ESTINYL Tablets contain ethinyl estradiol, USP, a potent synthetic estrogen, having the chemical name 19-Nor-17(alpha)-pregna-1,3,5(10)-trien-20-yne-3,17-diol; the chemical formula C ₂₀ H ₂₄ O ₂ ; molecular weight of 296.41; and the following structural formula:

Ethinyl estradiol is a white to creamy white, odorless, crystalline powder. It is insoluble in water, soluble in alcohol, chloroform, ether, and vegetable oils.

Biologically, estrogens may be defined as compounds capable of stimulating female secondary sex characteristics. Chemically, there are different groups of estrogens, depending on whether they are natural or synthetic, steroidal or nonsteroidal. Natural human estrogens are ultimately formed from either androstenedione or testosterone as immediate precursors. Ethinyl estradiol is a synthetic, steroidal estrogen.

ESTINYL, for oral administration, is available in tablets containing 0.02 or 0.05 mg ethinyl estradiol, USP.

The inactive ingredients for ESTINYL Tablets 0.02 mg include: acacia, butylparaben, calcium phosphate, calcium sulfate, carnauba wax, corn starch, FD&C Blue No. 2 Al Lake, FD&C Yellow No. 5, FD&C Yellow No. 5 Al Lake, FD&C Yellow No. 6 Al Lake, gelatin, lactose, magnesium stearate, potato starch, sodium phosphate, sugar, and white wax. May also contain talc.

The inactive ingredients for ESTINYL Tablets 0.05 mg include: acacia, butylparaben, calcium phosphate, calcium sulfate, carnauba wax, corn starch, FD&C Blue No. 1, FD&C Red No. 3, gelatin, lactose, magnesium stearate, potato starch, sodium phosphate, and white wax. May also contain talc.

Ethinyl estradiol is a synthetic derivative of the natural estrogen, estradiol.

Ethinyl estradiol, like estradiol, promotes growth of the endometrium and thickening, stratification, and cornification of the vagina. It causes growth of the ducts of the mammary glands, but inhibits lactation. It also inhibits the anterior pituitary and causes capillary dilatation, fluid retention, and protein anabolism.

Estradiol is the major estrogen in premenopausal women, with up to 100 to 600 mcg being secreted daily by the ovary. Natural estrogens are poorly effective when given by mouth. Apparently this is due to rapid clearance of the endogenous hormone from blood, along with a "first-pass-effect" after oral administration. The addition of a 17-alpha-ethinyl group to estradiol increases potency and enhances oral activity by impeding hepatic degradation. The oral efficacy of ethinyl estradiol is related to slower elimination than estradiol from the circulation. A part of ingested ethinyl estradiol is excreted in glucuronide form via urine in animals and in man, but also extensive metabolism of the steroid nucleus occurs. The major metabolism takes place mainly in the liver. Large amounts of ethinyl estradiol metabolites are excreted via human bile, much similar to what has been reported for estradiol. However, unlike estradiol, ethinyl estradiol metabolites do not exclusively leave via urine. Urinary recovery is much less than that of estradiol and substantial amounts of ethinyl estradiol metabolites appear in human feces. Quantitatively, the major metabolic pathway for ethinyl estradiol, both in rats and in humans, is aromatic hydroxylation, as it is for the natural estrogens.

Rapid and complete absorption follows oral intake of ethinyl estradiol. Elimination of ethinyl estradiol from plasma proceeds slower than that of estradiol. After oral administration, an initial peak occurs in plasma at 2 to 3 hours, with a secondary peak at about 12 hours after dosing; the second peak is interpreted as evidence for extensive enterohepatic circulation of ethinyl estradiol.

ESTINYL Tablets are indicated in the treatment of: 1) Moderate to severe vasomotor symptoms associated with the menopause. (There is no 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) Female hypogonadism. 3) Prostatic carcinoma-palliative therapy of advanced disease. 4) Breast cancer (for palliation only) in appropriately selected women, such as those who are more than 5 years postmenopausal with progressing inoperable or radiation-resistant disease.

