Estrogens, Esterified (USP) 1.25 MG / Methyltestosterone 2.5 MG Oral Tablet
WARNINGS
See BOXED .
Warnings Associated with Estrogens Cardiovascular Disorders Estrogen and estrogen/progestin 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, estrogens should be discontinued immediately.
Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.
Coronary Heart Disease and Stroke: In the Women’s Health Initiative (WHI) study, an increase in the number of myocardial infarctions and strokes was observed in women receiving CE compared to placebo.
The CE-only substudy has concluded.
The impact of those results are under review.
(See CLINICAL PHARMACOLOGY, Clinical Studies .
) In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 versus 30 per 10,000 women-years).
The increase in risk was observed in year 1 and persisted.
In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 versus 21 per 10,000 women-years).
The increase in risk was observed after the first year and persisted.
In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with CE/MPA (0.625 mg/2.5 mg per day) demonstrated no cardiovascular benefit.
During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease.
There were more CHD events in the CE/MPA-treated group than in the placebo group in year 1, but not during the subsequent years.
Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open-label extension of HERS, HERS II.
Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall.
Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in HERS, HERS II, and overall.
Large doses of estrogen (5 mg conjugated 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 men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.
Venous Thromboembolism (VTE.): In the Women’s Health Initiative (WHI) study, an increase in VTE was observed in women receiving CE compared to placebo.
The CE-only substudy has concluded.
The impact of those results are under review.
(See CLINICAL PHARMACOLOGY, Clinical Studies .
) In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo.
The rate of VTE was 34 per 10,000 women-years in the CE/MPA group compared to 16 per 10,000 women-years in the placebo group.
The increase in VTE risk was observed during the first year and persisted.
If feasible, estrogens 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.
Malignant Neoplasms Endometrial Cancer: The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer.
The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in non-users, and appears dependent on duration of treatment and on estrogen dose.
Most studies show no significant increased risk associated with use of estrogens for less than one year.
The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.
Clinical surveillance of all women taking estrogen/progestin combinations is important.
Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose.
Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
Breast Cancer: The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer.
The most important randomized clinical trial providing information about this issue is the Women’s Health Initiative (WHI) substudy of CE/MPA.
(See CLINICAL PHARMACOLOGY, Clinical Studies .
) The results from observational studies are generally consistent with those of the WHI clinical trial and report no significant variation in the risk of breast cancer among different estrogens or progestins, doses, or routes of administration.
The CE/MPA substudy of WHI reported an increased risk of breast cancer in women who took CE/MPA for a mean follow-up of 5.6 years.
Observational studies have also reported an increased risk for estrogen/progestin combination therapy, and a smaller increased risk for estrogen alone therapy, after several years of use.
In the WHI trial and from observational studies, the excess risk increased with duration of use.
From observational studies, the risk appeared to return to baseline in about five years after stopping treatment.
In addition, observational studies suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen/progestin combination therapy as compared to estrogen alone therapy.
In the CE/MPA substudy, 26% of the women reported prior use of estrogen alone and/or estrogen/progestin combination hormone therapy.
After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01-1.54), and the overall absolute risk was 41 versus 33 cases per 10,000 women-years, for CE/MPA compared with placebo.
Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE/MPA compared with placebo.
Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for CE/MPA compared with placebo.
In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group.
Metastatic disease was rare with no apparent difference between the two groups.
Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups.
The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation.
All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations.
In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.
Dementia In the Women’s Health Initiative Memory Study (WHIMS), 4,532 generally healthy postmenopausal women 65 years of age and older were studied, of whom 35% were 70 to 74 years of age and 18% were 75 or older.
After an average follow-up of 4 years, 40 women being treated with CE/MPA (1.8%, n = 2,229) and 21 women in the placebo group (0.9%, n = 2,303) received diagnoses of probable dementia.
The relative risk for CE/MPA versus placebo was 2.05 (95% confidence interval 1.21 – 3.48), and was similar for women with and without histories of menopausal hormone use before WHIMS.
The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years, and the absolute excess risk for CE/MPA was 23 cases per 10,000 women-years.
It is unknown whether these findings apply to younger postmenopausal women.
(See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use .
) The estrogen alone substudy of the Women’s Health Initiative Memory Study has concluded.
It is unknown whether these findings apply to estrogen alone.
Gallbladder Disease A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.
