1. ESTROGENS HAVE BEEN REPORTED TO INCREASE THE RISK OF ENDOMETRIAL CARCINOMA IN POSTMENOPAUSAL WOMEN.
    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 "natural" estrogens are more or less hazardous than "synthetic" estrogens at equi-estrogenic doses.
  2. ESTROGENS SHOULD NOT BE USED DURING PREGNANCY.
    There is no indication for estrogen therapy during pregnancy or during the immediate postpartum period. Estrogens are ineffective for the prevention or treatment of threatened or habitual abortion. Estrogens are not indicated for the prevention of postpartum breast engorgement.
    Estrogen therapy during pregnancy is associated with an increased risk of congenital defects in the reproductive organs of the fetus, and possibly other birth defects. Studies of women who received diethylstilbestrol (DES) during pregnancy have shown that female offspring have an increased risk of vaginal adenosis, squamous cell dysplasia of the uterine cervix, and clear cell vaginal cancer later in life; male offspring have an increased risk of urogenital abnormalities and possibly testicular cancer later in life. The 1985 DES Task Force concluded that use of DES during pregnancy is associated with a subsequent increased risk of breast cancer in the mothers, although a causal relationship remains unproven and the observed level of excess risk is similar to that for a number of other breast cancer risk factors.

DESCRIPTION

Premarin Intravenous (conjugated estrogens, USP) for injection contains a mixture of estrogens obtained exclusively from natural sources, occurring as the sodium salts of water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mares' urine. It is a mixture of sodium estrone sulfate and sodium equilin sulfate. It contains as concomitant components, as sodium sulfate conjugates, 17(alpha)-dihydroequilin, 17(alpha)-estradiol, and 17(beta)-dihydroequilin.

Each Secule® vial contains 25 mg of conjugated estrogens, USP, in a sterile lyophilized cake which also contains lactose 200 mg, sodium citrate 12.2 mg, and simethicone 0.2 mg. The pH is adjusted with sodium hydroxide or hydrochloric acid. A sterile diluent (5 mL) containing 2% benzyl alcohol in sterile water is provided for reconstitution. The reconstituted solution is suitable for intravenous or intramuscular injection.

CLINICAL PHARMACOLOGY

Estrogen drug products act by regulating the transcription of a limited number of genes. Estrogens diffuse through cell membranes, distribute themselves throughout the cell, and bind to and activate the nuclear estrogen receptor, a DNA-binding protein which is found in estrogen-responsive tissues. The activated estrogen receptor binds to specific DNA sequences, or hormone-response elements, which enhance the transcription of adjacent genes and in turn lead to the observed effects. Estrogen receptors have been identified in tissues of the reproductive tract, breast, pituitary, hypothalamus, liver, and bone of women.

Estrogens are important in the development and maintenance of the female reproductive system and secondary sex characteristics. By a direct action, they cause growth and development of the uterus, fallopian tubes, and vagina. With other hormones, such as pituitary hormones and progesterone, they cause enlargement of the breasts through promotion of ductal growth, stromal development, and the accretion of fat. Estrogens are intricately involved with other hormones, especially progesterone, in the processes of the ovulatory menstrual cycle and pregnancy, and affect the release of pituitary gonadotropins. They also contribute to the shaping of the skeleton, maintenance of tone and elasticity of urogenital structures, changes in the epiphyses of the long bones that allow for the pubertal growth spurt and its termination, and pigmentation of the nipples and genitals.

Estrogens occur naturally in several forms. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 micrograms of estradiol daily, depending on the phase of the menstrual cycle. This is converted primarily to estrone, which circulates in roughly equal proportion to estradiol, and to small amounts of estriol. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone--especially in its sulfate ester form--is the most abundant circulating estrogen in postmenopausal women. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than estrone or estriol at the receptor.

Conjugated estrogens used in therapy are soluble in water and 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 valerate or estradiol cypionate is absorbed over several weeks.

