeboa
(N=87)
Alora (estradiol transdermal system) a
0.025 mg/day
(N=89)
Alora (estradiol transdermal system) a
0.05 mg/day
(N=90)
Alora (estradiol transdermal system) a
0.075 mg/day
(N=89)
Alora (estradiol transdermal system) b
0.1 mg/day
(N=174)
Body As A Whole
  Accidental Injury 4 (4.6) 6 (6.7) 8 (8.9) 4 (4.5) 9 (5.2)
  Allergic Reaction 2 (2.3) 4 (4.5) 4 (4.4) 2 (2.2) 1 (0.6)
  Asthenia 4 (4.6) 7 (7.9) 4 (4.4) 0 (0) 4 (2.3)
  Cyst 3 (3.4) 0 (0) 6 (6.7) 3 (3.4) 0 (0)
  Flu Syndrome 9 (10.3) 8 (9) 12 (13.3) 9 (10.1) 6 (3.4)
  Headache 11 (12.6) 10 (11.2) 8 (8.9) 5 (5.6) 37 (21.3)
  Infection 2 (2.3) 2 (2.2) 3 (3.3) 3 (3.4) 2 (1.1)
  Infection Fungal 1 (1.1) 3 (3.4) 9 (10) 4 (4.5) 0 (0)
  Pain 11 (12.6) 9 (10.1) 5 (5.6) 6 (6.7) 16 (9.2)
  Pain Abdominal 4 (4.6) 7 (7.9) 5 (5.6) 1 (1.1) 5 (2.9)
  Pain Back 5 (5.7) 5 (5.6) 3 (3.3) 7 (7.9) 11 (6.3)
  Pain Chest 4 (4.6) 4 (4.5) 2 (2.2) 1 (1.1) 2 (1.1)
Cardiovascular
  Hypertension 3 (3.4) 3 (3.4) 3 (3.3) 6 (6.7) 0 (0)
  Migraine 2 (2.3) 6 (6.7) 2 (2.2) 0 (0) 2 (1.1)
  Vasodilation 13 (14.9) 6 (6.7) 2 (2.2) 1 (1.1) 0 (0)
Digestive
  Constipation 4 (4.6) 3 (3.4) 6 (6.7) 1 (1.1) 3 (1.7)
  Diarrhea 2 (2.3) 1 (1.1) 3 (3.3) 2 (2.2) 5 (2.9)
  Dyspepsia 1 (1.1) 8 (9) 4 (4.4) 3 (3.4) 2 (1.1)
  Flatulence 5 (5.7) 1 (1.1) 2 (2.2) 3 (3.4) 8 (4.6)
  Gastroenteritis 2 (2.3) 3 (3.4) 4 (4.4) 3 (3.4) 0 (0)
  Nausea 3 (3.4) 6 (6.7) 5 (5.6) 3 (3.4) 7 (4)
Metabolic And Nutritional
  Edema Peripheral 4 (4.6) 3 (3.4) 4 (4.4) 3 (3.4) 3 (1.7)
  Weight Increased 4 (4.6) 3 (3.4) 2 (2.2) 4 (4.5) 1 (0.6)
Musculoskeletal
  Arthralgia 12 (13.8) 5 (5.6) 10 (11.1) 11 (12.4) 2 (1.1)
  Bone Fracture Spontaneous 7 (8) 1 (1.1) 3 (3.3) 0 (0) 0 (0)
  Joint Disorder 2 (2.3) 4 (4.5) 4 (4.4) 1 (1.1) 0 (0)
  Myalgia 4 (4.6) 3 (3.4) 2 (2.2) 5 (5.6) 3 (1.7)
Nervous
  Anxiety 3 (3.4) 0 (0) 9 (10) 2 (2.2) 3 (1.7)
  Depression 8 (9.2) 1 (1.1) 3 (3.3) 1 (1.1) 6 (3.4)
  Dizziness 0 (0) 1 (1.1) 7 (7.8) 4 (4.5) 1 (0.6)
  Hypesthesia 2 (2.3) 3 (3.4) 3 (3.3) 0 (0) 0 (0)
  Insomnia 7 (8) 4 (4.5) 2 (2.2) 1 (1.1) 8 (4.6)
Respiratory
  Asthma 1 (1.1) 3 (3.4) 3 (3.3) 1 (1.1) 2 (1.1)
  Bronchitis 6 (6.9) 7 (7.9) 4 (4.4) 4 (4.5) 6 (3.4)
  Cough Increased 2 (2.3) 1 (1.1) 4 (4.4) 1 (1.1) 6 (3.4)
  Infection Respiratory 23 (26.4) 22 (24.7) 22 (24.4) 19 (21.3) 28 (16.1)
  Pharyngitis 1 (1.1) 4 (4.5) 2 (2.2) 2 (2.2) 4 (2.3)
  Pneumonia 4 (4.6) 4 (4.5) 4 (4.4) 1 (1.1) 1 (0.6)
  Sinusitis 16 (18.4) 9 (10.1) 11 (12.2) 6 (6.7) 13 (7.5)
Skin
  Application Site Reaction 51 (58.6) 47 (52.8) 51 (56.7) 49 (55.1) 10 (5.7)
  Hirsutism 0 (0) 2 (2.2) 2 (2.2) 4 (4.5) 1 (0.6)
  Pruritus 4 (4.6) 2 (2.2) 1 (1.1) 6 (6.7) 9 (5.2)
  Rash 5 (5.7) 6 (6.7) 8 (8.9) 4 (4.5) 5 (2.9)
Special Senses
  Conjunctivitis 2 (2.3) 2 (2.2) 3 (3.3) 2 (2.2) 0 (0)
  Otitis Media 2 (2.3) 3 (3.4) 2 (2.2) 1 (1.1) 0 (0)
Urogenital
  Breast Enlargement 3 (3.4) 1 (1.1) 2 (2.2) 6 (6.7) 4 (2.3)
  Infection Urinary Tract 2 (2.3) 5 (5.6) 4 (4.4) 2 (2.2) 3 (1.7)
  Leukorrhea 1 (1.1) 3 (3.4) 2 (2.2) 4 (4.5) 3 (1.7)
  Neoplasm Breast 6 (6.9) 3 (3.4) 5 (5.6) 1 (1.1) 3 (1.7)
  Pain Breast 7 (8) 13 (14.6) 16 (17.8) 31 (34.8) 12 (6.9)
  Vaginitis 6 (6.9) 0 (0) 3 (3.3) 0 (0) 14 (8)
  Vaginal Bleedingc 4 (12.9) NA 6 (8.7) NA 29 (33.3)
a – Adverse events for the three lower Alora (estradiol transdermal system) doses and placebo were obtained from the two-year prevention of osteoporosis study
b – Adverse events for the highest Alora (estradiol transdermal system) doses were obtained from two 12-week studies of the treatment of menopausal symptoms
c – Data reported for women with partially or fully intact uteri in the menopausal symptom study only (N=31 for Placebo; N=69 for Alora (estradiol transdermal system) 0.05 mg/day and N=87 for Alora (estradiol transdermal system) 0.1 mg/day) NA – data not available

