Hormone replacement

DESCRIPTION
PREMARIN® (conjugated estrogens tablets, USP) for oral administration contains a mixture of conjugated estrogens obtained exclusively from natural sources, occurring as the sodium salts of water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mares' urine. It is a mixture of sodium estrone sulfate and sodium equilin sulfate. It contains as concomitant components, as sodium sulfate conjugates, 17α-dihydroequilin, 17α-estradiol, and 17β-dihydroequilin. Tablets for oral administration are available in 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, and 1.25 mg strengths of conjugated estrogens.

PREMARIN 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, and 1.25 mg tablets also contain the following inactive ingredients: calcium phosphate tribasic, hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, sucrose, and titanium dioxide.

CLINICAL PHARMACOLOGY
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 gonadotropins seen in postmenopausal women.

INDICATIONS AND USAGE
PREMARIN therapy is indicated in the:
1]Treatment of moderate to severe vasomotor symptoms due to menopause.
2]Treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.
3]Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
4]Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease.
5]Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
6]Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate. (See CLINICAL STUDIES.)
The mainstays for decreasing the risk of postmenopausal osteoporosis are weight-bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400-800 IU/day may also be required to ensure adequate daily intake in postmenopausal women.

CONTRAINDICATIONS
PREMARIN therapy should not be used in individuals with any of the following conditions:

1]Undiagnosed abnormal genital bleeding.
2]Known, suspected, or history of cancer of the breast except in appropriately selected patients being treated for metastatic disease.
3]Known or suspected estrogen-dependent neoplasia.
4]Active deep vein thrombosis, pulmonary embolism or a history of these conditions.
5]Active or recent (within the past year) arterial thromboembolic disease (for example, stroke, myocardial infarction).
6]Liver dysfunction or disease.
7]Known hypersensitivity to any of the ingredients in PREMARIN.
8]Known or suspected pregnancy

DOSAGE AND ADMINISTRATION

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TABLETS
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When estrogen is prescribed for a postmenopausal woman with a uterus, 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 (for example at 3-month to 6-month intervals) to determine if treatment is still necessary (see PACKAGE INSERT FOR BOXED WARNINGS and WARNINGS). For women with 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.

PREMARIN may be taken without regard to meals.

For treatment of moderate to severe vasomotor symptoms and/or moderate to severe symptoms of vulvar and vaginal atrophy due to menopause:
When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.

Patients should be treated with the lowest effective dose. Generally, women should be started at 0.3 mg PREMARIN daily. Subsequent dosage adjustment may be made based upon the individual patient response. This dose should be periodically reassessed by the healthcare provider.

PREMARIN therapy may be given continuously, with no interruption in therapy, or in cyclical regimens (regimens such as 25 days on drug followed by five days off drug), as is medically appropriate on an individualized basis.

For prevention of postmenopausal osteoporosis:
When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should be considered only for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate. Patients should be treated with the lowest effective dose. Generally, women should be started at 0.3 mg PREMARIN daily. Subsequent dosage adjustment may be made based upon the individual clinical and bone mineral density responses. This dose should be periodically reassessed by the healthcare provider.

PREMARIN therapy may be given continuously, with no interruption in therapy, or in cyclical regimens (regimens such as 25 days on drug followed by five days off drug), as is medically appropriate on an individualized basis.

For treatment of female hypoestrogenism due to hypogonadism, castration, or primary ovarian failure:
Female hypogonadism — 0.3 mg or 0.625 mg daily, administered cyclically (e.g., three weeks on and one week off). Doses are adjusted depending on the severity of symptoms and responsiveness of the endometrium.

In clinical studies of delayed puberty due to female hypogonadism, breast development was induced by doses as low as 0.15 mg. The dosage may be gradually titrated upward at 6-to-12 month intervals as needed to achieve appropriate bone age advancement and eventual epiphyseal closure. Clinical studies suggest that doses of 0.15 mg, 0.3 mg, and 0.6 mg are associated with mean ratios of bone age advancement to chronological age progression (BA/CA) of 1.1, 1.5, and 2.1, respectively. (PREMARIN in the dose strength of 0.15 mg is not available commercially). Available data suggest that chronic dosing with 0.625 mg is sufficient to induce artificial cyclic menses with sequential progestin treatment and to maintain bone mineral density after skeletal maturity is achieved.

