Esterified Estrogens and Methyltestosterone

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.^1-3 This 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 treatment¹ and on estrogen dose.⁴ In 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,³ it 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-steriodal estrogen, have an increased risk of developing in later life a form of vaginal or cervical cancer that is ordinarily extremely rare.^5,6 This risk has been estimated as not greater than 4 per 1000 exposures.⁷ Furthermore, a high percentage of such exposed women (from 30 to 90 percent) have been found to have vaginal adenosis,^8-12 epithelial 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 study¹⁶ estimated 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 TABLETS 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.

3. CARDIOVASCULAR AND OTHER RISKS.

ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE TABLETS do not contain a progestin. ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE TABLETS are an Estrogen/Androgen product. Estrogens with or without progestins should not be used for the prevention of cardiovascular disease. The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women during 5 years of treatment with conjugated equine estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo (See CLINICAL PHARMACOLOGY , Clinical Studies). Other doses of conjugated estrogens with medroxyprogesterone and other combinations of estrogens and progestins were not studied in the WHI and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE TABLETS Full Strength: Each light green, capsule shaped, film-coated oral tablet contains: 1.25 mg of Esterified Estrogens, USP and 2.5 mg of Methyltestosterone, USP.

ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE TABLETS Half-Strength: Each light blue, capsule shaped, film-coated oral tablet contains: 0.625 mg of Esterified Estrogens, USP and 1.25 mg of Methyltestosterone, USP.

Esterified Estrogens

Esterified Estrogens, USP is a mixture of the sodium salts of the sulfate esters of the estrogenic substances, principally estrone, that are of the type excreted by pregnant mares. Esterified Estrogens contain not less than 75.0 percent and not more than 85.0 percent of sodium estrone sulfate, and not less than 6.0 percent and not more than 15.0 percent of sodium equilin sulfate, in such proportion that the total of these two components is not less than 90.0 percent.

Category: Estrogens

Methyltestosterone

Methyltestosterone, USP is an androgen. Androgens are derivatives of cyclopentano-perhydrophenanthrene. Endogenous androgens are C-19 steroids with a side chain at C-17, and with two angular methyl groups. Testosterone is the primary endogenous androgen. Fluoxymesterone and methyltestosterone are synthetic derivatives of testosterone.

Methyltestosterone is a white to light yellow crystalline substance that is virtually insoluble in water but soluble in organic solvents. It is stable in air but decomposes in light.

Methyltestosterone structural formula:

ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE TABLETS Full Strength and Half Strength contain the following inactive ingredients: lactose, magnesium stearate, microcrystalline cellulose, titanium dioxide, and other minor ingredients.

ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE TABLETS Full Strength also contain: FD&C Blue No. 1 and D&C Yellow No. 10 and PEG.

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 endogeneous 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.

ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE TABLETS Full Strength and Half Strength are indicated in the treatment of: Moderate to severe vasomotor symptoms 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 TABLETS Full Strength and 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).

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.

(See BOXED WARNINGS.)

Associated with Estrogens

1. Breast Cancer (See BOXED WARNINGS).
2. Induction of malignant neoplasms: Long term continuous administration of natural and synthetic estrogens in certain animal species increases this 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 Warning ).
   At the present time there is no satisfactory evidence that estrogens given to postmenopausal women increase the risk of cancer of the breast,¹⁸ although a recent long-term follow-up of a single physician’s practice has raised this possibility.¹⁸ 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.
3. Cardiovascular Disease: Estrogen with progestogen therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogen with progestogens should be discontinued immediately. Risk factors for cardiovascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) should be managed appropriately. If feasible, estrogens with progestins should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.
4. 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,18 similar to the 2-fold increase previously noted in users of oral contraceptives.19-24 In the case of oral contraceptives the increased risk appeared after two years of use.24
5. Effects similar to those caused by estrogen-progesterone 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 or postpartum breast engorgement 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 and women for postpartum breast engorgement.20-23
   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.24-31 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.32-33 An increased risk of postsurgery thromboembolic complications has also been reported in users of oral contraceptives.34-35 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 prolonged immobilization.
      While an increased rate of thromboembolic and thrombotic disease in postmenopausal users of estrogens has not been found,18-36 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 esterified 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 men³⁷ 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.^38-40 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 progestogen 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.30 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 menopause⁴¹ 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 of estrogen-containing oral contraceptives. For this reason, diabetic patients should be carefully observed while receiving estrogens.
6. 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.

Associated with Methyltestosterone

In patients with breast cancer, androgen therapy may cause hypercalcemia by stimulating osteolysis. In this case the drug should be discontinued.

Prolonged use of high doses of androgens has been associated with the development of peliosis hepatis and hepatic neoplasms including hepatocellular carcinoma. (See PRECAUTIONS – Carcinogenesis). Peliosis hepatis can be a life-threatening or fatal complication.

Cholestatic hepatitis and jaundice occur with 17-alpha-alkylandrogens at a relatively low dose. If cholestatic hepatitis with jaundice appears or if liver function tests become abnormal, the androgen should be discontinued and the etiology should be determined. Drug-induced jaundice is reversible when the medication is discontinued.

Edema with or without heart failure may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease. In addition to discontinuation of the drug, diuretic therapy may be required.