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

The lowest effective dose appropriate for the specific indication should be used. 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 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. The potential risks include adverse effects on carbohydrate and lipid metabolism. The choice of progestin and dosage may be important in minimizing these adverse effects.

CONTRAINDICATIONS

Estrogens should not be used in women (or men) 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 ).
4. Undiagnosed abnormal genital bleeding.
5. Active thrombophlebitis or thromboembolic disorders.
6. A past history of thrombophlebitis, thrombosis, or thromboembolic disorders associated with previous estrogen use (except when used in treatment of breast or prostatic malignancy).

1. Induction of malignant neoplasms. Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, cervix, vagina, and liver. There is now evidence that estrogens increase the risk of carcinoma of the endometrium in humans. (See boxed .)
   At the present time there is no satisfactory evidence that estrogens given to postmenopausal women increase the risk of cancer of the breast, ¹⁶ although a recent long-term follow-up of a single physician' practice has raised this possibility. ¹⁷ Because of the animal data, there is a need for caution in prescribing estrogens for women with a strong family history of breast cancer or who have breast nodules, fibrocystic disease, or abnormal mammograms.
   Estrogens have been reported to be associated with carcinoma of the male breast and suspicious lesions in males receiving estrogen therapy should be investigated accordingly.
2. Gallbladder disease. A recent study has reported a 2- to 3-fold increase in the risk of surgically confirmed gallbladder disease in women receiving postmenopausal estrogens, ¹⁶ similar to the 2-fold increase previously noted in users of oral contraceptives. ^18,22 In the case of oral contraceptives, the increased risk appeared after 2 years of use. ²²
3. Effects similar to those caused by estrogen-progestagen oral contraceptives. There are several serious adverse effects of oral contraceptives, most of which have not, up to now, been documented as consequences of postmenopausal estrogen therapy. This may reflect the comparatively low doses of estrogen used in postmenopausal women. It would be expected that the larger doses of estrogen used to treat prostatic or breast cancer are more likely to result in these adverse effects, and, in fact, it has been shown that there is an increased risk of thrombosis in men receiving estrogens for prostatic cancer. ^19-22
   1. Thromboembolic disease. It is now well established that users of oral contraceptives have an increased risk of various thromboembolic and thrombotic vascular diseases, such as thrombophlebitis, pulmonary embolism, stroke, and myocardial infarction. ^22-29 Cases of retinal thrombosis, mesenteric thrombosis, and optic neuritis have been reported in oral contraceptive users. There is evidence that the risk of several of these adverse reactions is related to the dose of the drug. ^30,31 An increased risk of postsurgery thromboembolic complications has also been reported in users of oral contraceptives. ^32,33 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 immobilization.
      While an increased rate of thromboembolic and thrombotic disease in postmenopausal users of estrogen has not been found, ^16,34 this does not rule out the possibility that such an increase may be present or that subgroups of women who have underlying risk factors or who are receiving relatively large doses of estrogens may have increased risk. Therefore, estrogens should not be used in persons with active thrombophlebitis or thromboembolic disorders, and they should not be used (except in treatment of malignancy) in persons with a history of such disorders in association with estrogen use. They should be used with caution in patients with cerebral vascular or coronary artery disease and only for those in whom estrogens are clearly needed.
      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 ³⁵ to increase the risk of nonfatal myocardial infarction, pulmonary embolism and thrombophlebitis. When estrogen doses of this size are used, any of the thromboembolic and thrombotic adverse effects associated with oral contraceptive use should be considered a clear risk.
   2. Hepatic adenoma. Benign hepatic adenomas appear to be associated with the use of oral contraceptives. ^36,38 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 progestagen 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. ³⁷ The relationship of this malignancy to these drugs is not known at this time.
   3. Elevated blood pressure. Increased blood pressure is not uncommon in women using oral contraceptives. There is now a report that this may occur with use of estrogens in the menopause ³⁹ and blood pressure should be monitored with estrogen use, especially if high doses are used.
   4. 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.
4. 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

