Professional Information

Estrogens (Systemic)

This monograph includes information on the following:

1) Conjugated Estrogens
2) Diethylstilbestrol
3) Esterified Estrogens
4) Estradiol
5) Estrone ^†
6) Estropipate
7) Ethinyl Estradiol

INN:
Diethylstilbestrol diphosphate—Fosfestrol

BAN:
Diethylstilbestrol diphosphate—Fosfestrol
Diethylstilbestrol—Stilboestrol
Estradiol—Oestradiol
Estrone—Oestrone

JAN:
Diethylstilbestrol diphosphate—Fosfestrol

VA CLASSIFICATION
Conjugated Estrogens
Primary: HS102
Secondary: AN500; HS104; MS900

Diethylstilbestrol
Primary: HS102
Secondary: AN500; HS104; MS900

Esterified Estrogens
Primary: HS102
Secondary: AN500; MS900

Estradiol
Primary: HS102
Secondary: AN500; MS900

Estrone
Primary: HS102
Secondary: AN500

Estropipate
Primary: HS102
Secondary: MS900

Ethinyl Estradiol
Primary: HS102
Secondary: AN500; HS104; MS900

Commonly used brand name(s): Alora⁴; Aquest⁵; C.E.S.¹; Climara⁴; Clinagen LA 40⁴; Congest¹; Delestrogen⁴; Depo-Estradiol⁴; Depogen⁴; Dioval 40⁴; Dioval XX⁴; Dura-Estrin⁴; Duragen-20⁴; E-Cypionate⁴; Estinyl⁷; Estra-L 40⁴; Estrace⁴; Estraderm⁴; Estragyn 5⁵; Estragyn LA 5⁴; Estratab³; Estro-A⁵; Estro-Cyp⁴; Estro-L.A.⁴; Estro-Span⁴; Estrofem⁴; Estrone `5"⁵; FemPatch⁴; Femogex⁴; Gynogen L.A. 20⁴; Gynogen L.A. 40⁴; Honvol²; Kestrone-5⁵; Menaval-20⁴; Menest³; Neo-Estrone³; Ogen⁶; Ogen .625⁶; Ogen 1.25⁶; Ogen 2.5⁶; Ortho-Est .625⁶; Ortho-Est 1.25⁶; Premarin¹; Premarin Intravenous¹; Stilbestrol²; Stilphostrol²; Valergen-10⁴; Valergen-20⁴; Valergen-40⁴; Vivelle⁴; Wehgen⁵; depGynogen⁴.

Other commonly used names are:
DES —Diethylstilbestrol
, Fosfestrol —Diethylstilbestrol diphosphate
, Oestradiol — Estradiol
, Oestrone — Estrone
, Piperazine Estrone Sulfate —Estropipate
, and Stilboestrol —Diethylstilbestrol
.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^†Not commercially available in Canada.

Category:

Estrogen (systemic)— Conjugated Estrogens; Diethylstilbestrol ; Esterified Estrogens; Estradiol; Estrone; Estropipate; Ethinyl Estradiol;

Antineoplastic—Conjugated Estrogens Tablets; Diethylstilbestrol; Esterified Estrogens; Estradiol; Estradiol Valerate; Estrone; Ethinyl Estradiol ;

Osteoporosis prophylactic— Conjugated Estrogens Tablets; Esterified Estrogens; Estradiol Tablets; Estradiol Transdermal System; Estropipate;

Ovarian hormone therapy agent— Conjugated Estrogens Tablets; Esterified Estrogens; Estradiol Tablets; Estradiol Transdermal System; Estropipate;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

General considerations
Estrogen deficiency in women without a uterus is best treated with unopposed estrogen therapy; combined estrogen-progestin therapy is not needed.

Accepted

Bleeding, uterine, hormonal imbalance–induced (treatment) —Conjugated estrogens for injection and estrone ^{13} are indicated in the treatment of abnormal uterine bleeding associated with a hypoplastic or atrophic endometrium without organic pathology. Continuous treatment with estrogen without a progestin may cause abnormal uterine bleeding with or without organic pathology. ^{10} ^{17} ^{21} ^{23} ^{25} ^{28} ^{41} ^{42} ^{72} ^{156}

Carcinoma, breast (treatment)—Conjugated estrogens tablets, esterified estrogens¹ , estradiol tablets¹ , and ethinyl estradiol are indicated for palliative treatment of metastatic breast carcinoma in selected men and postmenopausal or oophorectomized women ^{03} ^{04} ^{11} ^{17} ^{21} ^{25} ^{28} ^{37} ^{41} ^{50} ^{135}.

Carcinoma, prostatic (treatment)—Conjugated estrogens tablets, diethylstilbestrol, esterified estrogens¹ , estradiol tablets¹ , estradiol valerate, estrone, and ethinyl estradiol are indicated for treatment of advanced prostatic carcinoma ^{03} ^{04} ^{09} ^{11} ^{17} ^{21} ^{25} ^{28} ^{36} ^{41} ^{50} ^{72} ^{136}.

Estrogen deficiency, due to ovariectomy (treatment) or
Hypogonadism, female (treatment) or
Ovarian failure, primary (treatment)—Conjugated estrogens tablets, esterified estrogens, estradiol tablets ¹ , matrix-¹ or reservoir-type estradiol transdermal system, estrone, estropipate¹ , and ethinyl estradiol¹ are indicated to replace estrogen in the treatment of female hypogonadism, primary ovarian failure, or ovariectomy. Estradiol cypionate and estradiol valerate ¹ are indicated to replace estrogen in the treatment of female hypogonadism ^{31}. Estradiol valerate also is indicated for the treatment of estrogen deficiency resulting from an ovariectomy or primary ovarian failure. ^{02} ^{04} ^{05} ^{09} ^{11} ^{17} ^{20} ^{21} ^{25} ^{72}

Menopause, vasomotor symptoms of (treatment) or
Vaginitis, atrophic (treatment) or
Vulvar atrophy (treatment)—Conjugated estrogens tablets, esterified estrogens, estradiol tablets, matrix- or reservoir-type estradiol transdermal system, estradiol valerate, estrone, and estropipate are indicated to replace estrogen in the treatment of atrophic vaginitis, vulvar atrophy (also called kraurosis vulvae), and moderate to severe vasomotor symptoms associated with menopause. Also, estradiol cypionateand ethinyl estradiol are indicated for treatment of moderate to severe vasomotor symptoms of menopause. ^{02} ^{04} ^{05} ^{09} ^{11} ^{17} ^{19} ^{20} ^{21} ^{25} ^{27} ^{28} ^{31} ^{41} ^{42} ^{134}

Osteoporosis, postmenopausal (prophylaxis)—Conjugated estrogens tablets, esterified estrogens¹ , estradiol tablets, matrix-¹ or reservoir-type estradiol transdermal system, and estropipate ¹ are indicated in postmenopausal women to retard bone loss and estrogen deficiency–induced osteoporosis ^{05} ^{11} ^{25} ^{42} ^{51} ^{52}. Replacing estrogen can reduce the rate of bone loss and fractures in postmenopausal women ^{40} ^{77} ^{78} ^{79} ^{91} ^{98} ^{143} ^{149} ^{150}. Proper diet, calcium supplementation, and physical activity should also be encouraged along with estrogen replacement therapy ^{40} ^{78} ^{79} ^{98} ^{134} ^{149} ^{150}^{170}.

[Osteoporosis, premenopausal, estrogen deficiency–induced (prophylaxis)]¹—Conjugated estrogens tablets, esterified estrogens, estradiol tablets, matrix- or reservoir-type estradiol transdermal systems, and estropipate also are used in premenopausal women who are estrogen-deficient to protect them against bone loss ^{20}.

[Atherosclerotic disease (prophylaxis) ]¹—Estrogens may be effective in the prevention of cardiovascular disease in postmenopausal women ^{40} ^{96} ^{97} ^{98} ^{106} ^{107} ^{131} ^{140}.

