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.

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 Full and Half-Strength Tablets contain the following inactive ingredients: acacia, calcium carbonate, carnauba wax, citric acid, colloidal silicon dioxide, di-acetylated monoglycerides, gelatin, lactose, magnesium stearate, methylparaben, microcrystalline cellulose, pharmaceutical glaze, povidone, propylene glycol, propylparaben, shellac glaze, sodium benzoate, sodium bicarbonate, sorbic acid, starch, sucrose, talc, titanium dioxide, tromethamol, FD&C Blue No. 1 Aluminum Lake, and D&C Yellow No. 10 Aluminum Lake.

Esterified Estrogens and Methyltestosterone Tablets also contain: FD&C Yellow No. 6 Aluminum Lake.

Esterified Estrogens and Methyltestosterone Half-Strength Tablets also contain: FD&C Blue No. 2 Aluminum Lake and Iron Oxide Black.

Estrogens:

Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol at the receptor level.

The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.

Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

Estrogen Pharmacokinetics 

Distribution

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.

Metabolism

Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

Excretion

Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

Drug Interactions

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.

Clinical Studies

Women’s Health Initiative Studies

The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of oral 0.625 mg conjugated estrogens (CE) per day alone or the use of oral 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.

The CE-only substudy has concluded. The impact of those results are under review. The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index." Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 1 below.

For those outcomes included in the "global index," the absolute excess risks per 10,000 women-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the "global index" was 19 per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS and PRECAUTIONS.)

Women’s Health Initiative Memory Study

The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and WARNINGS, Dementia.)

Warnings Associated with Estrogens

Warnings 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 (Androgens)] 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.

General Precautions Associated with Estrogens

Addition of a progestin when a woman has not had a hysterectomy: Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.

There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast cancer.

Elevated blood pressure: In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use.

Hypertriglyceridemia: In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.

Impaired liver function and past history of cholestatic jaundice: Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued.

Hypothyroidism: Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

Fluid retention: Because estrogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.

Hypocalcemia: Estrogens should be used with caution in individuals with severe hypocalcemia.

Ovarian cancer: The CE/MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95% confidence interval 0.77 – 3.24) but was not statistically significant. The absolute risk for CE/MPA versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen alone, in particular for 10 or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations.

Exacerbation of endometriosis: Endometriosis may be exacerbated with administration of estrogens. A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.

Exacerbation of other conditions: Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

General Precautions Associated with Methyltestosterone

1.

Women should be observed for signs of virilization (deepening of the voice, hirsutism, acne, clitoromegaly, and menstrual irregularities). Discontinuation of drug therapy at the time of evidence of mild virilism is necessary to prevent irreversible virilization. Such virilization is usual following androgen use at high doses.

2.

Prolonged dosage of androgen may result in sodium and fluid retention. This may present a problem, especially in patients with compromised cardiac reserve or renal disease.

3.

Hypersensitivity may occur rarely.

4.

Protein-bound iodine (PBI) may be decreased in patients taking androgens.

5.

Hypercalcemia may occur. If this does occur, the drug should be discontinued.

Patient Information (Estrogens)

Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe Esterified Estrogens and Methyltestosterone Full and Half-Strength Tablets.

Patient Information (Androgens)

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 or ankle swelling.

Laboratory Tests (Estrogens)

Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response rather than by serum hormone levels (e.g., estradiol, FSH).

Laboratory Tests (Androgens)

1.

Women with disseminated breast carcinoma should have frequent determination of urine and serum calcium levels during the course of androgen therapy. (See WARNINGS.)

2.

Because of the hepatotoxicity associated with the use of 17-alpha-alkylated androgens, liver function tests should be obtained periodically.

3.

Hemoglobin and hematocrit should be checked periodically for polycythemia in patients who are receiving high doses of androgens.

Drug/Laboratory Test Interactions (Estrogens)

1.

Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.

2.

Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.

3.

Other binding proteins may be elevated in serum (i.e., corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG)) leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

4.

Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.

5.

Impaired glucose tolerance.

6.

Reduced response to metyrapone test.

Drug Interactions (Androgens)

Anticoagulants: C-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.

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

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

Drug/Laboratory Test Interferences (Androgens)

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility (Estrogens)

Long-term continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. (See BOXED WARNINGS, WARNINGS and PRECAUTIONS.)

Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

Carcinogenesis (Androgens)

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 increased risk for the development of prostatic hypertrophy and prostatic carcinoma.

Pregnancy (Estrogens)

Esterified Estrogens and Methyltestosterone Tablets and Esterified Estrogens and Methyltestosterone Half-Strength Tablets should not be used during pregnancy. (See CONTRAINDICATIONS.)

Pregnancy (Androgens)

Teratogenic Effects: Pregnancy Category X. (See CONTRAINDICATIONS.)

