Applies to esterified estrogens: oral tablet.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using esterified estrogens and call your doctor at once if you have:

• signs of a stroke--sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with vision or balance;

• signs of a blood clot in the lung--chest pain, sudden cough, wheezing, rapid breathing, coughing up blood;

• signs of a blood clot in your leg--pain, swelling, warmth, or redness in one or both legs;

• heart attack symptoms--chest pain or pressure, pain spreading to your jaw or shoulder, nausea, sweating;

• liver problems--severe stomach pain, fever, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

• high levels of calcium in your blood--nausea, vomiting, constipation, increased thirst or urination, muscle weakness, bone pain, confusion, lack of energy, or tired feeling;

• a change in the pattern or severity of migraine headaches;

• swelling in your hands, ankles, or feet;

• a breast lump; or

• severe skin reaction--fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common side effects may include:

• light vaginal bleeding or spotting;

• breast pain or tenderness;

• nausea, vomiting, bloating;

• skin color changes, increased facial hair, thinning scalp hair;

• headache, dizziness, mood changes, decreased sex drive;

• vaginal itching or discharge, very light menstrual periods; or

• problems with contact lenses.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.

For Healthcare Professionals

Applies to esterified estrogens: oral tablet.

General

The more commonly reported adverse effects have included headache, breast pain, stomach/abdominal cramps, bloating, hair loss, nausea and vomiting.^[Ref]

Gastrointestinal

Frequency not reported: Nausea, vomiting, abdominal cramps, bloating, gallbladder disease, pancreatitis

Oncologic

The increased risk of breast cancer due to use of estrogens is controversial. Several studies have suggested that long-term estrogen therapy may be associated with a slightly increased risk of breast cancer. Meta analysis of 51 studies (epidemiological data) supports a modest risk increase associated with long-term hormone replacement therapy (HRT).

Follow-up to the Nurses' Health Study of 1992 concluded, however, that there is an increased risk of breast cancer in women taking estrogen replacement therapy and that the risk is not reduced by concurrent use of progestins. (In that study, greater risk was associated with advanced age and prolonged duration of hormonal therapy.)

The Women's Health Initiative (WHI) which enrolled predominantly healthy postmenopausal women (n=27,000) to assess the risks and benefits of using conjugated estrogens 0.625 mg/day alone or with medroxyprogesterone acetate 2.5 mg/day compared to placebo has shown an absolute excess risk of 8 more invasive breast cancers per 10,000 women-years in the group treated with CE/MPA. Observational studies have also reported an increased risk of breast cancer in women using estrogen/progestin, with a smaller increased risk for estrogen alone.

The risk of endometrial cancer among unopposed estrogen users is about 2 to 12- fold greater than in non-users. Most studies have shown no significant increased risk with use for less than 1 year, but an increased risk of 15 to 24-fold with use for 5 to 10 years or more, persisting for at least 8 to 15 years after estrogen therapy is discontinued.

Frequency not reported: Ovarian cancer, endometrial hyperplasia, endometrial cancer, breast cancer, increase in abnormal mammograms, hepatocellular carcinomas

Cardiovascular

In the Women's Health Initiative study (WHI), an increase myocardial infarctions and strokes was observed in women receiving conjugated estrogens compared to placebo; a substudy of the WHI in which women were receiving conjugated estrogen plus progestin, showed an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) compared to placebo (37 vs 30 per 10,000 women-years). This increase was observed in year one and persisted. In a clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement study; HERS) in postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) use of conjugated estrogens with progestin demonstrated no cardiovascular benefit.

A substudy of the WHI showed a 2-fold greater rate of venous thromboembolism (VTE), including deep venous thrombosis and pulmonary embolism, in women receiving conjugated estrogen with medroxyprogesterone compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years compared to 16 per 10,000 women-years in the placebo group. This increase risk was observed during the first year and persisted.

Frequency not reported: Deep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, myocardial infarction, stroke, increase in blood pressure

Metabolic

Frequency not reported: Increase or decrease in weight, reduced carbohydrate tolerance, aggravation of porphyria, edema, hypocalcemia, increased triglycerides

Genitourinary

Frequency not reported: Changes in vaginal bleeding pattern, abnormal withdrawal bleeding or flow, breakthrough bleeding, spotting, dysmenorrhea, increase in size of uterine leiomyomata, vaginitis, including vaginal candidiasis, change in amount of cervical secretion, changes in cervical ectropion, endometrial hyperplasia, premenstrual like syndrome, amenorrhea during and after treatment; cystitis like syndrome

Hepatic

There are more reports of hepatic tumors occurring in women taking long-term oral contraceptives, but there are some reports in women taking isolated estrogen therapy.

Frequency not reported: Benign hepatic adenomas, hepatic hemangiomas

Hypersensitivity

Frequency not reported: Urticaria, angioedema, anaphylactoid/anaphylactic reactions

Nervous system

Frequency not reported: Migraine, dizziness, headache, exacerbation of epilepsy, dementia, chorea

Psychiatric

Frequency not reported: Mental depression, nervousness, mood disturbances, irritability

Ocular

Frequency not reported: Retinal vascular thrombosis, steepening of corneal curvature, intolerance to contact lenses

Dermatologic

Frequency not reported: Chloasma or melasma (may persist when drug is discontinued), scalp hair loss, hirsutism, erythema nodosum, hemorrhagic eruptions, erythema multiforme, rash, pruritus

Endocrine

Frequency not reported: Increased levels of thyroxin-binding globulin, breast tenderness, enlargement, pain, nipple discharge, galactorrhea, fibrocystic breast changes

Musculoskeletal

Frequency not reported: Arthralgias, leg cramps

Respiratory

Frequency not reported: Exacerbation of asthma