[Turner"s syndrome (treatment)]¹—Ethinyl estradiol is used in the treatment of Turner"s syndrome (gonadal dysgenesis).

Acceptance not established
Conjugated estrogens, diethylstilbestrol tablets, and ethinyl estradiol have been used as emergency contraception (also called intraception, morning-after treatment, or postcoital contraception) ^{40} ^{48} ^{53} ^{56} ^{76} ^{129} ^{130}. However, the combination oral contraceptive containing ethinyl estradiol with either norgestrel or levonorgestrel is more commonly prescribed for this indication ^{56} ^{129} ^{130}. Although the failure rate for postcoital contraception is higher (2% versus 1%) for these oral estrogen-progestin contraceptives compared to these estrogens used alone, the oral contraceptives cause fewer and less severe side effects (such as nausea or vomiting) and have better patient compliance ^{130}.

Unaccepted
The use of estrogens to reduce postpartum breast engorgement is not recommended ^{20} ^{30}. In many patients, postpartum breast engorgement is a benign, self-limited condition that may respond to breast support and mild analgesics, such as acetaminophen and ibuprofen ^{30}. Evidence supporting the efficacy of estrogens for this indication is lacking ^{30}. Therefore, the questionable benefits of administering the large doses of estrogens required for this indication are outweighed by the risk of increasing the incidence of puerperal thromboembolism ^{30} ^{130}.

Although a few studies show estrogens having some effect on brain neurotransmitters in improving memory and cognitive function, estrogens are not indicated or effective in treatment of clinical mental depression ^{158}.

Estradiol valerate, ethinyl estradiol, and the matrix-type estradiol transdermal system are indicated ^{169} to treat abnormal uterine bleeding due to a hormonal imbalance but are not recommended. These estrogens are considered obsolete for this use ^{156}.

Although estradiol valerate and estrone are indicated for palliative treatment of breast carcinoma, both have a long duration of action, making discontinuation of the medication or management of hypercalcemia more difficult if hypercalcemia develops. These estrogens are not recommended. These estrogens are considered obsolete for this use ^{110} ^{156}.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Physical description
    Two types of estradiol transdermal systems are available ^{137}:

• Drug-in-adhesive matrix on film (ethylene vinyl acetate and rubber) (matrix-type)—Three layers that include a polyester liner that must be removed before using, an adhesive matrix containing estradiol, and the back outermost layer, a flexible polyurethane protective film with epoxy resin ^{07} ^{15} ^{169}.

• Membrane-controlled drug reservoir (reservoir-type)—Five layers that include a protective liner to be removed before using, an adhesive layer, a membrane providing a slow release of estradiol, a drug reservoir containing the estradiol and alcohol gelled with hydroxypropyl cellulose, and the back outermost layer, a polyester protective film. ^{04}
Patch size may differ for products among different manufacturers and among products of different strengths from the same manufacturer. Generally, the matrix-type transdermal system is smaller and thinner than the reservoir-type transdermal system. ^{04} ^{07} ^{15}
Source—
    Naturally occurring compounds include estradiol (E ₂), conjugated estrogens (sodium estrone sulfate, sodium equilin sulfate, and others as found in equine urine), esterified estrogens (sodium sulfate esters of estrogenic substances, primarily estrone), and estrone (E ₁) ^{154}.
    Semisynthetic compounds include estradiol cypionate, estradiol valerate, estropipate, and ethinyl estradiol ^{154}.
    Synthetic compounds include diethylstilbestrol and diethylstilbestrol phosphate ^{154}.
Molecular weight—
    Diethylstilbestrol: 268.36 ^{32}
    Diethylstilbestrol diphosphate: 428.32 ^{32}
    Estradiol: 272.39 ^{32}
    Estradiol cypionate: 396.57 ^{32}
    Estradiol valerate: 356.51 ^{32}
    Estrone: 270.37 ^{32}
    Estropipate: 436.58 ^{32}
    Ethinyl estradiol: 296.41 ^{32}

Mechanism of action/Effect:

At the cellular level, estrogens increase the synthesis of DNA, RNA, and various proteins in target tissues ^{81} ^{139} ^{148} ^{151}. Pituitary mass is also increased. ^{81} Estrogens reduce the release of gonadotropin-releasing hormone ^{49} from the hypothalamus, leading to a reduction in release of follicle-stimulating hormone and luteinizing hormone from the pituitary. ^{74} ^{81} ^{132} ^{141} ^{151}

For ovarian hormone therapy:

In healthy females, endogenous estrogens maintain genitourinary function and vasomotor stability ^{05} ^{77} ^{147}. Replacing estrogens helps to alleviate or prevent symptoms caused by the decreased amounts of estrogens produced by the ovaries after natural or surgical menopause or other estrogen-deficiency states ^{05} ^{81} ^{145}.

For prevention of postmenopausal osteoporosis:

During periods of estrogen deficiency, the rate of bone resorption by osteoclasts greatly exceeds the rate of bone formation by osteoblasts ^{143} ^{149}. Replacing estrogen prevents this accelerated bone loss by inhibiting bone resorption to a level where the near equilibrium between bone resorption and formation is restored ^{93} ^{133} ^{138} ^{143} ^{149}. However, estrogens do not replace previously lost bone or significantly increase total bone mass ^{143}.

For prostatic carcinoma:

Inhibition of pituitary secretion of luteinizing hormone and a possible minor, direct effect on the testis, resulting in decreased serum concentrations of testosterone. ^{74}

Distribution:

To most tissues, especially breast, uterine, vaginal, hypothalamic, and pituitary tissues ^{11}; high affinity for adipose tissue. ^{46}

Protein binding:

Moderate to high (50 to 80% to albumin and sex hormone–binding globulin ^{41} ^{42} ^{46} ^{151}).

Biotransformation:

Primarily hepatic ^{05} ^{139}; some metabolism also occurs in muscle, kidneys, and gonads. ^{46} ^{139} The metabolic sites for all synthetic estrogens have not been completely determined, although some seem to undergo hepatic change. ^{37} ^{41} ^{42}

Elimination:
    Primarily renal excretion of metabolites ^{19} ^{37} ^{42} ^{108} ^{139}, some fecal ^{37} ^{46}; undergo extensive enterohepatic recirculation ^{42} ^{46}. Prolonged in obese patients ^{46} ^{139}.

Precautions to Consider

Carcinogenicity

Independent studies have shown an increased risk of endometrial cancer in postmenopausal women placed on unopposed (without a progestin) estrogen therapy for prolonged periods ^{05} ^{40} ^{98} ^{149} ^{152}. The risk of endometrial cancer in estrogen users, which appears to depend on duration of treatment and dose, was 5 to 10 times greater than in nonusers. However, studies have shown that administration of a progestin for at least 10 to 14 days of an estrogen cycle is associated with a lower incidence of endometrial hyperplasia and endometrial carcinoma than an estrogen-only cycle ^{05} ^{49} ^{89} ^{93} ^{140}. There is no risk of endometrial cancer in patients who have undergone hysterectomies and, therefore, no documented need for concurrent progestin therapy. ^{105}

Whether the use of systemic estrogens increases the incidence of breast cancer in some postmenopausal women is unresolved. Some large studies reported an increase in the relative risk for development of breast cancer for women taking high doses of estrogen or using estrogens for a prolonged period of time, especially longer than 10 years. At present, however, the majority of data have not shown an increased risk of breast cancer in women who have ever used ovarian hormone therapy ^{133}.

In certain animal species, long-term, continuous administration of estrogens increases the frequency of cancers of the breast, cervix, liver, pancreas, testis, uterus, and vagina ^{05} ^{19} ^{27}.

Estrogens have been reported to be associated with carcinoma of the male breast. Males treated with estrogens should have regular breast examinations.

Pregnancy/Reproduction

Pregnancy—
Estrogens are not recommended for use during pregnancy ^{04} ^{19} or during the immediate postpartum period. Studies suggest an association of congenital malformations with use of some estrogens during pregnancy ^{05} ^{06} ^{106} ^{113}.

