Boxed Warning

1. ESTROGENS HAVE BEEN REPORTED TO INCREASE THE RISK OF ENDOMETRIAL CARCINOMA

Three independent case control studies have reported an increased risk of endometrial cancer in postmenopausal women exposed to exogenous estrogens for prolonged periods. ^1-3This risk was independent of the other known risk factors for endometrial cancer. These studies are further supported by the finding that incidence rates of endometrial cancer have increased sharply since 1969 in eight different areas of the United States with population-based cancer reporting systems, an increase which may be related to the rapidly expanding use of estrogens during the last decade. ⁴

The three case control studies reported that the risk of endometrial cancer in estrogen users was about 4.5 to 13.9 times greater than in nonusers. The risk appears to depend on both duration of treatment ¹ and on estrogen dose. ³In view of these findings, when estrogens are used for the treatment of menopausal symptoms, the lowest dose that will control symptoms should be utilized and medication should be discontinued as soon as possible. When prolonged treatment is medically indicated, the patient should be reassessed on at least a semiannual basis to determine the need for continued therapy. Although the evidence must be considered preliminary, one study suggests that cyclic administration of low doses of estrogen may carry less risk than continuous administration, ³it therefore appears prudent to utilize such a regimen.

Close clinical surveillance of all women taking estrogens is important. In all cases of undiagnosed persistent or recurring abnormal vaginal bleeding, adequate diagnostic measures should be undertaken to rule out malignancy.

There is no evidence at present that "natural" estrogens are more or less hazardous than "synthetic" estrogens at equiestrogenic doses.

2. ESTROGENS SHOULD NOT BE USED DURING PREGNANCY

The use of female sex hormones, both estrogens and progestogens, during early pregnancy may seriously damage the offspring. It has been shown that females exposed in utero to diethylstilbestrol, a non-steroidal estrogen, have an increased risk of developing in later life a form of vaginal or cervical cancer that is ordinarily extremely rare. ^5,6This risk has been estimated as not greater than 4 per 1000 exposures. ⁷Furthermore, a high percentage of such exposed women (from 30 to 90 percent) have been found to have vaginal adenosis, ^8-12epithelial changes of the vagina and cervix. Although these changes are histologically benign, it is not known whether they are precursors of malignancy. Although similar data are not available with the use of other estrogens, it cannot be presumed they would not induce similar changes.

Several reports suggest an association between intrauterine exposure to female sex hormones and congenital anomalies, including congenital heart defects and limb reduction defects. ^13-16 One case control study ¹⁶estimated a 4.7 fold increased risk of limb reduction defects in infants exposed in utero to sex hormones (oral contraceptives, hormone withdrawal tests for pregnancy, or attempted treatment for threatened abortion). Some of these exposures were very short and involved only a few days of treatment. The data suggest that the risk of limb reduction defects in exposed fetuses is somewhat less than 1 per 1000.

In the past, female sex hormones have been used during pregnancy in an attempt to treat threatened or habitual abortion. There is considerable evidence that estrogens are ineffective for these indications, and there is no evidence from well controlled studies that progesterones are effective for these uses.

IF ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE FULL STRENGTH or ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE HALF STRENGTH is used during pregnancy, or if the patient becomes pregnant while taking this drug, she should be apprised of the potential risks to the fetus, and the advisability of pregnancy continuation.

Indications and Usage

ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE FULL STRENGTH and ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE HALF STRENGTH are indicated in the treatment of: Moderate to severe vasomotorsymptoms associated with the menopause in those patients not improved by estrogens alone. (There is no evidence that estrogens are effective for nervous symptoms or depression without associated vasomotor symptoms, and they should not be used to treat such conditions.)

ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE FULL STRENGTH and ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE HALF STRENGTH HAVE NOT BEEN SHOWN TO BE EFFECTIVE FOR ANY PURPOSE DURING PREGNANCY AND ITS USE MAY CAUSE SEVERE HARM TO THE FETUS (SEE BOXED WARNING).

Dosage and Administration

1. Given cyclically for short-term use only:

For treatment of moderate to severe vasomotor symptoms associated with the menopause in patients not improved by estrogen alone.

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 tablet of ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE FULL STRENGTH or 1 to 2 tablets of ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE HALF STRENGTH daily as recommended by the physician.

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.

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 thrombophlebitis or thromboembolic disorders.

6. A past history of thrombophlebitis, thrombosis, or thromboembolic disorders associated with previous estrogen use (except when in treatment of breast malignancy).

Methyltestosterone should not be used in:

1. The presence of severe liver damage.

2. Pregnancy and in breast-feeding mothers because of the possibility of masculinization of the female fetus or breast-fed infant.

Adverse Reactions

Associated with Estrogens

(See Warnings regarding induction of neoplasia, adverse effects on the fetus, increased incidence of gallbladder disease, and 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 erosion 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.

