throughout the cell, and bind to and activate the nuclear and conjugation with glucuronic acids (which are then estrogen receptor, a DNA-binding protein which is rapidly excreted in the urine). found in estrogen-responsive tissues. The activated ® When given orally, naturally-occurring estrogens and DELESTROGEN estrogen receptor binds to specific DNA sequences, or their esters are extensively metabolized (first pass (estradiol valerate injection, USP) hormone-response elements, which enhance the tran- effect) and circulate primarily as estrone sulfate, with scription of adjacent genes and in turn lead to the smaller amounts of other conjugated and unconjugated observed effects. Estrogen receptors have been identi- estrogenic species. This results in limited oral potency. WARNINGS fied in tissues of the reproductive tract, breast, pituitary, By contrast, synthetic estrogens, such as ethinyl estra- 1. ESTROGENS HAVE BEEN REPORTED TO hypothalamus, liver, and bone of women. diol and the nonsteroidal estrogens, are degraded very INCREASE THE RISK OF ENDOMETRIAL CARCI- Estrogens are important in the development and main- slowly in the liver and other tissues, which results in NOMA IN POSTMENOPAUSAL WOMEN. tenance of the female reproductive system and their high intrinsic potency. Estrogen drug products Close clinical surveillance of all women taking secondary sex characteristics. By a direct action, they administered by non-oral routes are not subject to first- estrogens is important. Adequate diagnostic meas- cause growth and development of the uterus, fallopian pass metabolism, but also undergo significant hepatic ures, including endometrial sampling when tubes, and vagina. With other hormones, such as pitu- uptake, metabolism, and enterohepatic recycling. indicated, should be undertaken to rule out malig- itary hormones and progesterone, they cause INDICATIONS AND USAGE nancy in all cases of undiagnosed persistent or enlargement of the breasts through promotion of ductal DELESTROGEN (estradiol valerate injection, USP) is recurring abnormal vaginal bleeding. There is no growth, stromal development, and the accretion of fat. indicated in the: evidence that “natural” estrogens are more or less Estrogens are intricately involved with other hormones, hazardous than “synthetic” estrogens at equiestro- especially progesterone, in the processes of the ovula- 1. Treatment of moderate to severe vasomotor symp- genic doses. tory menstrual cycle and pregnancy, and affect the toms associated with the menopause. There is no release of pituitary gonadotropins. They also contribute adequate evidence that estrogens are effective for 2. ESTROGENS SHOULD NOT BE USED DURING nervous symptoms or depression which might occur PREGNANCY. to the shaping of the skeleton, maintenance of tone and elasticity of urogenital structures, changes in the epi- during menopause and they should not be used to There is no indication for estrogen therapy during physes of the long bones that allow for the pubertal treat these conditions. pregnancy or during the immediate postpartum growth spurt and its termination, and pigmentation of 2. Treatment of vulval and vaginal atrophy. period. Estrogens are ineffective for the prevention the nipples and genitals. 3. Treatment of hypoestrogenism due to hypogo- or treatment of threatened or habitual abortion. nadism, castration or primary ovarian failure. Estrogens are not indicated for the prevention of Estrogens occur naturally in several forms. The primary postpartum breast engorgement. source of estrogen in normally cycling adult women is 4. Treatment of advanced androgen-dependent carci- the ovarian follicle, which secretes 70 to 500 micro- noma of the prostate (for palliation only). Estrogen therapy during pregnancy is associated grams of estradiol daily, depending on the phase of the with an increased risk of congenital defects in the CONTRAINDICATIONS menstrual cycle. This is converted primarily to estrone, reproductive organs of the fetus, and possibly other Estrogens should not be used in individuals with any of which circulates in roughly equal proportion to estradiol, birth defects. Studies of women who received the following conditions: and to small amounts of estriol. After menopause, most diethylstilbestrol (DES) during pregnancy have endogenous estrogen is produced by conversion of 1. Known or suspected pregnancy (see Boxed WARN- shown that female offspring have an increased risk androstenedione, secreted by the adrenal cortex, to INGS). Estrogens may cause fetal harm when of vaginal adenosis, squamous cell dysplasia of the estrone by peripheral tissues. Thus, estrone—especial- administered to a pregnant woman. uterine cervix, and clear cell vaginal cancer later in ly in its sulfate ester form—is the most abundant 2. Undiagnosed abnormal genital bleeding. life; male offspring have an increased risk of uro- circulating estrogen in postmenopausal women. 