Diethylstilbestrol: Daughters of women who took diethylstilbestrol (DES) during pregnancy have developed abnormalities of the reproductive tract and, in rare cases, cancer of the vagina and/or uterine cervix upon reaching childbearing age ^{04} ^{112}. In addition, sons of women who took DES during pregnancy have developed urogenital tract abnormalities ^{112}. Patients who become pregnant while taking estrogens should be informed of the potential risks to the fetus. ^{142}

FDA Pregnancy Category X ^{04} ^{05} ^{106} ^{113}.

Breast-feeding

Estrogens are distributed into breast milk ^{33}. Use by breast-feeding women is not recommended with estrogen doses larger than those used in oral contraceptives ^{05} ^{33} ^{99} ^{106}.

Ethinyl estradiol—Traces of ethinyl estradiol are distributed into breast milk when estrogen is given in high doses as an antineoplastic agent ^{99}. Also, use of oral contraceptives containing ethinyl estradiol during lactation has been associated with a decrease in milk production and in the milk protein and nitrogen content. ^{33} ^{94} However, the magnitude of these effects is small and probably of clinical significance only in malnourished mothers. ^{33} ^{94} ^{105}

Pediatrics

Estrogens may accelerate epiphyseal closure ^{81}. Therefore, estrogens should be used with caution in children and adolescents in whom bone growth is not complete.

Geriatrics

Studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of estrogens in the elderly. ^{107}

Dental

Estrogens may predispose the patient to bleeding of the gingival tissues. In addition, gingival hyperplasia may occur during estrogen therapy, usually starting as gingivitis or gum inflammation. A strictly enforced program of teeth cleaning by a professional, combined with plaque control by the patient, will minimize growth rate and severity of gingival enlargement. ^{66} ^{114}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication ^{122}.

Bromocriptine^{49}^{123}    (estrogens may interfere with the effects of bromocriptine; dosage adjustment may be needed ^{123})

Calcium supplements^{100}^{123}^{139}^{143}^{144}^{150}    (concurrent use with estrogens may increase calcium absorption and exacerbate nephrolithiasis in susceptible individuals; this can be used to therapeutic advantage to increase bone mass ^{123} ^{134} ^{139} ^{141} ^{143} ^{150})

Corticosteroids, glucocorticoid^{123}    (concurrent use with estrogens may alter the metabolism and protein binding of the glucocorticoids, leading to decreased clearance, increased elimination half-life, and increased therapeutic and toxic effects of the glucocorticoids; glucocorticoid dosage adjustment may be required during and following concurrent use ^{123})

Corticotropin (chronic therapeutic use)^{123}    (concurrent use with estrogens may potentiate the anti-inflammatory effects of endogenous cortisol induced by corticotropin ^{123})

» Cyclosporine^{62}^{123}    (estrogens have been reported to inhibit cyclosporine metabolism and thereby increase plasma concentrations of cyclosporine, possibly increasing the risk of hepatotoxicity and nephrotoxicity ^{57} ^{58} ^{59} ^{60} ^{61} ^{62} ^{63} ^{64} ^{65} ^{73} ^{123}; concurrent use is recommended only with great caution and frequent monitoring of blood cyclosporine concentrations and liver and renal function ^{63} ^{123})

» Hepatotoxic medications, especially dantrolene and isoniazid (see Appendix II )^{49}^{123}    (concurrent use of these medications with estrogens may increase the risk of hepatotoxicity ^{123} and fatal hepatitis has occurred; risk may be further increased with use in females over 35 years of age, prolonged use, or use in patients with a history of liver disease ^{06} ^{123})

Medications associated with pancreatitis, especially
Didanosine or
Lamividine or
Zalcitabine    (estrogens should be used with caution with medications that cause pancreatitis ^{159}, especially if the patient has pre-existing risk factors such as high triglyceride concentrations; however, physiologic doses of estrogen would not be expected to induce pancreatitis)

» Protease inhibitors, such as ritonavir    (ritonavir has decreased the area under the plasma concentration–time curve [AUC] of ethinyl estradiol by 40%; similar effects may occur with other estrogens or with other protease inhibitors ^{158})

Smoking, tobacco^{45}^{49}^{123}    (data from studies on tobacco smoking and the use of high-dose estrogen oral contraceptives indicate that there is an increased risk of serious cardiovascular side effects, including cerebrovascular accident, transient ischemic attacks, thrombophlebitis, and pulmonary embolism ^{123}; risk increases with increasing tobacco usage and with age, especially in women over 35 years of age ^{123}; it is not known whether any elevation of risk occurs with tobacco smoking during the use of ovarian hormone therapy ^{123})

    (metabolism of estrogens may also be increased by smoking, resulting in a decreased estrogenic effect ^{83} ^{84} ^{85} ^{86} ^{87} ^{88} ^{105} ^{123})

Somatrem or^{45}^{123}
Somatropin^{45}^{123}    (in prepubertal patients, concurrent use of estrogens with somatrem or somatropin may accelerate epiphyseal maturation ^{45} ^{49} ^{54} ^{123})

Tamoxifen^{123}    (concurrent use may interfere with therapeutic effect of tamoxifen ^{68} ^{123})

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Biopsy    (pathologist should be notified of relevant specimens ^{11})

Fasting blood sugar (FBS) and^{148}
Glucose tolerance test^{05}^{92}^{121}^{148}    (may be altered by large doses of estrogens ^{92} ^{121} ^{146} ^{148})

Metyrapone test^{05}^{45}    (reduced response ^{05} ^{148})

Norepinephrine-induced platelet aggregability^{05}    (may be increased)

Thyroid function tests, such as
Thyroxine (T ₄) determinations
Triiodothyronine (T ₃) determinations    (values for the T ₃ uptake test may be decreased because of an increase in thyroid-binding globulin [TBG]; free T ₃, thyroxine [T ₄], and thyroid-stimulating hormone [TSH] concentrations remain unaltered and patient remains euthyroid, even though the total thyroid hormone may be increased ^{05} ^{146} ^{148})

With physiology/laboratory test values
Antithrombin III, serum and^{05}^{141}
Cholesterol, total, serum and^{97}^{101}^{104}^{143}^{148}^{149}
Folate, serum and^{05}^{148}
Lipoproteins, low density (LDL), serum and^{95}^{96}^{104}^{138}^{143}^{149}
Pregnanediol, urine and^{05}^{47}
Pyridoxine, serum    (concentrations may be decreased ^{89} ^{104} ^{141} ^{148}; however, transdermal estradiol may have little effect on lowering LDL, total serum cholesterol, or serum antithrombin III concentrations ^{153} ^{157})

Calcium^{05}^{80}^{148}    (increased serum concentrations, especially for immobilized patients or for patients with bone cancer or metastatic breast cancer ^{49} ^{148})

Ceruloplasmin and^{148}
Clotting factors VII, VIII, IX, and X and^{05}^{115}
Cortisol and^{103}
Glucose—especially in diabetic or prediabetic patients taking larger doses of estrogens, and^{67}^{146}^{148}
Lipoproteins, high density (HDL) and^{67}^{77}^{95}^{96}^{101}^{138}^{143}^{148}^{149}
Phospholipids and^{05}^{77}
Prolactin and
Prothrombin and^{05}^{146}
Sodium and^{103}^{146}
Triglycerides^{05}^{96}^{103}    (serum concentrations may be increased ^{89} ^{146}. Transdermal estradiol may lower serum triglyceride concentrations and have little effect on increasing HDL or hepatic clotting factors ^{153} ^{157})

Renin substrate^{103}^{138}^{141}    (may be increased by conjugated estrogens and ethinyl estradiol ^{103}; this effect may also occur with other estrogens; however, transdermal estradiol does not affect renin substrate ^{153} ^{157})

