Brand names: Alora, Climara, Delestrogen, Depo-Estradiol, Elestrin, ... show all 17 brands Estrace, EstroGel, Estraderm, Estrasorb, Estring, Evamist, Femring, Femtrace, Menostar, Vagifem, Vivelle, Vivelle-Dot
Drug class: Estrogens

Medically reviewed by Drugs.com on Oct 10, 2024. Written by ASHP.

Introduction

Steroidal estrogen; a principal endogenous estrogen.^a

Uses for Estradiol (Systemic, Local)

Use of estrogens alone in postmenopausal women generally is referred to as estrogen replacement therapy (ERT); use of estrogens in combination with progestins usually is referred to as hormone replacement therapy (HRT) or postmenopausal hormone therapy.^b

Estrogen Replacement Therapy

Management of moderate to severe vasomotor symptoms associated with menopause.^{100 105 106 108 110 111 112 117 118 121 122 123 126 127 128 129 132 134 135 136 137 139} Also used in fixed combination with testosterone cypionate for this indication;¹¹⁸ FDA is reevaluating this combination.^{119 120}

Management of vulvar and vaginal atrophy associated with menopause.^{100 105 106 107 108 110 111 112 117 122 127 128 129 132 134} If used solely for this indication, consider use of topical vaginal preparations.^{117 122 127 129}

Management of urogenital symptoms (urinary urgency and dysuria).¹⁰⁷

Osteoporosis

Prevention of postmenopausal osteoporosis.^{100 101 105 108 110 111 123 125 128 129 133 136 k l v w x kk} Used adjunctively with other measures (e.g., diet, calcium, vitamin D, weight-bearing exercise, physical therapy) to retard further bone loss and progression of osteoporosis in postmenopausal women.^{100 101 105 110 111 123 125 128 129 136 i j k l m v w x bb kk}

Estrogens are effective for prevention of osteoporosis but are associated with a number of adverse effects.^{100 101 105 110 111} If prevention of postmenopausal osteoporosis is the sole indication for therapy, consider alternative therapy (e.g., alendronate, raloxifene, risedronate).^{114 115}

Has been effective in the treatment of osteoporosis in postmenopausal women.^{v w cc dd ee} Formerly recommended as first-line therapy; however, recommendations on appropriate use of HRT have been revised based on WHI study findings.^{qq r tt} (See Boxed Warning.) Evaluate risks and benefits of long-term HRT use in the management of osteoporosis, taking into account the increased risk of breast cancer and cardiovascular disease, availability of other pharmacologic modalities (e.g., alendronate, calcitonin, calcium, raloxifene, risedronate, vitamin D), and life-style factors that can be modified.^{v w x y z aa ii r uu ww xx}

Has been used in a limited number of anorexic women with chronic amenorrhea to reduce calcium loss^{† [off-label]} and, thereby, reduce risk of osteoporosis.^qq

Corticosteroid-induced Osteoporosis

Has been used to prevent bone loss in postmenopausal women receiving low- to moderate-dose corticosteroid therapy^{† [off-label]}.^{mm nn oo pp}

Hypoestrogenism

Treatment of hypoestrogenism secondary to hypogonadism, castration, or primary ovarian failure.^{100 105 106 110 111 112 121 132}

Metastatic Breast Carcinoma

Palliative treatment of metastatic breast cancer in selected women and men.^{a 106} One of several second-line agents.^a

Prostate Carcinoma

Palliative treatment of advanced androgen-dependent prostate carcinoma.^{101 132}

Cardiovascular Risk Reduction† [off-label]

ERT or HRT does not decrease the incidence of cardiovascular disease.^{100 105 106 108 110 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139 c f ff r ss ww xx aaa} AHA, American College of Obstetricians and Gynecologists, FDA, and manufacturers recommend that hormone therapy not be used to prevent heart disease in healthy women (primary prevention) or to protect women with preexisting heart disease (secondary prevention).^{100 105 106 108 110 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139 c f qq r tt ww xx fff}

Alzheimer’s Disease

Prior use of HRT, but not current HRT unless such use exceeds 10 years, associated with reduced risk of Alzheimer’s disease^{† [off-label]}.^vv Estrogens have not been shown to prevent progression of Alzheimer’s disease; American Academy of Neurology recommends that estrogens not be used for treatment of Alzheimer’s disease.^ll

Initiation of ERT or HRT in women ≥65 years of age not associated with an improvement in cognitive function.^{yy ccc ddd} Some women receiving ERT or HRT (specifically conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily or conjugated estrogens 0.625 mg daily) experience detrimental effects.^{yy zz ccc ddd} Incidence of probable dementia in women receiving ERT or HRT was higher than that in women receiving placebo.^{zz ccc} Use of ERT or HRT to prevent dementia or cognitive decline in women ≥65 years of age is not recommended.^{ccc ddd}

Postpartum Breast Engorgement

Used in the past for prevention of postpartum breast engorgement^{† [off-label]}; FDA has withdrawn approval of estrogen-containing drugs for this indication, since estrogens have not been shown to be safe for this use.^a

Pregnancy

Not effective for any purpose during pregnancy; use contraindicated in pregnant women.^{100 105 106 108 110 112 113 117 118 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