The following additional adverse reactions have been reported with estrogens and/or progestin therapy:

  1. Genitourinary system. Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; 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 gall bladder disease; pancreatitis; enlargement of hepatic hemangiomas.
  5. Skin. Chloasma or melasma, which may persist when drug is discontinued; erythema multiform; 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; arthalgias; leg cramps; changes in libido; anaphylactoid/anaphylactic reactions including urticaria and angioedema; hypocalcemia; exacerbation of asthma; increased triglycerides.

DRUG INTERACTIONS

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 HDL2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.
  5. Impaired glucose tolerance.
  6. Reduced response to the metyrapone test.

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 cardiovascular 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.

Coronary heart disease and stroke

In the Women’s Health Initiative (WHI) study an increased risk of stroke was 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 women-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 the 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 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.

Venous thromboembolism (VTE)

In the Women’s Health Initiative (WHI) study, an increased risk of deep vein thrombosis was 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 women-years in the CE/MPA group compared to 16 per 10,000 women-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.

Endometrial cancer.

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 use of estrogens for less than one 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 to 15 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.

Breast 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 WHI substudy of CE/MPA. 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 versus 33 cases per 10,000 women-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 women-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 women-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 EC/MPA group compared with the placebo group. Metastatic disease was rate 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 healthcare provider and perform monthly 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 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.

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.

Estrogen administration 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 should be 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 discontinued.

PRECAUTIONS

General

Addition of a progestin when 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:

  1. A possible increased risk of breast cancer
  2. Adverse effects on lipoprotein metabolism (e.g., lowering HDL, raising LDL)
  3. Impairment of glucose tolerance
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 estrogen therapy on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use.

Hypertriglyceridemia.

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

Impaired liver function and past history of cholestatic jaundice.

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.

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.

Fluid retention.

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

Ovarian cancer

The CE/MPA substudy of WHI reported that estrogen plus progestin increases the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95% confidence interval 0.77-3.24) but was not statistically significant. The absolute risk for CE/MPA versus placebo was 4.2 versus 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.

Exacerbation of endometriosis.

Endometriosis may be exacerbated with administration of estrogen therapy. 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.

Hypocalcemia.

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

Exacerbation of other conditions.

Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

Patient Information

Laboratory Tests

Estrogen administration should be guided by clinical response at the lowest dose for the treatment of vasomotor symptoms and vulvar and vaginal atrophy. Laboratory parameters may be useful in guiding dosage for the treatment of hypoestrogenism due to hypogonadism, castration and primary ovarian failure.

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.

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.

Pregnancy Category X

Alora should not be used during pregnancy.

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 estrogen therapy. Estrogens are not indicated for the prevention of postpartum breast engorgement. Caution should be exercised when Alora (estradiol transdermal system) is administered to a nursing woman.

Pediatric Use

Estrogen replacement 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 gynecomastia.

Geriatric Use

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.

With respect to efficacy in the approved indications, there have not been sufficient numbers of geriatric patients involved in studies utilizing Alora (estradiol transdermal system) to determine whether those over 65 years of age differ from younger subjects in their response to Alora (estradiol transdermal system).

OVERDOSE

Serious ill effects have not been reported following acute ingestion of large doses of estrogen containing oral contraceptives by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females.

CONTRAINDICATIONS

Alora (estradiol transdermal system) should not be used in individuals with any of the following conditions:

  1. Undiagnosed abnormal genital bleeding.
  2. Known, suspected, or history of cancer of the breast.
  3. Known or suspected estrogen-dependent neoplasia.
  4. Active deep vein thrombosis, pulmonary embolism or a history of these conditions.
  5. Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction).
  6. Liver dysfunction or disease.
  7. Alora (estradiol transdermal system) should not be used in patients with known hypersensitivity to its ingredients.
  8. Known or suspected pregnancy. There is no indication for Alora (estradiol transdermal system) 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.
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