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Estradiol

Pronunciation

Class: Estrogens
VA Class: GU500
CAS Number: 50-28-2
Brands: Activella, Alora, Angeliq, Climara, Climara Pro, CombiPatch, Delestrogen, Depo-Estradiol, Depo-Testadiol, Elestrin, Estrace, EstroGel, Estraderm, Estrasorb, Estring, Evamist, FemHRT, Femring, Femtrace, Menostar, Prefest, Vagifem, Vivelle, Vivelle-Dot

Warning(s)

Introduction

Steroidal estrogen; a principal endogenous estrogen.a

Uses for Estradiol

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 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

Slideshow: View Frightful (But Dead Serious) Drug Side Effects

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. Formerly recommended as first-line therapy; however, recommendations on appropriate use of HRT have been revised based on WHI study findings. (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.

Has been used in a limited number of anorexic women with chronic amenorrhea to reduce calcium loss and, thereby, reduce risk of osteoporosis.

Corticosteroid-induced Osteoporosis

Has been used to prevent bone loss in postmenopausal women receiving low- to moderate-dose corticosteroid therapy.

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

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 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

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. 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.

Initiation of ERT or HRT in women ≥65 years of age not associated with an improvement in cognitive function. 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. Incidence of probable dementia in women receiving ERT or HRT was higher than that in women receiving placebo. Use of ERT or HRT to prevent dementia or cognitive decline in women ≥65 years of age is not recommended.

Postpartum Breast Engorgement

Used in the past for prevention of postpartum breast engorgement; FDA has withdrawn approval of estrogen-containing drugs for this indication, since estrogens have not been shown to be safe for this use.a (See Lactation under Cautions.)

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 (See Pregnancy under Cautions.)

Estradiol 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 (See Precautions Specific to Topical Administration under Cautions.) 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 breasts124 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

Contraindications

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. (See Contraindications under Cautions.)

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 (See Contraindications under Cautions.)

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

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

Breast Cancer

ERT not associated with increased risk of breast cancer.139

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

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 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 (See Alzheimer’s Disease under Uses.)

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 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

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 (See Specific Drugs and Foods under Interactions and see Absorption under Pharmacokinetics.)

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 (See Absorption under Pharmacokinetics.)

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 (See Contraindications under Cautions.)

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 (See Dementia under Cautions.)

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 (See Contraindications under Cautions.)

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

Interactions for Estradiol

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

Drug or Food

Interaction

Comments

Anticoagulants, oral

Possible decreased anticoagulant actionb

Monitor; increase warfarin dosage it requiredb

Antifungals, azoles (itraconazole, ketoconazole)

Possible increased plasma estrogen concentrations; increased potential for adverse effects100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137

Carbamazepine

Possible decreased plasma estrogen concentrations; potential for decrease in therapeutic effects and/or changes in uterine bleeding100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137

Corticosteroids

Enhanced anti-inflammatory effects of hydrocortisone in patients with chronic inflammatory skin diseaseb

Observe for signs of excessive corticosteroid effects; adjust corticosteroid dosage when initiating or discontinuing estrogenb

Drugs that increase serum potassium concentrations (ACE inhibitors, angiotension II type 1 receptor antagonists, potassium-sparing diuretics, heparin)

Potential for increased serum potassium concentrations with estradiol in fixed combination with drospirenone (Angeliq)127

Angeliq: Monitor serum potassium concentrations during the first treatment cycle in high-risk women127

Grapefruit juice

Possible increased plasma estrogen concentrations; increased potential for adverse effects100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137

Macrolide antibiotics (clarithromycin, erythromycin)

Possible increased plasma estrogen concentrations; increased potential for adverse effects100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137

Norethindrone

Interaction unlikely128

Norgestimate

Decreased plasma concentrations of estradiol and estrone; increased plasma concentrations of estrone sulfate129

Clinical importance unknown129

Phenobarbital

Possible decreased plasma estrogen concentrations; potential for decrease in therapeutic effects and/or changes in uterine bleeding100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137

Rifampin

Possible decreased plasma estrogen concentrations; potential for decrease in therapeutic effects and/or changes in uterine bleeding100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137

Ritonavir

Possible increased plasma estrogen concentrations; increased potential for adverse effects100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137

St. John’s wort (Hypericum perforatum)

Possible decreased plasma estrogen concentrations; potential for decrease in therapeutic effects and/or changes in uterine bleeding100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137