Administered estrogens and their esters are handled within the body essentially the same as the endogenous hormones. Metabolic conversion of estrogens occurs primarily in the liver (first pass effect), but also at local target tissue sites. Complex metabolic processes result in a dynamic equilibrium of circulating conjugated and unconjugated estrogenic forms which are continually interconverted, especially between estrone and estradiol and between esterified and non-esterified forms. Although naturally-occurring estrogens circulate in the blood largely bound to sex hormone-binding globulin (SHBG) and albumin, only unbound estrogens enter target tissue cells. A significant proportion of the circulating estrogen exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogenic species. A certain proportion of the estrogen is excreted into the bile, then reabsorbed from the intestine and returned to the liver through the portal venous system. During this enterohepatic recirculation, estrogens are desulfated and resulfated and undergo degradation through conversion to less active estrogens (estriol and other estrogens), oxidation to nonestrogenic substances (catecholestrogens, which interact with catecholamine metabolism, especially in the central nervous system), and conjugation with glucuronic acids (which are then rapidly excreted in the urine).

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 estrogenic 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.

INDICATIONS AND USAGE

Premarin Intravenous (conjugated estrogens, USP) for injection is indicated in the treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology.

CONTRAINDICATIONS

Estrogens should not be used in individuals with any of the following conditions:

  1. Known or suspected pregnancy (see Boxed Warning ). Estrogens may cause fetal harm when administered to a pregnant woman.
  2. Undiagnosed abnormal genital bleeding.
  3. Known or suspected cancer of the breast except in appropriately selected patients being treated for metastatic disease.
  4. Known or suspected estrogen-dependent neoplasia.
  5. Active or past history of thrombophlebitis or thromboembolic disorders
  6. Premarin Intravenous for injection should not be used in patients hypersensitive to its ingredients.

WARNINGS

  1. INDUCTION OF MALIGNANT NEOPLASMS.
    Breast cancer . While the majority of studies have not shown an increased risk of breast cancer in women who have ever used estrogen replacement therapy, some studies have reported a moderately increased risk (relative risks of 1.3 to 2.0) in those women taking higher doses or those taking lower doses for prolonged periods of time, especially in excess of 10 years. Other studies have not shown this relationship.
    Women on this therapy should have regular breast examinations and should be instructed in breast self-examination, and women over the age of 40 should have regular mammograms.
    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. In three studies, persistence of risk was demonstrated for 8 to over 15 years after cessation of estrogen treatment. In one study a significant decrease in the incidence of endometrial cancer occurred six months after estrogen withdrawal. Concurrent progestin therapy may offset this risk but the overall health impact in postmenopausal women is not known (see Precautions ).
    Congenital lesions with malignant potential. Estrogen therapy during pregnancy is associated with an increased risk of fetal congenital reproductive tract disorders, and possibly other birth defects. Studies of women who received DES during pregnancy have shown that female offspring have an increased risk of vaginal adenosis, squamous cell dysplasia of the uterine cervix, and clear cell vaginal cancer later in life; male offspring have an increased risk of urogenital abnormalities and possibly testicular cancer later in life. Although some of these changes are benign, others are precursors of malignancy.
  2. GALLBLADDER DISEASE. Two studies have reported a 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in women receiving postmenopausal estrogens.
  3. THROMBOEMBOLIC DISORDERS
    VENOUS THROMBOEMBOLISM. Several epidemiologic studies have found an increased risk of venous thromboembolism (VTE) in users of estrogen replacement therapy (ERT) who did not have predisposing conditions for VTE, such as past history of cardiovascular disease or a recent history of pregnancy, surgery, trauma, or serious illness. The increased risk was found only in current ERT users; it did not persist in former users. The risk appeared to be higher in the first year of use and decreased thereafter. The findings were similar for ERT alone or with added progestins and pertain to commonly used oral and transdermal doses, with a possible dose-dependent effect on risk. The studies found the VTE risk to be about one case per 10,000 women per year among women not using ERT and without predisposing conditions. The risk in current ERT users was increased to 2-3 cases per 10,000 women per year.
    CARDIOVASCULAR DISEASE. Embolic cerebrovascular events and myocardial infarctions have been reported in women receiving postmenopausal estrogens (see Precautions ).
    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 myocardial infarction, pulmonary embolism, and thrombophlebitis.
    The physician should be aware of the possibility of thrombotic disorders (thrombophlebitis, retinal thrombosis, cerebral embolism, and pulmonary embolism) during estrogen replacement therapy and be alert to their earliest manifestations. Should any of these occur or be suspected, estrogen replacement therapy should be discontinued immediately. Patients who have risk factors for thrombotic disorders should be kept under careful observation.
  4. ELEVATED BLOOD PRESSURE. Occasional blood pressure increases during estrogen replacement therapy have been attributed to idiosyncratic reactions to estrogens. More often, blood pressure has remained the same or has dropped. One study showed that postmenopausal estrogen users have higher blood pressure than nonusers. Two other studies showed slightly lower blood pressure among estrogen users compared to nonusers. Blood pressure should be monitored at regular intervals with estrogen use.
  5. HYPERCALCEMIA. Administration of estrogens may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If this occurs, the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

