Rx only

DESCRIPTION

Each gram of Premarin® (conjugated estrogens) Vaginal Cream contains 0.625 mg conjugated estrogens, USP in a nonliquefying base containing cetyl esters wax, cetyl alcohol, white wax, glyceryl monostearate, propylene glycol monostearate, methyl stearate, benzyl alcohol, sodium lauryl sulfate, glycerin, and mineral oil. Premarin Vaginal Cream is applied intravaginally.

Premarin (conjugated estrogens) is 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 contains estrone, equilin, and 17 (alpha)-dihydroequilin, together with smaller amounts of 17 (alpha)-estradiol, equilenin, and 17 (alpha)-dihydroequilenin as salts of their sulfate esters.

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 axillary and pubic hair, and pigmentation of the nipples and genitals. Decline of estrogenic activity at the end of the 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 nonovulatory 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 may be absorbed from mucosal surfaces after local administration.

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.

Metabolism 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, therefore, ionized in body fluids, which favor excretion through the kidneys since tubular reabsorption is minimal.

INDICATIONS AND USAGE

Premarin (conjugated estrogens) Vaginal Cream is indicated in the treatment of atrophic vaginitis and kraurosis vulvae.

Premarin Vaginal Cream HAS NOT BEEN SHOWN TO BE EFFECTIVE FOR ANY PURPOSE DURING PREGNANCY AND ITS USE MAY CAUSE SEVERE HARM TO THE FETUS (SEE BOXED WARNING).

CONTRAINDICATIONS

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

1. Known or suspected cancer of the breast except in appropriately selected patients being treated for metastatic disease.
2. Known or suspected estrogen-dependent neoplasia.
3. Known or suspected pregnancy (see Boxed Warning).
4. Undiagnosed abnormal genital bleeding.
5. Active or past history of thrombophlebitis or thromboembolic disorders.
6. Premarin Vaginal Cream 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 of 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-examinations, 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 receive 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 chances are benign, others are precursors of malignancy.

2. Gallbladder disease. A study has reported a 2- to 3-fold increase in the risk of surgically confirmed gallbladder disease in women receiving post-menopausal estrogens, similar to the 2-fold increase previously noted in users of oral contraceptives.

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.

If feasible, estrogen should be discontinued at least 4 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

Cardiovascular disease. Embolic cerebrovascular events have been reported in women receiving postmenopausal estrogens.

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.

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 of 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.

6. Effects similar to those caused by estrogen-progestogen oral contraceptives.

1. Hepatic adenoma. Benign hepatic adenomas appear to be associated with the use of oral contraceptives. Although benign, and rare, these may rupture and may cause death through intra-abdominal hemorrhage. Such lesions have not yet been reported in association with other estrogen or progestogen preparations but should be considered in estrogen users having abdominal pain and tenderness, abdominal mass, or hypovolemic shock.
   Hepatocellular carcinoma has also been reported in women taking estrogen-containing oral contraceptives. The relationship of this malignancy to these drugs is not known at this time.
2. Glucose tolerance. A worsening of glucose tolerance has been observed in a significant percentage of patients on estrogen-containing oral contraceptives. For this reason, diabetic patients should be carefully observed while receiving estrogen.

PRECAUTIONS

A. General Precautions.

1. 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 through 5.
2. 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, estrogens 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. 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.
5. Certain patients may develop undesirable manifestations of excessive estrogenic stimulation, such as abnormal or excessive uterine bleeding, mastodynia, etc.
6. Endometriosis may be exacerbated with administration of estrogen therapy.
7. Prolonged administration of unopposed estrogen therapy has been reported to increase the risk of endometrial hyperplasia in some patients.
8. Oral contraceptives appear to be associated with an increased incidence of mental depression. Although it is not clear whether this is due to the estrogenic or progestogenic component of the contraceptive, patients with a history of depression should be carefully observed.
9. Preexisting uterine leiomyomata may increase in size during estrogen use.
10. The pathologist should be advised of estrogen therapy when relevant specimens are submitted.
11. Patients with a past history of jaundice during pregnancy have an increased risk of recurrence of jaundice while receiving estrogen-containing oral contraceptive therapy. If jaundice develops in any patient receiving estrogen, the medication should be discontinued while the cause is investigated.
12. Estrogens may be poorly metabolized in patients with impaired liver function and should be administered with caution in such patients.
13. Because estrogens influence the metabolism of calcium and phosphorus, they should be used with caution in patients with metabolic bone diseases that are associated with hypercalcemia or in patients with renal insufficiency.
14. Because of the effects of estrogens on epiphyseal closure, they should be used judiciously in young patients in whom bone growth is not yet complete.
15. Barrier contraceptives - Premarin Vaginal Cream exposure has been reported to weaken latex condoms. The potential for Premarin Vaginal Cream to weaken and contribute to the failure of condoms, diaphragms, or cervical caps made of latex or rubber should be considered.

