ESTROPIPATE- estropipate tablet
Mylan Pharmaceuticals Inc.
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 result 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 and 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 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.
Estropipate tablets, (formerly piperazine estrone sulfate), is a natural estrogenic substance prepared from purified crystalline estrone, solubilized as the sulfate and stabilized with piperazine. It is appreciably soluble in water and has almost no odor or taste — properties which are ideally suited for oral administration. The amount of piperazine in estropipate is not sufficient to exert a pharmacological action. Its addition ensures solubility, stability and uniform potency of the estrone sulfate. Chemically estropipate, molecular weight: 436.58, is represented by estra-1,3,5(10)-trien-17-one,3-(sulfooxy)-, compound with piperazine (1:1). The structural formula and molecular formula may be represented as follows:
C18 H22 O5 S • C4 H10 N2
Estropipate Tablets, USP are available for oral administration containing either 0.75 mg or 1.5 mg of estropipate, USP (calculated as sodium estrone sulfate 0.625 mg and 1.25 mg, respectively). In addition, each tablet contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The 0.75 mg tablet also contains D&C Yellow No. 10 Aluminum Lake and the 1.5 mg tablet also contains FD&C Yellow No. 6 Aluminum Lake.
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 mcg 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.
Estropipate is well absorbed through the skin and gastrointestinal tract. When applied for a local action, absorption is usually sufficient to cause systemic effects.
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.
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.
Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates.
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.
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 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/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:
|Event †|| |
Relative RiskCE/MPA vs.Placeboat 5.2 Years
|Absolute Risk per 10,000 Person-years|
|CHD events||1.29 (1.02 to 1.63)||30||37|
|Non-fatal MI||1.32 (1.02 to 1.72)||23||30|
|CHD death||1.18 (0.70 to 1.97)||6||7|
|Invasive breast cancer §||1.26 (1.00 to 1.59)||30||38|
|Stroke||1.41 (1.07 to 1.85)||21||29|
|Pulmonary embolism||2.13 (1.39 to 3.25)||8||16|
|Colorectal cancer||0.63 (0.43 to 0.92)||16||10|
|Endometrial cancer||0.83 (0.47 to 1.47)||6||5|
|Hip fracture||0.66 (0.45 to 0.98)||15||10|
|Death due to causes other than the events above||0.92 (0.74 to 1.14)||40||37|
|Global index†||1.15 (1.03 to 1.28)||151||170|
|Deep vein thrombosis ¶||2.07 (1.49 to 2.87)||13||26|
|Vertebral fractures¶||0.66 (0.44 to 0.98)||15||9|
|Other osteoporotic fractures¶||0.77 (0.69 to 0.86)||170||131|
For those outcomes included in the “global index,” the absolute excess risks per 10,000 person-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 absolute risk reductions per 10,000 person-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).
All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.