Sunscreen

Application of sunscreens may affect pharmacokinetics of some topically applied estradiol preparations.122 126 137 139

Elestrin: Apply sunscreen at least 25 minutes after application of Elestrin; do not apply sunscreen for ≥7 consecutive days to area where Elestrin is applied137

EstroGel: Concomitant use of sunscreen not evaluated122

Estrasorb: Do not apply in close proximity to sunscreen application126

Thyroid agents

Increased thyroid-binding globulin concentrations100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137

Increased dosages of thyroid replacement agents may be needed; monitor thyroid function100 105 106 108 110 111 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137

Estradiol 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

Preparations

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

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 (See Uses: Misuse and Abuse, in Testosterone 68:08.) 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 (See the introductory paragraph under Preparations, in Testosterone 68:08.) 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.

Estradiol

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Topical

Gel

0.06%

Elestrin (with alcohol)

Kenwood Therapeutics

EstroGel (with alcohol)

Ascend Therapeutics

Solution

1.53 mg/meter spray

Evamist (with alcohol)

Ther-Rx

Transdermal System

0.014 mg/24 hours (1 mg/3.25 cm2)

Menostar

Berlex

0.025 mg/24 hours (0.77 mg/9 cm2)

Alora

Watson

0.025 mg/24 hours (2 mg/6.5 cm2)

Climara

Berlex

0.025 mg/24 hours (0.97 mg/7.75 cm2)

Estradiol Transdermal System (once weekly)

Mylan

0.025 mg/24 hours (2.17 mg/7.25 cm2)

Vivelle (with propylene glycol)

Novartis

0.025 mg/24 hours (0.39 mg/2.5 cm2)

Vivelle-Dot (with povidone)

Novartis

0.0375 mg/24 hours (2.85 mg/9.375 cm2)

Climara

Berlex

0.0375 mg/24 hours (1.46 mg/11.625 cm2)

Estradiol Transdermal System (once weekly)

Mylan

0.0375 mg/24 hours (3.28 mg/11 cm2)

Vivelle (with propylene glycol)

Novartis

0.0375 mg/24 hours (0.585 mg/3.75 cm2)

Vivelle-Dot (with povidone)

Novartis

0.05 mg/24 hours (1.5 mg/18 cm2)

Alora

Watson

0.05 mg/24 hours (3.8 mg/12.5 cm2)

Climara

Berlex

0.05 mg/24 hours (4 mg/10 cm2)

Estraderm (with alcohol)

Novartis

0.05 mg/24 hours (1.94 mg/15.5 cm2)

Estradiol Transdermal System (once weekly)

Mylan

0.05 mg/24 hours (4.33 mg/14.5 cm2)

Vivelle (with propylene glycol)

Novartis

0.05 mg/24 hours (0.78 mg/5 cm2)

Vivelle-Dot (with povidone)

Novartis

0.06 mg/24 hours (4.55 mg/15 cm2)

Climara

Berlex

0.06 mg/24 hours (2.33 mg/18.6 cm2)

Estradiol Transdermal System (once weekly)

Mylan

0.075 mg/24 hours (2.3 mg/27 cm2)

Alora

Watson

0.075 mg/24 hours (5.7 mg/18.75 cm2)

Climara

Berlex

0.075 mg/24 hours (2.91mg/23.25 cm2)

Estradiol Transdermal System (once weekly)

Mylan

0.075 mg/24 hours (6.57 mg/22 cm2)

Vivelle (with propylene glycol)

Novartis

0.075 mg/24 hours (1.17 mg/7.5 cm2)

Vivelle-Dot (with povidone)

Novartis

0.1 mg/24 hours (3 mg/36 cm2)

Alora

Watson

0.1 mg/24 hours (7.6 mg/25 cm2)

Climara

Berlex

0.1 mg/24 hours (8 mg/20 cm2)

Estraderm (with alcohol)

Novartis

0.1 mg/24 hours (3.88 mg/31 cm2)

Estradiol Transdermal System (once weekly)

Mylan

0.1 mg/24 hours (8.66 mg/29 cm2)

Vivelle (with propylene glycol)

Novartis

0.1 mg/24 hours (1.56 mg/10 cm2)

Vivelle-Dot (with povidone)

Novartis

Vaginal

Cream

0.01%

Estrace (with methylparaben and propylene glycol)

Warner Chilcott

Ring

2 mg/ring (0.0075 mg/24 hours)

Estring

Pfizer

Estradiol Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, biphasic regimen

1 mg (15 tablets) and 1 mg with Norgestimate 0.09 mg (15 tablets)

