Inform Your Physician Before Taking This Drug If

• you have had an unfavorable reaction to estrogen therapy previously.

• you have a history of cancer of the breast or reproductive organs.

you have any of the following conditions: fibrocystic breast changes, fibroid tumors of the uterus, endometriosis, migrainelike headaches, epilepsy, asthma, heart disease, high blood pressure, gallbladder disease, diabetes or porphyria.

• you smoke tobacco on a regular basis.

• you plan to have surgery in the near future.

Possible Side-Effects (natural, expected and unavoidable drug actions) Fluid retention, weight gain, "breakthrough" bleeding (spotting in middle of menstrual cycle), altered menstrual pattern, resumption of menstrual flow (bleeding from the uterus) after a period of natural cessation (postmenopausal bleeding), increased susceptibility to yeast infection of the genital tissues.

Possible Adverse Effects (unusual, unexpected and infrequent reactions) If any of the following develop, consult your physician promptly for guidance.

Mild Adverse Effects

Allergic Reactions: Skin rash, hives, itching.

Headache, nervous tension, irritability, accentuation of migraine headaches.

Nausea, vomiting, bloating, diarrhea.

Tannish pigmentation of the face. Serious Adverse Effects

Idiosyncratic Reaction: Cutaneous porphyria - fragility and scarring of the skin.

Emotional depression, rise in blood pressure (in susceptible individuals).

Gallbladder disease, benign liver tumors, jaundice, rise in blood sugar.

Erosion of uterine cervix, enlargement of uterine fibroid tumors.

Thrombophlebitis (inflammation of a vein with formation of blood clot) — pain or tenderness in thigh or leg, with or without swelling of foot or leg.

Pulmonary embolism (movement of blood clot to lung) — sudden shortness of breath, pain in chest, coughing, bloody sputum.

Stroke (blood clot in brain)—headaches, blackout, sudden weakness or paralysis of any part of the body, severe dizziness, altered vision, slurred speech, inability to speak.

Retinal thrombosis (blood clot in eye vessels) — sudden impairment or loss of vision.

Heart attack (blood clot in coronary artery) — sudden pain in chest, neck, jaw or arm; weakness; sweating; nausea.

Possible Effects on Sexual Function

Swelling and tenderness of breasts, milk production. Increased vaginal secretions.

Possible Delayed Adverse Effects: Estrogens taken during pregnancy can predispose the female child to the later development of cancer of the vagina or cervix following puberty.

Adverse Effects That May Mimic Natural Diseases or Disorders

Liver reactions may suggest viral hepatitis.

Natural Diseases or Disorders That May Be Activated by This Drug

Latent hypertension, diabetes mellitus, acute intermittent porphyria.

Possible Effects on Laboratory Tests

Red blood cells, hemoglobin and platelets: decreased.

Blood calcium level: increased.

Blood total cholesterol level: decreased (treatment effect); increased in

post-menopausal women.

Blood LDL cholesterol level: decreased in post-menopausal women. Blood triglyceride level: no drug effect in postmenopausal women. Blood glucose level: increased. Glucose tolerance test (GTT): decreased. Blood thyroid hormone (T³ and T⁴) levels: increased. Blood uric acid level: decreased. Liver function tests: increased liver enzymes (ALT/GPT, AST/GOT and

alkaline phosphatase), increased bilirubin.

CAUTION

1. To avoid prolonged (uninterrupted) stimulation of breast and uterine tissues, estrogen should be taken in cycles of 3 weeks on and 1 week off of medication.

2. The estrogen in estrogen vaginal creams is absorbed systemically by the woman. It may also be absorbed through the penis during sexual intercourse and can cause enlargement and tenderness of male breast tissue.

Precautions for Use

By Those over 60 Years of Age: This drug has very limited usefulness after 60. Its use should be restricted to those women who are at increased risk for developing osteoporosis. In this age group, it is advisable to attempt relief of hot flushes with nonestrogenic medications. During use, report promptly any indications of impaired circulation: speech disturbances, altered vision, sudden hearing loss, vertigo, sudden weakness or paralysis, angina, leg pains.

Advisability of Use During Pregnancy

Pregnancy Category: X. See Pregnancy Code inside back cover.

Animal studies: Genital defects reported in mice and guinea pigs; cleft palate reported in rodents.

Human studies: Information from studies of pregnant women indicates that estrogens can masculinize the female fetus. In addition, limb defects and heart malformations have been reported.

It is now known that estrogens taken during pregnancy can predispose the female child to the development of cancer of the vagina or cervix following puberty. Avoid estrogens completely during entire pregnancy.

Advisability of Use if Breast-Feeding

Presence of this drug in breast milk: Yes, in minute amounts.

Estrogens in large doses can suppress milk formation. Breast-feeding is considered to be safe during the use of estrogens.

Habit-Forming Potential: None.

Effects of Overdosage: Headache, drowsiness, nausea, vomiting, fluid retention, abnormal vaginal bleeding, breast enlargement and discomfort.

Possible Effects of Long-Term Use: High blood pressure, gallbladder disease with gallstone formation, increased growth of benign fibroid tumors of the uterus. Several reports suggest possible association between the long-term use (3 + years) of estrogens and the development of cancer of the lining of the uterus. Further studies are needed to establish a definite cause-and-effect relationship. Prudence dictates that women with uterus intact should use estrogens only when symptoms justify it and with proper supervision.

Suggested Periodic Examinations While Taking This Drug (at physician's

discretion)

Regular (every 6 months) evaluation of the breasts and pelvic organs, including Pap smears. Liver function tests as indicated.

While Taking This Drug, Observe the Following

Foods: Avoid excessive use of salt if fluid retention occurs.

Beverages: No restrictions. May be taken with milk.

Alcohol: No interactions expected.

Tobacco Smoking: Recent studies indicate that heavy smoking (15 or more cigarettes daily) in association with the use of estrogen-containing oral contraceptives significantly increases the risk of heart attack (coronary thrombosis). Avoid heavy smoking during long-term estrogen therapy.

Other Drugs Estrogens taken concurrently with

• antidiabetic drugs may cause unpredictable fluctuations of blood sugar.

• tricyclic antidepressants (Elavil, Sinequan, etc.) may enhance their adverse effects and reduce their antidepressant effectiveness.

• warfarin (Coumadin) may cause unpredictable alterations of prothrombin activity.

The following drugs may decrease the effects of estrogens

• carbamazepine (Tegretol).

• phenobarbital.

• phenytoin (Dilantin).

• primidone (Mysoline).

• rifampin (Rifadin, Rimactane).

Driving, Hazardous Activities: Usually no restrictions. Consult your physician for assessment of individual risk and for guidance regarding specific restrictions.

Aviation Note: Usually no restrictions. However, it is advisable to observe for the rare occurrence of disturbed vision and to restrict activities accordingly. Consult a designated Aviation Medical Examiner.

Exposure to Sun: Use caution until full effect is known. These drugs can cause photosensitivity.

Discontinuation: It is advisable to discontinue estrogens periodically to determine if a need for them still exists. Reduce the dose gradually to prevent acute withdrawal hot flushes. Avoid continual, uninterrupted use of large doses. Discontinue altogether when a definite indication for replacement therapy no longer exists. Ask your physician for guidance.

TEXT 6. Read the following text and give the written translation of the sentences dealing with the manifestations of possible side-effects.