3. Known or suspected cancer of the breast except in genital abnormalities and possibly testicular cancer Although circulating estrogens exist in a dynamic equi- appropriately selected patients being treated for later in life. The 1985 DES Task Force concluded librium of metabolic interconversions, estradiol is the metastatic disease. that use of DES during pregnancy is associated principal intracellular human estrogen and is substan- with a subsequent increased risk of breast cancer 4. Known or suspected estrogen-dependent neoplasia. tially more potent than estrone or estriol at the receptor. in the mothers, although a causal relationship 5. Active thrombophlebitis or thromboembolic disorders. remains unproven and the observed level of excess Estrogens used in therapy are well absorbed through the WARNINGS skin, mucous membranes, and gastrointestinal tract. risk is similar to that for a number of other breast 1. Induction of malignant neoplasms. cancer risk factors. When applied for a local action, absorption is usually sufficient to cause systemic effects. When conjugated Endometrial cancer. The reported endometrial can- with aryl and alkyl groups for parenteral administration, cer risk among unopposed estrogen users is about 2 DESCRIPTION the rate of absorption of oily preparations is slowed with to 12 fold greater than in nonusers, and appears dependent on duration of treatment and on estrogen DELESTROGEN® (estradiol valerate injection, USP) con- a prolonged duration of action, such that a single intra- tains estradiol valerate, a long-acting estrogen in sterile muscular injection of estradiol valerate or estradiol dose. Most studies show no significant increased oil solutions for intramuscular use. These solutions are cypionate is absorbed over several weeks. risk associated with use of estrogens for less than one year. The greatest risk appears associated with clear, colorless to pale yellow. Formulations (per mL): Administered estrogens and their esters are handled prolonged use—with increased risks of 15 to 24- 10 mg estradiol valerate in a vehicle containing 5 mg within the body essentially the same as the endogenous fold for five to ten years or more. In three studies, chlorobutanol (chloral derivative/preservative) and hormones. Metabolic conversion of estrogens occurs sesame oil; 20 mg estradiol valerate in a vehicle con- primarily in the liver (first pass effect), but also at local persistence of risk was demonstrated for 8 to over taining 224 mg benzyl benzoate, 20 mg benzyl alcohol target tissue sites. Complex metabolic processes result 15 years after cessation of estrogen treatment. In (preservative), and castor oil; 40 mg estradiol valerate in a dynamic equilibrium of circulating conjugated and one study a significant decrease in the incidence of in a vehicle containing 447 mg benzyl benzoate, 20 mg unconjugated estrogenic forms which are continually endometrial cancer occurred six months after estro- benzyl alcohol, and castor oil. interconverted, especially between estrone and estradi- gen withdrawal. Concurrent progestin therapy may offset this risk but the overall health impact in post- Estradiol valerate is designated chemically as estra- ol and between esterified and non-esterified forms. menopausal women is not known. 1,3,5(10)-triene-3, 17-diol(17β)-, 17-pentanoate. Although naturally-occurring estrogens circulate in the Graphic formula: blood largely bound to sex hormone-binding globulin Breast Cancer. While some epidemiologic studies and albumin, only unbound estrogens enter target tis- suggest a very modest increase in breast cancer risk sue cells. A significant proportion of the circulating for estrogen alone users versus non-users, other estrogen exists as sulfate conjugates, especially studies have not shown any increased risk. The estrone sulfate, which serves as a circulating reservoir addition of progestin to estrogen may increase the for the formation of more active estrogenic species. A risk for breast cancer over that noted in non-hor- certain proportion of the estrogen is excreted into the mone users more significantly (by about 24-40%), bile and then reabsorbed from the intestine. During this although this is based solely on epidemiologic stud- ies, and definitive conclusions await prospective, C H O MW 356.50 enterohepatic recirculation, estrogens are desulfated 23 32 3 and resulfated and undergo degradation through con- controlled clinical trials. CLINICAL PHARMACOLOGY version to less active estrogens (estriol and other Women without a uterus who require hormone Estrogen drug products act by regulating the transcrip- estrogens), oxidation to nonestrogenic substances (cat- replacement should receive estrogen-alone therapy, tion of a limited number of genes. Estrogens diffuse echolestrogens, which interact with catecholamine and should not be exposed unnecessarily to prog- through cell membranes, distribute themselves metabolism, especially in the central nervous system), estins. Women with a uterus who are candidates for short-term combination estrogen/progestin therapy and raising LDL) which could diminish the pur- relief of symptoms for those indications in which (for relief of vasomotor symptoms) are not felt to be ported cardioprotective effect of estrogen therapy symptoms are observable. at a substantially increased risk for breast cancer. (see PRECAUTIONS); (2) impairment of glucose D. Drug/Laboratory Test Interactions. Women with a uterus who are candidates for long- tolerance; and (3) possible enhancement of mitot- 1. Accelerated prothrombin time, partial thrombo- term use of estrogen/progestin therapy should be ic activity in breast epithelial tissue, although few plastin time, and platelet aggregation time; advised of potential benefits and risks (including the epidemiological data are available to address this increased platelet count; increased factors II, VII potential for increased risk of breast cancer). All point (see WARNINGS). antigen, VIII antigen, VIII coagulant activity, IX, X, women should receive yearly breast exams by a The choice of progestin, its dose, and its regimen XII, VII-X complex, II-VII-X complex, and beta- health care provider and perform monthly breast- may be important in minimizing these adverse thromboglobulin; decreased levels of anti-factor self examinations. In addition, mammography effects, but these issues will require further study Xa and antithrombin III, decreased antithrombin examinations should be scheduled as suggested by before they are clarified. III activity; increased levels of fibrinogen and fib- providers based on patient age and risk factors. 2. Cardiovascular risk. The effects of estrogen rinogen activity; increased plasminogen antigen Congenital lesions with malignant potential. replacement on the risk of cardiovascular disease and activity. Estrogen therapy during pregnancy is associated have not been adequately studied. However, data 2. Increased thyroid-binding globulin (TBG) leading with an increased risk of fetal congenital reproduc- from the Heart and Estrogen/Progestin to increased circulating total thyroid hormone, as tive tract disorders, and possibly other birth Replacement Study (HERS), a controlled clinical measured by protein-bound iodine (PBI), T4 levels defects. Studies of women who received DES dur- trial of secondary prevention of 2,763 post- (by column or by radioimmunoassay) or T3 levels ing pregnancy have shown that female offspring menopausal women with documented heart by radioimmunoassay. T3 resin uptake is have an increased risk of vaginal adenosis, squa- disease, demonstrated no benefit. During an aver- decreased, reflecting the elevated TBG. Free T4 mous cell dysplasia of the uterine cervix, and clear age follow-up of 4.1 years, treatment with oral and free T3 concentrations are unaltered. cell vaginal cancer later in life; male offspring have conjugated estrogen plus medroxyprogesterone 3. Other binding proteins may be elevated in an increased risk of urogenital abnormalities and acetate did not reduce the overall rate of coronary serum, i.e., corticosteroid binding globulin possibly testicular cancer later in life. Although heart disease (CHD) events in post-menopausal (CBG), sex hormone-binding globulin (SHBG), some of these changes are benign, others are pre- women with established coronary disease. There leading to increased circulating corticosteroids cursors of malignancy. were more CHD events in the hormone treated and sex steroids, respectively. Free or biologi- 2. Gallbladder disease. Two studies have reported a group than in the placebo group in year 1, but cally active hormone concentrations are 2- to 4-fold increase in the risk of gallbladder dis- fewer events in years 3 through 5. unchanged. Other plasma proteins may be ease requiring surgery in women receiving 3. Physical examination. A complete medical and increased (angiotensinogen/renin substrate, postmenopausal estrogens. family history should be taken prior to the initia- alpha-1-antitrypsin, ceruloplasmin). 3. Cardiovascular disease. Large doses of estrogen (5 tion of any estrogen therapy. The pretreatment 4. Increased plasma HDL and HDL-2 subfraction mg conjugated estrogens per day), comparable to and periodic physical examinations should concentrations, reduced LDL cholesterol concen- those used to treat cancer of the prostate and include special reference to blood pressure, tration, increased triglycerides levels. breasts, abdomen, and pelvic organs, and should breast, have been shown in a large prospective clin- 5. Impaired glucose tolerance. ical trial in men to increase the risks of nonfatal include a Papanicolaou smear. As a general rule, myocardial infarction, pulmonary embolism, and estrogen should not be prescribed for longer than 6. Reduced response to metyrapone test. thrombophlebitis. These risks cannot necessarily be one year without reexamining the patient. 7. Reduced serum folate concentration. extrapolated from men to women. However, to avoid 4. Hypercoagulability. Some studies have shown E. Carcinogenesis, Mutagenesis, and Impairment of the theoretical cardiovascular risk to women caused that women taking estrogen replacement therapy Fertility. Long term continuous administration of by high estrogen doses, the dose for estrogen have hypercoagulability, primarily related to natural and synthetic estrogens in certain animal replacement therapy should not exceed the lowest decreased antithrombin activity. This effect species increases the frequency of carcinomas of effective dose. appears dose- and duration-dependent and is the breast, uterus, cervix, vagina, testis, and liver. 4. Elevated blood pressure. Occasional blood pres- less pronounced than that associated with oral See CONTRAINDICATIONS and WARNINGS. sure increases during estrogen replacement therapy contraceptive use. Also, postmenopausal women F. Pregnancy Category X. Estrogens should not be have been attributed to idiosyncratic reactions to tend to have increased coagulation parameters at used during pregnancy. See CONTRAINDICATIONS estrogens. More often, blood pressure has remained baseline compared to premenopausal women. and Boxed WARNINGS. the same or has dropped. One study showed that There is some suggestion that low dose post- G. Nursing Mothers. As a general principle, the admin- postmenopausal estrogen users have higher blood menopausal mestranol may increase the risk of istration of any drug to nursing mothers should be pressure than nonusers. Two other studies showed thromboembolism, although the majority of stud- done only when clearly necessary since many drugs slightly lower blood pressure among estrogen users ies (of primarily conjugated estrogens users) are excreted in human milk. In addition, estrogen compared to nonusers. Postmenopausal estrogen report no such increase. There is insufficient administration to nursing mothers has been shown use does not increase the risk of stroke. information on hypercoagulability in women who to decrease the quantity and quality of the milk. Nonetheless, blood pressure should be monitored at have had previous thromboembolic disease. H. Pediatric Use. Safety and effectiveness in pediatric regular intervals with estrogen use. 5. Familial hyperlipoproteinemia. Estrogen thera- patients have not been established. Large and 5. Hypercalcemia. Administration of estrogens may py may be associated with massive elevations of repeated doses of estrogen over an extended period lead to severe hypercalcemia in patients with breast plasma triglycerides leading to pancreatitis and of time may accelerate epiphyseal closure. cancer and bone metastases. If this occurs, the drug other complications in patients with familial Therefore, periodic monitoring of bone maturation should be stopped and appropriate measures taken defects of lipoprotein metabolism. and effects on epiphyseal centers is recommended to reduce the serum calcium level. 6. Fluid retention. Because estrogens may cause in patients in whom bone growth is not complete. PRECAUTIONS some degree of fluid retention, conditions which ADVERSE REACTIONS A. General might be exacerbated by this factor, such as asth- The following additional adverse reactions have ma, epilepsy, migraine, and cardiac or renal 1. Addition of a progestin. Studies of the addition been reported with estrogen therapy (see WARN- dysfunction, require careful observation. of a progestin for 10 or more days of a cycle of INGS regarding induction of neoplasia, adverse estrogen administration have reported a lowered 7. Uterine bleeding and mastodynia. Certain effects on the fetus, increased incidence of gallblad- incidence of endometrial hyperplasia than would patients may develop undesirable manifestations der disease, cardiovascular disease, elevated blood be induced by estrogen treatment alone. of estrogenic stimulation, such as abnormal uter- pressure, and hypercalcemia). Morphological and biochemical studies of ine bleeding and mastodynia. 