PRECAUTIONS

A. GENERAL

  1. Addition of a progestin . Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Morphological and biochemical studies of endometria suggest that 10 to 14 days of progestin are needed to provide maximal maturation of the endometrium and to reduce the likelihood of hyperplastic changes.
    There are, however, possible risks which may be associated with the use of progestins in estrogen replacement regimens. The potential risks include adverse effects on lipoprotein metabolism, impairment of glucose tolerance, and possible enhancement of mitotic activity in breast epithelial tissue, although few epidemiological data are available to address this point (see Precautions below).
    The choice of progestin, its dose, and its regimen may be important in minimizing these adverse effects, but these issues will require further study before they are clarified.
  2. Cardiovascular risk . The effects of estrogen replacement on the risk of cardiovascular disease have not been adequately studied. However, data from the Heart and Estrogen/Progestin Replacement Study (HERS), a controlled clinical trial of secondary prevention of 2,763 postmenopausal women with documented heart disease, demonstrated no benefit. During an average follow-up of 4.1 years, treatment with oral conjugated estrogens plus medroxyprogesterone acetate did not reduce the overall rate of coronary heart disease (CHD) events in postmenopausal women with established coronary disease. There were more CHD events in the hormone treated group than in the placebo group in year 1, but fewer events in years 3 though 5.
    A causal relationship between estrogen replacement therapy and reduction of cardiovascular disease in postmenopausal women has not been proven. Furthermore, the effect of added progestins on this putative benefit is not yet known.
    In recent years many published studies have suggested that there may be a cause-effect relationship between postmenopausal oral estrogen replacement therapy without added progestins and a decrease in cardiovascular disease in women. Although most of the observational studies which assessed this statistical association have reported a 20% to 50% reduction in coronary heart disease risk and associated mortality in estrogen takers, the following should be considered when interpreting these reports:
    1. Because only one of these studies was randomized and it was too small to yield statistically significant results, all relevant studies were subject to selection bias. Thus, the apparently reduced risk of coronary artery disease cannot be attributed with certainty to estrogen replacement therapy. It may instead have been caused by life-style and medical characteristics of the women studied with the result that healthier women were selected for estrogen therapy. In general, treated women were of higher socioeconomic and educational status, more slender, more physically active, more likely to have undergone surgical menopause, and less likely to have diabetes than the untreated women. Although some studies attempted to control for these selection factors, it is common for properly designed randomized trials to fail to confirm benefits suggested by less rigorous study designs. Thus, ongoing and future large-scale randomized trials may fail to confirm this apparent benefit.
    2. Current medical practice often includes the use of concomitant progestin therapy in women with intact uteri (see Precautions and Warnings ). While the effects of added progestins on the risk of ischemic heart disease are not known, all available progestins reverse at least some of the favorable effects of estrogens on HDL and LDL cholesterol levels.
    3. While the effects of added progestins on the risk of breast cancer are also unknown, available epidemiological evidence suggests that progestins do not reduce, and may enhance, the moderately increased breast cancer incidence that has been reported with prolonged estrogen replacement therapy (see Warnings ).