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Except under special circumstances, this medication should not be used when the following medical problems exist:
» Genital or uterine bleeding, abnormal and undiagnosed^{05}^{125}^{146}    (use of estrogens may delay diagnosis; on occurrence, estrogen should be discontinued awaiting clinical evaluation. Condition may worsen if cause of abnormal uterine bleeding is endometrial hyperplasia or uterine cancer ^{125})

» Neoplasia, estrogen-dependent, known or suspected^{05}    (possible promotion of tumor growth or estrogen may interfere with the action of antiestrogen treatment regimens; when these conditions are present, estrogen therapy usually is discontinued ^{115} ^{117} ^{49} ^{124} ^{125})

For all indications, except for the treatment of breast cancer or prostatic cancer:
» Thrombophlebitis or thromboembolic disorders, active^{05}^{125}    (estrogens should be discontinued if thromboembolic events occur ^{125})

Risk-benefit should be considered when the following medical problems exist
Endometriosis^{05}^{49}^{125}    (endometrial implants may be aggravated by use of estrogens ^{49} ^{91} ^{117} ^{124} ^{125})

Gallbladder disease, or history of, especially gallstones^{05}^{49}^{72}^{75}^{77}^{89}^{90}^{91}^{116}^{125}    (conflicting evidence exists as to whether an increased risk of recurrence or exacerbation occurs secondary to oral estrogen use ^{72} ^{75} ^{89} ^{90} ^{91} ^{125})

Hepatic function impairment, severe, including
Jaundice, or history of, during pregnancy^{05}^{125}
Porphyria, hepatic—acute, intermittent, or variegate or^{19}^{49}^{125}
Hyperlipoproteinemia, familial or
Pancreatitis    (may cause these conditions to worsen or recur; estrogens given to achieve serum concentrations at the premenopausal level can rarely increase triglycerides to concentrations that result in pancreatitis, especially in patients with familial defects in lipoprotein metabolism. Metabolism of estrogens may be impaired with hepatic function impairment ^{125})

» Hypercalcemia associated with bone or metastatic breast cancer^{05}^{28}^{49}^{71}^{125}    (severe hypercalcemia may occur in patients with bone cancer or metastatic breast cancer who are treated with estrogens ^{04}; estrogens may aggravate breast cancer–induced hypercalcemia through alterations in the metabolism of calcium and phosphorus ^{71} ^{125}; appropriate monitoring is recommended ^{05} ^{135} ^{125})

Leiomyoma, uterine^{05}^{91}^{125}^{146}    (may increase in size during estrogen therapy ^{49} ^{125})

Sensitivity to estrogens
For all indications, except for the treatment of breast cancer or prostatic cancer:
» Thrombophlebitis, thrombosis, or thromboembolic disorders, estrogen-induced, history of^{125}    (resumption of estrogen therapy may result in recurrence ^{125}. Hypercoagulability information for postmenopausal women taking ovarian hormone therapy is not available. Estrogens can be used cautiously in women with predisposing risk factors and should be discontinued if thromboembolic events occur ^{125} ^{161})

For treatment of male breast cancer or prostatic cancer only (in addition to those conditions listed above):
Cerebrovascular disease or^{125}
Coronary artery disease^{125} or
Thrombophlebitis, active or^{125}
Thromboembolic disorders^{125}    (the large doses of estrogens used in males to treat breast and prostatic cancer have been associated with an increased risk of myocardial infarction, pulmonary embolism, and thrombophlebitis ^{05} ^{125})

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood pressure determinations^{05}^{130}^{141}    (blood pressure elevations that generally occur within a short time after initiation of therapy are due to a reversible effect on the renin-angiotensin system and have only been documented during the use of conjugated estrogens and high-dose combination oral contraceptives ^{05} ^{130}; hypertension occurring during the treatment of gonadal dysgenesis also may be a result of worsening of the disease state itself, and may not necessarily be attributable to estrogen therapy ^{130})

Bone age determinations^{130}    (x-ray of hand and wrist recommended every 6 months for children and adolescents to determine rate of bone maturation and effects on epiphyseal centers ^{130})

Breast examinations^{05}^{130}^{138}    (should be performed routinely by patient and physician for early detection of possible breast cancer; teaching patient about periodic self-examination of breasts ^{118} ^{119} ^{130} ^{138})

Endometrial biopsy^{49}^{130}^{138}^{141}^{149}    (should be considered periodically as necessary in patients with an intact uterus ^{130} ^{138} ^{141}; patients with a uterus should be monitored for signs of endometrial cancer and malignancy should be ruled out in cases of persistent or abnormal vaginal bleeding ^{130}; there is no risk of endometrial cancer in patients who have undergone a hysterectomy ^{105} ^{130})

Hepatic function determinations^{19}^{130}^{146}    (recommended at regular intervals, especially during therapy in patients who have or are suspected of having hepatic disease ^{130})

Lipid profile determinations, serum^{106}^{130}^{138}^{141}^{146}    (recommended annually in women who are receiving ovarian hormone therapy, especially if taking a progestin ^{40} ^{130})

Mammogram^{49}^{118}^{119}^{130}^{138}    (every 12 months, or as determined by physician ^{130} ^{138} ^{141})

    (sensitivity or specificity of mammography testing is decreased with concurrent use of estrogens due to detection problems caused by estrogen-induced breast tissue growth, especially if the postmenopausal breast is fibrous. Ordering mammography during week of no hormonal use or after cessation of therapy may help in recognizing false-positive or false-negative mammograms ^{155})

Papanicolaou (Pap) test and^{05}^{130}
Physical examinations^{05}^{130}    (every year or more frequently when so determined by physician, with special attention being given to abdomen, breast, and pelvic organs ^{05} ^{130})

Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent

Breast pain or tenderness —in females as well as in males treated for prostatic cancer^{05}^{74}^{111}^{109}^{128}^{138}^{141}

enlargement of breasts —in females^{05}^{111}^{109}^{128}

gynecomastia (increased breast size)—in males treated for prostatic cancer^{74}^{111}^{109}^{128}

peripheral edema ^{05}^{103}^{128}(swelling of feet and lower legs; rapid weight gain)

Incidence less frequent or rare

Amenorrhea ^{128}(stopping of menstrual bleeding), breakthrough bleeding ^{05}^{128}^{138}(heavier vaginal bleeding between regular menses), menorrhagia ^{05}^{128}^{138}(prolonged or heavier menses), or spotting ^{05}^{128}(lighter vaginal bleeding between regular menses)

breast tumors (breast lumps; discharge from breast)^{128}

gallbladder obstruction^{05}^{89}^{90}^{128}^{146}
hepatitis^{128}
or pancreatitis (pains in stomach, side, or abdomen; yellow eyes or skin)^{128}

Note: If persistent or recurring abnormal vaginal bleeding occurs, malignancy should be ruled out ^{128}. However, withdrawal bleeding will frequently occur in patients placed on cyclic estrogen therapy with a progestin who have not undergone hysterectomy ^{77} ^{128} ^{149}. Any unusual uterine bleeding persisting longer than 3 to 6 months should be investigated. With continuous estrogen-progestin therapy, withdrawal bleeding is eliminated, endometrial atrophy and amenorrhea are produced in most patients after 2 to 3 months and, in the remaining patients, after 7 to 13 months. Amenorrhea is highly desired by many women and not considered by them to be a true adverse effect. ^{160} ^{161} ^{162}

For treatment of male breast cancer or prostatic cancer only (in addition to those listed above)

Thromboembolism^{05}^{128} or thrombus formation^{05}^{128} (severe or sudden headache; sudden loss of coordination; pains in chest, groin, or leg, especially calf; sudden and unexplained shortness of breath; sudden slurred speech; sudden vision changes; weakness or numbness in arm or leg^{89}^{105}^{120}^{128}^{138}^{141}^{149})
Note: The use of large doses of estrogens (5 mg a day) in males to treat breast and prostate cancer has been associated with an increased risk of myocardial infarction, pulmonary embolism, and thrombophlebitis ^{05} ^{69} ^{74} ^{77} ^{140} ^{128}.