Concomitant Progestin Use:

The lowest effective dose appropriate for the specific indication should be utilized. Studies of the addition of a progestin for 7 or more days of a cycle of estrogen administration have reported a lowered incidence of endometrial hyperplasia. Morphological and biochemical studies of the endometrium suggest that 10 to 13 days of progestin are needed to provide maximal maturation of the endometrium and to eliminate any hyperplastic 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. If concomitant progestin therapy is used, potential risks may include adverse effects on carbohydrate and lipid metabolism. The choice of progestin and dosage may be important in minimizing these adverse effects.

B. Information For Patients

(See text which appears after the " HOW SUPPLIED " section.)

C. Drug/Laboratory Test Interactions

Certain endocrine and liver function tests may be affected by estrogen-containing oral contraceptives. The following similar changes may be expected with larger doses of estrogen:

1. Increased sulfobromophthalein retention.
2. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.
3. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by PBI, T ₄ by column, or T ₄ by radioimmunoassay. Free T ₃ resin uptake is decreased, reflecting the elevated TBG; free T ₄ concentration is unaltered.
4. Impaired glucose tolerance.
5. Decreased pregnanediol excretion.
6. Reduced response to metyrapone test.
7. Reduced serum folate concentration.
8. Increased serum triglyceride and phospholipid concentration.

D. Carcinogenesis, Mutagenesis, Impairment Of Fertility

(See WARNINGS section for information on carcinogenesis.)

E. Pregnancy Category X

(See CONTRAINDICATIONS and Boxed Warning.)

F. Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from estrogens, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

G. Pediatric Use

Safety and effectiveness 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, hypercalcemia, and effects similar to those caused by estrogen-progestogen oral contraceptives; see " Warnings " and " Precautions " regarding cardiovascular risk).

1.    Genitourinary system: Breakthrough bleeding, spotting, change in menstrual flow; dysmenorrhea; premenstrual-like syndrome; amenorrhea during and after treatment; increase in size of uterine fibromyomata; vaginal candidiasis; change in cervical erosion and in degree of cervical secretion; cystitis-like syndrome.
2.    Breasts:  Tenderness, enlargement, secretion.
3.    Gastrointestinal Nausea, vomiting, abdominal cramps, bloating; cholestatic jaundice, pancreatitis; ; increased incidence of gallbladder disease.
4.    Skin:  Chloasma or melasma which may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism.
5.    Cardiovascular   Venous thromboembolism, pulmonary embolism.
6.    Eyes:  Steepening of corneal curvature; intolerance to contact lenses.
7.    CNS:  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

Numerous reports of ingestion of large doses of estrogen-containing oral contraceptives by young children indicate that acute serious ill effects do not occur. Overdosage of estrogens may cause nausea, and withdrawal bleeding may occur in females.

DOSAGE AND ADMINISTRATION

Given cyclically for short-term use only:

For treatment of atrophic vaginitis, or kraurosis vulvae.

The lowest dose that will control symptoms should be chosen and medication should be discontinued as promptly as possible.

Administration should be cyclic (e.g., three weeks on and one week off).

Attempts to discontinue or taper medication should be made at three- to six-month intervals.

Usual Dosage Range:

¹ / ₂   to 2 g daily, intravaginally, depending on the severity of the condition.

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.