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:

1. 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.
2. Breasts.
   Tenderness, enlargement, secretion.
3. Gastrointestinal.
   Nausea, vomiting.
   Abdominal cramps, bloating.
   Cholestatic jaundice.
4. Skin.
   Chloasma or melasma which may persist when drug is discontinued.
   Erythema multiforme.
   Erythema nodosum.
   Hemorrhagic eruption.
   Loss of scalp hair.
   Hirsutism.
5. Eyes.
   Steepening of corneal curvature.
   Intolerance to contact lenses.
6. Central Nervous System.
   Headache, migraine, dizziness.
   Mental depression.
   Chorea.
7. Miscellaneous
   Increase or decrease in weight.
   Reduced carbohydrate tolerance.
   Aggravation of porphyria.
   Edema.
   Changes in libido.

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.

There have been no reports of acute overdosage with the androgens.

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 TABLETS Full Strength or 1 to 2 tablets of ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE TABLETS 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.

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

ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE TABLETS Full Strength light green, capsule-shaped, film-coated oral tablets, debossed “SYNTHO” on one side and “231” on other. Contains: 1.25 mg of Esterified Estrogens, USP and 2.5 mg of Methyltestosterone, USP.

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

ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE TABLETS Half Strength light blue, capsule-shaped, film-coated oral tablets, debossed “SYNTHO” on one side and “230” on other. Contains 0.625 mg of Esterified Estrogens, USP and 1.25 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

1. Ziel, H.K. et al.: N. Engl. J. Med. 293: 1167-1170, 1975.
2. Smith, D.C., et al.: N. Engl. J. Med. 293: 1164-1167, 1975.
3. Mack, T.M., et al.: N. Engl. J. Med. 294: 1262-1267, 1976.
4. Weiss, N.S. et al.: N. Engl. J. Med. 294: 1259-1262, 1976.
5. Herbst, A.L. et al.: N. Engl. J. Med. 284: 878-881, 1971.
6. Greenwald, P., et al.: N. Engl. J. Med. 285: 390-392, 1971.
7. Lanier, A., et al.: Mayo Clin. Proc. 48: 793-799, 1973.
8. Herbst, A., et al.: Obstet. Gynecol. 40: 287-298, 1972.
9. Herbst, A., et al.: Am. J. Obstet. Gynecol. 118: 607-615, 1974.
10. Herbst, A., et al.: N. Engl. J. Med. 292: 334-339, 1975.
11. Stafl, A., et al.: Obstet. Gynecol. 43: 118-128, 1974.
12. Sherman, A.I., et al.: Obstet. Gynecol. 44: 531-545, 1974.
13. Gal, I., et al.: Nature 216: 83 1967.
14. Levy, E.P., et al.: Lancet 1: 611, 1973.
15. Nora, J., et al.: Lancet 1: 941-942, 1973.
16. Janerich, D.T., et al.: N. Engl. J. Med. 291: 697-700, 1974.
17. Estrogens for Oral or Parenteral Use: Federal Register 40: 8212, 1975.
18. Boston Collaborative Drug Surveillance Program: N. Engl. J. Med. 290: 15-19. 1974.
    18a.Hoover, R. et al.: N. Engl. J. Med. 295: 401-405, 1976.
19. Boston Collaborative Drug Surveillance Program: Lancet 1: 1399-1404, 1973.
20. Daniel, D.G., et al.: Lancet 2: 287-289, 1967.
21. The Veterans Administration Cooperative Urological Research Group: J. Urol, 98: 516-522, 1967.
22. Bailar, J.C.: Lancet 2: 560, 1967.
23. Blackard, C., et al.: Cancer 26: 249-256, 1970.
24. Royal College of General Practitioners: J.R. Coll, Gen. Pract. 13: 267-279, 1967.
25. Inman, W.H.W., et al.: Br. Med. J. 2: 193-199, 1968.
26. Vessey, M.P., et al.: Br. Med. J. 2: 651-657, 1969.
27. Sartwell, P.E., et al.: Am. J. Epidemiol, 90: 365-380, 1969.
28. Collaborative Group for the Study of Stroke in Young Women: N. Engl. J. Med. 288: 871-878, 1973.
29. Collaborative Group for the Study of Stroke in Young Women: J.A.M.A 231: 718-722, 1975.
30. Mann, J.I., et al.: Br. Med. J. 2: 245-248, 1975.
31. Mann, J.I., et al., Br. Med. J. 2: 241-245, 1975.
32. Inman, W.H.W., et al., Br. Med. J. 2: 203-209, 1970.
33. Stolley, P.D., et al., Am. J. Epidemiol. 102: 197-208, 1975.
34. Vessey, M.P., et al., Br. Med. J. 3: 123-126, 1970.
35. Greene, G.R., et al., Am. J. Public Health 62: 680-685, 1972.
36. Rosenberg, L., et al., N. Engl. J. Med. 294: 1256-1259, 1976.
37. Coronary Drug Project Research Group: J.A.M.A. 214: 1303-1313, 1970.
38. Baum, J., et al., Lancet 2: 926-928, 1973.
39. Mays, E.T., et al.: J.A.M.A 235: 730-732, 1976.
40. Edmondson, H.A., et al.: N. Engl. J. Med. 294: 470-472, 1976.
41. Pfeffer, R.I., et al.: Am. J. Epidemiol. 103: 445-456, 1976.