1. Genitourinary system. endometria suggest that 10 to 14 days of prog- 8. Impaired liver function. Estrogens may be poor- Changes in vaginal bleeding pattern and abnor- estin are needed to provide maximal maturation ly metabolized in patients with impaired liver mal withdrawal bleeding or flow; breakthrough of the endometrium and to reduce the likelihood function and should be administered with caution. bleeding, spotting. of hyperplastic changes. B. Information for the Patient. See text of Patient Increase in size of uterine leiomyomata. There are, however, possible risks which may be Package Insert. Vaginal candidiasis. associated with the use of progestins in estrogen C. Laboratory Tests. Estrogen administration should Change in amount of cervical secretion. replacement regimens. These include: (1) adverse generally be guided by clinical response at the 2. Breasts. effects on lipoprotein metabolism (lowering HDL smallest dose, rather than laboratory monitoring, for Tenderness, enlargement. 3. Gastrointestinal. appropriate diagnostic measures should be taken to carry virtually the same labeling information as their Nausea, vomiting. rule out malignancy in the event of persistent or recur- brand name versions.) Abdominal cramps, bloating. ring abnormal vaginal bleeding. • To reduce moderate or severe menopausal Cholestatic jaundice. See PRECAUTIONS A.1 concerning addition of a progestin. symptoms. Increased incidence of gallbladder disease. HOW SUPPLIED Estrogens are hormones made by the ovaries of 4. Skin. DELESTROGEN® (estradiol valerate injection, USP) normal women. Between ages 45 and 55, the Chloasma or melasma that may persist when drug Multiple Dose Vials ovaries normally stop making estrogens. This leads is discontinued. 10 mg/mL (5 mL): NDC 61570-180-01 to a drop in body estrogen levels which causes the Erythema multiforme. “change of life’’ or menopause (the end of monthly 20 mg/mL (5 mL): NDC 61570-181-01 Erythema nodosum. menstrual periods). If both ovaries are removed dur- Hemorrhagic eruption. 40 mg/mL (5 mL): NDC 61570-182-01 ing an operation before natural menopause takes Loss of scalp hair. Storage place, the sudden drop in estrogen levels causes Hirsutism. Store at room temperature. “surgical menopause”. 5. Eyes. When the estrogen levels begin dropping, some Steepening of corneal curvature. women develop very uncomfortable symptoms, such Intolerance to contact lenses. as feelings of warmth in the face, neck, and chest, 6. Central Nervous System. or sudden intense episodes of heat and sweating Information for the Patient About Headache, migraine, dizziness. (“hot flashes” or “hot flushes”). Using estrogen Mental depression. drugs can help the body adjust to lower estrogen Chorea. DELESTROGEN® levels and reduce these symptoms. Most women 7. Miscellaneous. (estradiol valerate injection, USP) have only mild menopausal symptoms or none at all Increase or decrease in weight. and do not need to use estrogen drugs for these Reduced carbohydrate tolerance. INTRODUCTION symptoms. Others may need to take estrogens for a Aggravation of porphyria. few months while their bodies adjust to lower estro- Edema. This leaflet describes when and how to use estrogens, gen levels. The majority of women do not need Changes in libido. and the risks and benefits of estrogen treatment. estrogen replacement for longer than six months for OVERDOSAGE Estrogens have important benefits but also some risks. these symptoms. Serious ill effects have not been reported following You must decide, with your doctor, whether the risks to •To treat vulval and vaginal atrophy (itching, burn- acute ingestion of large doses of estrogen-containing you of estrogen use are acceptable because of their ing, dryness in or around the vagina, difficulty or oral contraceptives by young children. Overdosage of benefits. If you use estrogens, check with your doctor to burning on urination) associated with menopause. be sure you are using the lowest possible dose that estrogen may cause nausea and vomiting, and with- •To treat certain conditions in which a young drawal bleeding may occur in females. works, and that you don’t use them longer than neces- sary. How long you need to use estrogens will depend woman’s ovaries do not produce enough estro- DOSAGE AND ADMINISTRATION on the reason for use. gen naturally. Care should be taken to inject deeply into the upper, •To treat certain types of abnormal vaginal bleed- outer quadrant of the gluteal muscle following the usual WARNINGS ing due to hormonal imbalance when your doctor precautions for intramuscular administration. By virtue has found no serious cause of the bleeding. of the low viscosity of the vehicles, the various prepa- 1. ESTROGENS INCREASE THE RISK OF CANCER OF •To treat certain cancers in special situations, in rations of DELESTROGEN (estradiol valerate injection, THE UTERUS IN WOMEN WHO HAVE HAD THEIR men and women. USP) may be administered with a small gauge needle. MENOPAUSE (“CHANGE OF LIFE”). Since the 40 mg potency provides a high concentration If you use any estrogen-containing drug, it is •To prevent thinning of bones. in a small volume, particular care should be observed to important to visit your doctor regularly and report Osteoporosis is a thinning of the bones that makes administer the full dose. any unusual vaginal bleeding right away. Vaginal them weaker and allows them to break more easily. DELESTROGEN should be visually inspected for particu- bleeding after menopause may be a warning sign The bones of the spine, wrists and hips break most late matter and color prior to administration; the solution of uterine cancer. Your doctor should evaluate any often in osteoporosis. Both men and women start to is clear, colorless to pale yellow. Storage at low temper- unusual vaginal bleeding to find out the cause. lose bone mass after about age 40, but women lose atures may result in the separation of some crystalline 2. ESTROGENS SHOULD NOT BE USED DURING bone mass faster after the menopause. Using estro- material which redissolves readily on warming. PREGNANCY. gens after the menopause slows down bone thinning Note: A dry needle and syringe should be used. Use of Estrogens do not prevent miscarriage (sponta- and may prevent bones from breaking. Lifelong ade- a wet needle or syringe may cause the solution to neous abortion) and are not needed in the days quate calcium intake, either in the diet (such as dairy become cloudy; however, this does not affect the following childbirth. If you take estrogens during products) or by calcium supplements (to reach a potency of the material. pregnancy, your unborn child has a greater than total daily intake of 1000 milligrams per day before menopause or 1500 milligrams per day after 1. For treatment of moderate to severe vasomotor usual chance of having birth defects. The risk of menopause), may help to prevent osteoporosis. symptoms, vulval and vaginal atrophy associated developing these defects is small, but clearly larg- Regular weight-bearing exercise (like walking and with the menopause, the lowest dose and regi- er than the risk in children whose mothers did not running for an hour, two or three times a week) may men that will control symptoms should be take estrogens during pregnancy. These birth also help to prevent osteoporosis. Before you change chosen and medication should be discontinued defects may affect the baby’s urinary system and sex organs. Daughters born to mothers who took your calcium intake or exercise habits, it is important as promptly as possible. DES (an estrogen drug) have a higher than usual to discuss these lifestyle changes with your doctor to Attempts to discontinue or taper medication should chance of developing cancer of the vagina or find out if they are safe for you. be made at 3-month to 6-month intervals. cervix when they become teenagers or young Since estrogen use has some risks, only women who The usual dosage is 10 to 20 mg DELESTROGEN adults. Sons may have a higher than usual chance are likely to develop osteoporosis should use estro- every four weeks. of developing cancer of the testicles when they gens for prevention. Women who are likely to 2. For treatment of female hypoestrogenism due become teenagers or young adults. develop osteoporosis often have the following char- to hypogonadism, castration, or primary ovari- acteristics: white or Asian race, slim, cigarette an failure. USES OF ESTROGEN smokers, and a family history of osteoporosis in a The usual dosage is 10 to 20 mg DELESTROGEN mother, sister, or aunt. Women who have relatively (Not every estrogen drug is approved for every use every four weeks. early menopause, often because their ovaries were listed in this section. If you want to know which of 3. For treatment of advanced androgen-dependent removed during an operation (“surgical these possible uses are approved for the medicine pre- menopause”), are more likely to develop osteoporo- carcinoma of the prostate, for palliation only. scribed for you, ask your doctor or pharmacist to show The usual dosage is 30 mg or more administered sis than women whose menopause happens at the you the professional labeling. You can also look up the average age. every one or two weeks. specific estrogen product in a book called the Treated patients with an intact uterus should be moni- “Physicians’ Desk Reference”, which is available in WHO SHOULD NOT USE ESTROGENS tored closely for signs of endometrial cancer, and many book stores and public libraries. Generic drugs Estrogens should not be used: • During pregnancy (see Boxed WARNINGS). women taking the combined therapy. Breast lumps (possible breast cancer; ask your doc- If you think you may be pregnant, do not use any form If you do not have your uterus, there is no need for tor or health professional to show you how to of estrogen-containing drug. Using estrogens while combined estrogen/progestin therapy since estro- examine your breasts monthly) you are pregnant may cause your unborn child to have gen alone therapy is sufficient and may pose less Yellowing of the skin or eyes (possible liver problem) birth defects. Estrogens do not prevent miscarriage. risk for breast cancer. Pain, swelling, or tenderness in the abdomen (possi- • If you have unusual vaginal bleeding which If you do have your uterus, you should discuss the ble gallbladder problem) has not been evaluated by your doctor (see benefits and risks of combined estrogen/progestin OTHER INFORMATION Boxed WARNINGS). therapy with your health care provider. Regular 1. Estrogens increase the risk of developing a condition breast exams by a health professional and monthly Unusual vaginal bleeding can be a warning sign of (endometrial hyperplasia) that may lead to cancer of self-exams are recommended for all women. cancer of the uterus, especially if it happens after the lining of the uterus. Taking progestins, another Mammography may also be recommended depend- menopause. Your doctor must find out the cause of hormone drug, with estrogens lowers the risk of ing on your age and risk factors. the bleeding so that he or she can recommend the developing this condition. Therefore, if your uterus proper treatment. Taking estrogens without visiting • Gallbladder disease. has not been removed, your doctor may prescribe a your doctor can cause you serious harm if your vagi- Women who use estrogens after menopause are progestin for you to take together with the estrogen. nal bleeding is caused by cancer of the uterus. more likely to develop gallbladder disease needing You should know, however, that taking estrogens • If you have had cancer. surgery than women who do not use estrogens. with progestins may have additional risks. These Since estrogens increase the risk of certain types of • Abnormal blood clotting. include: (a) unhealthy effects on blood fats (espe- cially the lowering of HDL blood cholesterol, the cancer, you should not use estrogens if you have Taking estrogens may cause changes in your blood “good” blood fat which protects against heart dis- ever had cancer of the breast or uterus, unless your clotting system. These changes allow the blood to doctor recommends that the drug may help in the ease); (b) unhealthy effects on blood sugar (which clot more easily, possibly allowing clots to form in cancer treatment. (For certain patients with breast or might make a diabetic condition worse); and (c) a your bloodstream. If blood clots do form in your prostate cancer, estrogens may help.) possible further increase in breast cancer risk which bloodstream, they can cut off the blood supply to may be associated with long-term estrogen use. • If you have any circulation problems. vital organs, causing serious problems. These prob- Estrogen drugs should not be used except in unusu- lems may include a stroke (by cutting off blood to the Some research has shown that estrogens taken ally special situations in which your doctor judges brain), a heart attack (by cutting off blood to the without progestins may protect women against that you need estrogen therapy so much that the heart), a pulmonary embolus (by cutting off blood to developing heart disease. However, this is not cer- risks are acceptable. Men and women with abnor- the lungs), or other problems. Any of these condi- tain. The protection shown may have been caused mal blood clotting conditions should avoid estrogen tions may cause death or serious long term by the characteristics of the estrogen-treated use (see DANGERS OF ESTROGENS). disability. However, most studies of low dose estro- women, and not by the estrogen treatment itself. In general, treated women were slimmer, more physi- • When they do not work. gen usage by women do not show an increased risk of these complications. cally active, and were less likely to have diabetes During menopause, some women