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent

Abdominal cramping or bloating^{05}^{128}^{141}

anorexia (loss of appetite)^{45}^{128}

nausea^{05}^{74}^{76}^{128}^{138}

skin irritation and redness —with transdermal system^{05}^{20}^{128}

Incidence less frequent

Diarrhea, mild^{128}

dizziness, mild^{05}^{128}

headaches, mild^{05}^{54}^{128}^{138}

intolerance to contact lenses^{128}

libido decrease —in males^{45}^{128}

libido increase —in females^{05}^{109}^{128}

migraine headaches^{05}^{128}

vomiting —primarily of central origin; usually with high doses^{74}^{128}

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Estrogens (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to estrogens

Carcinogenicity—
Increased risk of endometrial cancer for patients with intact uteri placed on unopposed estrogen therapy; decreased risk occurs when used with a progestin; male breast cancer has occurred in association with estrogen use; continuous, long-term estrogen use in animal studies increased frequency of cancers of the breast, cervix, and liver

Pregnancy—Use of some estrogens may be associated with congenital abnormalities. Physician should be informed immediately if pregnancy is suspected

Breast-feeding—Use is not recommended because estrogens are distributed into breast milk and may have unpredictable effects

Use in children—Use in children or growing adolescents may slow or stop growth

Other medications, especially cyclosporine; hepatotoxic medications; or protease inhibitors
Other medical problems, especially abnormal or undiagnosed genital or uterine bleeding; active thrombophlebitis or thromboembolic disorders; estrogen-dependent neoplasia; history of estrogen-induced thrombophlebitis, thrombosis, or thromboembolic disorders; or hypercalcemia associated with bone cancer or metastatic breast cancer

Proper use of this medication
» Reading patient package insert carefully

» Compliance with therapy

For oral or parenteral dosage forms
Taking with or immediately after food to reduce nausea

For transdermal estradiol
Washing and drying hands thoroughly before and after application

Applying to clean, dry, nonoily, hairless, intact area of skin on the lower abdomen, hips below the waistline, or buttocks; not applying over cuts or irritation. The manufacturer of the 0.025-mg matrix transdermal system recommends applying its patch to the buttocks only, rotating the application site from left buttock to right buttock every 7 days

» Not applying to breasts; not applying to waistline or other areas where tight clothes may rub disk loose

Pressing the disk firmly in place with palm for about 10 seconds; making sure there is good contact, especially around edges

Reapplying disk if it comes loose, or discarding and applying a new one

Applying each patch to different area of skin on lower abdomen, hips below waistline, or buttocks so at least 1 week elapses before the area is used again to help prevent skin irritation

» Proper dosing
Taking or using as soon as possible; not using if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Regular visits to physician every year, or more often, as determined by physician

Possibility of dental problems, such as tenderness, swelling, or bleeding of gums; brushing and flossing teeth, massaging gums, and having dentist clean teeth regularly; checking with dentist if there are questions about care of teeth or gums or if tenderness, swelling, or bleeding of gums is noticed

» Checking breast by self-examination regularly and having clinical examination and mammography as required by physician; reporting unusual breast lumps or discharge

» Understanding that menstrual bleeding may begin again but, with continuous therapy, will stop by 10 months

» Understanding that intermenstrual uterine bleeding will occur for the first 3 months; importance of not stopping medicine; checking with doctor immediately if uterine bleeding is unusual or continuous, missed period occurs, or pregnancy is suspected

If scheduled for laboratory tests, telling physician about taking estrogens; certain blood tests and tissue biopsies are affected

Side/adverse effects
Withdrawal bleeding will occur in many postmenopausal patients with an intact uterus who are placed on cyclic estrogen therapy with a progestin

Signs of potential side effects, especially breast pain or tenderness, enlargement of breasts in females, gynecomastia in males treated for prostatic cancer, peripheral edema, amenorrhea, breakthrough bleeding, menorrhagia, or spotting; breast tumors; gallbladder obstruction, hepatitis, or pancreatitis; for treatment of prostatic cancer and male breast cancer only—thromboembolism or thrombus formation

General Dosing Information
It is recommended that the patient package insert be given to patients.

As a general rule, estrogen therapy should be administered at the lowest effective dosage ^{05}. If prolonged therapy is necessary, the patient should be re-evaluated at least every year to determine the need for continued therapy ^{05}.

With chronic administration of estrogens in patients with the uterus in situ , the concurrent use of a progestin for at least 10 to 14 days of the cycle should be considered ^{105} ^{141}. Administration of a progestin decreases the risk of occurrence of endometrial hyperplasia and endometrial carcinoma ^{105} ^{138}. There is no risk of endometrial hyperplasia or endometrial carcinoma in patients who do not have an intact uterus ^{105}.

An estrogen may be administered for the entire period of estrogen deficiency ^{77} ^{82}. Estrogens may be administered on a cyclic or continuous regimen when used to treat estrogen deficiency states, for prevention of osteoporosis, and for prevention of atherosclerotic disease ^{105}. Some patients are placed on a cyclic regimen consisting of 3 weeks of estrogen therapy, with a progestin concurrently administered (if indicated) for the first or last 10 to 14 days of the 3-week period ^{105} ^{141}. During the fourth and final week of the cycle, no medication is administered. ^{105} Other physicians advocate the use of continuous estrogen dosing with continuous progestin administration ^{105}.

Use of the continuous regimen for both conjugated estrogen and medroxyprogesterone is a good choice for women who do not want to resume menses ^{162}. If spotting or uterine bleeding occurs during the first 6 months, a higher dose of progestin may be used for a short time until endometrial atrophy occurs.

For ovarian hormone therapy
Decisions to treat menopausal symptoms with hormones for a limited time (1 to 5 years) or to use hormones to prevent diseases in postmenopausal women for a longer period of time (10 to 20 years), or a lifetime, should be made separately ^{163} ^{164} ^{165} ^{167}.

Counseling asymptomatic postmenopausal women about the benefits and risks of using long-term ovarian hormone therapy to prevent osteoporosis and coronary heart disease and to increase life expectancy is complex ^{167}. Risk estimates are based on observational studies; the true estimates for long-term risks and benefits await controlled clinical trials ^{164} ^{166} ^{161}. Women should understand that the benefits and risks of preventive hormone therapy depend on their risk status, and that women at higher risk for developing osteoporosis or coronary heart disease can derive the greatest benefit ^{163} ^{164} ^{165}.

For women with a uterus, adding a progestin to estrogen therapy may benefit postmenopausal women at risk for osteoporosis, slightly reduce estrogen's protective effect against coronary heart disease, and slightly increase the risk of breast cancer over that of nonusers ^{163} ^{164} ^{165}.

Diet/Nutrition
Estrogen therapy with either the oral or parenteral dosage form may cause nausea, especially in the morning. Although this nausea is primarily of central origin, eating solid food often provides some relief.

For parenteral dosage forms only
Intramuscular injections should be administered slowly and deeply into a large muscle area such as the upper outer quadrant of the buttock.

Rapid intravenous injections may cause perineal or vaginal burning ^{49}.

A dry syringe and needle of at least 21 gauge should be used for the oil-vehicle preparations.

For estradiol transdermal dosage forms
Patients who are currently taking oral estrogens should wait 1 week after withdrawal of oral estrogens before the transdermal dosage system is initiated ^{05} ^{07} ^{15}.

Transdermal estradiol generally is administered on a continuous regimen, with repeating cycles of 3 weeks on and 1 week off. ^{107} ^{118} ^{120} In women with an intact uterus, administration of a progestin for at least 10 to 14 days of each month is recommended. For women who have had a hysterectomy, transdermal estradiol may be given continuously or cyclically without adding a progestin to the therapeutic regimen ^{07} ^{15}.

