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 currently no evidence that natural estrogens are more or less hazardous than "synthetic" estrogens at equiestrogenic doses

2. ESTROGENS SHOULD NOT BE USED DURING PREGNANCY

Estrogen therapy during pregnancy is associated with an increased risk of congenital defects In the reproductive organs of the male and female fetus, and increased risk of vagina adenosis, squamouscell dysplasia of the uterine cervix and vaginal cancer in the female later in life. The 1985 DES Task Force concluded that women who used DES during their pregnancies may subsequently experience an increased risk of breast cancer. However a cause relationship is still unproven and the observed level of risk is is similar to that for a number of other breast cancer risk factors.

There is no indication for estrogen therapy during pregnancy. Estrogens are ineffective for the prevention or treatment of threatened or habitual abortion.

Description:
Premarin (r) (conjugated estrogens tablets USP) for oral administration contains a mixture of estrogens obtained exclusively from natural sources, occuring as the sodium salts of watersoluble estrogen sulfates blended to represent the average composition of material derived from pregnant mares' urine. It contains estrone, equilin, and 17-alpha-dihydroequlin, together with smaller amounts of 17-alpha-estradiol equilenin and 17-alphadihydroequilenin as salts of their sulfate esters. Tablets for oral administration are available in 0.3 mg, 0.525 mg, 0.9 mg, 1.25 mg, and 2.5 mg strengths of conjugated estrogens

Premarin tablets contain the following inactive ingredients: calcium phosphate tribasic, calcium sulfate, carnauba wax, cellulose, glyceryl monooleate, lactose, magnesium stearate, methylcellulose, pharmaceutical glaze, polyethylene glycol, stearic acid, sucrose, talc, titanium dioxide.

-0.3 mg tablets also contain: D&C; Yellow No 1O, FD&C; Blue No 1, FD&C; Bue No 2, FDA&C; Yellow No 6;
-0.625 mG tablets also contain: FD&C; Blue No 2, D&C; Red No 27, FD&C; Red No 40;
-0.9 mg tablets also contain D & C Red No 6, D & C Red No 7, polysorbate 20;
-1.25 mg tablets also contain: black iron oxide, D & C Yellow No 10, F D & C Yellow No 6;
-2.5 mg tablets also contain: F D & C Blue No 2, D & C Red No 7.

Clinical Pharmacology
Estrogens are important in the development and maintenance of the female reproductive system and secondary sex characteristics. They promote growth and development of the vagina, uterus, and fallopian tubes and enlargement of the breasts. Indirectly they 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 growth of ancillary and pubic hair and pigmentation of nipples and genitals.

Decline of estrogenic activity at the end of menstrual cycle can bring on menstruation although the cessation of progesterone secretion is the most important factor in the mature ovulatory cycle. However in the preovulatory or non-ovulatory cycle estrogen is the primary determinant in the onset of menstruation. Estrogens also affect the release of pituitary gonadotropins.

The pharmacologic effects of conjugated estrogens are similar to those of endogenous estrogens. They are soluble in water and are well absorbed from the gastrointestinal tract. In responsive tissues (female genital organs, breasts, hypothalamus, pituitary) estrogens enter the cell and are transported into the nucleus. As a result of estrogen action, specific RNA and protein synthesis occurs. Metsbolism and inactivation occur primarily in the liver. Some estrogens are excreted into the bile; however, they are reabsorbed from the intestine and returned to the liver through the portal venous system. Water-soluble estrogen conjugates are strongly acidic and are ionized in body fluids which favor excretion through the kidneys since tubular reabsorption is minimal.

Indications and Usage
Premarin (conjugated estrogens tablets USP) is indicated in the treatment of:

1. Moderate to severe vasomotor symptoms associated with the menopause. There is no adequate evidence that estrogens are effective for nervous symptoms or depression which might occur during menopause and they should not be used to treat these conditions.

2. Atrophic vaginitis

3. Osteoporosis (loss of bone mass.) The mainstays of prevention and management of osteoporosis are estrogen and calcium; exercise and nutrition may be important adjuncts.

