ESTROPIPATE TABLETS, USP

Rev SEPTEMBER 2002

21007270102

Rx only

(Three Patient Information Leaflets Enclosed - Tear at Perforation)

Estropipate, (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 Tablets is not sufficient to exert a pharmacological action. Its addition ensures solubility, stability, and uniform potency of the estrone sulfate. Chemically estropipate is represented by estra-1,3,5(10)-trien-17-one, 3-(sulfooxy)-, compound with piperazine (1:1). The structural formula may be represented as follows:

Estropipate Tablets are available for oral administration containing 0.75 mg, 1.5 mg or 3 mg estropipate (calculated as sodium estrone sulfate 0.625 mg, 1.25 mg and 2.5 mg, respectively).

Inactive Ingredients: Colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate, and pregelatinized starch. The 0.75 mg also contains D&C yellow no. 10 aluminum lake and FD&C yellow no. 6 aluminum lake. The 1.5 mg also contains FD&C yellow no. 6 aluminum lake. The 3 mg also contains FD&C blue no. 2 aluminum lake.

Estrogen drug products act by regulating the transcription of a limited number of genes. Estrogens diffuse through cell membranes, distribute themselves throughout the cell, and bind to and activate the nuclear estrogen receptor, a DNA-binding protein which is found in estrogen-responsive tissues. The activated estrogen receptor binds to specific DNA sequences, or hormone-response elements, which enhance the transcription of adjacent genes and in turn lead to the observed effects. Estrogen receptors have been identified in tissues of the reproductive tract, breast, pituitary, hypothalamus, liver, and bone of women.

Estrogens are important in the development and maintenance of the female reproductive system and secondary sex characteristics. By a direct action, they cause growth and development of the uterus, Fallopian tubes, and vagina. With other hormones, such as pituitary hormones and progesterone, they cause enlargement of the breasts through promotion of ductal growth, stromal development, and the accretion of fat. Estrogens are intricately involved with other hormones, especially progesterone, in the processes of the ovulatory menstrual cycle and pregnancy, and affect the release of pituitary gonadotropins. They also 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, and pigmentation of the nipples and genitals.

Estrogens occur naturally in several forms. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 micrograms of estradiol daily, depending on the phase of the menstrual cycle. This is converted primarily to estrone, which circulates in roughly equal proportion to estradiol, and to small amounts of estriol. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone—especially in its sulfate ester form—is the most abundant circulating estrogen in postmenopausal women. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than estrone or estriol at the receptor.

Estrogens used in therapy are well absorbed through the skin, mucous membranes, and gastrointestinal tract. When applied for a local action, absorption is usually sufficient to cause systemic effects. When conjugated with aryl and alkyl groups for parenteral administration, the rate of absorption of oily preparations is slowed with a prolonged duration of action, such that a single intramuscular injection of estradiol valerate or estradiol cypionate is absorbed over several weeks.

Administered estrogens and their esters are handled within the body essentially the same as the endogenous hormones. Metabolic conversion of estrogens occurs primarily in the liver (first pass effect), but also at local target tissue sites. Complex metabolic processes result in a dynamic equilibrium of circulating conjugated and unconjugated estrogenic forms which are continually interconverted, especially between estrone and estradiol and between esterified and non-esterified forms. Although naturally-occurring estrogens circulate in the blood largely bound to sex hormone-binding globulin and albumin, only unbound estrogens enter target tissue cells. A significant proportion of the circulating estrogen exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogenic species. A certain proportion of the estrogen is excreted into the bile and then reabsorbed from the intestine. During this enterohepatic recirculation, estrogens are desulfated and resulfated and undergo degradation through conversion to less active estrogens (estriol and other estrogens), oxidation to nonestrogenic substances (catecholestrogens, which interact with catecholamine metabolism, especially in the central nervous system), and conjugation with glucuronic acids (which are then rapidly excreted in the urine).

When given orally, naturally-occurring estrogens and their esters are extensively metabolized (first pass effect) and circulate primarily as estrone sulfate, with smaller amounts of other conjugated and unconjugated estrogenic species. This results in limited oral potency. By contrast, synthetic estrogens, such as ethinyl estradiol and the nonsteroidal estrogens, are degraded very slowly in the liver and other tissues, which results in their high intrinsic potency. Estrogen drug products administered by non-oral routes are not subject to first-pass metabolism, but also undergo significant hepatic uptake, metabolism, and enterohepatic recycling.

Estropipate tablets are indicated in the:

• Treatment of moderate to severe vasomotor symptoms associated with menopause. There is no adequate evidence that estrogens are effective for nervous symptoms or depression which might occur during menopause and they should not be used to treat these conditions.
• Treatment of vulval and vaginal atrophy.
• Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
• Prevention of osteoporosis.

Since estrogen administration is associated with risk, selection of patients should ideally be based on prospective identification of risk factors for developing osteoporosis. Unfortunately, there is no certain way to identify those women who will develop osteoporotic fractures. Most prospective studies of efficacy for this indication have been carried out in white menopausal women, without stratification by other risk factors, and tend to show a universally salutary effect on bone. Thus, patient selection must be individualized based on the balance of risks and benefits. A more favorable risk/benefit ratio exists in a hysterectomized woman because she has no risk of endometrial cancer (see Boxed WARNINGS).

Estrogen replacement therapy reduces bone resorption and retards or halts postmenopausal bone loss. Case-control studies have shown an approximately 60 percent reduction in hip and wrist fractures in women whose estrogen replacement was begun within a few years of menopause. Studies also suggest that estrogen reduces the rate of vertebral fractures. Even when started as late as 6 years after menopause, estrogen prevents further loss of bone mass for as long as the treatment is continued. The results of a double-blind, placebo-controlled two-year study have shown that treatment with one tablet of estropipate 0.75 mg daily for 25 days (of a 31-day cycle per month) prevents vertebral bone mass loss in postmenopausal women. When estrogen therapy is discontinued, bone mass declines at a rate comparable to the immediate postmenopausal period. There is no evidence that estrogen replacement therapy restores bone mass to premenopausal levels.

At skeletal maturity there are sex and race differences in both the total amount of bone present and its density, in favor of men and blacks. Thus, women are at higher risk than men because they start with less bone mass and, for several years following natural or induced menopause, the rate of bone mass decline is accelerated. White and Asian women are at higher risk than black women.

Early menopause is one of the strongest predictors for the development of osteoporosis. In addition, other factors affecting the skeleton which are associated with osteoporosis include genetic factors (small build, family history), endocrine factors (nulliparity, thyrotoxicosis, hyperparathyroidism, Cushing’s syndrome, hyperprolactinemia, Type I diabetes), lifestyle (cigarette smoking, alcohol abuse, sedentary exercise habits) and nutrition (below average body weight, dietary calcium intake).

The mainstays of prevention and management of osteoporosis are estrogen, an adequate lifetime calcium intake, and exercise. Postmenopausal women absorb dietary calcium less efficiently than premenopausal women and require an average of 1500 mg/day of elemental calcium to remain in neutral calcium balance. By comparison, premenopausal women require about 1000 mg/day and the average calcium intake in the USA is 400-600 mg/day. Therefore, when not contraindicated, calcium supplementation may be helpful.

Weight-bearing exercise and nutrition may be important adjuncts to the prevention and management of osteoporosis. Immobilization and prolonged bed rest produce rapid bone loss, while weight-bearing exercise has been shown both to reduce bone loss and to increase bone mass. The optimal type and amount of physical activity that would prevent osteoporosis have not been established, however in two studies an hour of walking and running exercises twice or three times weekly significantly increased lumbar spine bone mass.

Estrogens should not be used in individuals with any of the following conditions:

• Known or suspected pregnancy (see Boxed WARNINGS). Estrogens may cause fetal harm when administered to a pregnant woman.
• Undiagnosed abnormal genital bleeding.
• Known or suspected cancer of the breast except in appropriately selected patients being treated for metastatic disease.
• Known or suspected estrogen-dependent neoplasia.
• Active thrombophlebitis or thromboembolic disorders.

Two studies have reported a 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in women receiving postmenopausal estrogens.

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. These risks cannot necessarily be extrapolated from men to women. However, to avoid the theoretical cardiovascular risk to women caused by high estrogen doses, the dose for estrogen replacement therapy should not exceed the lowest effective dose.

Occasional blood pressure increases during estrogen replacement therapy have been attributed to idiosyncratic reactions to estrogens. More often, blood pressure has remained the same or has dropped. One study showed that postmenopausal estrogen users have higher blood pressure than nonusers. Two other studies showed slightly lower blood pressure among estrogen users compared to nonusers. Postmenopausal estrogen use does not increase the risk of stroke. Nonetheless, blood pressure should be monitored at regular intervals with estrogen use.

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.

See div of Patient Package Leaflet below.

Estrogen administration should generally be guided by clinical response at the smallest dose, rather than laboratory monitoring, for relief of symptoms for those indications in which symptoms are observable. For prevention and treatment of osteoporosis, however, see DOSAGE AND ADMINISTRATION section.

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 anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.

Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, 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.

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

Increased plasma HDL and HDL-2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.

Impaired glucose tolerance.

Reduced response to metyrapone test.

Reduced serum folate concentration.

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. See CONTRAINDICATIONS and WARNINGS.

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. In addition, estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk.