General:   

1. 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 1 year without another physical examination being performed.
2. Fluid retention--Because estrogens may cause some degree of fluid retention, conditions which might be influenced by this factor, such as epilepsy, migraine, and cardiac or renal dysfunction, require careful observation.
3. Certain patients may develop undesirable manifestations of excessive estrogenic stimulation, such as abnormal or excessive uterine bleeding, mastodynia, etc.
4. Oral contraceptives appear to be associated with an increased incidence of mental depression. ²² Although it is not clear whether this is due to the estrogenic or progestagenic component of the contraceptive, patients with a history of depression should be carefully observed.
5. Preexisting uterine leiomyomata may increase in size during estrogen use.
6. The pathologist should be advised of estrogen therapy when relevant specimens are submitted.
7. 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.
8. Estrogens may be poorly metabolized in patients with impaired liver function and they should be administered with caution in such patients.
9. 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.
10. Because of the effects of estrogens on epiphyseal closure, they should be used judiciously in young patients in whom bone growth is not complete.
11. ESTINYL Tablets, 0.02 mg, contain FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

Information for the Patient:   See text of Patient Package Insert .

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:

Increased sulfobromophthalein retention; increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregation; 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; impaired glucose tolerance; decreased pregnanediol excretion; reduced response to metyrapone test; reduced serum folate concentration; increased serum triglyceride and phospholipid concentration.

Carcinogenesis, Mutagenesis, Impairment of Fertility:   See boxed .

Pregnancy Category X:   See CONTRAINDICATIONS and boxed .

Nursing Mothers:   Because of the potential for tumorigenicity shown for ethinyl estradiol in animal and human studies, 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.

Pediatric Use:   Safety and effectiveness in children have not been established.

ADVERSE REACTIONS

(See regarding induction of neoplasia, adverse effects on the fetus, increased incidence of gallbladder disease, the adverse effects similar to those of oral contraceptives, including thromboembolism.) The following additional adverse reactions have been reported with estrogenic therapy, including oral contraceptives:

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 eversion and in degree of cervical secretion; cystitis-like syndrome.

Breasts:   Tenderness, enlargement, secretion.

Gastrointestinal:   Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice.

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

Eyes:   Steepening of corneal curvature; intolerance to contact lenses.

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

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

DOSAGE AND ADMINISTRATION

1. Given cyclically for short-term use only.
   For treatment of moderate to severe vasomotor symptoms associated with the menopause. The lowest dose that will control symptoms should be chosen and medication should be discontinued as promptly as possible. Administration should be cyclic (eg, 3 weeks on and 1 week off). Attempts to discontinue or taper medication should be made at 3- to 6-month intervals. The usual dosage range is 0.02 mg to 0.05 mg daily. In some instances, the effective dose may be as low as 0.02 mg every other day. A useful dosage schedule for early menopause, while spontaneous menstruation continues, is 0.05 mg once a day for 21 days and then a rest period for 7 days. For the initial treatment of the late menopause, the same regimen is indicated with a dose of 0.02 mg for the first few cycles, after which 0.05 mg dosage may be substituted. In more severe cases, such as those due to surgical and roentgenologic castration, a dose of 0.05 mg may be administered three times daily at the start of treatment. With adequate clinical improvement, usually obtainable in a few weeks, the dosage may be reduced to 0.05 mg daily and the patient continued thereafter on a maintenance dosage as in the average case.
2. Given cyclically.
   Female hypogonadism: A dose of 0.05 mg is given one to three times daily during the first 2 weeks of a theoretical menstrual cycle. This is followed by progesterone during the last half of the arbitrary cycle. This regimen is continued for 3 to 6 months. The patient is then allowed to go untreated for 2 months to determine whether or not she can maintain the cycle without hormonal therapy. If not, additional courses of therapy may be prescribed.
3. Given chronically.
   Inoperable progressing prostatic cancer: A dose ranging from 0.15 mg to 2.0 mg may be administered daily for palliation.
   Inoperable progressing breast cancer in appropriately selected postmenopausal women (See ): A 1.0 mg dose three times daily for palliation.
   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.