    Because relatively long-term use of estrogens by a woman with a uterus has been shown to increase the risk of endometrial cancer, physicians often recommend that these women should take progestins as well as estrogens. When considering prescribing concomitant estrogens and progestins for hormone replacement therapy, physicians and patients are advised to carefully weigh the potential benefits and risks of the added progestin. Large-scale randomized, placebo-controlled, clinical trials and future epidemiological studies are required to clarify these issues.
    Treated patients with an intact uterus should be monitored closely for signs of endometrial cancer, and appropriate diagnostic measures should be taken to rule out malignancy in the event of persistent or recurring abnormal vaginal bleeding.
  3. Physical examination . A complete medical and family history should be taken prior to the initiation of any estrogen therapy. The pretreatment and periodic physical examinations should include special reference to blood pressure, breasts, abdomen, and pelvic organs, and should include a Papanicolaou smear. As a general rule, estrogen should not be prescribed for longer than one year without reexamining the patient.
  4. Hypercoagulability . Some studies have shown that women taking estrogen replacement therapy have hypercoagulability, 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 premenopausal women. There is some suggestion that low dose postmenopausal mestranol may increase the risk of thromboembolism. There is insufficient information on hypercoagulability in women who have had previous thromboembolic disease.
  5. Thromboembolism . Based on data obtained with oral contraceptives, estrogens should be discontinued at least four weeks before surgery of the type associated with an increased risk of thromboembolism if feasible, or during periods of prolonged immobilization (see Warnings ).
  6. Familial hyperlipoproteinemia . Estrogen therapy may be associated with massive elevations of plasma triglycerides leading to pancreatitis and other complications in patients with familial defects of lipoprotein metabolism.
  7. Fluid retention . Because estrogens may cause some degree of fluid retention, conditions which might be exacerbated by this factor, such as asthma, epilepsy, migraine, and cardiac or renal dysfunction, require careful observation.
  8. Exacerbation of endometriosis . Endometriosis may be exacerbated with administration of estrogen therapy.
  9. Uterine bleeding and mastodynia . Certain patients may develop undesirable manifestations of estrogenic stimulation, such as abnormal uterine bleeding and mastodynia.
  10. Impaired liver function . Estrogens may be poorly metabolized in patients with impaired liver function and should be administered with caution.
  11. Uterine fibroids. Pre-existing uterine leiomyomata may increase in size during estrogen use.
  12. Hypocalcemia . Estrogens should be used with caution in individuals with metabolic bone disease associated with severe hypocalcemia.

B. INFORMATION FOR THE PATIENT.   See text of Patient Package Insert which appears after the How Supplied section.

C. LABORATORY TESTS.   Estrogen administration should generally be guided by clinical response at the smallest dose, rather than laboratory monitoring, for relief of symptoms for those indications in which symptoms are observable.

D. DRUG/LABORATORY TEST INTERACTIONS.

  1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
  2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered.
  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 or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
  4. Increased plasma HDL and HDL 2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglyceride levels.
  5. Impaired glucose tolerance.
  6. Reduced response to metyrapone test.
  7. Reduced serum folate concentration.

E. CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY.   Long term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. See Contraindications and Warnings .

F. PREGNANCY CATEGORY X.   Estrogens should not be used during pregnancy. See Contraindications and Boxed Warning .

G. NURSING MOTHERS.   As a general principle, the administration of any drug to nursing mothers should be done only when clearly necessary since many drugs are excreted in human milk. In addition, estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk.

H. PEDIATRIC USE.   Premarin Intravenous for injection is not indicated for pediatric use; therefore, safety and effectiveness of conjugated estrogens for injection in pediatric patients have not been established.