Estradiol (Systemic, Local) Dosage and Administration

General

• A progestin generally is added to estrogen therapy (HRT) in women with an intact uterus.^a Addition of a progestin for ≥10 days per cycle of estrogen administration or daily with estrogen reduces incidence of endometrial hyperplasia and attendant risk of endometrial carcinoma in women with an intact uterus.^a

• Menostar: Administer a progestin for 14 days every 6–12 months in women with an intact uterus.¹²⁵

• ERT is appropriate in women who have undergone a hysterectomy (avoids unnecessary exposure to progestins).^{100 105 106 108 110 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

• When estrogen is used for prevention of osteoporosis, response can be assessed by biochemical markers and bone mineral density (BMD).^{105 108 125 128 133}

Administration

Administer estradiol orally, intravaginally, percutaneously by topical application of transdermal system, and by topical application of a gel, emulsion, or transdermal spray to the skin.^{100 105 106 107 110 111 112 122 123 124 125 126 127 128 129 134 136 137 139}

Administer estradiol acetate orally or intravaginally.^{117 135}

Administer estradiol cypionate and estradiol valerate IM.^{118 121 132}

Administer ethinyl estradiol orally.¹³³

Estrogen therapy generally is administered in a continuous daily dosage regimen or, alternatively, in a cyclic regimen.^{100 105 106 107 108 110 111 112 117 118 121 122 123 125 126 127 128 132 133 139} When administered cyclically, estrogen usually is given once daily for 3 weeks followed by 1 week without the drug; regimen is repeated as necessary.^{100 106 108 110 111}

Oral Administration

Administer 1–3 times daily.¹⁰⁶

IM Administration

Administer by deep IM injection into a large muscle mass.¹³²

Topical Administration

Transdermal Systems

Apply transdermal system to clean, dry, and not excessively hairy area of intact skin on the trunk (preferably abdomen or buttocks) by firmly pressing the system with the adhesive side touching the skin.^{100 101 102 105 108 110 111 112 123 125 136} Press system firmly in place with palm of hand for about 10 seconds, ensuring good contact, particularly around the edges.^{100 101 102 105 108 110 111 112 123 125 136} Application site should not be oily, damaged, or irritated.^{100 101 102 105 108 110 111 112 123 125 136} Do not apply transdermal system to the breasts; avoid application at waistline, since system could be rubbed off.^{100 102 105 108 110 111 112 123 125 136}

Apply system immediately after removal from its protective pouch and removal of the protective liner.^{100 102 105 108 110 111 112 123 125 136}

If system inadvertently comes off, reapply the system or, if necessary, apply a new system; in either case, continue the application schedule employed.^{100 102 105 108 110 111 112 123 125 136}

To minimize and/or prevent potential skin irritation, apply each transdermal system at a different site, with ≥1 week between applications to a particular site.^{100 101 102 105 106 108 110 111 112 123 125 136}

Apply estradiol transdermal systems once (Climara, Climara Pro, Estradiol Transdermal System [Mylan], Menostar) or twice (Alora, Combipatch, Estraderm, Vivelle, Vivelle-Dot) weekly; remove and discard the system in use, and apply a new system.^{100 101 102 105 108 110 111 112 123 125 136}

Transdermal systems for application twice weekly are commercially available in a dispensing package that is designed to aid user in complying with prescribed dosage regimen (same 2 days each week).^{100 101 102 108 110 111 112}

If system is not changed on designated day, replace it as soon as possible.^{100 102 105 106 108 110 111 112}

In women who are currently not receiving an oral estrogen, initiate transdermal therapy at any time.^{100 105 108 110 111 136} In women who are currently receiving an oral estrogen, initiate transdermal therapy 1 week after discontinuance of oral therapy (or sooner if symptoms reappear).^{100 105 108 110 111 136}

In women who are currently not receiving estrogen or estrogen/progestin therapy, initiate transdermal estradiol in fixed combination with a progestin (CombiPatch, Climara Pro) at any time.^{112 123} Women receiving estrogen or estrogen/progestin therapy should complete current cycle of therapy before initiating CombiPatch or Climara Pro.^{112 123}

Transdermal Spray

Apply transdermal spray (Evamist) once daily at the same time each day to clean, dry, intact skin on the inside of the forearm between the elbow and the wrist.¹³⁹ To apply estradiol transdermal spray, remove the cover, hold the applicator upright and place the cone section of the applicator flat against the skin and depress the pump.¹³⁹ Apply 1, 2, or 3 sprays to non-overlapping areas of the inner forearm, starting near the elbow.¹³⁹ Do not massage or rub application site.¹³⁹ Do not apply to any area other than the inner forearm; do not apply to breasts or around the vagina.¹³⁹

Allow application site to dry for up for 2 minutes before dressing.¹³⁹ Allow site to dry 30 minutes before washing the area.¹³⁹

Do not allow other individuals to have direct contact with the skin at the application site for at least 30 minutes following administration.^{139 141} Keep children and pets away from the skin at the application site to prevent inadvertent drug exposure.¹⁴⁰ If a child comes in direct contact with the application site, wash the general area of contact with soap and water as soon as possible.¹⁴⁰ If such contact with children cannot be avoided, advise patients to wear clothing with long sleeves to cover the application site.¹⁴⁰