Associated with Methyltestosterone

A. Endocrine and Urogenital.

1. Female:The most common side effects of androgen therapy are amenorrhea and other menstrual irregularities, inhibition of gonadotropin secretion, and virilization, including deepening of the voice and clitoral enlargement. The latter usually is not reversible after androgens are discontinued. When administered to a pregnant woman androgens cause virilization of external genitalia of the female fetus.

2. Skin and Appendages:Hirsutism, male pattern of baldness, and acne.

3. Fluid and Electrolyte Disturbances:Retention of sodium, chloride, water, potassium, calcium, and inorganic phosphates.

4. Gastrointestinal:Nausea, cholestatic jaundice, alterations in liver function test, rarely hepatocellular neoplasms, and peliosis hepatis (see WARNINGS).

5. Hematologic:Suppression of clotting factors, II, V, VII, and X, bleeding in patients on concomitant anticoagulant therapy, and polycythemia.

6. Nervous System:Increased or decreased libido, headache, anxiety, depression, and generalized paresthesia.

7. Metabolic:Increased serum cholesterol.

8. Miscellaneous:Inflammation and pain at site of intramuscular injection or subcutaneous implantation of testosterone containing pellets, stomatitis with buccal preparations, and rarely anaphylactoid reactions.

Drug Interactions

D. Drug Interactions

1. AnticoagulantsC-17 substituted derivatives of testosterone, such as methandrostenolone, have been reported to decrease the anticoagulant requirements of patients receiving oral anticoagulants. Patients receiving oral anticoagulant therapy require close monitoring, especially when androgens are started or stopped.

2. Oxyphenbutazone. Concurrent administration of oxyphenbutazone and androgens may result in elevated serum levels of oxyphenbutazone.

3. Insulin. In diabetic patients the metabolic effects of androgens may decrease blood glucose and insulin requirements.

Clinical Pharmacology

Estrogens

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 esterified estrogens are similar to those of endogenous estrogens. They are soluble in water and are well absorbed from the gastrointestinal tract.

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.

Estrogen Pharmacokinetics

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 esterified estrogens are strongly acidic and are ionized in body fluids, which favor excretion through the kidneys since tubular reabsorption is minimal.

Androgens

Endogenous androgens are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as beard, pubic, chest and axillary hair, laryngeal enlargement, vocal cord thickening, alterations in body musculature, and fat distribution. Drugs in this class also cause retention of nitrogen, sodium, potassium, phosphorus, and decreased urinary excretion of calcium. Androgens have been reported to increase protein anabolism and decrease protein catabolism. Nitrogen balance is improved only when there is sufficient intake of calories and protein. Androgens are responsible for the growth spurt of adolescence and for the eventual termination of linear growth centers. In children, exogenous androgens accelerate linear growth rates, but may cause a disproportionate advancement in bone maturation. Use over long periods may result in fusion of the epiphyseal growth centers and termination of growth process. Androgens have been reported to stimulate the production of red blood cells by enhancing the production of erythropoietic stimulating factor.

Androgen Pharmacokinetics

Testosterone given orally is metabolized by the gut and 44 percent is cleared by the liver in the first pass. Oral doses as high as 400 mg per day are needed to achieve clinically effective blood levels for full replacement therapy. The synthetic androgens (methyltestosterone and fluoxymesterone) are less extensively metabolized by the liver and have longer half-lives. They are more suitable than testosterone for oral administration.

Testosterone in plasma is 98 percent bound to a specific testosterone estradiol binding globulin, and about 2 percent is free. Generally, the amount of this sex-hormone binding globulin in the plasma will determine the distribution of testosterone between free and bound forms, and the free testosterone concentration will determine its half-life.

About 90 percent of a dose of testosterone is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6 percent of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver. Testosterone is metabolized to various 17-keto steroids through two different pathways. There are considerable variations of the half-life of testosterone as reported in the literature, ranging from 10 to 100 minutes.

In many tissues the activity of testosterone appears to depend on reduction to dihydrotestosterone, which binds to cytosol receptor proteins. The steroid-receptor complex is transported to the nucleus where it initiates transcription events and cellular changes related to androgen action.

How Supplied / Storage and Handling

ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE TABLETS Full Strength in bottles of 100.

ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE TABLETS Full Strength light pink, capsule-shaped, film-coated, oral tablets, debossed "C020" on obverse and plain on the reverse. Contains: 0.625 mg of Esterified Estrogens, USP and 1.25 mg of Methyltestosterone, USP.

ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE TABLETS Half Strength in bottles of 100.

ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE TABLETS Half Strength light yellow, capsule-shaped, film-coated, oral tablets, debossed "C010" on one side and plain on the reverse. Contains: 1.25 mg of Esterified Estrogens, USP and 2.5 mg of Methyltestosterone, USP.

Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature.]

Rx only

Professional Information — ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE