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CLINICAL PHARMACOLOGY Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. Pharmacokinetics Absorption Estrogens used in therapy are well absorbed through the skin, mucous membranes, and gastrointestinal tract. When applied for a local action, absorption is usually sufficient to cause systemic effects. When conjugated with aryl and alkyl groups for parenteral administration, the rate of absorption of oily preparations is slowed with a prolonged duration of action, such that a single intramuscular injection of estradiol valer-ate or estradiol cypionate is absorbed over several weeks. Distribution The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. 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 glu-curonide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. When given orally, naturally-occurring estrogens and their esters are extensively metabolized (first pass effect) and circulate primarily as estrone sulfate, with smaller amounts of other conjugated and unconjugated estro-genic species. This results in limited oral potency. By contrast, synthetic estrogens, such as ethinyl estradiol and the nonsteroidal estrogens, are degraded very slowly in the liver and other tissues, which results in their high intrinsic potency. Estrogen drug products administered by non-oral routes are not subject to first-pass metabolism, but also undergo significant hepatic uptake, metabolism, and enterohepatic recycling. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Drug Interactions In vitroand 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, clar-ithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects. Clinical Studies Women's Health Initiative Studies The Women's Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either 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) (nonfatal 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, colorec-tal cancer, hip fracture, or death due to other cause. 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 1 below: Table 1. RELATIVE AND ABSOLUTE RISK SEEN IN THE CE/MPA SUBSTUDY OF WHIa Eventc Relative Risk CE/MPA vs placebo at 5.2 Years (95% CI*) Placebo n = 8102 CE/MPA n = 8506 Absolute Risk per 10,000 Person-years CHD events 1.29 (1.02-1.63) 30 37 Non-fatal MI 1.32 (1.02-1.72) 23 30 CHD death 1.18 (0.70-1.97) 6 7 Invasive breast cancerb 1.26 (1.00-1.59) 30 38 Stroke 1.41 (1.07-1.85) 21 29 Pulmonary embolism 2.13 (1.39-3.25) 8 16 Colorectal cancer 0.63 (0.43-0.92) 16 10 Endometrial cancer 0.83 (0.47-1.47) 6 5 Hip fracture 0.66 (0.45-0.98) 15 10 Death due to causes other than the events above 0.92 (0.74-1.14) 40 37 Global Indexc 1.15 (1.03-1.28) 151 170 Deep vein thrombosisd 2.07 (1.49-2.87) 13 26 Vertebral fracturesd 0.66 (0.44-0.98) 15 9 Other osteoporotic fracturesd 0.77 (0.69-0.86) 170 131 a adapted from JAMA, 2002; 288:321-333 bincludes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer c a subset of the events was combined in a "global index", defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes dnot included in Global Index *nominal confidence intervals unadjusted for multiple looks and multiple comparisons For those outcomes included in the "global index," the 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 WARNING, WARNINGS, and PRECAUTIONS.) Women's Health Initiative Memory Study 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 WARNING and WARNINGS, Dementia.)

Find Lowest Prices on DELESTROGEN® (estradiol valerate) Injection, USP ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of "natural" estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses. (See WARNINGS, Malignant neoplasms, Endometrial cancer.) CARDIOVASCULAR AND OTHER RISKS Estrogens and progestins should not be used for the prevention of cardiovascular disease. (See WARNINGS, Cardiovascular disorders.) The Women's Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo. (See CLININAL PHARMACOLOGY, Clinical Studies.) The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative to placebo. It is unknown whether this finding applies to younger postmenopausal women or to women taking estrogen alone therapy. (See CLINICAL PHARMACOLOGY, Clinical Studies.) Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. DESCRIPTION DELESTROGEN® (estradiol valerate injection, USP) contains estradiol valerate, a long-acting estrogen in sterile oil solutions for intramuscular use. These solutions are clear, colorless to pale yellow. Formulations (per mL): 10 mg estradiol valerate in a vehicle containing 5 mg chlorobutanol (chloral derivative/preservative) and sesame oil; 20 mg estradiol valerate in a vehicle containing 224 mg benzyl benzoate, 20 mg ben-zyl alcohol (preservative), and castor oil; 40 mg estradiol valerate in a vehicle containing 447 mg benzyl benzoate, 20 mg benzyl alcohol, and castor oil. Estradiol valerate is designated chemically as estra-1,3,5(10)-triene-3, 17-diol(17β)-, 17-pentanoate. Graphic formula: C23H32O3...................MW 356.50

INDICATIONS DELESTROGEN (estradiol valerate injection, USP) is indicated in the: Treatment of moderate to severe vasomotor symptoms associated with the menopause. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure. Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only). DOSAGE AND ADMINISTRATION 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 for 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 (See BOXED WARNINGS and WARNINGS). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding. Care should be taken to inject deeply into the upper, outer quadrant of the gluteal muscle following the usual precautions for intramuscular administration. By virtue of the low viscosity of the vehicles, the various preparations of DELESTROGEN (estradiol valerate injection, USP) may be administered with a small gauge needle. Since the 40 mg potency provides a high concentration in a small volume, particular care should be observed to administer the full dose. DELESTROGEN (estradiol valerate) should be visually inspected for particulate matter and color prior to administration; the solution is clear, colorless to pale yellow. Storage at low temperatures may result in the separation of some crystalline material which redissolves readily on warming. NOTE: A dry needle and syringe should be used. Use of a wet needle or syringe may cause the solution to become cloudy; however, this does not affect the potency of the material. Patients should be started at the lowest dose for the indication. The lowest effective dose of DELESTROGEN (estradiol valerate) has not been determined for any indication. Treated patients with an intact uterus should be monitored closely for signs of endometrial cancer, and appropriate diagnostic measures should be taken to rule our malignancy in the event of persistent or recurring abnormal vaginal bleeding. See PRECAUTIONS concerning addition of a progestin. For treatment of moderate to severe vasomotor symptoms, vulvar and vaginal atrophy associated with the menopause, the lowest dose and regimen that will control symptoms should be chosen and medication should be discontinued as promptly as possible. The usual dosage is 10 to 20 mg DELESTROGEN (estradiol valerate) every four weeks. Attempts to discontinue or taper medication should be made at 3-month to 6-month intervals. For treatment of female hypoestrogenism due to hypogonadism, castration, or primary ovarian failure. The usual dosage is 10 to 20 mg DELESTROGEN (estradiol valerate) every four weeks. For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation only. The usual dosage is 30 mg or more administered every one or two weeks. HOW SUPPLIED DELESTROGEN® (estradiol valerate injection, USP) Multiple Dose Vials 10 mg/mL (5 mL): NDC 42023-110-01 20 mg/mL (5 mL): NDC 42023-111-01 40 mg/mL (5 mL): NDC 42023-112-01 Storage Store at room temperature. Keep out of reach of children. Prescribing Information as of April 2007. Manufactured and Distributed by: JHP Pharmaceuticals, LLC, Rochester, MI 48307. FDA rev date: 10/11/2007

PATIENT INFORMATION DELESTROGEN® (estradiol valerate injection, USP) Read this Patient Information before you start taking DELESTROGEN (estradiol valerate) and read what you get each time you refill DELESTROGEN (estradiol valerate) . 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 THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT DELESTROGEN (estradiol valerate) (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 with progestins may increase your risk of dementia. You and your healthcare provider should talk regularly about whether you still need treatment with DELESTROGEN (estradiol valerate) . What is DELESTROGEN (estradiol valerate) ? DELESTROGEN (estradiol valerate) is a medicine that contains estrogen hormones. What is DELESTROGEN (estradiol valerate) used for? DELESTROGEN (estradiol valerate) 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 to 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 feeling 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 DELESTROGEN (estradiol valerate) . treat moderate to severe dryness, itching, and burning in and around the vagina. You and your healthcare provider should talk regularly about whether you still need treatment with DELESTROGEN (estradiol valerate) to control these problems. If you use DELESTROGEN (estradiol valerate) 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. Who should not take DELESTROGEN (estradiol valerate) ? Do not start taking DELESTROGEN (estradiol valerate) 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 had cancer, talk with your healthcare provider about whether you should take DELESTROGEN (estradiol valerate) . had a stroke or heart attack in the past year. currently have or have had blood clots. currently have or have had liver problems. are allergic to DELESTROGEN (estradiol valerate) or any of its ingredients. See the end of this leaflet for a list of ingredients in DELESTROGEN (estradiol valerate) . think you may be pregnant. Tell your healthcare provider: if you are breastfeeding. The hormone in DELESTROGEN (estradiol valerate) 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, endometrio-sis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. about all the medicines you take. This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how DELESTROGEN (estradiol valerate) works. DELESTROGEN (estradiol valerate) may also affect how your 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 DELESTROGEN (estradiol valerate) ? DELESTROGEN (estradiol valerate) should be injected deeply into the upper, outer quadrant of the gluteal muscle following the usual precautions for intramuscular administration. By virtue of the low viscosity of the vehicles, the various preparations of DELESTROGEN (estradiol valerate injection, USP) may be administered with a small gauge needle. Since the 40 mg potency provides a high concentration in a small volume, particular care should be observed to administer the full dose. DELESTROGEN (estradiol valerate) should be visually inspected for particulate matter and color prior to administration; the solution is clear, colorless to pale yellow. Storage at low temperatures may result in the separation of some crystalline material which redissolves readily on warming. NOTE: A dry needle and syringe should be used. Use of a wet needle or syringe may cause the solution to become cloudy; however, this does not affect the potency of the material. Start at the lowest dose and talk to your healthcare provider about how well that dose is working for you. Estrogens should be used at the lowest dose possible for your treatment only as long as needed. The lowest effective dose of DELESTROGEN (estradiol valerate) has not been determined. 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 DELESTROGEN (estradiol valerate) . 