HOW SUPPLIED

ESTINYL Tablets 0.02 mg, beige, sugar-coated tablets branded in black with the Schering trademark and either product identification number 298, or letters ER; bottles of 100 (NDC 0085-0298-03) and 250 (NDC 0085-0298-06).

ESTINYL Tablets 0.05 mg, pink, sugar-coated tablets branded in black with the Schering trademark and either product identification number 070, or letters EM; bottles of 100 (NDC 0085-0070-03) and 250 (NDC 0085-0070-06).

Store between 2° and 30°C (36° and 86°F).

PHYSICIAN REFERENCES

1. Ziel, H. K. and W. D. Finkle, "Increased Risk of Endometrial Carcinoma Among Users of Conjugated Estrogens," N Engl J Med. 293:1167-1170, 1975.
2. Smith, D. C., R. Prentic, D. J. Thompson, and W. L. Hermann, "Association of Exogenous Estrogen and Endometrial Carcinoma," N Engl J Med. 293:1164-1167, 1975.
3. Mack, T. M., M. C. Pike, B. E. Henderson, et al. "Estrogens and Endometrial Cancer in a Retirement Community," N Engl J Med. 294:1262-1267, 1976.
4. Weiss, N. S., D. R. Szekely, and D. F. Austin, "Increasing Incidence of Endometrial Cancer in the United States," N Engl J Med. 294:1259-1262, 1976.
5. Herbst, A. L., H. Ulfelder, and D. C. Poskanzer, "Adeno-carcinoma of Vagina," N Engl J Med. 284:878-881, 1971.
6. Greenwald, P., J. Barlow, P. Nasca, and W. Burnett, "Vaginal Cancer after Maternal Treatment with Synthetic Estrogens," N Engl J Med. 285:390-392, 1971.
7. Lanier, A., K. Noller, D. Decker, L. Elveback, and L. Kurland, "Cancer and Stilbestrol. A Follow-up of 1,719 Persons Exposed to Estrogens In Utero and Born 1943-1959," Mayo Clin Proc. 48:793-799, 1973.
8. Herbst, A., R. Kurman, and R. Scully, "Vaginal and Cervical Abnormalities After Exposure to Stilbestrol In Utero," Obstet Gynecol. 40:287-298, 1972.
9. Herbst, A., D. Poskanzer, S. Robboy, L. Friedlander, and R. Scully, "Prenatal Exposure to Stilbestrol, A Prospective Comparison of Exposed Female Offspring with Unexposed Controls," N Engl J Med. 292:334-339, 1975.
10. Stafl, A., R. Mattingly, D. Foley, and W. Fetherston, "Clinical Diagnosis of Vaginal Adenosis," Obstet Gynecol. 43:118-128, 1974.
11. Sherman, A. I., M. Goldrath, A. Berlin, et al. "Cervical-Vaginal Adenosis After In Utero Exposure to Synthetic Estrogens," Obstet Gynecol. 44:531-545, 1974.
12. Gal, I., B. Kirman, and J. Stern, "Hormone Pregnancy Tests and Congenital Malformation," Nature. 216:83, 1967.
13. Levy, E. P., A. Cohen, and F. C. Fraser, "Hormone Treatment During Pregnancy and Congenital Heart Defects," Lancet 1:611, 1973.
14. Nora, J. and A. Nora, "Birth Defects and Oral Contraceptives," Lancet 1:941-942, 1973.
15. Janerich, D. T., J. M. Piper, and D. M. Glebatis, "Oral Contraceptives and Congenital Limb-Reduction Defects," N Engl J Med. 291:697-700, 1974.
16. Boston Collaborative Drug Surveillance Program, "Surgically Confirmed Gallbladder Disease, Venous Thromboembolism and Breast Tumors in Relation to Post-Menopausal Estrogen Therapy," N Engl J Med. 290:15-19, 1974.
17. Hoover, R., L. A. Gray, Sr., P. Cole, and B. MacMahon, "Menopausal Estrogens and Breast Cancer," N Engl J Med. 295:401-405, 1976.
18. Boston Collaborative Drug Surveillance Program, "Oral Contraceptives and Venous Thromboembolic Disease, Surgically Confirmed Gallbladder Disease, and Breast Tumors," Lancet 1:1399-1404, 1973.
