Applies to esterified estrogens / methyltestosterone: oral tablet.

Serious side effects

Along with its needed effects, esterified estrogens/methyltestosterone may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking esterified estrogens / methyltestosterone:

More common

• Absent, missed, or irregular menstrual periods
• acne or oily skin
• decreased breast size
• enlarging clitoris
• hoarseness or deepening of the voice
• menstrual changes
• stopping of menstrual bleeding
• unnatural hair growth or loss

Rare

• Continuing nausea
• cough
• dark-colored urine
• difficulty with swallowing
• dizziness
• fast heartbeat
• fever
• hives
• itching
• light-colored stools
• loss of appetite
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• purple or red-colored spots on the body or inside the mouth or nose
• shortness of breath
• skin rash
• sore throat
• tightness in the chest
• unusual tiredness or weakness
• vomiting
• wheezing

Incidence not known

• Abdominal or stomach bloating, cramps, or pain
• anxiety
• bleeding from gums or nose
• blistering, peeling, or loosening of the skin
• bloating
• bloody or cloudy urine
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• change in vaginal discharge
• changes in skin color, pain, or tenderness
• chest pain or discomfort
• chills
• clay-colored stools
• clear or bloody discharge from nipple
• confusion
• constipation
• convulsions
• darkening of urine
• decrease in amount of urine
• diarrhea
• difficult, burning, or painful urination
• difficulty with breathing
• difficulty with moving
• difficulty with speaking
• dimpling of the breast skin
• dizziness or lightheadedness
• double vision
• eye pain
• fainting
• fever
• fluid-filled skin blisters
• frequent urge to urinate
• headache
• heavy bleeding
• inability to move the arms, legs, or facial muscles
• inability to speak
• indigestion
• inverted nipple
• irregular heartbeats
• itching of the vagina or genital area
• joint or muscle pain
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• light-colored stools
• loss of appetite
• lump in the breast or under the arm
• mood or mental changes
• muscle cramps in the hands, arms, feet, legs, or face
• muscle pain or stiffness
• nausea
• noisy, rattling breathing
• numbness and tingling around the mouth, fingertips, or feet
• pain
• pain during sexual intercourse
• pain in the ankles or knees
• pain or discomfort in the arms, jaw, back, or neck
• pain or feeling of pressure in pelvis
• painful, red lumps under the skin, mostly on the legs
• pains in the stomach, side, or abdomen, possibly radiating to the back
• pelvic pain
• persistent crusting or scaling of the nipple
• pinpoint red or purple spots on the skin
• poor insight and judgment problems with memory or speech
• red, irritated eyes
• redness or swelling of the breast
• ringing in the ears
• sensitivity to the sun
• shortness of breath
• skin thinness
• slow speech
• sore on the skin of the breast that does not heal
• sore throat
• sores, ulcers, or white spots in the mouth or on the lips
• stomach pain
• sudden shortness of breath or troubled breathing
• sweating
• swelling
• swelling of the fingers, hands, feet, or lower legs
• tenderness of the breast
• thick, white curd-like vaginal discharge without odor or with mild odor
• tiredness
• tremor
• trouble recognizing objects
• trouble thinking and planning
• trouble walking
• troubled breathing at rest
• unexpected or excess milk flow from breasts
• unpleasant breath odor
• vaginal bleeding
• vision changes
• vomiting of blood
• weakness
• weight gain
• yellow eyes or skin

Other side effects

Some side effects of esterified estrogens / methyltestosterone may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.

Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Incidence not known

• Blemishes on the skin
• brown, blotchy spots on the exposed skin
• decreased interest in sexual intercourse
• depression
• headache, severe and throbbing
• inability to have or keep an erection
• increase or decrease in weight
• increased hair growth, especially on the face
• increased in sexual ability, desire, drive, or performance
• increased interest in sexual intercourse
• irritability
• leg cramps
• loss in sexual ability, desire, drive, or performance
• loss of hair
• mental depression
• pimples
• redness of the skin
• swelling or inflammation of the mouth
• twitching, uncontrolled movements of the tongue, lips, face, arms, or legs

For Healthcare Professionals

Applies to esterified estrogens / methyltestosterone: oral tablet.

General

General side effects have included increase or decrease in weight, edema, arthralgias, and leg cramps.^[Ref]

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.^[Ref]

Estrogens:

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

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.^[Ref]

Estrogen:

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

Methyltestosterone:

Frequency not reported: Hepatocellular carcinoma^[Ref]

Genitourinary

Estrogen:

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

Methyltestosterone:

Frequency not reported: Amenorrhea and other menstrual irregularities, clitoral enlargement^[Ref]

Gastrointestinal

Endocrine:

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

Methyltestosterone:

Frequency not reported: Nausea^[Ref]

Dermatologic

Estrogens:

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

Methyltestosterone:

Frequency not reported: Hirsutism, male pattern baldness, acne^[Ref]

Ocular

Estrogen:

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

Nervous system

Estrogen:

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

Methyltestosterone:

Frequency not reported: Increased or decreased libido, headache, anxiety, depression, generalized paresthesia^[Ref]

Hematologic

Methyltestosterone:

Frequency not reported: Suppression of clotting factors II, V, VII, and X, bleeding in patients on concomitant anticoagulant therapy, polycythemia^[Ref]

Hypersensitivity

Estrogen:

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

Methyltestosterone:

Frequency not reported: Anaphylactoid/anaphylactic reactions.^[Ref]

Respiratory

Estrogen:

Frequency not reported: Exacerbation of asthma^[Ref]

Metabolic

Estrogen:

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

Methyltestosterone:

Frequency not reported: Retention of sodium, chloride, water, potassium, calcium, and inorganic phosphates; increased serum cholesterol^[Ref]

Musculoskeletal

Estrogen:

Frequency not reported: Arthralgias, leg cramps

Psychiatric

Estrogen:

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

Hepatic

Estrogen:

Frequency not reported: Benign hepatic adenomas, hepatic hemangiomas

Methyltestosterone:

Frequency not reported: Cholestatic jaundice, alterations in liver function tests, peliosis hepatis

Endocrine

Endocrine:

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

Methyltestosterone:

Frequency not reported: Inhibition of gonadotropin secretin, virilization