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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.
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.
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.
Estrogens should not be used in individuals with any of the following conditions:
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.
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.
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).
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.
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.
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.
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.
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.
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(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.
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.
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.
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.
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.
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.
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.
In addition to the risks listed above, the following side effects have been reported with estrogen use:
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.
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:
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