19. The Veterans Administration Cooperative Urological Research Group, "Carcinoma of the Prostate: Treatment Comparisons," J Urol. 98:516-522, 1967.
20. Bailar, J. C., "Thromboembolism and Oestrogen Therapy," Lancet 2:560, 1967.
21. Blackard, C., R. Doe, G. Mellinger, and D. Byar, "Incidence of Cardiovascular Disease and Death in Patients Receiving Diethylstilbestrol for Carcinoma of the Prostate," Cancer 26:249-256, 1970.
22. Royal College of General Practitioners, "Oral Contraception and Thromboembolic Disease," J R Coll Gen Pract. 13:267-279, 1967.
23. Inman, W. H. W. and M. P. Vessey, "Investigation of Deaths from Pulmonary, Coronary, and Cerebral Thrombosis and Embolism in Women of Child-Bearing Age," Br Med J. 2:193-199, 1968.
24. Vessey, M. P. and R. Doll, "Investigation of Relation Between Use of Oral Contraceptives and Thromboembolic Disease. A Further Report," Br Med J. 2:651-657, 1969.
25. Sartwell, P. E., A. T. Masi, F. G. Arthes, G. R. Greene, and H. E. Smith, "Thromboembolism and Oral Contraceptives: An Epidemiological Case Control Study," Am J Epidemiol. 90:365-380, 1969.
26. Collaborative Group for the Study of Stroke in Young Women, "Oral Contraception and Increased Risk of Cerebral Ischemia or Thrombosis," N Engl J Med. 288:871-878, 1973.
27. Collaborative Group for the Study of Stroke in Young Women, "Oral Contraceptives and Stroke in Young Women: Associated Risk Factors," JAMA. 231:718-722, 1975.
28. Mann, J. I. and W. H. W. Inman, "Oral Contraceptives and Death from Myocardial Infarction," Br Med J. 2:245-248, 1975.
29. Mann, J. I., M. P. Vessey, M. Thorogood, and R. Doll, "Myocardial Infarction in Young Women with Special Reference to Oral Contraceptive Practice," Br Med J. 2:241-245, 1975.
30. Inman, W. H. W., M. P. Vessey, B. Westerholm, and A. Engelund, "Thromboembolic Disease and the Steroidal Content of Oral Contraceptives," Br Med J. 2:203-209, 1970.
31. Stolley, P. D., J. A. Tonascia, M. S. Tockman, P. E. Sartwell, A. H. Rutledge, and M. P. Jacobs, "Thrombosis With Low-Estrogen Oral Contraceptives," Am J Epidemiol. 102:197-208, 1975.
32. Vessey, M. P., R. Doll, A. S. Fairbairn, and G. Glober, "Post-Operative Thromboembolism and the Use of the Oral Contraceptives," Br Med J. 3:123-126, 1970.
33. Greene, G. R. and P. E. Sartwell, "Oral Contraceptive Use in Patients With Thromboembolism Following Surgery, Trauma or Infection," Am J Public Health. 62:680-685, 1972.
34. Rosenberg, L., M. B. Armstrong, and H. Jick, "Myocardial Infarction and Estrogen Therapy in Postmenopausal Women," N Engl J Med. 294:1256-1259, 1976.
35. Coronary Drug Project Research Group, "The Coronary Drug Project: Initial Findings Leading to Modifications of its Research Protocol," JAMA. 214:1303-1313, 1970.
36. Baum, J., F. Holtz, J. J. Bookstein, and E. W. Klein, "Possible Association Between Benign Hepatomas and Oral Contraceptives," Lancet 2:926-928, 1973.
37. Mays, E. T., W. M. Christopherson, M. M. Mahr, and H. C. Williams, "Hepatic Changes in Young Women Ingesting Contraceptive Steroids: Hepatic Hemorrhage and Primary Hepatic Tumors," JAMA. 235:730-782, 1976.
38. Edmondson, H. A., B. Henderson, and B. Benton, "Liver Cell Adenomas Associated With the Use of Oral Contraceptives," N Engl J Med. 294:470-472, 1976.
39. Pfeffer, R. I. and S. Van Den Noort, "Estrogen Use and Stroke Risk in Postmenopausal Women," Am J Epidemiol. 103:445-456, 1976.