Glucose Tolerance A worsening of glucose tolerance has been observed in a significant percentage of patients on estrogen-containing oral contraceptives.
For this reason, diabetic patients should be carefully observed while receiving estrogens.
Hypercalcemia Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases.
If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.
Visual Abnormalities Retinal vascular thrombosis has been reported in patients receiving estrogens.
Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine.
If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.
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.
OVERDOSAGE
Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing drug products by young children.
Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females.
There have been no reports of acute overdosage with the androgens.
DESCRIPTION
Esterified Estrogens and Methyltestosterone Tablets: Each green, oval, aqueous film coated tablet debossed “IP 78” on obverse and plain on the reverse contains: 1.25 mg of Esterified Estrogens, USP and 2.5 mg of Methyltestosterone, USP.
Esterified Estrogens and Methyltestosterone Tablets H.S.
(Half Strength): Each light blue, capsule-shaped, aqueous film coated tablet debossed “IP 77” on obverse and plain on the reverse 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.
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 and Esterified Estrogens and Methyltestosterone Tablets H.S.
contain the following inactive ingredients: Anhydrous Lactose, Colloidal Silicon Dioxide, D&C Yellow #10 Aluminum Lake, FD&C Blue #1 Aluminum Lake, Magnesium Stearate, Microcrystalline Cellulose, Polyethylene Glycol, Polyvinyl Alcohol, Sodium Bicarbonate, Talc and Titanium Dioxide.
chemical structure
HOW SUPPLIED
Esterified Estrogens and Methyltestosterone Tablets, a combination of Esterified Estrogens and Methyltestosterone.
Each green, oval, aqueous film coated tablet debossed “IP 78” on obverse and plain on the reverse contains: 1.25 mg of Esterified Estrogens, USP and 2.5 mg of Methyltestosterone, USP.
Available in bottles of 100: NDC 13925-172-01 Esterified Estrogens and Methyltestosterone Tablets H.S.
“Half Strength,” a combination of Esterifed Estrogens and Methyltestosterone.
Each light blue, capsule- shaped, aqueous film coated tablet debossed “IP 77” on obverse and plain on the reverse contains: 0.625 mg of Esterified Estrogens, USP and 1.25 mg of Methyltestosterone, USP.
Available in bottles of 100: NDC 13925-171-01 Keep Esterified Estrogens and Methyltestosterone Tablets and Esterified Estrogens and Methyltestosterone Tablets H.S.
out of reach of children.
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).
[ See USP Controlled Room Temperature.] ‡ This product has not obtained FDA pre-market approval applicable for new drugs.
Manufactured by: Amneal Pharmaceuticals of NY Hauppauge, NY 11788 Distributed by: Seton Pharmaceuticals Manasquan, NJ 08736 Rev.
04-2014
INDICATIONS AND USAGE
Esterified Estrogens and Methyltestosterone Tablets and Esterified Estrogens and Methyltestosterone Tablets H.S.
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 and Esterified Estrogens and Methyltestosterone Tablets H.S.
have not been shown to be effective for any purpose during pregnancy and its use may cause severe harm to the fetus.
BOXED WARNING
ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER Close clinical surveillance of all women taking estrogens is important.
Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
There is no evidence that the use of “natural” estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses.
(See WARNINGS, Malignant Neoplasms, Endometrial Cancer .) CARDIOVASCULAR AND OTHER RISKS Estrogens with or without progestins should not be used for the prevention of cardiovascular disease.
(See WARNINGS, Cardiovascular Disorders .) 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 (50 to 79 years of age) during 5 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo.
(See CLINICAL PHARMACOLOGY, Clinical Studies .) The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative to placebo.
It is unknown whether this finding applies to younger postmenopausal women or to women taking estrogen alone therapy.
(See CLINICAL PHARMACOLOGY, Clinical Studies .) Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials 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.
DOSAGE AND ADMINISTRATION
When estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be initiated to reduce the risk of endometrial cancer.
A woman without a uterus does not need progestin.
Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman.
Patients should be reevaluated periodically as clinically appropriate (e.g., 3-month to 6-month intervals) to determine if treatment is still necessary.
(See BOXED WARNINGS and WARNINGS .) For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
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 or 1 to 2 tablets of Esterified Estrogens and Methyltestosterone Tablets H.S.
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.