Estrogen replacement therapy is the most effective single modality for the prevention of osteoporosis in women. Estrogen reduces bone resorption and retards or halts postmenopausal bone loss. Case controlled studies have shown an approximately 60 percent reduction in hip and wrist fractures in women whose estrogen replacement was begun within a few years of menopause. Studies also suggest that estrogen reduces the rateof vertebral fractures. Even when started as late as 6 years after menopause, estrogen prevents further loss of bone mass but does not restore it to postmenopausal levels. The lowest effective dose for prevention and treatment of osteoporosis should be utilized (See "Dosage an Administration." )

Women are at higher risk than men because they have less bone mass and for several years following natural or induced menopause, the rate of bone mass decline is accelerated. Early menopause is one of the strongest predictors for the development of osteoporosis. White women are at higher risk than black women and white men are at higher risk than black men. Women who are underweight also have osteoporosis more often than overweight women. Cigarette smoking may be an additional factor in increasing risk. Calcium deficiency has been implicated in the pathogenesis of this disease. Therefore, when not contraindicated , it is recommended that postmenopausal women receive an elemental calcium intake of 1000 to 1500 mg/day

Immobilization and prolonged bed rest produce rapid bone loss while weight-bearing exercise has been shown both to reduce bone loss and to increase bone mass. The optimal type and amount of physical activity that would prevent osteoporosis have not been es established.

4. Hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.

5. Breast cancer (for palliation only) in appropriately selected women and men with metastatic disease.

6. Advanced androgendependent carcinoma of the prostate (for palliation only)

Contraindications
Estrogens should not be used in women (or men) with any of the following conditions:

1. Known or suspected pregnancy (see Boxed Warning.) Estrogen may cause fetal harm when administered to a pregnant woman.
2. Known or suspected cancer of the breast exceptappropriately selected patients being treated for metastatic disease.
3. Known or suspected estrogendependent neoplasia.
4. Undiagnosed abnormal genital bleeding.
5. Atlive thrombophlebitis or thromboembolic disorders.
6. Women on estrogen replacement therapy have not been reported to have an increased risk of thrombophlebitis and/or thromboemolic disease.
7. Premarin tablets should not be used in patients hypersensitive to their ingredients.

Warnings
1. Induction of malignant neoplasms. Some studies have suggested a possible increased incidence of breast cancer in those women on estrogen therapy taking higher doses for prolonged periods of time.

The majority of studies however have not shown an association with the usual doses used for estrogen replacement therapy. Women on this therapy should have regular breast examinations and should be instructed in breast selfexamination. The reported endometrial cancer risk among estrogen users was about 4-fold or greater than in nonusers and appears dependent on duration of treatment and on estrogen dose. There is no significant increased risk associated with the use of estrogens for less than one year. The greatest risk appears associated with prolonged use-five years or more. In one study persistence of risk was demonstrated for 10 years after cessation of estrogen treatment. In another study a significant decrease in the incidence of endometrial cancer occurred six months after estrogen withdrawal.

Estrogen therapy during pregnancy is associated with an increased risk of fetal congenital reproductivetract disorders. In females there is an increased risk of vaginal adenosis squamouscell dysplasia of the cervix and cancer later In life; in the male urogenital abnormalities. Although some of these changes are benign, it is not known whether they are precursors of a malignancy.

2. Gallbladder Disease. A recent study has reported a 2.5fold increase in the risk of surgically confirmed gallbladder disease in women receiving postmenopausal estrogens.

3. Cardiovascular disease .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 risk of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis. It cannot necessarily be exptrapolated from men to women. Howewer to avoid the theoretical cardiovascular risk caused by high estrogen doses, the doses for estrogen replacement therapy should not exceed the recommended dose.

4. Elevated blood pressure. There is no evidence that this may occur with use of estrogens in the menopause. However blood pressure should be monitored with estrogen use, especially if high doses are used.

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 Ievel.

Precautions
A. GENERAL

1. Addition of a progestin . Studies of the addition on of a progestin for seven or more days of a cycle of estrogen administration have reported a lowered incidence of endometrial hyperplasia. Morphological and biochemical studies of endometrium suggest that 10 to 13 days of progestin are needed to provide maximum maturation of the endometrium and to eliminate any hypeplastic changes. Whether this will provide protection from endometrial carcinoma has not been clearly established. There are possible additional risks which may be associated with the Inclusion of progestin in estrogen replacement regimens. The potential risks include adverse erects on carbohydrate and lipid metabolism. The choice of progestin and dosage may be important in minimizing these adverse effects.