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 These are not all the possible side effects of DELESTROGEN (estradiol valerate) . For more information, ask your healthcare provider or pharmacist. What can I do to lower my chances of a serious side effect with DELESTROGEN (estradiol valerate) ? Talk with your healthcare provider regularly about whether you should continue taking DELESTROGEN (estradiol valerate) . 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 DELESTROGEN (estradiol valerate) . 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 DELESTROGEN (estradiol valerate) Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take DELESTROGEN (estradiol valerate) for conditions for which it was not prescribed. Do not give DELESTROGEN (estradiol valerate) to other people, even if they have the same symptoms you have. It may harm them. Keep DELESTROGEN (estradiol valerate) out of the reach of children. This leaflet provides a summary of the most important information about DELESTROGEN (estradiol valerate) . If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about DELESTROGEN (estradiol valerate) that is written for health professionals. You can get more information by calling the toll free number 1-866-923-2547. What are the ingredients in DELESTROGEN (estradiol valerate) ? DELESTROGEN (estradiol valerate) is supplied in three 5 mL multiple dose vials; 10 mg/mL, 20 mg/mL, and 40 mg/mL strengths. The 10 mg/mL strength contains 10 mg estradiol valerate in a solution of chlorobutanol and sesame oil. The 20 mg/mL strength contains 20 mg estradiol valerate in a solution of benzyl benzoate, ben-zyl alcohol, and castor oil. The 40 mg/mL strength contains 40 mg estradiol valerate in a solution of ben-zyl benzoate, benzyl alcohol, and castor oil.

WARNINGS 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 has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogens should be discontinued immediately. Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercho-lesterolemia, 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 increase in the number of myocardial infarctions and strokes has been observed in women receiving CE compared to placebo. These observations are preliminary. (See CLINICAL PHARMACOLOGY, Clinical Studies.) 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 (0.625mg/2.5mg 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 increase in VTE has been observed in women receiving CE compared to placebo. These observations are preliminary. (See CLINICAL PHARMACOLOGY, Clinical Studies.) 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 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 hormone 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 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 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 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 healthcare 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 women-years, and the absolute excess risk for CE/MPA was 23 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use.) It is unknown whether these findings apply to estrogen alone therapy. 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 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 propto-sis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently 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 a possible increased risk of breast cancer. 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, patients with conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed. Hypocalcemia Estrogens should be used with caution in individuals with severe hypocalcemia. Ovarian cancer The CE/MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA 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 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. Exacerbation of other conditions 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. Hypercoagulability Some studies have shown that women taking estrogen replacement therapy have hypercoagulabil-ity, primarily related to decreased antithrombin activity. This effect appears dose- and duration-dependent and is less pronounced than that associated with oral contraceptive use. Also, postmenopausal women tend to have increased coagulation parameters at baseline compared to pre-menopausal women. There is some suggestion that low dose postmenopausal mestranol may increase the risk of thromboembolism, although the majority of studies (of primarily conjugated estrogens users) report no such increase. Uterine bleeding and mastodynia Certain patients may develop undesirable manifestations of estrogenic stimulation, such as abnormal uterine bleeding and mastodynia. Patient Information Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe DELESTROGEN (estradiol valerate) . Laboratory Tests Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response rather than by serum hormone levels (e.g., estradiol, FSH). Carcinogenesis, Mutagenesis, and Impairment of Fertility Long-term continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. (See BOXED WARNINGS, WARNINGS and PRECAUTIONS.) Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. Pregnancy DELESTROGEN (estradiol valerate) should not be used during pregnancy. (See CONTRAINDICATIONS.) 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 DELESTROGEN (estradiol valerate) is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Large and repeated doses of estrogen over an extended period of time may accelerate epiphyseal closure. Therefore, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended in patients in whom bone growth is not complete. Geriatric Use Clinical studies of estradiol valerate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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 the women that were older than 70. (See WARNINGS, Dementia.) It is unknown whether these findings apply to estrogen alone therapy.