Female castration or primary ovarian failure — 1.25 mg daily, cyclically. 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.

For treatment of breast cancer, for palliation only, in appropriately selected women and men with metastatic disease:
Suggested dosage is 10 mg three times daily, for a period of at least three months.

For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation only:
1.25 mg to 2 x 1.25 mg three times daily. The effectiveness of therapy can be judged by phosphatase determinations as well as by symptomatic improvement of the patient.
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UNLABELED USES:
Abnormal uterine bleeding: 
Acute hemorrhagic episode: 2.5 mg PO q6h or 25 mg IV q4h for 48 hours; followed by addition of a progestin when acute bleeding stops.  Chronic anovulatory bleeding in perimenopause: 0.625-1.250 mg/day PO for 1 month; add a progestin for 10-12 days/month.  Alternatively:  1.25 mg ORALLY, may repeat every 4 hours for 24 hours, followed by 1.25 mg once daily for 7-10 days.  OR  I.M., I.V.: 25 mg, may repeat in 6-12 hours if needed.   Note: Treatment should be followed by a progestin such as medroxyprogesterone acetate or use a low-dose oral contraceptive.    Nonacute bleeding: 1.25 mg orally once daily for 7-10 days.  For additional info check out the following link (Dysfunctional Uterine Bleeding).

HOW SUPPLIED  - PREMARIN® (conjugated estrogens tablets, USP)

— Each oval yellow tablet contains 1.25 mg, in bottles of 100 (NDC 0046-1104-81) and 1,000 (NDC 0046-1104-91).

— Each oval white tablet contains 0.9 mg, in bottles of 100 (NDC 0046-1103-81).

— Each oval maroon tablet contains 0.625 mg, in bottles of 100 (NDC 0046-1102-81) and 1,000 (NDC 0046-1102-91).

— Each oval blue tablet contains 0.45 mg, in bottles of 100 (NDC 0046-1101-81).

— Each oval green tablet contains 0.3 mg, in bottles of 100 (NDC 0046-1100-81) and 1,000 (NDC 0046-1100-91).
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CREAM
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Treatment of Atrophic Vaginitis and Kraurosis Vulvae
PREMARIN Vaginal Cream is administered intravaginally in a cyclic regimen (daily for 21 days and then off for 7 days). Generally, women should be started at the 0.5 g dosage strength. Dosage adjustments (0.5 to 2 g) may be made based on individual response [see Dosage Forms and Strengths (3)].

Treatment of Moderate to Severe Dyspareunia, a Symptom of Vulvar and Vaginal Atrophy, due to Menopause
PREMARIN Vaginal Cream (0.5 g) is administered intravaginally in a twice-weekly (for example, Monday and Thursday) continuous regimen or in a cyclic regimen of 21 days of therapy followed by 7 days off of therapy [see Dosage Forms and Strengths (3)].

DOSAGE FORMS AND STRENGTHS
Each gram contains 0.625 mg conjugated estrogens, USP.

Combination package: Each contains a net wt. 1.5 oz (42.5 g) tube with one plastic applicator calibrated in 0.5 g increments to a maximum of 2 g.

The chemical name for medroxyprogesterone acetate is pregn-4-ene-3, 20-dione, 17-(acetyloxy)-6-methyl-, (6α)-.

CLINICAL PHARMACOLOGY
Medroxyprogesterone acetate (MPA) administered orally or parenterally in the recommended doses to women with adequate endogenous estrogen, transforms proliferative into secretory endometrium. Androgenic and anabolic effects have been noted, but the drug is apparently devoid of significant estrogenic activity. While parenterally administered MPA inhibits gonadotropin production, which in turn prevents follicular maturation and ovulation, available data indicate that this does not occur when the usually recommended oral dosage is given as single daily doses.