Nursing Mothers (Estrogens)

Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when Esterified Estrogens and Methyltestosterone Tablets Full and Half-Strength Tablets are administered to a nursing woman.

Nursing Mothers (Androgens)

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.

Pediatric Use

Esterified Estrogens and Methyltestosterone Tablets Full and Half-StrengthTablets are not indicated for use in children.

Geriatric Use

Clinical studies of Esterified Estrogens and Methyltestosterone Full and Half-Strength Tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

In the Women's Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n = 3,729) were 65 to 74 while 18% (n = 803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Alzheimer's disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of women that were older than 70. (See WARNINGS, Dementia.)

The estrogen alone substudy of the Women's Health Initiative Memory Study has concluded. It is unknown whether these findings apply to estrogen alone.

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 estrogen and/or progestin therapy.

Genitourinary System: Changes in vaginal bleeding pattern and 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; ovarian cancer; endometrial hyperplasia; endometrial cancer; cystitis-like syndrome.

Breasts: Tenderness; enlargement; pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer.

Cardiovascular: Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure.

Gastrointestinal: Nausea; vomiting; abdominal cramps; bloating; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis, enlargement of hepatic hemangiomas.

Skin: Chloasma or melasma that may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash.

Eyes: Retinal vascular thrombosis, steepening of corneal curvature, intolerance to contact lenses.

Central Nervous System: Headache, migraine, dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia.

Miscellaneous: Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthralgias; leg cramps; changes in libido; urticaria, angioedema, anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides.

Associated with Methyltestosterone

Endocrine and Urogenital

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.

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

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

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

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

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

Metabolic: Increased serum cholesterol.

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

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 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.

What are Esterified Estrogens and Methyltestosterone Tablets and Esterified Estrogens and Methyltestosterone Half-Strength Tablets?

Esterified Estrogens and Methyltestosterone Full and Half-Strength Tablets are medicines that contain estrogen and androgen hormones.

What are Esterified Estrogens and Methyltestosterone Tablets and Esterified Estrogens and Methyltestosterone Half-Strength Tablets used for?

Esterified Estrogens and Methyltestosterone Full and Half-Strength Tablets are used after menopause to:

•

reduce moderate to severe hot flashes. Estrogens are hormones made by a woman's ovaries. The ovaries normally stop making estrogens when a woman is between 45 to 55 years old. This drop in body estrogen levels causes the "change of life" or menopause (the end of monthly menstrual periods). Sometimes, both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes "surgical menopause."



When the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating ("hot flashes" or "hot flushes"). In some women, the symptoms are mild, and they will not need estrogens. In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether you still need treatment with Esterified Estrogens and Methyltestosterone Full and Half-Strength Tablets

•

treat moderate to severe dryness, itching, and burning in and around the vagina. You and your healthcare provider should talk regularly about whether you still need treatment with Esterified Estrogens and Methyltestosterone Full and Half-Strength Tablets to control these problems. If you use Esterified Estrogens and Methyltestosterone Full and Half-Strength Tablets only to treat your dryness, itching, and burning in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you.

Who should not take Esterified Estrogens and Methyltestosterone Tablets and Esterified Estrogens and Methyltestosterone Half-Strength Tablets?

Do not start taking Esterified Estrogens and Methyltestosterone Full and Half-Strength Tablets if you:

•

have unusual vaginal bleeding.

•

currently have or have had certain cancers. Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or had cancer, talk with your healthcare provider about whether you should take Esterified Estrogens and Methyltestosterone Full and Half-Strength Tablets.

•

had a stroke or heart attack in the past year.

•

currently have or have had blood clots.

•

currently have or have had liver problems.

•

are allergic to Esterified Estrogens and Methyltestosterone Tablets and Esterified Estrogens and Methyltestosterone Half-Strength Tablets or any of their ingredients. See the end of this leaflet for a list of ingredients in Esterified Estrogens and Methyltestosterone Full and Half-Strength Tablets.

•

think you may be pregnant.

Tell your healthcare provider:

•

if you are breastfeeding. The hormones in Esterified Estrogens and Methyltestosterone Full and Half-Strength Tablets can pass into your milk.

•

about all of your medical problems. Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.

•

about all the medicines you take. This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how Esterified Estrogens and Methyltestosterone Full and Half-Strength Tablets work. Esterified Estrogens and Methyltestosterone Full and Half-Strength Tablets may also affect how your other medicines work.

•

if you are going to have surgery or will be on bed rest. You may need to stop taking estrogens.

How should I take Esterified Estrogens and Methyltestosterone Tablets and Esterified Estrogens and Methyltestosterone Half-Strength Tablets?