Prime pump by holding applicator upright with the cover on and depressing pump 3 times before using the pump for the first dose.¹³⁹

Gel

Apply gel once daily at the same time each day to clean, dry, intact skin.^{122 124 137} To apply Elestrin, hold the pump with the tip facing the arm and depress the pump firmly and fully; apply the gel to the upper arm and shoulder using 2 fingers.¹³⁷ To apply EstroGel, collect the gel in the palm of the hand by pressing the pump firmly and fully; apply the gel to one arm from shoulder to wrist using the hand.¹²⁴ Do not apply to breasts^{124 137} or in or around the vagina.¹³⁷

Allow application site to dry for up for 5 minutes before dressing.^{124 137} Wash hands with soap and water after application of the gel.^{124 137}

Not known how long bathing and swimming should be delayed after application of the gel.^{122 124 137} Apply after bathing; the time between application and swimming should be as long as possible (at least 2 hours).^{124 137}

Elestrin: Prime pump by fully depressing the pump 10 times before using the pump for the first dose; discard gel so that household members or pets are not exposed to the gel.¹³⁷

EstroGel: Prime pump by fully depressing the 93-g pump twice or the 25-g pump 3 times before using the pump for the first dose; discard gel so that household members or pets are not exposed to the gel.¹²⁴

Emulsion

Apply emulsion to clean, dry skin every morning.¹²⁶ Open 1 pouch and place contents on left thigh; rub emulsion into entire thigh and calf for 3 minutes until absorbed; rub any excess on the buttocks.¹²⁶ Open another pouch and place contents on right thigh; rub emulsion into entire thigh and calf for 3 minutes until absorbed; rub any excess on the buttocks.¹²⁶

Allow application site to dry before dressing.¹²⁶ Wash hands with soap and water after application of the emulsion.¹²⁶

Vaginal Administration

Administer intravaginally as a vaginal ring (Estring, Femring), tablet (Vagifem), or cream (Estrace).^{107 113 117 134}

Vaginal ring should remain in place for 3 months.^{107 117} If ring is expelled, rinse with lukewarm water and reinsert.^{107 117}

Administer vaginal tablets at the same time each day.¹¹³

Dosage

Individualize dosage according to the condition being treated and the tolerance and therapeutic response of the patient.^{100 105 106 107 108 110 111 112 117 118 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

To minimize risk of adverse effects, use the lowest possible effective dosage.^{100 105 106 107 108 110 111 112 117 118 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139} Because of the potential increased risk of cardiovascular events, breast cancer, and venous thromboembolic events, limit estrogen and estrogen/progestin therapy to the lowest effective doses and shortest duration of therapy consistent with treatment goals and risks for the individual woman.^{100 105 106 107 108 110 111 112 117 118 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

Periodically reevaluate estrogen and estrogen/progestin therapy (i.e., at 3- to 6-month intervals).^{100 105 106 107 108 110 111 112 117 118 121 122 123 125 126 127 128 129 132 133 134 139}

Estradiol transdermal spray (Evamist): Each depression of the pump delivers 90 mcL of spray (1.53 mg of estradiol).¹³⁹ Pump delivers 56 sprays.¹³⁹

Estradiol 0.06% topical gel (Elestrin): Each depression of the pump delivers 0.87 g of gel (0.52 mg of estradiol).¹³⁷ Pump delivers 100 metered doses.¹³⁷

Estradiol 0.06% topical gel (EstroGel): Each depression of the pump delivers 1.25 g of gel (0.75 mg of estradiol).¹²² The pump containing 93 g of gel delivers 64 metered doses; the pump containing 25 g of gel delivers 14 doses.¹²²

Estradiol topical emulsion (Estrasorb): Each pouch contains 1.74 g of emulsion (4.35 mg of estradiol hemihydrate).¹²⁶

Adults

ERT

Vasomotor Symptoms

Oral

Estradiol: 1–2 mg daily in a cyclic regimen (3 weeks on, 1 week off).¹⁰⁶

Estradiol Acetate: Available in tablets containing 0.45, 0.9, or 1.8 mg of estradiol that are given once daily.¹³⁵ Initiate therapy with lowest dose.¹³⁵

Estradiol in fixed combination with norethindrone acetate (Activella): Estradiol 1 mg with norethindrone acetate 0.5 mg daily.¹²⁸

Estradiol in fixed combination with drospirenone (Angeliq): Estradiol 1 mg with drospirenone 0.5 mg daily.¹²⁷

Ethinyl estradiol in fixed combination with norethindrone acetate (FemHRT): Available as tablets containing ethinyl estradiol 2.5 mcg and norethindrone acetate 0.5 mg and ethinyl estradiol 5 mcg and norethindrone acetate 1 mg that are given once daily.¹³³ Initiate therapy with lowest dose.¹³³

Estradiol with norgestimate (Prefest): Estradiol 1 mg daily on days 1–3, then estradiol 1 mg with norgestimate 0.09 mg daily on days 4–6; repeat the pattern continuously.¹²⁹

IM

Estradiol cypionate: 1–5 mg every 3–4 weeks.¹²¹

Estradiol valerate: 10–20 mg every 4 weeks.¹³²

Estradiol cypionate in fixed combination with testosterone cypionate: Estradiol cypionate 2 mg with testosterone cypionate 50 mg every 4 weeks.¹¹⁸

Topical (estradiol transdermal system)

Estradiol (Alora, Estraderm): Initially, 1 system delivering 0.05 mg/24 hours twice weekly in a continuous regimen (women without a uterus) or cyclic regimen (women with a uterus).^{100 108}

Estradiol (Climara, Estradiol Transdermal System [Mylan]): Initially, 1 system delivering 0.025 mg/24 hours once weekly in a continuous regimen.^{105 136}

Estradiol (Vivelle, Vivelle-Dot): Initially, 1 system delivering 0.0375 mg/24 hours twice weekly in a continuous regimen (women without a uterus) or cyclic regimen (women with a uterus).^{110 111}

Topical (estradiol/progestin transdermal system)

Estradiol in fixed combination with norethindrone acetate (CombiPatch) continuous combined regimen: 1 system delivering 0.05 mg/24 hours of estradiol and 0.14 mg/24 hours of norethindrone acetate twice weekly in a continuous regimen.¹¹² If necessary, increase dosage of norethindrone acetate by using dosage system that delivers 0.25 mg/24 hours of norethindrone acetate.¹¹²

Estradiol in fixed combination with norethindrone acetate (CombiPatch) continuous sequential regimen: 1 system of transdermal estradiol delivering 0.05 mg/24 hours (i.e., Vivelle) twice weekly for the first 14 days of a 28-day cycle, then 1 estradiol/norethindrone acetate (CombiPatch) system delivering 0.05 mg/24 hours of estradiol and 0.14 mg/24 hours of norethindrone acetate twice weekly for the remaining 14 days of the cycle.¹¹² If necessary, increase dosage of norethindrone acetate by using dosage system that delivers 0.25 mg/24 hours of norethindrone acetate.¹¹²

Estradiol in fixed combination with levonorgestrel (Climara Pro) continuous combined regimen: 1 system delivering 0.045 mg/24 hours of estradiol and 0.015 mg/24 hours of levonorgestrel once weekly in a continuous regimen.¹²³

Topical (transdermal spray)

Estradiol (Evamist): Initially, 1 spray (1.53 mg of estradiol) once daily.¹³⁹ Adjust dose based on clinical response; 1, 2, or 3 sprays each morning can be used.¹³⁹

Topical (gel)

Estradiol 0.06% (Elestrin): Initially, apply 0.87 g of gel (0.52 mg of estradiol) once daily.¹³⁷ Adjust dosage as necessary.¹³⁷

Estradiol 0.06% (EstroGel): Apply 1.25 g of gel (0.75 mg of estradiol) once daily.¹²² Lowest effective dose not determined.¹²²

Topical (emulsion)

Estradiol (Estrasorb): Apply contents of 2 pouches (3.48 g of emulsion delivering 0.05 mg/24 hours) once daily.¹²⁶ Lowest effective dose not determined.¹²⁶

Vaginal

Estradiol acetate vaginal ring (Femring): Initially, 1 ring delivering estradiol 0.05 mg/24 hours inserted into the vaginal vault; ring should remain in place for 3 months.¹¹⁷ After 3 months, remove the ring and, if appropriate, replace with a new ring.¹¹⁷

Vulvar and Vaginal Atrophy

Oral

Estradiol: 1–2 mg daily in a cyclic regimen (3 weeks on, 1 week off).¹⁰⁶

Estradiol in fixed combination with norethindrone acetate (Activella): Estradiol 1 mg with norethindrone acetate 0.5 mg daily.¹²⁸

Estradiol in fixed combination with drospirenone (Angeliq): Estradiol 1 mg with drospirenone 0.5 mg daily.¹²⁷

Estradiol with norgestimate (Prefest): Estradiol 1 mg daily on days 1–3, then estradiol 1 mg with norgestimate 0.09 mg daily on days 4–6; repeat the pattern continuously.¹²⁹ This may not be the lowest effective dosage for this indication.¹²⁹

IM

Estradiol valerate: 10–20 mg every 4 weeks.¹³²

Topical (estradiol transdermal system)

Estradiol (Alora, Estraderm): Initially, 1 system delivering 0.05 mg/24 hours twice weekly in a continuous regimen (women without a uterus) or cyclic regimen (women with a uterus).^{100 108}

Estradiol (Vivelle, Vivelle-Dot): Initially, 1 system delivering 0.0375 mg/24 hours twice weekly in a continuous regimen (women without a uterus) or cyclic regimen (women with a uterus).^{110 111}

Topical (estradiol/progestin transdermal system)

Estradiol in fixed combination with norethindrone acetate (CombiPatch) continuous combined regimen: 1 system delivering 0.05 mg/24 hours of estradiol and 0.14 mg/24 hours of norethindrone acetate twice weekly in a continuous regimen.¹¹² If necessary, increase dosage of norethindrone acetate by using dosage system that delivers 0.25 mg/24 hours of norethindrone acetate.¹¹²

Estradiol in fixed combination with norethindrone acetate (CombiPatch) continuous sequential regimen: 1 system of transdermal estradiol delivering 0.05 mg/24 hours (i.e., Vivelle) twice weekly for the first 14 days of a 28-day cycle, then 1 estradiol/norethindrone acetate (CombiPatch) system delivering 0.05 mg/24 hours of estradiol and 0.14 mg/24 hours of norethindrone acetate twice weekly for the remaining 14 days of the cycle.¹¹² If necessary, increase dosage of norethindrone acetate by using dosage system that delivers 0.25 mg/24 hours of norethindrone acetate.¹¹²

Topical (gel)

Estradiol 0.06% (EstroGel): Apply 1.25 g of gel (0.75 mg of estradiol) once daily.¹²² Lowest effective dose not determined.¹²²

Vaginal

Estradiol vaginal ring (Estring): 1 ring delivering estradiol 0.0075 mg/24 hours inserted into the upper third of the vaginal vault; ring should remain in place for 3 months.¹⁰⁷ After 3 months, remove the ring and, if appropriate, replace with a new ring.¹⁰⁷

Estradiol acetate vaginal ring (Femring): Initially, 1 ring delivering estradiol 0.05 mg/24 hours inserted into the vaginal vault; ring should remain in place for 3 months.¹¹⁷ After 3 months, remove the ring and, if appropriate, replace with a new ring.¹¹⁷

Estradiol vaginal tablet (Vagifem): Initially, 25 mcg once daily for 2 weeks; maintenance, 25 mcg twice weekly.¹¹³

Estradiol vaginal cream (Estrace): Initially, 2–4 g of 0.01% cream daily for 1–2 weeks; reduce to one-half the initial dosage for 2 weeks.¹³⁴ Maintenance, 1 g 1 to 3 times weekly.¹³⁴

Osteoporosis

Prevention in Postmenopausal Women

Oral

Estradiol: 0.5 mg daily in a cyclic regimen has been used.¹⁰⁶ Lowest effective dose not determined.¹⁰⁶

Estradiol in fixed combination with norethindrone acetate (Activella): Estradiol 1 mg with norethindrone acetate 0.5 mg daily.¹²⁸ This may not be the lowest effective dosage.¹²⁸

Estradiol with norgestimate (Prefest): Estradiol 1 mg daily on days 1–3, then estradiol 1 mg with norgestimate 0.09 mg daily on days 4–6; repeat the pattern continuously.¹²⁹ This may not be the lowest effective dosage.¹²⁹

Ethinyl estradiol in fixed combination with norethindrone acetate (FemHRT): Available as tablets containing ethinyl estradiol 2.5 mcg and norethindrone acetate 0.5 mg and ethinyl estradiol 5 mcg and norethindrone acetate 1 mg that are given once daily.¹³³ Initiate therapy with lowest dose.¹³³

Topical (estradiol transdermal system)

Estradiol (Alora, Vivelle, Vivelle-Dot): Initially, 1 system delivering 0.025 mg/24 hours twice weekly in a continuous regimen (women without a uterus) or cyclic regimen (women with a uterus).^{108 110 111} Adjust dosage as necessary.^{108 110 111}

Estradiol (Climara): Initially, 1 system delivering 0.025 mg/24 hours once weekly in a continuous regimen.¹⁰⁵ Adjust dosage based on biochemical markers and BMD.¹⁰⁵

Estradiol (Estraderm): Initially, 1 system delivering 0.05 mg/24 hours twice weekly in a continuous regimen (women without a uterus) or cyclic regimen (women with a uterus).¹⁰⁰ Adjust dosage as necessary.¹⁰⁰

Estradiol (Menostar): 1 system delivering 0.014 mg/24 hours once weekly in a continuous regimen.¹²⁵

Topical (estradiol/progestin transdermal system)

Estradiol in fixed combination with levonorgestrel (Climara Pro) continuous combined regimen: 1 system delivering 0.045 mg/24 hours of estradiol and 0.015 mg/24 hours of levonorgestrel once weekly in a continuous regimen.¹²³

Hypoestrogenism

Oral

Estradiol: 1–2 mg daily; adjust dosage as necessary to control symptoms.¹⁰⁶

IM

Estradiol cypionate: 1.5–2 mg every month.¹²¹

Estradiol valerate: 10–20 mg every 4 weeks.¹³²

Metastatic Breast Carcinoma

Oral

Estradiol: 10 mg 3 times daily for ≥3 months.¹⁰⁶

Prostate Carcinoma

Oral

Estradiol: 1–2 mg 3 times daily.¹⁰⁶

IM

Estradiol valerate: ≥30 mg every 1–2 weeks.¹³²

Cautions for Estradiol (Systemic, Local)

Contraindications

• Undiagnosed abnormal genital bleeding.^{100 105 106 107 108 110 111 112 113 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

• Known or suspected breast cancer or history of breast cancer (except when used for palliative treatment of metastatic disease in appropriately selected individuals).^{100 105 106 107 108 110 111 112 113 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

• Known or suspected estrogen-dependent neoplasia.^{100 105 106 107 108 110 111 112 113 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

• Active DVT or pulmonary embolism; history of DVT or pulmonary embolism.^{100 105 106 107 108 110 111 112 113 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

• Active or recent (within past year) arterial thromboembolic disease (e.g., stroke, MI).^{100 105 106 107 108 110 111 112 113 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

• Porphyria.¹¹³

• Liver disease or impairment.^{100 105 106 107 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

• Known or suspected pregnancy.^{100 105 106 107 108 110 111 112 113 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

• Known hypersensitivity to estrogens or any ingredient in the formulation.^{100 105 106 107 108 110 111 112 113 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137}

• Estradiol in fixed combination with drospirenone (Angeliq) should not be used in women predisposed to hyperkalemia (i.e., those with renal impairment, hepatic impairment, or adrenal insufficiency).¹²⁷

Warnings/Precautions

Warnings

Cardiovascular Disorders

Estrogen/progestin therapy associated with increased risk of MI, stroke, DVT, and pulmonary embolism.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139} Estrogen therapy associated with increased risk of stroke and DVT.^{137 139} (See Boxed Warning.) Discontinue estrogens immediately if any of these events occur or are suspected.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139} Use of ERT or HRT is not advised in women with a history of stroke or transient ischemic attacks.^bbb

Appropriately manage risk factors for cardiovascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, obesity) and/or venous thromboembolism (personal or family history of venous thromboembolism, obesity, systemic lupus erythematosus).^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

Discontinue estrogens, whenever feasible, at least 4–6 weeks prior to surgery that is associated with an increased risk of thromboembolism or during prolonged immobilization.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139 gg}

Endometrial Cancer

Use of unopposed estrogen therapy in women who have a uterus is associated with increased risk of endometrial cancer.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139} Clinical surveillance and evaluation are essential.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139} Perform diagnostic tests to rule out malignancy in women with undiagnosed, persistent or recurring abnormal vaginal bleeding.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

Incidence of endometrial hyperplasia is reduced substantially when progestins are used concomitantly.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139 n r s t u}

Breast Cancer

ERT not associated with increased risk of breast cancer.^{139 qq aaa fff}

HRT associated with increased risk of breast cancer.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139 o p q hh ii jj}

All postmenopausal women should receive yearly breast examinations by a clinician and perform monthly self-examinations.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139} Schedule periodic mammography based on patient age and risk factors.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

Dementia

ERT or HRT in women ≥65 years of age has been associated with increased risk of developing probable dementia.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139 yy zz ccc ddd} Whether these findings apply to younger women is unknown.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139 yy zz}

Gallbladder Disease

ERT associated with increased risk of gallbladder disease requiring surgery.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

Hypercalcemia

Estrogens may cause severe hypercalcemia in patients with breast cancer and bone metastases.^{100 105 106 107 108 110 111 112 113 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139} Discontinue the drug and initiate appropriate measures to reduce serum calcium concentrations if hypercalcemia occurs.^{100 105 106 107 108 110 111 112 113 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

Ocular Effects

Retinal thrombosis reported.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139} Discontinue pending examination if sudden partial or complete loss of vision, or sudden onset of proptosis, diplopia, or migraine occurs.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139} Discontinue estrogen if papilledema or retinal vascular lesions noted on examination.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

Flammability

Alcohol-based preparations (e.g., Elestrin, EstroGel, Evamist) are flammable.^{122 137 139} Avoid flames, fire, and cigarettes until gel or spray has dried.^{122 137 139}

General Precautions

Elevated BP

Rarely, substantial increases in BP attributed to idiosyncratic reactions to estrogen.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139} ERT generally is not associated with elevated BP.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139 d e g h} Monitor BP at regular intervals.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139 d e g h}

Hypertriglyceridemia

Estrogen therapy may be associated with increases in plasma triglyceride concentrations resulting in pancreatitis in women with increased serum lipids.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

Fluid Retention

Estrogens may cause some degree of fluid retention; use with caution and careful monitoring in patients with conditions that might be aggravated by fluid retention (e.g., cardiac or renal impairment).^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

Hypocalcemia

Use with caution in patients with severe hypocalcemia.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

Ovarian Cancer

Long-term estrogen therapy associated with increased incidence of ovarian cancer in some epidemiologic studies.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139} Other studies did not show a clinically important association.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

Endometriosis

Estrogens may exacerbate endometriosis.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

Malignant transformation of residual endometrial implants reported rarely in women receiving unopposed estrogen following hysterectomy.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139} Consider the addition of progestin in women with residual endometriosis following hysterectomy.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

Other Conditions

Estrogens may exacerbate asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas; use with caution in patients with these conditions.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

Precautions Specific to Topical Administration

Whether topical application of estradiol gel is associated with photosensitivity or photoallergy not evaluated.^{122 137}

Topical application of estradiol emulsion or estradiol gel (Elestrin) in close proximity to application of sunscreen increases estradiol absorption.^{126 137}

FDA is reviewing reports of adverse effects with estradiol transdermal spray (Evamist) in children and pets following possible inadvertent drug exposure through skin contact with women receiving the drug.¹⁴⁰ Children exposed to the drug may experience signs of premature puberty (e.g., nipple swelling and breast development in females, breast enlargement in males).¹⁴⁰ If such a child shows signs of premature puberty (e.g., nipple or breast swelling, breast tenderness or enlargement), advise the parents to contact the child’s clinician and to inform the clinician of the child’s possible exposure to the drug.¹⁴⁰

Application of estradiol transdermal spray (Evamist) before application of sunscreen results in a slight decrease in estradiol absorption.¹³⁹

Precautions Specific to Vaginal Administration

Estradiol vaginal ring (Estring) may not be suitable for women with narrow, short, or stenosed vaginas; such patients may be more susceptible to ulceration or irritation associated with the ring.¹⁰⁷ Remove Estring during treatment with other vaginally administered preparations.¹⁰⁷

Estradiol acetate vaginal ring (Femring) may not be suitable for women with conditions that predispose the vagina to irritation or ulceration or make ring expulsion more likely (i.e., narrow or stenosed vagina, vaginal infection, cervical prolapse, rectoceles and cystoceles).¹¹⁷ If local therapy for a vaginal infection is needed, Femring can remain in place during such therapy.¹¹⁷

Tartrazine Sensitivity

Estrace 2-mg tablets contain tartrazine (FD&C yellow No. 5), which may cause allergic reactions including bronchial asthma in susceptible individuals.¹⁰⁶ Incidence of tartrazine sensitivity is low, but it frequently occurs in patients who are sensitive to aspirin.¹⁰⁶

Chlorobutanol

Depo-Estradiol and Depo-Testadiolcontain chlorobutanol anhydrous as a preservative; chlorobutanol can be habit forming.^{118 121}

Combination Therapy

If used in fixed combination with testosterone cypionate, drospirenone, levonorgestrel, norgestimate, or norethindrone acetate or in conjunction with a progestin, consider the precautions, cautions, and contraindications associated with the concomitant agent.^{112 118 123 127 128 129 133}

Specific Populations

Pregnancy

Category X.^{100 105 106 107 108 110 111 112 113 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

In utero exposure of females to diethylstilbestrol (DES [no longer commercially available in US]), is associated with increased risk of vaginal adenosis, squamous cell dysplasia of the cervix, or clear-cell vaginal cancer in later life.^b

In utero exposure of males is associated with an increased risk of genital abnormalities and possibly testicular cancer later in life.^b

Women who receive DES during pregnancy may be at increased risk of breast cancer; causal relationship unproven.^b

Lactation

Administration of estrogens to nursing women has been associated with decreased amounts and lower quality of milk.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139} Detectable amounts of estrogens have been identified in milk of women receiving these drugs.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139} Caution advised.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137}

Pediatric Use

Estrogen therapy has been used for induction of puberty in adolescents with some forms of pubertal delay.^{100 105 106 108 110 111 134 136} Safety and efficacy of estrogens in children not otherwise established.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137}

Use estrogen therapy with caution and careful monitoring when bone growth is not yet complete, since estrogens may cause premature epiphyseal closure.^{100 105 106 108 110 111 134 136}

Estrogen therapy in prepubertal girls induces premature breast development and vaginal cornification and may induce vaginal bleeding.^{100 105 106 108 110 111 134 136} Estrogen therapy in boys may modify the normal pubertal process.^{100 105 106 108 110 111 134 136}

Geriatric Use

Insufficient experience with many estradiol-containing preparations in geriatric patients to determine whether geriatric patients respond differently than younger women.^{100 105 108 113 117 122 123 126 127 128 129 132 133 134 135 136 137 139} Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential concomitant disease and drug therapy.^{100 106 108 113 117}

Possible increased risk of developing probable dementia in women ≥65 years of age.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139 yy zz ccc ddd}

No substantial differences in safety and efficacy of Estring in women ≥65 years of age compared with younger women; possibility of greater sensitivity to the drug in some geriatric individuals.¹⁰⁷

No substantial differences in safety and efficacy of Menostar in women ≥65 years of age compared with younger women.¹²⁵

Hepatic Impairment

Estrogens may be poorly metabolized in patients with hepatic impairment.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

Caution advised in patients with a history of cholestatic jaundice associated with previous estrogen use or with pregnancy; discontinue if jaundice recurs.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

Renal Impairment

Use with caution.^{100 105 106 108 110 111 112 113 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139} (See Fluid Retention under Cautions.)

Common Adverse Effects

Abdominal pain, leg cramps, headache, breast tenderness, vaginal hemorrhage, vaginal moniliasis, skin irritation (transdermal preparations).^{100 105 106 107 108 110 111 112 113 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

Drug Interactions

Appears to be metabolized partially by CYP3A4.^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137}

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased plasma estrogen concentrations).^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137}

CYP3A4 inducers: Potential pharmacokinetic interaction (decreased plasma estrogen concentrations).^{100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137}

Specific Drugs and Foods

Estradiol (Systemic, Local) Pharmacokinetics

Absorption

Bioavailability

Estradiol is well absorbed through skin and mucous membranes and from the GI tract.^{100 105 106 107 108 110 111 112 113 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137}

Elestrin: Application of sunscreen 10 minutes before application of Elestrin increased estradiol exposure by 55%; application of sunscreen 25 minutes after application of Elestrin did not alter estradiol exposure.¹³⁷ Application of sunscreen for 7 days increased estradiol exposure 2-fold; this effect noted when sunscreen applied before and after application of Elestrin.¹³⁷

Estrasorb: Application of sunscreen 10 minutes before application of Estrasorb increases exposure to estradiol by 35%; application of sunscreen 25 minutes after application of Estrasorb increases exposure to estradiol by 15%.¹²⁶