CONTRAINDICATIONS
Medroxyprogesterone Acetate should not be used in women with any of the following conditions:

1]Undiagnosed abnormal genital bleeding.
2]Known, suspected, or history of cancer of the breast.
3]Known or suspected estrogen- or progesterone-dependent neoplasia.
4]Active deep vein thrombosis, pulmonary embolism or a history of these conditions.
5]Active or recent (within the past year) arterial thromboembolic disease (for example, stroke and myocardial infarction).
6]Known liver dysfunction or disease.
7]Missed abortion.
8]As a diagnostic test for pregnancy.
9]Known hypersensitivity to the ingredients in medroxyprogesterone acetate tablets.
10]Known or suspected pregnancy.

See PACKAGE INSERT FOR BOXED WARNINGS, GENERAL WARNINGS.

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TABLETS
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INDICATIONS AND USAGE
Medroxyprogesterone Acetate Tablets are a progestin indicated for the treatment of secondary amenorrhea and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as fibroids or uterine cancer. Medroxyprogesterone Acetate Tablets are also indicated to reduce the incidence of endometrial hyperplasia in nonhysterectomized postmenopausal women receiving daily oral conjugated estrogens 0.625 mg tablets.

DOSAGE AND ADMINISTRATION

Secondary Amenorrhea
Medroxyprogesterone acetate tablets may be given in dosages of 5 or 10 mg daily for 5 to 10 days. A dose for inducing an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen is 10 mg of medroxyprogesterone acetate daily for 10 days. In cases of secondary amenorrhea, therapy may be started at any time. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing medroxyprogesterone acetate therapy.

Abnormal Uterine Bleeding Due to Hormonal Imbalance in the Absence of Organic Pathology
Beginning on the calculated 16th or 21st day of the menstrual cycle, 5 or 10 mg of medroxyprogesterone acetate may be given daily for 5 to 10 days. To produce an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen, 10 mg of medroxyprogesterone acetate daily for 10 days beginning on the 16th day of the cycle is suggested. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing therapy with medroxyprogesterone acetate. Patients with a past history of recurrent episodes of abnormal uterine bleeding may benefit from planned menstrual cycling with medroxyprogesterone acetate.

Reduction of Endometrial Hyperplasia in Postmenopausal Women Receiving Daily 0.625 mg Conjugated Estrogens
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 re-evaluated periodically as clinically appropriate (for example, 3-month to 6-month intervals) to determine if treatment is still necessary (see PACKAGE INSERT FOR 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.

Medroxyprogesterone acetate tablets may be given in dosages of 5 or 10 mg daily for 12 to 14 consecutive days per month, in postmenopausal women receiving daily 0.625 mg conjugated estrogens, either beginning on the 1st day of the cycle or the 16th day of the cycle.

Patients should be started at the lowest dose.

The lowest effective dose of medroxyprogesterone acetate has not been determined.

HOW SUPPLIED
Medroxyprogesterone Acetate Tablets, USP are available as:
2.5 MG, 5 MG, 10 MG

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Aqueous Suspension [400 mg/mL in 2.5 mL vials]
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INDICATIONS AND USES
Adjunctive therapy and palliative treatment of inoperable, recurrent, and metastatic endometrial or renal carcinoma.

DOSAGE AND ADMINISTRATION
The suspension is intended for intramuscular administration only.

Endometrial or renal carcinoma— doses of 400 mg to 1000 mg of DEPO-PROVERA Sterile Aqueous Suspension per week are recommended initially. If improvement is noted within a few weeks or months and the disease appears stabilized, it may be possible to maintain improvement with as little as 400 mg per month. Medroxyprogesterone acetate is not recommended as primary therapy, but as adjunctive and palliative treatment in advanced inoperable cases including those with recurrent or metastatic disease.

When multi-dose vials are used, special care to prevent contamination of the contents is essential (See PACKAGE INSERT FOR WARNINGS).

HOW SUPPLIED
DEPO-PROVERA Sterile Aqueous Suspension is available as 400 mg/mL in 2.5 mL vials.

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Medroxyprogesterone Acetate Injectable Suspension - 150 mg/mL - 1 mL vial
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INDICATIONS AND USAGE
Medroxyprogesterone Acetate Injectable Suspension, USP is indicated only for the prevention of pregnancy. The loss of bone mineral density (BMD) in women of all ages and the impact on peak bone mass in adolescents should be considered, along with the decrease in BMD that occurs during pregnancy and/or lactation, in the risk/benefit assessment for women who use Medroxyprogesterone Acetate Injectable Suspension, USP long-term (see WARNINGS.) It is a long-term injectable contraceptive in women when administered at 3-month (13-week) intervals. Dosage does not need to be adjusted for body weight.