2. 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 another physical examination being performed.

3. Fluid retention. because estrogens may cause some degree of fluid retention, conditions which might be influenced by this factor, such as asthma, epilepsy, migraine, and cardiac or renal dysfunction, require careful observation.

4. Uterine bleeding and mastodynia. Certain patients may develop undesirable manifestations of estrogenic stimulation such as abnormal uterine bleeding and mastodynia.

5.Uterine fibroids. Preexisting uterine leiomyomata may increase in size during prolonged highdose estrogen use.

6. Impaired liver function . Estrogens may he poorly metabolized in patients with impaired liver function and should be administered with caution.

7. Hypercalcemia and renal insufficiency. Prolonged use of estrogens can alter the metabolism of calcium and phosphorus. Estrogens should be used with caution in patients with metabolic bone disease.

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

C. LABORATORY TESTS.
Clinical response at the smallest dose should generally be the guide to estrogen administration for relief of symptoms for those indications in which symptoms are observable. However, for prevention and treatment of osteoporosis, see "Dosage and Administration" section. Tests used to measure adequacy of estrogen replacement therapy include serum estrone and estradiol levels and suppression of serum gonadotrophin levels.

D. DRUG/LABORATORY TEST INTERACTIONS.

Some of these drug/laboratory test interactions have been observed only with estrogen-progestin combinations (oral contraceptives):

1. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased nore-pinephrineinduced platelet aggregability, decreased fibrinolysis.

2. Increased thyroidbinding globulin (TBG) leading to increased circulatory total thyroid hormone, as measured by T4 levels determined either by column or by radioimmunoassay. Free T3 resin uptake is decreased reflecting the elevated TBG; free T4 concentration is unaltered.

3. Impaired glucose tolerance

4. Reduced response to metyrapone test.

5. Reduced serum folate concentration.

E. MUTAGENESIS AND CARCINOGENESIS

Longterm continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, cervix, vagina, and liver.

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.

Adverse Reactions

(See "Warnings" regarding induction of neoplasia, adverse effects on the fetus, increased incidence of gallbladder disease.) The following additional adverse reactions have been reported with estrogen therapy.

1. Genitourinary system. Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow. Breakthrough bleeding, spotting. Increase in size of uterine fibromyomata. Vaginal candidiasis. Change in amount of cervical secretion.

2. Breasts. Tenderness, enlargement.

3. GastrointestinaI Nausea. Vomiting; abdominal cramps, bloating; cholestatic jaundice.

4. Skin Chloasma or melasma that may persist when drug is discontinued; erythema multiforme; erytheme nodosum hemorrhagic eruption; loss of scalp hair; hirsutism.

5. Eyes. Steepening of corneal curvature; intolerance of contact lenses.

6. CNS. Headache, migraine, dizziness; mental depression; chorea.

7. Miscellaneous. Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; changes in libido.

Acute Overdosage

Numerous reports of ingestion of large doses of estrogencontaining oral contraceptives by young children indicate that acute serious ill effects do not occur. Overdosage of estrogen may cause nausea and vomiting.

Dosage and Administration

1. For treatment of moderate to severe vasomotor symptoms and atrophic vaginitis associated with the menopause The lowest dose that will control symptoms should be chosen and medication should be discontinued as promptly as possible

Attempts to discontinue or taper medication should be made at 3month to 6 month intervals.

USUAL DOSAGE RANGES:

Vasomotor symptoms-1.25 mg daily. If the patient has not menstruated within the last two months or more cyclic administration is started arbitrarily If the patient is menstruating, cyclic (e.g. three weeks on and one week off) administration is started on day 5 of bleeding.

Alrophic vaginitis-0.3 mg to 1.25 mg or more daily depending upon the tissue response of the individual patient. Administer cyclically.