The adhesive side of the transdermal system should be placed on a clean, dry area of the skin on the trunk of the body. The lower abdomen is the preferred site, although the patch may be applied to the buttocks or sides of hip below the waist instead. However, the manufacturer of the 0.025-mg matrix transdermal system recommends applying its patch to the buttock site only, rotating the site of application between left and right buttocks. None of the transdermal systems should be applied to the breasts or waistline ^{169}. The area selected should not be oily or irritated and the skin should not be broken. The application site should be rotated, and no site should be reused until 1 week has passed. ^{05}

The system should be applied immediately after removal from the pouch and removal of the protective liner. It should not be stored unprotected. The system should be pressed firmly in place with the palm of the hand for about 10 seconds, making sure there is good contact, especially around the edges. ^{05}

If a transdermal system loosens or falls off, it may be reapplied or a new system may be applied instead. In either case, the patient should continue with the original treatment schedule. ^{05}

CONJUGATED ESTROGENS

Oral Dosage Forms

CONJUGATED ESTROGENS TABLETS USP

Usual adult dose
Atrophic vaginitis or
Menopausal (vasomotor) symptoms or
Vulvar atrophy
Oral, 300 mcg (0.3 mg) to 1.25 mg a day, cyclically ^{11} or continuously. ^{11} ^{25} ^{42}

Note: May be used in conjunction with vaginal dosage forms.

Breast carcinoma (inoperable and progressing in selected men and postmenopausal women)
Oral, 10 mg three times a day for at least three months. ^{11} ^{25} ^{42}

Estrogen deficiency, due to ovariectomy or
Primary ovarian failure
Oral, 1.25 mg a day, cyclically or continuously. For maintenance, adjust estrogen dose to lowest level that provides control ^{11}.

Female hypogonadism
Oral, 2.5 to 7.5 mg a day, in divided doses, cyclically ^{11} ^{25}.

Osteoporosis, postmenopausal (prophylaxis)
Oral, 625 mcg (0.625 mg) a day, cyclically or continuously as appropriate ^{11} ^{24} ^{25}.

Prostatic carcinoma (inoperable and progressing)
Oral, 1.25 to 2.5 mg three times a day. ^{11} ^{25} ^{42}

Strength(s) usually available
U.S.—

300 mcg (0.3 mg) (Rx) [Premarin^{11}]

625 mcg (0.625 mg) (Rx) [Premarin^{11}]

Note: Premarin 0.625 mg is available as either white or purple tablets ^{35}.

900 mcg (0.9 mg) (Rx) [Premarin^{11}]

1.25 mg (Rx) [Premarin^{11}]

2.5 mg (Rx) [Premarin^{11}]

Canada—

300 mcg (0.3 mg) (Rx) [C.E.S.^{24}] [Congest^{18}] [Premarin^{25}]

625 mcg (0.625 mg) (Rx) [C.E.S.^{24}] [Congest^{18}] [Premarin^{25}][Generic]^{38}

900 mcg (0.9 mg) (Rx) [C.E.S.^{24}] [Congest^{18}] [Premarin^{25}]

1.25 mg (Rx) [C.E.S.^{24}] [Congest^{18}] [Premarin^{25}][Generic]^{38}

2.5 mg (Rx) [C.E.S.^{24}] [Congest^{18}] [Premarin^{25}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Note: Include mandatory patient package insert (PPI) when dispensing.

Parenteral Dosage Forms

CONJUGATED ESTROGENS FOR INJECTION

Usual adult dose
Uterine bleeding, hormonal imbalance–induced
Intramuscular or intravenous, 25 mg, repeated in six to twelve hours if needed. ^{10} ^{23}

Note: Intravenous administration is preferred because of the more rapid response obtained ^{10}. To reduce the possibility of a flushing reaction, the medication should be administered slowly. ^{10}

Size(s) usually available:
U.S.—

25 mg (Rx) [Premarin Intravenous (benzyl alcohol 2%—diluent )^{10}]

Canada—

25 mg (Rx) [Premarin Intravenous^{23}]

Packaging and storage:
Prior to reconstitution, store between 2 and 8 °C (36 and 46 °F), unless otherwise specified by manufacturer.

Preparation of dosage form:
With aseptic technique, at least 5 mL of air should be withdrawn from the container of dry powder. Then 5 mL of the sterile diluent provided should be added slowly against the side of the container. The vial should be agitated gently to dissolve the contents. Do not shake vigorously. ^{10} ^{23}

Stability:
When stored between 2 and 8 °C (36 and 46 °F), the reconstituted solution retains potency for about 60 days ^{10} ^{23}. Do not use if solution has darkened or if a precipitate is present. ^{10} ^{23}

Incompatibilities:
The prepared injection is compatible with normal saline, dextrose, and invert sugar solutions ^{10}. It is not compatible with solutions having an acid pH, such as protein hydrolysate or ascorbic acid. ^{10}

Note: Include mandatory patient package insert (PPI) if dispensed to patient.

DIETHYLSTILBESTROL

Oral Dosage Forms

DIETHYLSTILBESTROL TABLETS USP

Usual adult dose
Prostatic carcinoma (inoperable and progressing)
Oral, 1 to 3 mg initially and increased as needed in advanced cases, with the dosage later reduced to 1 mg a day. ^{03} ^{37}

Note: Doses used to treat prostatic carcinoma have been found to have a maximal effect in maintenance doses of up to 1 mg a day. Higher doses do not appreciably increase the therapeutic results, but may increase the risk of cardiovascular embolism.

Strength(s) usually available
U.S.—
Not commercially available.

Canada—

100 mcg (0.1 mg) (Rx) [Stilbestrol]^{37}

500 mcg (0.5 mg) (Rx) [Stilbestrol]^{37}

1 mg (Rx) [Stilbestrol]^{37}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Note: Include patient package insert (PPI) when dispensing.

DIETHYLSTILBESTROL DIPHOSPHATE TABLETS

Usual adult dose
Prostatic carcinoma (inoperable and progressing)
Oral, 50 to 166 mg three times a day ^{36}; the dosage being increased gradually to 200 mg or more, three times a day as needed and tolerated. ^{06} ^{36}

Usual adult prescribing limits
Oral, 1 gram a day. ^{06}

Strength(s) usually available
U.S.—

50 mg (Rx) [Stilphostrol (scored)^{06}]

Canada—

83 mg (diethylstilbestrol diphosphate sodium 100 mg) (Rx) [Honvol ( scored)^{36}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Note: Include mandatory patient package insert (PPI) when dispensing.

Parenteral Dosage Forms

DIETHYLSTILBESTROL DIPHOSPHATE INJECTION USP

Usual adult dose
Prostatic carcinoma (inoperable and progressing)
Induction: Intravenous infusion, initially 500 mg in 250 mL of Sodium Chloride Injection USP or 5% Dextrose Injection USP administered at a rate of 1 mL per minute during the first ten to fifteen minutes; then the flow is adjusted to permit dose completion within one hour ^{06} ^{36} ^{102}. The dosage is increased to 1 gram a day for the subsequent five or more days as needed for relief. ^{06} ^{102}

Maintenance: Intravenous infusion, 250 to 500 mg in 250 mL of Sodium Chloride Injection USP or 5% Dextrose Injection USP ^{36} administered one or two times a week at the same rate as during induction. ^{06} ^{36} ^{102}

Strength(s) usually available
U.S.—

50 mg per mL (Rx) [Stilphostrol^{06}]

Canada—

50 mg per mL (diethylstilbestrol diphosphate sodium 60 mg) (Rx) [Honvol^{36}]

Packaging and storage:
Store below 21 °C (70 °F), unless otherwise specified by manufacturer. Protect from freezing.

Note: Include mandatory patient package insert (PPI) if dispensed to patient.

ESTERIFIED ESTROGENS

Oral Dosage Forms

ESTERIFIED ESTROGENS TABLETS USP

Usual adult dose
Atrophic vaginitis or
Vulvar atrophy
Oral, 300 mcg (0.3 mg) to 1.25 mg or more a day, cyclically or continuously as appropriate. ^{12} ^{42}

Note: May be used in conjunction with vaginal dosage forms.