Evamist: Application of sunscreen 1 hour after application of Evamist decreased estradiol absorption by 11%; application of sunscreen 1 hour before application of Evamist did not alter absorption to estradiol.¹³⁹

Topical, vaginal, and IM administration circumvent first-pass metabolism.^{106 112 113 121 122 123 125 132 134}

Single IM injections of estradiol cypionate or estradiol valerate oil solutions: Absorption begins promptly and continues for several days.^{106 121 b}

Food

Activella: Food does not affect bioavailability of estradiol.¹²⁸

Femtrace: Food does not affect AUC of estradiol.¹³⁵

Prefest: High-fat meal does not substantially affect systemic availability of estradiol.¹²⁹

Distribution

Extent

Widely distributed; highest concentrations found in sex hormone target organs.^{105 110 111 123 125 126 127 128 129 139}

Plasma Protein Binding

50–80%.^b

Elimination

Metabolism

Metabolized in the liver; the kidney, gonads, and muscle tissue involved to some extent.^b Estrogens metabolized partially by CYP3A4.^{111 117 123 125 126 127 128 129}

Extensive metabolic conversion takes place in the liver (e.g., estradiol converted to estrone, both converted to estriol).^{105 110 111 117 123 125 126 127 128 129}

Estrogens undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption.^{105 110 111 117 128}

Elimination Route

Estradiol, estrone, and estriol and their metabolites excreted mainly in urine.^{105 110 111 117 123 125 126 127 128 129 139}

Half-life

Estradiol: 2–3 hours.¹¹²

Estradiol transdermal systems: Approximately 2–7.5 hours reported.^{105 108 110 111}

Estradiol 0.06% gel (EstroGel): 36 hours.¹²²

Estradiol cypionate IM: 5 days.¹¹⁸

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).^{106 127 128 129 133 135} Protect from light.^{106 128 129}

Parenteral

Injection

Room temperature.^{118 121 132} Storage at lower temperatures may result in formation of crystals, which redissolve on warming.^{118 121 132}

Topical

Transdermal System

Generally <30°C.^{100 105 110 123 125 136}

CombiPatch: 2–8°C before dispensing; may store at 25°C for up to 6 months.¹¹²

Transdermal Spray

Evamist: 25°C (may be exposed to 15–30°C).¹³⁹ Do not freeze.¹³⁹

Gel and Emulsion

20–25°C (may be exposed to 15–30°C).^{122 126 137}

Vaginal

Tablets

25°C (may be exposed to 15–30°C).¹¹³

Ring

25°C (may be exposed to 15–30°C).^{107 117}

Cream

Room temperature (<40°C).¹³⁴

Actions

• Estradiol is the principal and most active endogenous estrogen.^a Estradiol may be obtained from natural sources or prepared synthetically.^a

• Ethinyl estradiol is one of the most potent synthetic estrogens.^a

• Exogenous estrogens elicit, to varying degrees, all the pharmacologic responses usually produced by endogenous estrogens.^a

Advice to Patients

• Importance of providing patient a copy of the manufacturer’s patient information.^{100 105 106 107 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139 140}

• Risk of cancer of the uterus in postmenopausal women.^{100 105 106 107 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139} Importance of reporting any unusual vaginal bleeding to clinicians.^{100 105 106 107 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

• Risk of MI, stroke, breast cancer, and venous thromboembolism.^b Importance of not using estrogens to prevent heart disease, MI, or strokes.^b

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{100 105 106 107 108 110 111 112 113 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

• Importance of instructing patients in the proper disposal of estradiol preparations (e.g., unused gel, transdermal systems).^{122 123 125 137 139}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.^{100 105 106 107 108 110 111 112 113 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139}

• Elestrin: Important of not applying sunscreen until at least 25 minutes after application of the gel; importance of not applying sunscreen for 7 consecutive days to the area where the gel is applied.¹³⁷ Importance of avoiding fire, flames, and smoking until gel has dried.¹³⁷

• Estrasorb: Importance of not applying the emulsion in close proximity to application of sunscreen.¹²⁶

• EstroGel: Importance of avoiding fire, flames, and smoking until gel has dried.¹²²

• Evamist: Risk of inadvertent exposure in children and pets through skin contact with women receiving the drug.¹⁴⁰ Importance of informing patients to avoid direct contact with others at the application site.¹³⁹ Importance of parents contacting a clinician if a child shows signs of premature puberty and to inform the clinician of the child’s possible exposure to the drug.¹⁴⁰ Importance of avoiding fire, flames, and smoking until spray has dried.¹³⁹

• Importance of informing patients of other important precautionary information.^{100 105 106 107 108 110 111 112 113 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139} (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Most preparations containing androgenic anabolic steroid hormones are subject to control under the Federal Controlled Substances Act of 1970, as amended by the Anabolic Steroids Control Act of 1990 and 2004, as schedule III (C-III) drugs.^{103 131} However, manufacturers of certain preparations containing androgenic anabolic steroids (principally combinations that also include estrogens) have applied for and obtained for their product(s) an exemption from the record-keeping and other regulatory requirements of the Federal Controlled Substances Act.^{104 130} Because regulatory requirements for a given preparation containing an androgenic anabolic steroid may be subject to change under the provisions of the Act, the manufacturer should be contacted when specific clarification about a preparation’s status is required.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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