2. Hypoestrogenism due to:

a: Female hypogonadism-2.5 mg to 7.5 mg daily in divided doses for 20 days followed by a rest period of 10 days duration. If bleeding does not occur by the end of this period, the same dosage schedule is repeated The number of courses of estrogen therapy necessary to produce bleeding may vary depending on the responsiveness of the endometrium. If bleeding occurs before the end of the 10day period begin a 20day estrogenprogestin cyclic regimen with Premarin 2 5 mg to 7.5 mg daily in divided doses for 20 days. During the last five days of estrogen therapy give an oral progestin. If bleeding occurs before this regimen is concluded therapy is discontinued and may be resumed on the fifth day of bleeding.

b. Female castration or primary ovarian failure-1.25 mg daily, cyclically. Adjust dosage upward or downward according to severity of symptoms and response to the patient. For maintenance adjust dosage to lowest level that will provide effective control.

3. Osteoporosis (loss of bone mass)-0.625 mg daily. Administration should be cyclic (e.g. three weeks on and one week off).

4. Advanced androgendependent carcinoma of the prostate for palliation only-1.25 mg to 2.5 mg three times daily. The effectiveness of therapy can be judged by phosphatase determinations as well as bysymptomatic improvement of the patient.

5. Breast cancer (for palliation only) in appropriately selected women and men with metastatic disease. Suggested dosage is 10 mg three times daily for a period of at least three months.

Treated patients with an intact uterus should be monitored closely for signs ol endometrial cancer. and appropriate diagnostic measures should be taken to rule out malignancy in the event of persistent or recurring abnormal vaginal bleeding.

How Supplied Premarin(R) (conjugated estrogens tablets USP)

-Each oval purple tablet contains 2.5 mg in bottles of 100 (NDC 00460865-81 ) and 1, 000 (NCC 0046-0865-91)

-Each oval yellow tablet Contains 1.25 mg in bottles ol 100 (NDC 0046 086681);1000 (NDC 0046 0866-91); 5,000 (NDC 00460865-95); and UnitDose packages of 100 (NDC 00460866 99)

-Each oval white tablet contains 0.9 mg in bottles of 100 (NDC 0046066481)

-Each oval maroon tablet contains 0.625 mg in bottles of 100 (NDC 0046086781 ); 1,000 (NDC 0046-086791); 5 000 (NDC 0046 086795 ); and Unit Dose packages of 100 (NDC 0046086799)

-Each oval Green tablet contains 0.3 mg in bottles of 100 (NDC 0046086881) and 1,000 (NDC 00460868-91)

The appearance of these tablets is a trademark of WyethAyerst Laboratories.

Store at room temperature (approximately 25 deg. C).

Dispense In a wellclosed container as defined in the USP.

Intormation for the Patient

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

Estrogen Drugs uses of estrogen

To reduce menopausal symptoms. Estrogens are hormones produced by the ovaries. The decrease in the amount of estrogen that occurs in all women, usually between ages 45 and 55, causes the menopause. Sometimes the ovaries are removed by an operation, causing "surgical menopause." When the amount of estrogen begins to decrease, 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"). The use of drugs containing estrogens can help the body adjust to lower estrogen levels.

Most women have none or only mild menopausal symptoms and do not need estrogens. Other women may need estrogens for a few months while their bodies adjust to lower estrogen levels. The majority of women do not need estrogen replacement for longer than six months for these symptoms.

To prevent brittle bones, After age 40 and especially after menopause some women develop osteoporosis. This is a thinning of the bones that makes them weaker and more likely to break, often leading to fracture of vertebrae, hip, and wrist bones. Taking estrogens after the menopause slows down bone loss and may prevent bones from breaking. Eating foods that are high in calcium (such as milk products) or taking calcium supplements (1000 to 1500 milligrams per day) and certain types of exercise may also help prevent osteoporosis.

Since estrogen use is associated with some risk, its use in prevention of osteoporosis should be confined to women who appear to be susceptible to this condition. The following characteristics are often present in women who are likely to develop osteoperosis: white race, thinness, and cigarette smoking.

Women who had their menopause by the surgical removal of their ovaries at a relatively young age are good candidates for estrogen replacement therapy to prevent osteoporosis.

To treat certain types of abnormal uterine bleeding due to hormonal imbalance.

To treat atrophic vaginitis (itching, burning, dryness in or around the vagina.)

To treat certain cancers

When Estrogens Should Not Be Used:

During Pregnancy. Although the possibility is fairly small, there is a greater risk of having a child born with birth defect if you take estrogens during pregnancy. A male child may have an increased risk of developing abnormalities of the urinary system and sex organs. A female child may have an increased risk of developing cancer of thee vagina or cervix in her teens or twenties. Estrogen is not effective in preventing miscarriage (abortion.)