Breast carcinoma (inoperable and progressing in selected men and postmenopausal women)¹
Oral, 10 mg three times a day for at least three months. ^{12} ^{42}

Estrogen deficiency, due to ovariectomy or
Primary ovarian failure
Oral, 1.25 mg a day, cyclically or continuously. For maintenance, adjust estrogen dose to lowest level that provides control ^{11}.

Female hypogonadism
Oral, 2.5 to 7.5 mg a day, in divided doses, cyclically or continuously ^{12} ^{42}.

Menopausal (vasomotor) symptoms
Oral, 625 mcg (0.625 mg) to 1.25 mg a day, cyclically or continuously as appropriate ^{12} ^{42}.

Osteoporosis, postmenopausal (prophylaxis)¹
Oral, 300 mcg (0.3 mg) to 1.25 mg a day, cyclically or continuously ^{42}.

Prostatic carcinoma (inoperable and progressing)¹
Oral, 1.25 to 2.5 mg three times a day. ^{12} ^{42}

Strength(s) usually available
U.S.—

300 mcg (0.3 mg) (Rx) [Estratab^{12}] [Menest^{21}]

625 mcg (0.625 mg) (Rx) [Estratab^{12}] [Menest^{21}]

1.25 mg (Rx) [Estratab^{12}] [Menest^{21}]

2.5 mg (Rx) [Estratab^{12}] [Menest^{21}]

Canada—

300 mcg (0.3 mg) (Rx) [Neo-Estrone^{39}]

625 mcg (0.625 mg) (Rx) [Neo-Estrone^{39}]

1.25 mg (Rx) [Neo-Estrone^{39}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Note: Include mandatory patient package insert (PPI) when dispensing.

ESTRADIOL

Oral Dosage Forms

ESTRADIOL TABLETS USP

Usual adult dose
Atrophic vaginitis or
Estrogen deficiency, due to ovariectomy ¹ or
Female hypogonadism¹ or ^{04}
Menopausal (vasomotor) symptoms or
Primary ovarian failure¹ or
Vulvar atrophy ^{04}
Oral, 500 mcg (0.5 mg) to 2 mg a day, cyclically ^{04} ^{19} or continuously ^{04} as appropriate.

Breast carcinoma (inoperable and progressing in selected men and postmenopausal women)¹
Oral, 10 mg three times a day for at least three months. ^{04}

Prostatic carcinoma (inoperable and progressing)¹
Oral, 1 to 2 mg three times a day. ^{04}

Osteoporosis, postmenopausal (prophylaxis)
Oral, 0.5 mg (500 mcg) a day, cyclically ^{19} (twenty-three days on and five days off per month).

Strength(s) usually available
U.S.—

500 mcg (0.5 mg) (Rx) [Estrace (scored)^{04}][Generic] (scored)^{01}

1 mg (Rx) [Estrace (scored)^{04}][Generic] (scored)^{01}

2 mg (Rx) [Estrace (scored)^{04}][Generic] (scored)^{01}

Canada—

500 mcg (0.5 mg) (Rx) [Estrace (scored)^{19}]

1 mg (Rx) [Estrace (scored)^{19}]

2 mg (Rx) [Estrace (scored)^{19}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.

Note: Include mandatory patient package insert (PPI) when dispensing.

Parenteral Dosage Forms

ESTRADIOL CYPIONATE INJECTION USP

Usual adult dose
Female hypogonadism
Intramuscular, 1.5 to 2 mg administered at monthly intervals. ^{02}

Menopausal (vasomotor) symptoms
Intramuscular, 1 to 5 mg once a week for three to four weeks, usually administered cyclically (three weeks on and one week off). ^{02}

Strength(s) usually available
U.S.—

5 mg per mL (Rx) [depGynogen (chlorobutanol) (cottonseed oil)] [Depo-Estradiol (chlorobutanol 5.4 mg) (cottonseed oil)^{02}] [Depogen (chlorobutanol) ( cottonseed oil)] [Dura-Estrin (chlorobutanol) (cottonseed oil)] [E-Cypionate^{29}] [Estragyn LA 5^{44}] [Estro-Cyp (chlorobutanol ) (cottonseed oil)] [Estrofem ( chlorobutanol) (cottonseed oil)] [Estro-L.A.^{44}][Generic]^{08}

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a light-resistant container, unless otherwise specified by manufacturer. Protect from freezing.

Note: Include mandatory patient package insert (PPI) if dispensed to patient.

ESTRADIOL VALERATE INJECTION USP

Usual adult dose
Atrophic vaginitis or
Estrogen deficiency, due to ovariectomy or
Female hypogonadism¹ or
Menopausal (vasomotor) symptoms or
Primary ovarian failure or
Vulvar atrophy
Intramuscular, 10 to 20 mg repeated every four weeks as needed ^{09} ^{17} ^{41}.

Prostatic carcinoma (inoperable and progressing)
Intramuscular, 30 mg every one or two weeks, the dose being adjusted as needed. ^{09} ^{17} ^{41}

Strength(s) usually available
U.S.—

10 mg per mL (Rx) [Delestrogen (chlorobutanol 5 mg) (sesame oil)^{09}] [Valergen-10 (chlorobutanol) (sesame oil)][Generic]

20 mg per mL (Rx) [Delestrogen (benzyl alcohol) (benzyl benzoate) (castor oil)^{09}] [Dioval XX (benzyl alcohol ) (benzyl benzoate) ( castor oil)] [Duragen-20 (benzyl alcohol) (benzyl benzoate) (castor oil)] [Gynogen L.A. 20 (benzyl alcohol) ( benzyl benzoate) (castor oil)] [Menaval-20^{44}] [Valergen-20 (benzyl alcohol) (benzyl benzoate) (castor oil)^{44}][Generic]^{44}

40 mg per mL (Rx) [Clinagen LA 40^{44}] [Delestrogen (benzyl alcohol) (benzyl benzoate) (castor oil)^{09}] [Dioval 40 (benzyl alcohol) (benzyl benzoate) (castor oil)] [Estra-L 40 (benzyl alcohol ) (benzyl benzoate) ( castor oil)] [Estro-Span^{44}] [Gynogen L.A. 40 (benzyl alcohol) (benzyl benzoate) (castor oil)] [Valergen-40 (benzyl alcohol ) (benzyl benzoate) ( castor oil)^{43}][Generic]

Canada—

10 mg per mL (Rx) [Delestrogen (chlorobutanol 0.5%) (sesame oil)^{17}]

20 mg per mL (Rx) [Femogex (chlorobutanol 0.5%)^{22}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a light-resistant container. Protect from freezing.

Note: Include mandatory patient package insert (PPI) if dispensed to patient.

Topical Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

ESTRADIOL TRANSDERMAL SYSTEM (Matrix-type)

Usual adult dose
Atrophic vaginitis or
Estrogen deficiency, due to ovariectomy ¹ or
Female hypogonadism¹ or
Menopausal (vasomotor) symptoms or
Osteoporosis, postmenopausal (prophylaxis) ¹or
Primary ovarian failure¹ or
Vulvar atrophy
Topical, to the skin, one transdermal system delivering 25 mcg to 50 mcg a day is worn continuously and replaced, depending on the product, every seven days^{15}^{169} or every three or four days (two times a week) for three weeks^{07}^{168}^{170} of a four-week cycle. No patch is worn for the fourth week of the cycle, although estrogen treatment may be continued uninterrupted for appropriate patients. After the first thirty days, the dosage may be adjusted and then reevaluated every three to six months for treatment continuance. If osteoporosis is established, a higher dose of 100 mcg may be used initially^{07}^{15}.

