ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE - esterified estrogens and methyltestosterone tablet, film coated
Tal Pharma LLC
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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, 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.
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:
C20H30O2 302.46 Androst-4-en-3-one, 17-hydroxy-17-methyl-,(17β)-. Category: Androgen.
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.
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.
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:
Methyltestosterone should not be used in:
(See BOXED WARNINGS.)
Associated with Estrogens
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.
D. Nursing Mothers. As a general principle, the administration of any drug to nursing mothers should be done only when clearly necessary since many drugs are excreted in human milk.
The physician should instruct patients to report any of the following side effects of androgens:
Women: Hoarseness, acne, changes in menstrual periods, or more hair on the face.
All Patients: Any nausea, vomiting, changes in skin color of ankle swelling.
Androgens may decrease levels of thyroxine-binding globulin, resulting in decreased T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.
Animal Data: Testosterone has been tested by subcutaneous injection and implantation in mice and rats. The implant induced cervical-uterine tumors in mice, which metastasized in some cases. There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats.
Human Data: There are rare reports of hepatocellular carcinoma in patients receiving long-term therapy with androgens in high doses. Withdrawal of the drugs did not lead to regression of the tumors in all cases.
Geriatric Patients treated with androgens may be at an increased risk for the development of prostatic hypertrophy and prostatic carcinoma.
Teratogenic Effects: Pregnancy Category X (see CONTRAINDICATIONS).
It is not known whether androgens are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from androgens, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
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:
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.]
Estrogens are female hormones produced by the ovaries. The ovaries make several different kinds of estrogens. In addition, scientists have been able to make a variety of synthetic estrogens. As far as we know, all these estrogens have similar properties and therefore much the same usefulness, side effects, and risks. This leaflet is intended to help you understand what estrogens are used for, the risks involved in their use, and how to use them as safely as possible.
This leaflet includes the most important information about estrogens, but not all the information. If you want to know more, you can ask your doctor or pharmacist to let you read the package insert prepared for the doctor.
Estrogens are prescribed by doctors for a number of purposes, including:
THERE IS NO PROPER USE OF ESTROGEN IN A PREGNANT WOMAN.
ESTROGENS IN THE MENOPAUSE
In the natural course of their lives, all women eventually experience a decrease in estrogen production. This usually occurs between ages 45 and 55 but may occur earlier or later. Sometimes the ovaries may need to be removed before natural menopause by an operation, producing a “surgical menopause.”
When the amount of estrogen in the blood begins to decrease, many women may develop typical symptoms: Feelings of warmth in the face, neck, and chest or sudden intense episodes of heat and sweating throughout the body (called “hot flashes” or “hot Flushes”). These symptoms are sometimes very uncomfortable. A few women eventually develop changes in the vagina (called “atrophic vaginitis”) which cause discomfort, especially during and after intercourse.
Estrogens can be prescribed to treat these symptoms of the menopause. It is estimated that considerably more than half of all women undergoing the menopause have only mild symptoms or no symptoms at all and therefore do not need estrogens. Other women may need estrogens for a few months, while their bodies adjust to lower estrogen levels. Sometimes the need will be for periods longer than six months. In an attempt to avoid overstimulation of the uterus (womb), estrogens are usually given cyclically during each month of use, that is three weeks of pills followed by one week without pills.
Sometimes women experience nervous symptoms or depression during menopause. There is no evidence that estrogens are effective for such symptoms and they should not be used to treat them, although other treatment may be needed.
You may have heard that taking estrogens for long periods (years) after the menopause will keep your skin soft and supple and keep you feeling young. There is no evidence that this is so, however, and such long-term treatment carries important risks.
You should not receive estrogen if you are pregnant. If this should occur, there is a greater than usual chance that the developing child will be born with a birth defect, although the possibility remains fairly small. A female child may have an increased risk of developing cancer of the vagina or cervix later in life (in the teens or twenties). Every possible effort should be made to avoid exposure to estrogens during pregnancy. If exposure occurs, see your doctor.
In addition to the serious known risks of estrogens described above, estrogens have the following side effects and potential risks:
Estrogens have important uses, but they have serious risks as well. You must decide, with your doctor, whether the risks are acceptable to you in view of the benefits of the treatment. Except where your doctor has prescribed estrogens for use in special cases of cancer of the breast or prostate, you should not use estrogens if you have cancer of the breast or uterus, are pregnant, have undiagnosed abnormal vaginal bleeding, or have had a stroke, heart attack or angina, or clotting in the legs or lungs in the past while you were taking estrogens.
You can use estrogens as safely as possible by understanding that your doctor will require regular physical examinations while you are taking them and will try to discontinue the drug as soon as possible and use the smallest dose possible. Be alert for signs of trouble including:
Based on his or her assessment of your medical needs, your doctor has prescribed this drug for you. Do not give the drug to anyone else.
ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE TABLETS Half Strength a combination of Esterified Estrogens and Methyltestosterone. Each capsule-shaped, light blue, film-coated tablet contains: 0.625 mg of Esterified
Estrogens, USP and 1.25 mg of Methyltestosterone, USP.
ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE TABLETS Full Strength a combination of Esterified Estrogens and Methyltestosterone. Each capsule-shaped, light green, film-coated tablet contains: 1.25 mg of Esterified Estrogens, USP and 2.5 mg of Methyltestosterone, USP.
All prescription substitutions using this product shall be pursuant to state statutes as applicable. This is not an Orange Book product.
Distributed By: Tal Pharma LLC
Manufactured By: Syntho Pharmaceuticals, Inc.
Farmingdale, NY 11735
|ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE
esterified estrogens and methyltestosterone tablet, film coated
|ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE
esterified estrogens and methyltestosterone tablet, film coated
|Labeler - Tal Pharma LLC (832524784)|
|Syntho Pharmaceuticals Inc.||088797407||MANUFACTURE|