ADVERSE REACTIONS

The following additional adverse reactions have been reported with estrogen therapy (see Warnings regarding induction of malignant neoplasms, gallbladder disease, thromboembolic disorders, elevated blood pressure, and hypercalcemia; see Warnings and Precautions regarding cardiovascular risk).

  1. Genitourinary system .
    Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding, spotting.
    Increase in size of uterine leiomyomata.
    Vaginal candidiasis.
    Change in amount of cervical secretion.
  2. Breasts .
    Tenderness, enlargement.
  3. Gastrointestinal.
    Nausea, vomiting.
    Abdominal cramps, bloating.
    Cholestatic jaundice.
    Increased incidence of gallbladder disease.
    Pancreatitis.
  4. Skin
    Chloasma or melasma that may persist when drug is discontinued.
    Erythema multiforme.
    Erythema nodosum.
    Hemorrhagic eruption.
    Loss of scalp hair.
    Hirsutism.
  5. Cardiovascular
    Venous thromboembolism.
    Pulmonary embolism.
    Myocardial infarction.
    Stroke.
  6. Eyes .
    Steepening of corneal curvature.
    Intolerance to contact lenses.
  7. Central Nervous System.
    Headache.
    Migraine
    Dizziness.
    Mental depression.
    Chorea.
  8. Miscellaneous.
    Increase or decrease in weight.
    Reduced carbohydrate tolerance.
    Aggravation of porphyria.
    Edema.
    Changes in libido.
    Anaphylactoid/anaphylactic reactions.

OVERDOSAGE

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.

DOSAGE AND ADMINISTRATION

For treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology:

One 25 mg injection, intravenously or intramuscularly. Intravenous use is preferred since more rapid response can be expected from this mode of administration. Repeat in 6 to 12 hours if necessary. The use of Premarin Intravenous for injection does not preclude the advisability of other appropriate measures.

One should adhere to the usual precautionary measures governing intravenous administration. Injection should be made SLOWLY to obviate the occurrence of flushes.

Infusion of Premarin Intravenous for injection with other agents is not generally recommended. In emergencies, however, when an infusion has already been started it may be expedient to make the injection into the tubing just distal to the infusion needle. If so used, compatibility of solutions must be considered.

COMPATIBILITY OF SOLUTIONS: Premarin Intravenous is compatible with normal saline, dextrose, and invert sugar solutions. It is not compatible with protein hydrolysate, ascorbic acid, or any solution with an acid pH.

DIRECTIONS FOR STORAGE AND RECONSTITUTION

STORAGE BEFORE RECONSTITUTION: Store package in refrigerator, 2° to 8°C (36° to 46°F).

TO RECONSTITUTE: First withdraw air from Secule® vial so as to facilitate introduction of sterile diluent. Then, flow the sterile diluent slowly against the side of Secule® vial and agitate gently. Do not shake violently.

STORAGE AFTER RECONSTITUTION: It is common practice to utilize the reconstituted solution within a few hours. If it is necessary to keep the reconstituted solution for more than a few hours, store the reconstituted solution under refrigeration (2° to 8°C). Under these conditions, the solution is stable for 60 days, and is suitable for use unless darkening or precipitation occurs.

HOW SUPPLIED

NDC 0046-0749-05--Each package provides: (1) One Secule® vial containing 25 mg of conjugated estrogens, USP, for injection (also lactose 200 mg, sodium citrate 12.2 mg, and simethicone 0.2 mg). The pH is adjusted with sodium hydroxide or hydrochloric acid. (2) One 5 mL ampul of sterile diluent with 2% benzyl alcohol in sterile water.

Premarin Intravenous (conjugated estrogens, USP) for injection is prepared by cryodesiccation.

SECULE®-Registered trademark to designate a vial containing an injectable preparation in dry form.

INFORMATION FOR THE PATIENT

Introduction

This leaflet describes when and how to use estrogens, and the risks and benefits of estrogen treatment.