Strength(s) usually available
U.S.—

Once–weekly transdermal system

25 mcg (0.025 mg) delivered per day (Rx) [FemPatch^{169}]

50 mcg (0.05 mg) delivered per day (Rx) [Climara^{15}]

100 mcg (0.1 mg) delivered per day (Rx) [Climara^{15}]

Twice–weekly transdermal system

25.0 mcg (0.025 mg) delivered per day (Rx) [Vivelle^{07}]

37.5 mcg (0.0375 mg) delivered per day (Rx) [Vivelle^{07}]

50 mcg (0.05 mg) delivered per day (Rx) [Alora^{168}] [Vivelle^{07}]

75 mcg (0.075 mg) delivered per day (Rx) [Alora^{168}] [Vivelle^{07}]

100 mcg (0.1 mg) delivered per day (Rx) [Alora^{168}] [Vivelle^{07}]

Canada—

Twice-weekly transdermal system

37.5 mcg (0.0375 mg) delivered per day (Rx) [Vivelle^{26}]

50 mcg (0.05 mg) delivered per day (Rx) [Vivelle^{26}]

75 mcg (0.075 mg) delivered per day (Rx) [Vivelle^{26}]

100 mcg (0.1 mg) delivered per day (Rx) [Vivelle^{26}]

Packaging and storage:
Store below 30 °C (86 °F).

Auxiliary labeling:
• Do not store unpouched. Application must be immediately after removal from protective pouch.

Note: Include mandatory patient package insert (PPI) when dispensing.

ESTRADIOL TRANSDERMAL SYSTEM (Reservoir-type)

Usual adult dose
Atrophic vaginitis or
Estrogen deficiency, due to ovariectomy or
Female hypogonadism or
Menopausal (vasomotor) symptoms or
Osteoporosis, postmenopausal (prophylaxis) or
Primary ovarian failure or
Vulvar atrophy
Topical, to the skin, one 50-mcg transdermal system delivering 50 mcg a day, worn continuously and replaced every three or four days (two times a week) for three weeks of a four-week cycle ^{07} ^{05} ^{20}. No patch is worn for the fourth week of the cycle, although estrogen treatment may be continued uninterrupted for appropriate patients. After the first thirty days, the dosage may be adjusted and then reevaluated every three to six months for treatment continuance. If osteoporosis is established, a higher dose of 100 mcg may be used initially ^{07} ^{15}.

Strength(s) usually available
U.S.—

Twice–weekly transdermal system

50 mcg (0.05 mg) delivered per day (Rx) [Estraderm^{05}]

100 mcg (0.1 mg) delivered per day (Rx) [Estraderm^{05}]

Canada—

Twice–weekly transdermal system

25 mcg (0.025 mg) delivered per day (Rx) [Estraderm^{20}]

50 mcg (0.05 mg) delivered per day (Rx) [Estraderm^{20}]

100 mcg (0.1 mg) delivered per day (Rx) [Estraderm^{20}]

Packaging and storage:
Store below 30 °C (86 °F).

Note: Include mandatory patient package insert (PPI) when dispensing.

ESTRONE

Parenteral Dosage Forms

ESTRONE INJECTABLE SUSPENSION USP

Usual adult dose
Atrophic vaginitis or ^{13}
Menopausal (vasomotor) symptoms or
Vulvar atrophy
Intramuscular, 100 to 500 mcg (0.1 to 0.5 mg) two or three times a week, cyclically or continuously as appropriate ^{13}.

Estrogen deficiency, due to ovariectomy or
Female hypogonadism or
Primary ovarian failure
Intramuscular, 100 mcg (0.1 mg) to 1 mg a week, administered as a single dose or in divided doses, cyclically or continuously. A few patients may need doses of up to 2 mg a week.

Prostatic carcinoma (inoperable and progressing)
Intramuscular, 2 to 4 mg two or three times a week. ^{13}

Uterine bleeding, abnormal (hormonal imbalance–induced)
Intramuscular, 2 to 5 mg a day for several days. ^{13}

Strength(s) usually available
U.S.—

2 mg estrone per mL (Rx) [Aquest^{43}] [Wehgen][Generic]

5 mg estrone per mL (Rx) [Estragyn 5^{44}] [Estro-A^{44}] [Estrone `5"] [Kestrone-5][Generic]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Note: Include mandatory patient package insert (PPI) if dispensed to patient.

ESTROPIPATE

Oral Dosage Forms

ESTROPIPATE TABLETS USP

Usual adult dose
Atrophic vaginitis or
Menopausal (vasomotor) symptoms or
Vulvar atrophy
Oral, 750 mcg (0.75 mg) to 6 mg of estropipate a day, cyclically or continuously ^{14} ^{27}.

Estrogen deficiency, due to ovariectomy¹ or
Primary ovarian failure¹
Oral, 1.5 to 9 mg of estropipate a day, cyclically or continuously. For maintenance, adjust dose to lowest level that provides control. ^{14} ^{27}

Female hypogonadism¹
Oral, 1.5 to 9 mg of estropipate a day, cyclically or continuously.

Osteoporosis, postmenopausal (prophylaxis)¹
Oral, 750 mcg (0.75 mg) a day for twenty-five days of a thirty-one–day cycle and continued cyclically ^{14}.

Strength(s) usually available
U.S.—

750 mcg (0.75 mg) estropipate—equivalent to 625 mcg (0.625 mg) sodium estrone sulfate (Rx) [Ogen .625 (scored)] [Ortho-Est .625^{44}][Generic]^{34}

1.5 mg estropipate—equivalent to 1.25 mg sodium estrone sulfate (Rx) [Ogen 1.25 (scored)] [Ortho-Est 1.25^{44}][Generic]^{34}

3 mg estropipate—equivalent to 2.5 mg sodium estrone sulfate (Rx) [Ogen 2.5 (scored)^{14}][Generic]^{34}

6 mg estropipate—equivalent to 5 mg sodium estrone sulfate (Rx)[Generic] (may be scored)^{34}

Canada—

750 mcg (0.75 mg) estropipate—equivalent to 625 mcg (0.625 mg) sodium estrone sulfate (Rx) [Ogen (scored)^{27}]

1.5 mg estropipate—equivalent to 1.25 mg sodium estrone sulfate (Rx) [Ogen (scored)^{27}]

3 mg estropipate—equivalent to 2.5 mg sodium estrone sulfate (Rx) [Ogen (scored)^{27}]

Note: Estropipate previously was called piperazine estrone sulfate and the strengths were calculated as sodium estrone sulfate (0.625 mg, 1.25 mg, 2.5 mg, and 5 mg). Both strengths may appear on the manufacturer's labeling. ^{34}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Note: Include mandatory patient package insert (PPI) when dispensing.

ETHINYL ESTRADIOL

Oral Dosage Forms

ETHINYL ESTRADIOL TABLETS USP

Usual adult dose
Breast carcinoma (inoperable and progressing in selected men and postmenopausal women)
Oral, 1 mg three times a day.

Estrogen deficiency, due to ovariectomy¹ or
Primary ovarian failure¹
Oral, 50 mcg (0.05 mg) three times a day for a few weeks, then reduced to 50 mcg (0.05 mg) once a day, cyclically ^{28} or continuously.

Female hypogonadism¹
Oral, 50 mcg (0.05 mg) one to three times a day, cyclically or continuously, followed by a progestin during the last half of the menstrual cycle. This treatment cycle can be repeated for three to six months to establish a normal menses ^{31}.

Menopausal (vasomotor) symptoms
Oral, 20 to 50 mcg (0.02 to 0.05 mg) a day, cyclically ^{28} or continuously.

Prostatic carcinoma (inoperable and progressing)
Oral, 150 mcg (0.15 mg) to 3 mg a day. ^{28}

Strength(s) usually available
U.S.—

20 mcg (0.02 mg) (Rx) [Estinyl^{31}]

50 mcg (0.05 mg) (Rx) [Estinyl^{31}]

500 mcg (0.5 mg) (Rx) [Estinyl (scored)^{31}]

Canada—

20 mcg (0.02 mg) . Not commercially available (Rx)
Note: Withdrawn from the Canadian market in November 1998.

50 mcg (0.05 mg) (Rx) [Estinyl^{28}]

500 mcg (0.5 mg) (Rx) [Estinyl (scored)^{28}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Note: Include mandatory patient package insert (PPI) when dispensing.

Revised: 01/16/2001

References

Estradiol package insert (Estradiol Table

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