If you have had any heart or circulation problems, estrogen therapy should be used only after consultation with your physician and only in recommended doses. Patients with a tendency for abnormal blood clotting should avoid estrogen use (see below).

If you have had cancer. Since estrogens increase the risk of certain cancers you should not take estrogens if you have ever had cancer of the breast or uterus. In certain situations your doctor may choose to use estrogen in the treatment of breast cancer.

When they are ineffective. Sometimes women experience nervous symptoms or depression during menopause. There is no evidence that estrogens are effective for such symptoms. You may have heard that taking estrogens for long periods (years) after menopause will keep your skin soft and supple and keep you feeling young. There is no evidence that this is so and such longterm treatment may carry serious risks.

Dangers of Estrogens

Cancer of the uterus. The risk of cancer of the uterus increases the longer estrogens are used and when larger doses are taken. One Study showed that when estrogens are discontinued this increased risk of cancer seems to fall off quickly. In another study the persistence of risk was demonstrated for 10 years after stopping estrogen treatment. Because of this risk it is important to take the lowest dose of estrogen that will control your symptoms and to take it only as long as you need it. There is a higher risk of cancer of the uterus if you are overweight, diabetic, or have high blood pressure.

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

Cancer of the breast. The majority of studies have shown no association with the usual doses used for estrogen replacement therapy and breast cancer. Some studies have suggested a possible increased incidence of breast cancer in those women taking estrogens for prolonged periods of time and especially if high doses are used.

Regular breast examinations by a health professional and selfexamination are recommended for women receiving estrogen therapy as they are for all women.

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

Abnormal blood clotting. Taking estrogens may increase the risk of blood clots. These clots can cause a stroke, heart attack or pulmonary embolus, any of which may be fatal.

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 of the uterus.

· Retention ol 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 decide to take estrogens you can reduce your risks by carefully monitoring your treatment.

See your doctor regularly. While you are taking estrogens, it is important that you visit your doctor at least once a year for a physical examination. If members of your family have had breast cancer or if you have ever had breast nodules or an abnormal mammogram (breast x-ray) you may need to have more frequent breast examinations.

Reevaluate your need for estrogens. You and your doctor should reevaluate your need for estrogens at least every six months.

Be alert for signs of trouble. Report these or any other unusual side effects to your doctor immediately:

· Abnormal bleeding from the vagina.

· Pains in the calves or chest, a sudden shortness of breath or coughing blood (indicating possible clots in the legs, heart, or lungs.)

· Severe headache, dizziness, faintness, or changes in vision indicating possible clots in the brain or eye.

· Breast lumps.

· Yellowing of the skin.

· Pain, swelling, or tenderness in the abdomen.

Other Information

Some physicians may choose to prescribe another hormonal drug to be used in association with estrogen treatment. These drugs, progestins, have been reported to lower the frequency of occurrence of a possible precancerous condition of the uterine lining. Whether this will provide protection from uterine cancer has not been clearly established There are possible additional risks that may be associated with the inclusion of a progestin in estrogen treatment. The possible risks include unfavorable effects on blood fats and sugars. The choice of progestin and its dosage may be important in minimizing these effects.

Your doctor has prescribed this drug for you and you alone. Do not give the drug to anyone else.

If you will be taking calcium supplements as part of the treatment to help prevent osteoporosis, check with your doctor about the amounts recommended.

Keep this and all drugs out of the reach of children. In case of overdose, call your doctor, hospital, or poison control center immediately.

This leaflet provides the most important information about estrogens If you want to read more, ask your doctor or pharmacist to let you read the professional labeling.

How Supplied

Premarin (r) (conjugated estrogens tablets USP)- tablets for oral administration.

Each oval purple tablet contains 2.5 mg.

Each oval yellow tablet contains 1.25 mg.

Each oval white tablet contains 0.9 mg.

Each oval maroon tablet contains 0.625 mg .

Each oval green tablet contains 0.3 mg.

The appearance of these tablets is a trademark of Wyeth Ayerst Laboratories.

AYERST LAEORATORIES INC.
A Wyeth-Ayerst Company
Philadelphia, PA 19101
Revised May 13, 1993