Prefest

Barr

Tablets, film-coated

1 mg with Norethindrone Acetate 0.5 mg

Activella (28 tablets)

Novo Nordisk

1 mg with Drospirenone 0.5 mg

Angeliq (28 tablets; with povidone)

Berlex

Topical

Transdermal System

0.045 mg and 0.015 mg Levonorgestrel/24 hours (4.4 mg and 1.39 mg Levonorgestrel/22 cm2)

Climara Pro

Berlex

0.05 mg and 0.14 mg Norethindrone Acetate/24 hours (0.62 mg and 2.7 mg Norethindrone Acetate/9 cm2)

CombiPatch

Novartis

0.05 mg and 0.25 mg Norethindrone Acetate/24 hours (0.51 mg and 4.8 mg Norethindrone Acetate/16 cm2)

CombiPatch

Novartis

Estradiol (Hemihydrate)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Topical

Emulsion

0.25%

Estrasorb

Espirit

Vaginal

Tablets, film-coated

25 mcg (of estradiol)

Vagifem (available as disposable applicators)

NovoNordisk

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

Estradiol (Micronized)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

0.5 mg*

Estrace (scored)

Warner Chilcott

1 mg*

Estrace (scored)

Warner Chilcott

2 mg*

Estrace (with tartrazine; scored)

Warner Chilcott

Estradiol Acetate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

0.45 mg

Femtrace (with povidone)

Warner Chillcott

0.9 mg

Femtrace (with povidone)

Warner Chillcott

1.8 mg

Femtrace (with povidone)

Warner Chilcott

Vaginal

Ring

12.4 mg/ring (0.05 mg estradiol/24 hours)

Femring

Warner Chilcott

24.8 mg/ring (0.1 mg estradiol/24 hours)

Femring

Warner Chilcott

Estradiol Cypionate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection (in oil)

5 mg/mL

Depo-Estradiol (with chlorobutanol)

Pfizer

Estradiol Cypionate Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection (in oil)

2 mg/mL with Testosterone Cypionate 50 mg/mL

Depo-Testadiol (with chlorobutanol)

Pfizer

Estradiol Valerate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection (in oil)

10 mg/mL

Delestrogen (with chlorobutanol)

Monarch

20 mg/mL

Delestrogen (with benzyl alcohol)

Monarch

40 mg/mL

Delestrogen (with benzyl alcohol)

Monarch

Ethinyl Estradiol Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

2.5 mcg with Norethindrone Acetate 0.5 mg

FemHRT

Warner Chillcott

5 mcg with Norethindrone Acetate 1 mg

FemHRT

Warner Chillcott

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Alora 0.05MG/24HR Patches (WATSON LABS): 8/$67.83 or 24/$186.53

Alora 0.08MG/24HR Patches (WATSON LABS): 8/$69.96 or 24/$202.46

Alora 0.1MG/24HR Patches (WATSON LABS): 8/$70.99 or 24/$197.97

Climara 0.025MG/24HR Patches (BAYER HEALTHCARE PHARMA): 4/$94.99 or 12/$264.96

Climara 0.0375MG/24HR Patches (BAYER HEALTHCARE PHARMA): 4/$97.99 or 12/$272.92

Climara 0.05MG/24HR Patches (BAYER HEALTHCARE PHARMA): 4/$95.99 or 12/$272.92

Climara 0.06MG/24HR Patches (BAYER HEALTHCARE PHARMA): 4/$97.99 or 12/$272.92

Climara 0.075MG/24HR Patches (BAYER HEALTHCARE PHARMA): 4/$94.99 or 12/$264.96

Climara 0.1MG/24HR Patches (BAYER HEALTHCARE PHARMA): 4/$97.99 or 12/$272.98

Divigel 0.25MG/0.25GM Gel (UPSHER-SMITH): 30/$85.99 or 90/$239.96

Divigel 0.5MG/0.5GM Gel (UPSHER-SMITH): 30/$86.99 or 90/$234.97

Divigel 1MG/GM Gel (UPSHER-SMITH): 30/$84.99 or 90/$235.96

Estrace 0.1MG/GM Cream (WARNER CHILCOTT PROF PROD DIV): 43/$135.99 or 128/$389.98