Estrogens should be used at the lowest dose possible for your treatment only as long as needed. The lowest effective dose of Esterified Estrogens and Methyltestosterone Full and Half-Strength Tablets has not been determined. You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about the dose you are taking and whether you still need treatment with Esterified Estrogens and Methyltestosterone Full and Half-Strength Tablets

What are the possible side effects of estrogens?

Less common but serious side effects include:

•

Breast cancer

•

Cancer of the uterus

•

Stroke

•

Heart attack

•

Blood clots

•

Dementia

•

Gallbladder disease

•

Ovarian cancer

These are some of the warning signs of serious side effects:

•

Breast lumps

•

Unusual vaginal bleeding

•

Dizziness and faintness

•

Changes in speech

•

Severe headaches

•

Chest pain

•

Shortness of breath

•

Pains in your legs

•

Changes in vision

•

Vomiting

Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptom that concerns you.

Common side effects include:

•

Headache

•

Breast pain

•

Irregular vaginal bleeding or spotting

•

Stomach/abdominal cramps, bloating

•

Nausea and vomiting

•

Hair loss

Other side effects include:

•

High blood pressure

•

Liver problems

•

High blood sugar

•

Fluid retention

•

Enlargement of benign tumors of the uterus ("fibroids")

•

Vaginal yeast infection

These are not all the possible side effects of Esterified Estrogens and Methyltestosterone Full and Half-Strength Tablets.  For more information, ask your healthcare provider or pharmacist.

What can I do to lower my chance of a serious side effect with Esterified Estrogens and Methyltestosterone Tablets and Esterified Estrogens and Methyltestosterone Half-Strength Tablets?

•

Talk with your healthcare provider regularly about whether you should continue taking Esterified Estrogens and Methyltestosterone Full and Half-Strength Tablets.

•

If you have a uterus, talk to your healthcare provider about whether the addition of a progestin is right for you.

•

See your healthcare provider right away if you get vaginal bleeding while taking Esterified Estrogens and Methyltestosterone Full and Half-Strength Tablets.

•

Have a breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often.

•

If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease. Ask your healthcare provider for ways to lower your chances for getting heart disease.

General information about safe and effective use of Esterified Estrogens and Methyltestosterone Tablets and Esterified Estrogens and Methyltestosterone Half-Strength Tablets

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take Esterified Estrogens and Methyltestosterone Full and Half-Strength Tablets for conditions for which it was not prescribed. Do not give Esterified Estrogens and Methyltestosterone Full and Half-Strength Tablets to other people, even if they have the same symptoms you have. It may harm them.

Keep Esterified Estrogens and Methyltestosterone Tablets and Esterified Estrogens and Methyltestosterone Half-Strength Tablets out of the reach of children.

This leaflet provides a summary of the most important information about Esterified Estrogens and Methyltestosterone Full and Half-Strength Tablets. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Esterified Estrogens and Methyltestosterone Full and Half-Strength Tablets that is written for health professionals. You can get more information by calling the toll free number 1-800-308-6755.

What are the ingredients in Esterified Estrogens and Methyltestosterone Tablets and Esterified Estrogens and Methyltestosterone Half-Strength Tablets?

Esterified Estrogens and Methyltestosterone Half-Strength Tablets is a combination of Esterified Estrogens and Methyltestosterone. Each light green, capsule shaped, sugar-coated tablet imprinted with “1507" contains the following active ingredients: 0.625 mg of Esterified Estrogens, USP and 1.25 mg of Methyltestosterone, USP.

Esterified Estrogens and Methyltestosterone Tablets is a combination of Esterified Estrogens and Methyltestosterone. Each dark green, capsule shaped, sugar-coated tablet imprinted with “1490” contains the following active ingredients: 1.25 mg of Esterified Estrogens, USP and 2.5 mg of Methyltestosterone, USP.

Esterified Estrogens and Methyltestosterone Full and Half-Strength Tablets contain the following inactive ingredients: acacia, calcium carbonate, carnauba wax, citric acid, colloidal silicon dioxide, di-acetylated monoglycerides, gelatin, lactose, magnesium stearate, methylparaben, microcrystalline cellulose, pharmaceutical glaze, povidone, propylene glycol, propylparaben, shellac glaze, sodium benzoate, sodium bicarbonate, sorbic acid, starch, sucrose, talc, titanium dioxide, tromethamol, FD&C Blue No. 1 Aluminum Lake, and D&C Yellow No. 10 Aluminum Lake.

Esterified Estrogens and Methyltestosterone Tablets also contain: FD&C Yellow No. 6 Aluminum Lake.

Esterified Estrogens and Methyltestosterone Half-Strength Tablets also contain: FD&C Blue No. 2 Aluminum Lake and Iron Oxide Black.

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

†This product has not obtained FDA pre-market approval applicable for new drugs.

DEA Order Form Required

Manufactured by:

ANI Pharmaceuticals, Inc.

Baudette, MN 56623

9574 Rev 02/13