develop nervous than the untreated women. These characteristics symptoms or depression. Estrogens do not relieve SIDE EFFECTS are known to be associated with a reduced risk for these symptoms. You may have heard that taking In addition to the risks listed above, the following side heart disease. estrogens for years after menopause will keep your effects have been reported with estrogen use. You are cautioned to discuss very carefully with skin soft and supple and keep you feeling young. Nausea and vomiting. your doctor or health care provider all the possi- There is no evidence for these claims and such long- Breast tenderness or enlargement. ble risks and benefits of long-term estrogen and term estrogen use may have serious risks. progestin treatment as they affect you personally. Enlargement of benign tumors (“fibroids”) of the uterus. • After childbirth or when breastfeeding a baby. 2. Your doctor has prescribed this drug for you and you Estrogens should not be used to try to stop the Retention of excess fluid. This may make some condi- alone. Do not give the drug to anyone else. breasts from filling with milk after a baby is born. tions worsen, such as asthma, epilepsy, migraine, heart disease, or kidney disease. 3. If you will be taking calcium supplements as part of Such treatment may increase the risk of developing the treatment to help prevent osteoporosis, check blood clots (see DANGERS OF ESTROGENS). A spotty darkening of the skin, particularly on the face. with your doctor about how much to take. If you are breastfeeding, you should avoid using any REDUCING RISK OF ESTROGEN USE 4. Keep this and all drugs out of the reach of children. drugs because many drugs pass through to the baby If you use estrogens, you can reduce your risks by doing In case of overdose, call your doctor, hospital or poi- in the milk. While nursing a baby, you should take these things: son control center immediately. drugs only on the advice of your health care provider. • See your doctor regularly. 5. This leaflet provides a summary of the most impor- DANGERS OF ESTROGENS While you are using estrogens, it is important to visit tant information about estrogens. If you want more • Cancer of the uterus. your doctor at least once a year for a check-up. If information, ask your doctor or pharmacist to show Your risk of developing cancer of the uterus gets you develop vaginal bleeding while taking estrogens, you the professional labeling. The professional label- higher the longer you use estrogens and the larger you may need further evaluation. If members of your ing is also published in a book called the doses you use. One study showed that after women family have had breast cancer or if you have ever “Physicians’ Desk Reference,” which is available in stop taking estrogens, this higher cancer risk quick- had breast lumps or an abnormal mammogram book stores and public libraries. Generic drugs carry ly returns to the usual level of risk (as if you had (breast x-ray), you may need to have more frequent virtually the same labeling information as their brand never used estrogen therapy). Three other studies breast examinations. name versions. showed that the cancer risk stayed high for 8 to • Reassess your need for estrogens. more than 15 years after stopping estrogen treat- ment. Because of this risk, IT IS IMPORTANT TO You and your doctor should reevaluate whether or not TAKE THE LOWEST DOSE THAT WORKS AND TO you still need estrogens at least every six months. TAKE IT ONLY AS LONG AS YOU NEED IT. • Be alert for signs of trouble. Using progestin therapy together with estrogen thera- If any of these warning signals (or any other unusu- py may reduce the higher risk of uterine cancer related al symptoms) happen while you are using estrogens, to estrogen use (but see OTHER INFORMATION). call your doctor immediately: If you have had your uterus removed (total hys- Abnormal bleeding from the vagina (possible terectomy), there is no danger of developing cancer uterine cancer) Distributed by: Monarch Pharmaceuticals, Inc., Bristol, of the uterus. Pains in the calves or chest, sudden shortness of TN 37620 • Cancer of the breast. breath, or coughing blood (possible clot in the legs, heart, or lungs) Manufactured by: Bristol-Myers Squibb Company, Studies examining the risk of breast cancer among Princeton, NJ 08543 USA women using estrogen alone and combined estro- Severe headache or vomiting, dizziness, faintness, gen/progestin therapy have suggested that there changes in vision or speech, weakness or numbness may be a mildly increased risk of breast cancer in of an arm or leg (possible clot in the brain or eye) 1-1716-1 Revised February 2002