PATIENT LABELING

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 can ask your doctor or pharmacist to let you read the package insert prepared for the doctor.

USES OF ESTROGEN

Estrogens are prescribed by doctors for a number of purposes, including:

1. To provide estrogen during a period of adjustment when a woman's ovaries no longer produce it, in order to prevent certain uncomfortable symptoms of estrogen deficiency. (All women normally stop producing estrogens, generally between the ages of 45 and 55; this is called the menopause.)
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 progestagen, another female hormone; these combinations are called oral contraceptives and they will not be discussed in this leaflet).
4. To treat certain cancers in women and men.
   THERE IS NO PROPER USE OF ESTROGENS IN A PREGNANT WOMAN.

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. A few women eventually develop changes in the vagina (called "atrophic vaginitis") which 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 6 months. In an attempt to avoid overstimulation of the uterus (womb), estrogens are usually given cyclically during each month of use, that is, 3 weeks of pills followed by 1 week without pills.

Sometimes women experience nervous symptoms or depression during menopause. There is no evidence that estrogens are effective for such symptoms and they should not be used to treat them, although other treatment may be needed.

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, however, and such long-term treatment carries important risks.

THE DANGERS OF ESTROGENS

1. Cancer of the uterus. If estrogens are used in the postmenopausal period for more than a year, there is an increased risk of endometrial cancer (cancer of the uterus). Women taking estrogens have roughly 5 to 10 times as great a chance of getting this cancer as women who take no estrogens. To put this another way, while a postmenopausal woman not taking estrogens has one chance in 1,000 each year of getting cancer of the uterus, a woman taking estrogens has 5 to 10 chances in 1,000 each year. For this reason it is important to take estrogens only when you really need them.
   The risk of this cancer is greater the longer estrogens are used and also seems to be greater when larger doses are taken. For this reason it is important to take the lowest dose of estrogen that will control symptoms and to take it only as long as it is needed. If estrogens are needed for longer periods of time, your doctor will want to reevaluate your need for estrogens at least every 6 months.
   Women using estrogens should report any irregular vaginal bleeding to their doctors; such bleeding may be of no importance, but it can be an early warning of cancer of the uterus. If you have undiagnosed vaginal bleeding, you should not use estrogens until a diagnosis is made and you are certain there is no cancer of the uterus.
   If you have had your uterus completely removed (total hysterectomy), there is no danger of developing cancer of the uterus.
2. Other possible cancers. Estrogens can cause development of other tumors in animals, such as tumors of the breast, cervix, vagina, or liver, when given for a long time. At present there is no good evidence that women using estrogens in the menopause have an increased risk of such tumors, but there is no way yet to be sure they do not; and one study raises the possibility that use of estrogens in the menopause may increase the risk of breast cancer many years later. This is a further reason to use estrogens only when clearly needed. While you are taking estrogens, it is important that you go to your doctor at least once a year for a physical examination.
   Also, if members of your family have had breast cancer or if you have breast nodules or abnormal mammograms (breast x-rays), your doctor may wish to carry out more frequent examinations of your breasts.
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. Oral contraceptives 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 (clot in a blood vessel of the heart), or a pulmonary embolus (a clot which forms in the legs or pelvis, then breaks off and travels to the lungs). Any of these can be fatal.
   At this time, use of estrogens in the menopause is not known to cause such blood clotting, but this has not been fully studied and there could still prove to be such a risk. It is recommended that if you have had clotting in the legs or lungs or a heart attack or stroke while you were using estrogens or birth control pills, you should not use estrogens (unless they are being used to treat cancer of the breast or prostate). If you have had a stroke or heart attack or if you have angina pectoris, estrogens should be used with great caution and only if clearly needed (for example, if you have severe symptoms of the menopause).
   The larger doses of estrogen used to prevent swelling of the breasts after pregnancy have been reported to cause clotting in the legs and lungs.