Estrogens have important benefits but also some risks. You must decide, with your doctor, whether the risks to you of estrogen use are acceptable because of their benefits. If you decide to start taking estrogens, check with your doctor to make sure you are using the lowest possible effective dose, and that you use them for only as long as necessary. How long you need to use estrogens will depend on the reason for use.

  1. ESTROGENS INCREASE THE RISK OF CANCER OF THE UTERUS IN WOMEN WHO HAVE HAD THEIR MENOPAUSE ("CHANGE OF LIFE").
    If you use any estrogen-containing drug, it is important to visit your doctor regularly and report any unusual vaginal bleeding right away. Vaginal bleeding after menopause may be a warning sign of uterine cancer. Your doctor should evaluate any unusual vaginal bleeding to find out the cause.
  2. ESTROGENS SHOULD NOT BE USED DURING PREGNANCY.
    Estrogens do not prevent miscarriage (spontaneous abortion) and are not needed in the days following childbirth. If you take estrogens during pregnancy, your unborn child has a greater than usual chance of having birth defects. The risk of developing these defects is small, but clearly larger than the risk in children whose mothers did not take estrogens during pregnancy. These birth defects may affect the baby' urinary system and sex organs. Daughters born to mothers who took DES (an estrogen drug) have a higher than usual chance of developing cancer of the vagina or cervix when they become teenagers or young adults. Sons may have a higher than usual chance of developing cancer of the testicles when they become teenagers or young adults

Uses of Estrogen

(Not every estrogen drug is approved for every use listed in this section. If you want to know which of these possible uses are approved for the medicine prescribed for you, ask your doctor or pharmacist to show you the professional labeling. You can also look up the specific estrogen product in a book called The Physician' Desk Reference , which is available in many book stores and public libraries. Generic drugs carry virtually the same labeling information as their brand name versions.)

To reduce moderate to severe menopausal symptoms.

Estrogens are hormones made by the ovaries of normal women. Between ages 45 and 55, the ovaries normally stop making estrogens. This leads to a drop in body estrogen levels which causes the "change of life" or menopause (the end of monthly menstrual periods). If both ovaries are removed during an operation before natural menopause takes place, the sudden drop in estrogen levels causes "surgical menopause."

When the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden intense episodes of heat and sweating ("hot flashes" or "hot flushes"). Using estrogen drugs can help the body adjust to lower estrogen levels and reduce these symptoms. In some women the symptoms are mild; in others they can be severe. These symptoms may last only a few months or longer. Conjugated estrogens can alleviate these symptoms. If you are not taking estrogen for other reasons, such as the prevention of osteoporosis, you should use conjugated estrogens only as long as you need them for relief from your menopausal symptoms.

To treat vulvar and vaginal atrophy (itching, burning, dryness in or around the vagina, difficulty or burning on urination) associated with menopause.

To treat certain conditions in which a young woman's ovaries do not produce enough estrogen naturally.

To treat certain types of abnormal uterine bleeding due to hormonal imbalance when your doctor has found no serious cause of the bleeding.

To treat certain cancers in special situations, in men and women.

To prevent thinning of bones.

Osteoporosis is a thinning of the bones that makes them weaker and allows them to break more easily. The bones of the spine, wrists and hips break most often in osteoporosis. Both men and women start to lose bone mass after about age 40, but women lose bone mass faster after the menopause. Using estrogens after the menopause slows down bone thinning and may prevent bones from breaking. Lifelong adequate calcium intake, either in the diet (such as dairy products) or by calcium supplements (to reach a total daily intake of 1000 milligrams per day before menopause or 1500 milligrams per day after menopause), may help to prevent osteoporosis. Regular weight-bearing exercise (like walking and running for an hour, two or three times a week) may also help to prevent osteoporosis. Before you change your calcium intake or exercise habits, it is important to discuss these lifestyle changes with your doctor to find out if they are safe for you.