DOSAGE AND ADMINISTRATION
Both the 1 mL vial and the 1 mL prefilled syringe of medroxyprogesterone acetate injectable suspension should be vigorously shaken just before use to ensure that the dose being administered represents a uniform suspension.

The recommended dose is 150 mg of medroxyprogesterone acetate injectable suspension every 3 months (13 weeks) administered by deep, IM injection in the gluteal or deltoid muscle. To ensure the patient is not pregnant at the time of the first injection, the first injection MUST be given ONLY during the first 5 days of a normal menstrual period; ONLY within the first 5 days postpartum if not breast-feeding; and if exclusively breast-feeding, ONLY at the sixth postpartum week. If the time interval between injections is greater than 13 weeks, the physician should determine that the patient is not pregnant before administering the drug. The efficacy of medroxyprogesterone acetate injectable suspension depends on adherence to the dosage schedule of administration.

HOW SUPPLIED
Medroxyprogesterone Acetate Injectable Suspension, USP is available as:
150 mg/mL - 1 mL vial

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, which is secreted by the adrenal cortex, to estrone in the 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 gonadotropins seen in postmenopausal women.

Parenterally administered medroxyprogesterone acetate (MPA) inhibits gonadotropin production, which in turn prevents follicular maturation and ovulation; although available data indicate that this does not occur when the usually recommended oral dosage is given as single daily doses. MPA may achieve its beneficial effect on the endometrium in part by decreasing nuclear estrogen receptors and suppression of epithelial DNA synthesis in endometrial tissue. Androgenic and anabolic effects of MPA have been noted, but the drug is apparently devoid of significant estrogenic activity.

INDICATIONS AND USAGE
1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause
1.2 Treatment of Moderate to Severe Vulvar and Vaginal Atrophy due to Menopause
1.3 Prevention of Postmenopausal Osteoporosis

DOSAGE AND ADMINISTRATION
General Dosing Information
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. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary.

Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause:
PREMPRO therapy consists of a single tablet to be taken orally once daily.

PREMPHASE therapy consists of two separate tablets: one maroon 0.625 mg Premarin (conjugated estrogens) tablet taken daily on days 1 through 14 and one light-blue tablet containing 0.625 mg conjugated estrogens and 5 mg of medroxyprogesterone acetate taken on days 15 through 28.

Treatment of Moderate to Severe Vulvar and Vaginal Atrophy due to Menopause:
PREMPRO therapy consists of a single tablet to be taken orally once daily.

PREMPHASE therapy consists of two separate tablets: one maroon 0.625 mg Premarin [conjugated estrogens (CE)] tablet taken daily on days 1 through 14 and one light-blue tablet containing 0.625 mg CE and 5 mg of medroxyprogesterone acetate (MPA) taken on days 15 through 28.

When prescribing solely for the treatment of moderate to severe vulvar and vaginal atrophy, topical vaginal products should be considered.

Prevention of Postmenopausal Osteoporosis:
PREMPRO therapy consists of a single tablet to be taken orally once daily.

PREMPHASE therapy consists of two separate tablets: one maroon 0.625 mg Premarin (conjugated estrogens) tablet taken daily on days 1 through 14 and one light-blue tablet containing 0.625 mg conjugated estrogens and 5 mg of medroxyprogesterone acetate taken on days 15 through 28.

CONTRAINDICATIONS
PREMPRO or PREMPHASE therapy should not be used in women with any of the following conditions:

-Undiagnosed abnormal genital bleeding
-Known, suspected, or history of breast cancer
-Known or suspected estrogen-dependent neoplasia
-Active deep vein thrombosis, pulmonary embolism or a history of these conditions
-Active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions
-Known liver dysfunction or disease
-Known or suspected pregnancy

SEE PACKAGE INSERT FOR WARNINGS AND PRECAUTIONS....

DOSAGE FORMS AND STRENGTHS