SPECIAL WARNING ABOUT PREGNANCY

You should not receive estrogens if you are pregnant. If this should occur, there is a greater than usual chance that the developing child will be born with a birth defect, although the possibility remains fairly small. A female child may have an increased risk of developing cancer of the vagina or cervix later in life (in the teens or twenties). Every possible effort should be made to avoid exposure to estrogens during pregnancy. If exposure occurs, see your doctor.

OTHER EFFECTS OF ESTROGENS

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

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 and may cause the breasts to secrete a liquid. These effects are not dangerous.
3. Effects on the uterus. Estrogens may cause benign fibroid tumors of the uterus to get larger. Some women will have menstrual bleeding when estrogens are stopped. But if the bleeding occurs on days you are still taking estrogens, you should report this to your doctor.
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. 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 excess fluid to be retained in the body. This may make some conditions worse, such as epilepsy, migraine, heart disease, or kidney disease.

DOSAGE AND ADMINISTRATION

Use this medication as directed by your doctor. Generally, it may be prescribed one of three ways:

1. Cyclically for short-term use only.
   Administration is cyclic, that is, 3 weeks on and 1 week off. The usual dosage range is 0.02 mg or 0.05 mg daily.
2. Cyclically.
   0.05 mg taken one to three times daily for 2 weeks followed by progesterone (another kind of hormone) for 2 weeks. This schedule is maintained for several months.
3. Chronically.
   A dose ranging from 0.15 mg to 2.0 mg may be administered daily.
   The above dosages are intended as guidelines only. Your doctor will tell you how to take this medication to suit your particular needs.

SUMMARY

Estrogens have important uses, but they have serious risks as well. You must decide, with your doctor, whether the risks are acceptable to you in view of the benefits of treatment. Except where your doctor has prescribed estrogens for use in special cases of cancer of the breast or prostate, you should not use estrogens if you have cancer of the breast or uterus, are pregnant, have undiagnosed abnormal vaginal bleeding, clotting in the legs or lungs, or have had a stroke, heart attack or angina, or clotting in the legs or lungs in the past while you were taking estrogens.

You can use estrogens as safely as possible by understanding that your doctor will require regular physical examinations while you are taking them and will try to discontinue the drug as soon as possible and use the smallest dose possible. Be alert for signs of trouble including:

1. Abnormal bleeding from the vagina.
2. Pains in the calves or chest or sudden shortness of breath, or coughing blood (indicating possible clots in the legs, heart, or lungs).
3. Severe headache, dizziness, faintness, or changes in vision (indicating possible developing clots in the brain or eye).
4. Breast lumps (you should ask your doctor how to examine your own breasts).
5. Jaundice (yellowing of the skin).
6. Mental depression.

Based on his or her assessment of your medical needs, your doctor has prescribed this drug for you. Do not give the drug to anyone else.

HOW SUPPLIED

ESTINYL Tablets are available in two different strengths:

ESTINYL 0.02 mg Tablets are beige in color and branded with either the number 298, or the letters ER.

These tablets contain FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

ESTINYL 0.05 mg Tablets are pink in color and branded with either the number 070, or the letters EM.

ESTINYL Tablets should be stored between 2° and 30°C (36° and 86°F).

Schering Corporation

Kenilworth, NJ 07033 USA

Rev. 1/99                                                          17406949

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