Since estrogen use has some risks, only women who are likely to develop osteoporosis should use estrogens for prevention. Women who are likely to develop osteoporosis often have the following characteristics: white or Asian race, slim, cigarette smokers, and a family history of osteoporosis in a mother, sister, or aunt. Women who have relatively early menopause, often because their ovaries were removed during an operation ("surgical menopause"), are more likely to develop osteoporosis than women whose menopause happens at the average age.

Who Should Not Use Estrogens

Estrogens should not be used:

During pregnancy (see Boxed Warning ).

If you think you may be pregnant, do not use any form of estrogen-containing drug. Using estrogens while you are pregnant may cause your unborn child to have birth defects. Estrogens do not prevent miscarriage.

If you have unusual vaginal bleeding which has not been evaluated by your doctor (see Boxed Warning ).

Unusual vaginal bleeding can be a warning sign of cancer of the uterus, especially if it happens after menopause. Your doctor must find out the cause of the bleeding so that he or she can recommend the proper treatment. Taking estrogens without visiting your doctor can cause you serious harm if your vaginal bleeding is caused by cancer of the uterus.

If you have had cancer.

Since estrogens increase the risk of certain types of cancer, you should not use estrogens if you have ever had cancer of the breast or uterus, unless your doctor recommends that the drug may help in the cancer treatment. (For certain patients with breast or prostate cancer, estrogens may help.)

If you have any circulation problems.

Estrogen drugs should not be used except in unusually special situations in which your doctor judges that you need estrogen therapy so much that the risks are acceptable. Men and women with abnormal blood clotting conditions should avoid estrogen use (see Risks of Estrogens , below).

When they do not work.

During menopause, some women develop nervous symptoms or depression. Estrogens do not relieve these symptoms. You may have heard that taking estrogens for years after menopause will keep your skin soft and supple and keep you feeling young. There is no evidence for these claims and such long-term estrogen use may have serious risks.

After childbirth or when breastfeeding a baby.

Estrogens should not be used to try to stop the breasts from filling with milk after a baby is born. Such treatment may increase the risk of developing blood clots (see Risks of Estrogens , below).

If you are breastfeeding, you should avoid using any drugs because many drugs pass through to the baby in the milk. While nursing a baby, you should take drugs only on the advice of your health-care provider.

Risks of Estrogens

Cancer of the uterus.

Your risk of developing cancer of the uterus gets higher the longer you use estrogens and the larger doses you use. One study showed that after women stop taking estrogens, this higher cancer risk quickly returns to the usual level of risk (as if you had never used estrogen therapy). Three other studies showed that the cancer risk stayed high for 8 to more than 15 years after stopping estrogen treatment. Because of this risk, IT IS IMPORTANT TO TAKE THE LOWEST DOSE THAT WORKS AND TO TAKE IT ONLY AS LONG AS YOU NEED IT .

Using progestin therapy together with estrogen therapy may reduce the higher risk of uterine cancer related to estrogen use (but see Other Information , below).

If you have had your uterus removed (total hysterectomy), there is no risk of developing cancer of the uterus.

Cancer of the breast .

Most studies have not shown a higher risk of breast cancer in women who have ever used estrogens. However, some studies have reported that breast cancer developed more often (up to twice the usual rate) in women who used estrogens for long periods of time (especially more than 10 years), or who used higher doses for shorter time periods.

Regular breast examinations by a health professional and monthly self-examination are recommended for women receiving estrogen therapy, as they are for all women. Regular mammograms are recommended for all women over 40 years of age.

Gallbladder disease.

Women who use estrogens after menopause are more likely to develop gallbladder disease needing surgery than women who do not use estrogens.

Inflammation of the Pancreas (Pancreatitis).

Women with high triglyceride levels may have an increased risk of developing inflammation of the pancreas.

Abnormal blood clotting.