The following additional adverse reactions have been reported with estrogen therapy: (see WARNINGS regarding induction of neoplasia, adverse effects on the fetus, increased incidence of gallbladder disease, cardiovascular disease, elevated blood pressure, and hypercalcemia.)

Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding, spotting.

Increase in size of uterine leiomyomata.

Vaginal candidiasis.

Change in amount of cervical secretion.

Tenderness, enlargement.

Nausea, vomiting.

Abdominal cramps, bloating.

Cholestatic jaundice.

Increased incidence of gallbladder disease.

Chloasma or melasma that may persist when drug is discontinued.

Erythema multiforme.

Erythema nodosum.

Hemorrhagic eruption.

Loss of scalp hair.

Hirsutism.

Steepening of corneal curvature.

Intolerance to contact lenses.

Headache, migraine, dizziness.

Mental depression.

Chorea.

Increase or decrease in weight.

Reduced carbohydrate tolerance.

Aggravation of porphyria.

Edema.

Changes in libido.

Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing oral contraceptives by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females.

• For treatment of moderate to severe vasomotor symptoms, vulval and vaginal atrophy associated with the menopause, the lowest dose and regimen that will control symptoms should be chosen and medication should be discontinued as promptly as possible.
  Attempts to discontinue or taper medication should be made at 3 to 6 month intervals.
  Usual dosage ranges:
  Vasomotor symptoms: Estropipate tablets 0.75 mg to 6 mg per day. The lowest dose that will control symptoms should be chosen. If the patient has not menstruated within the last two months or more, cyclic administration is started arbitrarily. If the patient is menstruating, cyclic administration is started on day 5 of bleeding.
  Vulval and vaginal atrophy: Estropipate tablets 0.75 mg to 6 mg daily, depending upon the tissue response of the individual patient. The lowest dose that will control symptoms should be chosen. Administer cyclically.
• For treatment of female hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.
  Usual dosage ranges:
  Female hypogonadism: A daily dose of 1.5 mg to 9 mg of estropipate tablets may be given for the first three weeks of a theoretical cycle, followed by a rest period of eight to ten days. The lowest dose that will control symptoms should be chosen. If bleeding does not occur by the end of this period, the same dosage schedule is repeated. The number of courses of estrogen therapy necessary to produce bleeding may vary depending on the responsiveness of the endometrium. If satisfactory withdrawal bleeding does not occur, an oral progestogen may be given in addition to estrogen during the third week of the cycle.
  Female castration or primary ovarian failure: A daily dose of 1.5 mg to 9 mg of estropipate tablets may be given for the first three weeks of a theoretical cycle, followed by a rest period of eight to ten days. Adjust dosage upward or downward according to severity of symptoms and response of the patient. For maintenance, adjust dosage to lowest level that will provide effective control.
  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.
• For prevention of osteoporosis. A daily dose of 0.75 mg of estropipate tablets for 25 days of a 31-day cycle per month.

Estropipate Tablets, USP are available as:

0.75 mg: (calculated as sodium estrone sulfate 0.625 mg)

Yellow, round, flat-faced, beveled-edge, scored tablet. Debossed with stylized Barr on one side and 555/727 on the scored side. Available in bottles of:

21 NDC 0555-0727-38

100 NDC 0555-0727-02

500 NDC 0555-0727-04

1000 NDC 0555-0727-05

1.5 mg: (calculated as sodium estrone sulfate 1.25 mg)

Peach, round, flat-faced, beveled-edge, scored tablet. Debossed with stylized Barr on one side and 555/728 on the scored side. Available in bottles of:

21 NDC 0555-0728-38

100 NDC 0555-0728-02

500 NDC 0555-0728-04

1000 NDC 0555-0728-05

3 mg:(calculated as sodium estrone sulfate 2.5 mg)

Blue, round, flat-faced, beveled-edge, scored tablet. Debossed with stylized Barr on one side and 555/729 on the scored side. Available in bottles of:

21 NDC 0555-0729-38

100 NDC 0555-0729-02

500 NDC 0555-0729-04

1000 NDC 0555-0729-05

Dispense with a child-resistant closure in a tight, light-resistant container.

Store at controlled room temperature 15°-30°C (59°-86°F) [See USP].

ESTROPIPATE TABLETS, USP

INTRODUCTION:

This leaflet describes when and how to use estrogens, and the risks and benefits of estrogen treatment.

Estrogens have important benefits but also some risks. You must decide, with your doctor, whether the risks to you of estrogen use are acceptable because of their benefits. If you use estrogens, check with your doctor to be sure you are using the lowest possible dose that works, and that you don't use them longer than necessary. How long you need to use estrogens will depend on the reason for use.

MANUFACTURED BY

BARR LABORATORIES, INC.

POMONA, NY 10970

PL-727,728,729 Rev SEPTEMBER 2002