Instructions for Use of Gentle Measure ^TM Applicator

1.   Remove cap from tube.
2.   Screw nozzle end of applicator onto tube.
3.    Gently squeeze tube from the bottom to force sufficient cream into the barrel to provide the prescribed dose. Use the marked stopping points on the applicator as a guideline to measure the correct dose.
4.   Unscrew applicator from tube.
5.   Lie on back with knees drawn up. To deliver medication, gently insert applicator deeply into vagina and press plunger downward to its original position.
   TO CLEANSE: Pull plunger to remove it from barrel. Wash with mild soap and warm water.
   DO NOT BOIL OR USE HOT WATER.

HOW SUPPLIED

Premarin® (conjugated estrogens) Vaginal Cream--Each gram contains 0.625 mg conjugated estrogens, USP.

Combination package:  Each contains Net Wt. 1 ¹ / ₂ oz (42.5 g) tube with one plastic applicator calibrated in ¹ / ₂ g increments to a maximum of 2 g (NDC 0046-0872-93).

Also Available--Refill package:  Each contains Net Wt. 1 ¹ / ₂ oz (42.5 g) tube (NDC 0046-0872-01).

Store at room temperature (approximately 25° C).

PRODUCT PHOTO(S):

PHYSICIAN REFERENCES

1. Ziel, H. K. et al: N. Engl. J. Med. 293  :1167-1170, 1975.
2. Smith, D. C. et al: N. Engl. J. Med. 293  :1164-1167, 1975.
3. Mack, T. M. et al: N. Engl. J. Med 294  :1262-1267, 1976.
4. Weiss, N. S. et al: N. Engl. J. Med. 294  :1259-1262, 1976.
5. Herbst, A. L. et al: N. Engl. J. Med. 284  :878-881, 1971.
6. Greenwald, P. et al: N. Engl. J. Med. 285  :390-392, 1971.
7. Lanier, A. et al: Mayo Clin. Proc. 48  :793-799, 1973.
8. Herbst, A. et al: Obstet. Gynecol. 40  :287-298, 1972.
9. Herbst, A. et al: Am. J. Obstet. Gynecol. 118  :607-615, 1974.
10. Herbst, A. et al: N. Engl. J. Med. 292  :334-339, 1975.
11. Stafl, A. et al: Obstet. Gynecol. 43  :118-128, 1974.
12. Sherman, A. I. et al: Obstet. Gynecol. 44  :531-545, 1974.
13. Gal, I. et al: Nature 216  :83, 1967.
14. Levy, E. P. et al: Lancet 1  :611, 1973.
15. Nora, J. et al: Lancet 1  :941-942, 1973.
16. Janerich, D. T. et al: N. Engl. J. Med. 291  :697-700, 1974.
17. Boston Collaborative Drug Surveillance Program: N. Engl. J. Med. 290  :15-19, 1974.
18. Hoover, R. et al: N. Engl. J. Med. 295  :401-405, 1976.
19. Boston Collaborative Drug Surveillance Program: Lancet 1  :1399-1404, 1973.
20. Daniel, D. G. et al: Lancet 2  :287-289, 1967.
21. The Veterans Administration Cooperative Urological Research Group: J. Urol. 98  :516-522, 1967.
22. Bailar, J. C.: Lancet 2  :560, 1967.
23. Blackard, C. et al: Cancer 26  :249-256, 1970.
24. Royal College of General Practitioners: J. R. Coll. Gen. Pract. 13  :267-279, 1967. 
    24a. Royal College of General Practitioners: Oral Contraceptives and Health, New York, Pitman Corp., 1974.
25. Inman, W. H. W. et al: Br. Med. J. 2  :193-199, 1968.
26. Vessey, M. P. et al: Br. Med. J. 2  :651-657, 1969.
27. Sartwell, P. E. et al: Am. J. Epidemiol. 90  :365-380, 1969.
28. Collaborative Group for the Study of Stroke in Young Women: N. Engl. J. Med. 288  :871-878, 1973.
29. Collaborative Group for the Study of Stroke in Young Women: J.A.M.A. 231  :718-722, 1975.
30. Mann, J. I. et al: Br. Med. J. 2  :245-248, 1975.
31. Mann, J. I. et al: Br. Med. J. 2  :241-245, 1975.
32. Inman, W. H. W. et al: Br. Med. J. 2  :203-209, 1970.
33. Stolley, P. D. et al: Am. J. Epidemiol. 102  :197-208, 1975.
34. Vessey, M. P. et al: Br. Med. J. 3  :123-126, 1970.
35. Greene, G. R. et al: Am. J. Public Health 62  :680-685, 1972.
36. Coronary Drug Project Research Group: J.A.M.A. 214  :1303-1313, 1970.
37. Baum, J. et al: Lancet 2  :926-928, 1973.
38. Mays, E. T. et al: J.A.M.A. 235  :730-732, 1976.
39. Edmondson, H. A. et al: N. Engl. J. Med. 294  :470-472, 1976.
40. Pfeffer, R. I. et al: Am. J. Epidemiol. 103  :445-456, 1976.

INFORMATION FOR THE PATIENT

WHAT YOU SHOULD KNOW ABOUT ESTROGENS

Estrogens are female hormones produced by the ovaries. The ovaries make several different kinds of estrogens. In addition, scientists have been able to make a variety of synthetic estrogens. As far as we know, all these estrogens have similar properties and, therefore, much the same usefulness, side effects, and risks. This leaflet is intended to help you understand what estrogens are used for, the risks involved in their use, and how to use them as safely as possible.

This leaflet includes the most important information about estrogens, but not all the information. If you want to know more, you should ask your doctor for more information or you can ask your doctor or pharmacist to let you read the package insert prepared for the doctor.

USES OF ESTROGEN

THERE IS NO PROPER USE OF ESTROGENS IN A PREGNANT WOMAN.

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.

1. To provide estrogen during a period of adjustment when a woman's ovaries stop producing a majority of her estrogens, in order to prevent certain uncomfortable symptoms of estrogen deficiency. (With the menopause, which generally occurs between the ages of 45 and 55, women produce a much smaller amount of estrogens.)
2. To prevent symptoms of estrogen deficiency when a woman's ovaries have been removed surgically before the natural menopause.
3. To prevent pregnancy. (Estrogens are given along with a progestogen, another female hormone; these combinations are called oral contraceptives, or birth-control pills. Patient labeling is available to women taking oral contraceptives and they will not be discussed in this leaflet.)
4. To treat certain cancers in women and men.

ESTROGENS IN THE MENOPAUSE

In the natural course of their lives, all women eventually experience a decrease in estrogen production. This usually occurs between ages 45 and 55, but may occur earlier or later. Sometimes the ovaries may need to be removed before natural menopause by an operation, producing a "surgical menopause."

When the amount of estrogen in the blood begins to decrease, many women may develop typical symptoms: feelings of warmth in the face, neck, and chest, or sudden intense episodes of heat and sweating throughout the body (called "hot flashes" or "hot flushes"). These symptoms are sometimes very uncomfortable. Some women may also develop changes in the vagina (called "atrophic vaginitis") that cause discomfort, especially during and after intercourse.

Estrogens can be prescribed to treat these symptoms of the menopause. It is estimated that considerably more than half of all women undergoing the menopause have only mild symptoms or no symptoms at all and, therefore, do not need estrogens. Other women may need estrogens for a few months, while their bodies adjust to lower estrogen levels. Sometimes the need will be for periods longer than six months.

Sometimes women experience nervous symptoms or depression during menopause. There is no evidence that estrogens are effective for such symptoms without associated vasomotor symptoms. In the absence of vasomotor symptoms, estrogens should not be used to treat nervous symptoms, although other treatment may be needed.

You may have heard that taking estrogens for long periods (years) after the menopause will keep your skin soft and supple and keep you feeling young. There is no evidence that this is so, however, and such long-term treatment carries important risks.

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).

Whey 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 sop 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.

RISK OF ESTROGENS

1. 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.
2. 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-examinations 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.
3. Gallbladder disease. Women who use estrogens after menopause are more likely to develop gallbladder disease needing surgery than women who do not use estrogens. Birth-control pills have a similar effect.
4. Abnormal blood clotting. Taking estrogens may increase the risk of blood clotting in various parts of the body. This can result in a stroke (if the clot is in the brain), a heart attack (a clot in a blood vessel of the heart), a pulmonary embolus (a clot which forms in the legs or pelvis, then breaks off and travels to the lungs), retinal thrombosis (a clot in the blood vessels in the eye), or other problems. Any of these conditions may cause death or serious long term disability.
5. Inflammation of the pancreas (Pancreatitis). Women with high triglyceride levels may have increased risk of developing inflammation of the pancreas.
6. Endometriosis. Administration of estrogens may worsen endometriosis. If you have had endometriosis, speak with your health professional.
7. 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

OTHER EFFECTS OF ESTROGEN

In addition to the serious known risks of estrogens described above, estrogens have the following side effects and potential risk:

1. Nausea and vomiting. The most common side effect of estrogen therapy is nausea. Vomiting is less common.
2. Effects on breasts. Estrogens may cause breast tenderness or enlargement an may cause the breasts to secrete a liquid.
3. Effects on the uterus. Estrogens may cause benign fibroid tumors of the uterus to get larger.
4. Effects on liver. Women taking oral contraceptives develop, on rare occasions, a tumor of the liver which can rupture and bleed into the abdomen and may cause death. So far, these tumors have not been reported in women using estrogens in the menopause, but you should report any swelling or unusual pain or tenderness in the abdomen to your doctor immediately.
   Women with a past history of jaundice (yellowing of the skin and white parts of the eyes) may get jaundice again during estrogen use. If this occurs, stop taking estrogens and see your doctor.
5. Other effects. Estrogens may cause excessive fluid to be retained in the body. This may make some conditions worse, such as asthma, epilepsy, migraine, heart disease, or kidney disease.

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 you family have had breast cancer of if you have ever had breast lumps or an abnormal mammogram (breast X-ray), you may need to have more frequent breast examination.

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:

• Abnormal bleeding from the vagina (possible uterine cancer)
• Pains in the calves or chest, sudden shortness of breath, or coughing blood (possible clot in the legs, heart, or lungs)
• Severe headache or vomiting, dizziness, faintness, changes in vision or speech, weakness or numbness of an arm or leg (possible clot in the brain or eye)
• Breast lumps (possible breast cancer; ask your doctor or health professional to show you how to examine your breasts monthly)
• Yellowing of the skin or eyes (possible liver problem)
• Pain, swelling, or tenderness in the abdomen (possible gallbladder problem)

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). However, while it has been reported that some estrogen and progestin combinations have an unfavorable effect on blood fats, studies of Premarin given with medroxyprogesterone acetate (MPA) (0.625 mg Premarin with either 2.5 mg MPA continuously or 5 mg of MPA cyclically) have shown decreases in LDL ("bad" cholesterol) and increases in HDL ("good" cholesterol). Other risks include unhealthy effects on blood sugars, which might make a diabetic condition worse, and a possible further 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. There characteristics are known to protect against heart disease.
   You are cautioned do 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. Premarin Vaginal Cream exposure has been reported to weaken latex condoms. The potential for Premarin Vaginal Cream to weaken and contribute to the failure of condoms, diaphragms, or cervical caps made of latex or rubber should be considered.
6. 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

Premarin® (conjugated estrogens) Vaginal Cream--Each gram contains 0.625 mg conjugated estrogens, USP.

Combination package:   Each contains Net Wt. 1 ¹ / ₂ oz (42.5 g) tube with one plastic applicator calibrated in ¹ / ₂ g increments to a maximum of 2 g (NDC 0046-0872-93).

Also Available --Refill package:   Each contains Net Wt. 1 ¹ / ₂ oz (42.5 g) tube (NDC 0046-0872-01).

Store at room temperature (approximately 25° C).

INSTRUCTIONS FOR USE OF PREMARIN®

(conjugated estrogens)

Vaginal Cream Gentle Measure ^TM Applicator

The Gentle Measure Applicator has been specifically designed for comfortable, easy use.

1.   Remove cap from tube.
2.   Screw nozzle end of applicator onto tube.
3.    Gently squeeze tube from the bottom to force sufficient cream into the barrel to provide the prescribed dose. Use the marked stopping points on the applicator as a guideline to measure the correct dose.
4.   Unscrew applicator from tube.
5.   Lie on back with knees drawn up. To deliver medication, gently insert applicator deeply into vagina and press plunger downward to its original position.

TO CLEANSE: Pull plunger to remove it from barrel. Wash with mild soap and warm water.

DO NOT BOIL OR USE HOT WATER.

Manufactured by:

Ayerst Laboratories Inc.

A Wyeth-Ayerst Company

Philadelphia, PA 19101

CI 4856-3     Revised May 5, 1998