Taking estrogens may cause changes in your blood clotting system. These changes allow the blood to clot more easily, possibly allowing clots to form in your bloodstream. If blood clots do form in your bloodstream, they can cut off the blood supply to vital organs, causing serious problems. These problems may include a stroke (cutting off blood to the brain), a heart attack (cutting off blood to the heart), a pulmonary embolus (cutting off blood to the lungs), retinal thrombosis (cutting off blood vessels in the eye), or other problems. Any of these conditions may cause death or serious long term disability.

Endometriosis

Administration of estrogens may worsen endometriosis. If you have had endometriosis, speak with your health professional.

Cardiovascular Disease

A recent 4-year study suggests that women with a history of coronary heart disease may have an increased risk of serious cardiac events during the first year of treatment with estrogen/progestin therapy. Therefore, if you have had a heart attack, or you have been told you have blocked coronary arteries (arteries to your heart) or have any heart problem, you should consult your physician regarding the potential benefits and risks of estrogen/progestin therapy.

Side Effects

In addition to the risks listed above, the following side effects have been reported with estrogen use:

Nausea and vomiting.

Breast tenderness or enlargement.

Enlargement of benign tumors ("fibroids") of the uterus.

Retention of excess fluid. This may make some conditions worsen, such as asthma, epilepsy, migraine, heart disease, or kidney disease.

A spotty darkening of the skin, particularly on the face.

Reducing Risk of Estrogen Use

If you use estrogens, you can reduce your risks by doing these things:

See your doctor regularly.

While you are using estrogens, it is important to visit your doctor at least once a year for a check-up. If you develop vaginal bleeding while taking estrogens, you may need further evaluation. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram (breast x-ray), you may need to have more frequent breast examinations.

Reassess your need for estrogens.

You and your doctor should reevaluate whether or not you still need estrogens at least every six months.

Be alert for signs of trouble.

If any of these warning signals (or any other unusual symptoms) happen while you are using estrogens, call your doctor immediately:

Other Information

  1. Estrogens increase the risk of developing a condition (endometrial hyperplasia) that may lead to cancer of the lining of the uterus. Taking progestins, another hormonal drug, with estrogens lowers the risk of developing this condition. Therefore, if your uterus has not been removed, your doctor may prescribe a progestin for you to take together with the estrogen.
    You should know, however, that taking estrogens with progestins may have additional risks. These may include unhealthy effects on blood fats (especially the lowering of HDL blood cholesterol, the "good" blood fat which protects against heart disease). Other risks include unhealthy effects on blood sugars, which might make a diabetic condition worse, and a possible increase in breast cancer risk which may be associated with long-term estrogen use.
    Some research has shown that estrogens taken without progestins may protect women against developing heart disease. However, this is not certain. The protection shown may have been caused by the characteristics of the estrogen-treated women, and not by the estrogen treatment itself. In general, treated women were slimmer, more physically active, and were less likely to have diabetes than the untreated women. These characteristics are known to protect against heart disease.
    You are cautioned to discuss very carefully with your doctor or health-care provider all the possible risks and benefits of long-term estrogen and progestin treatment as they affect you personally.
  2. Your doctor has prescribed this drug for you and you alone. Do not give the drug to anyone else.
  3. If you will be taking calcium supplements as part of the treatment to help prevent osteoporosis, check with your doctor about the amounts recommended.
  4. Keep this and all drugs out of the reach of children. In case of overdose, call your doctor, hospital or poison control center immediately.
  5. This leaflet provides a summary of the most important information about estrogens. If you want more information, ask your doctor or pharmacist to show you the professional labeling. The professional labeling is also published in a book called The Physicians' Desk Reference, which is available in bookstores and public libraries. Generic drugs carry virtually the same labeling information as their brand name versions.

HOW SUPPLIED

Each Premarin Intravenous (conjugated estrogens, USP) for injection package provides 25 mg of conjugated estrogens, USP, in dry form and 5 mLs of sterile diluent for intravenous or intramuscular use.

Manufactured by:

Ayerst Laboratories

A Wyeth-Ayerst Company

Philadelphia, PA 19101

CI 7412-1                          Revised July 23, 2001



Copyright© 2002 Medical Economics