Estraderm 0.1MG/24HR Patches (NOVARTIS): 8/$77.99 or 24/$204.96

Estradiol 0.025MG/24HR Patches (MYLAN): 4/$65.99 or 12/$175.96

Estradiol 0.0375MG/24HR Patches (ALVOGEN): 4/$69.99 or 12/$179.96

Estradiol 0.05MG/24HR Patches (MYLAN): 4/$61.99 or 12/$165.97

Estradiol 0.06MG/24HR Patches (MYLAN): 4/$63.97 or 12/$159.91

Estradiol 0.075MG/24HR Patches (MYLAN): 4/$61.99 or 12/$165.97

Estradiol 0.1MG/24HR Patches (MYLAN): 4/$68.99 or 12/$186.97

Estrasorb 4.35MG/1.74GM Emulsion (GRACEWAY PHARMACEUTICALS): 111/$69.98 or 336/$189.98

Estrogel 0.75 MG/1.25 GM(0.06%) Gel (ASCEND THERAPEUTICS): 50/$89.99 or 150/$252.96

Evamist 1.53MG/SPRAY Solution (THER RX): 8/$89.99 or 16/$177.98

Menostar 14MCG/24HR Patches (BAYER HEALTHCARE PHARMA): 4/$97.99 or 12/$275.98

Vivelle-Dot 0.025MG/24HR Patches (NOVARTIS): 8/$75.99 or 24/$204.96

Vivelle-Dot 0.0375MG/24HR Patches (NOVARTIS): 8/$72.99 or 24/$198.97

Vivelle-Dot 0.05MG/24HR Patches (NOVARTIS): 8/$71.99 or 24/$195.98

Vivelle-Dot 0.075MG/24HR Patches (NOVARTIS): 8/$71.99 or 24/$195.98

Vivelle-Dot 0.1MG/24HR Patches (NOVARTIS): 8/$72.99 or 24/$195.98

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 1, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

100. Novartis. Estraderm (estradiol transdermal system) prescribing information. East Hanover, NJ; 2006 May.

101. Ciba Pharmaceutical Company. Estraderm to replace your body’s own estrogen: questions and answers. Publication No. 109-7682-A. Summit, NJ; 1986 Jun.

102. Ciba Pharmaceutical Company. Estraderm information for the patient. Summit, NJ; 1987 Feb.

103. Drug Enforcement Administration (DEA), Department of Justice. Schedules of controlled substances: anabolic steroids. Final rule. [21 CFR Part 1308] Fed Regist. 1991; 56:5753-4.

104. Drug Enforcement Administration (DEA), Department of Justice. Schedules of controlled substances: exempt anabolic products. Final rule. [21 CFR Part 1308] Fed Regist. 1992; 57:55090-1.

105. Berlex. Climara (estradiol transdermal system) prescribing information. Montville, NJ: 2005 Jul.

106. Warner Chilcott. Estrace (estradiol tablets) prescribing information. Rockaway, NJ; 2005 Dec.

107. Pfizer. Estring (estradiol vaginal ring) prescribing information. New York, NY; 2006 Jun.

108. Watson Pharma. Alora (estradiol transdermal system) prescribing information. Corona, CA; 2005 May.

109. Pfizer & Upjohn. Lunelle Monthly Contraceptive Injection (medroxyprogesterone acetate and estradiol cypionate) prescribing information. Kalamazoo, MI; 2000 Oct.

110. Novartis. Vivelle (estradiol transdermal system) prescribing information (dated 2004 Aug). From PDR Electronic Library.

111. Novartis. Vivelle-Dot (estradiol transdermal system) prescribing information. East Hanover, NJ; 2004 Aug.

112. Novartis. Combipatch (estradiol /norethindrone acetate transdermal system) prescribing information. East Hanover, NJ; 2005 Nov.

113. Novo Nordisk. Vagifem (estradiol vaginal tablets) prescribing information. Princeton, NJ; 2003 Jul.

114. U.S. Preventive Services Task Force. Postmenopausal hormone replacement therapy for primary prevention of chronic conditions: recommendations and rationale. Ann Intern Med. 2002; 137:834-9.

115. American College of Obstetricians and Gynecologists. Questions and answers on hormone replacement therapy. Washington DC; August 2002. From the American College of Obstetricians and Gynecologists web site.

116. American Heart Association. Q & A about hormone replacement therapy. November 20, 2002. From the American Heart Association web site.

117. Warner Chilcott. Femring (estradiol acetate vaginal ring) prescribing information. Rockaway, NJ; 2005 Aug.

118. Pfizer & Upjohn Company. Depo-Testadiol (testosterone cypionate-estradiol cypionate) injection prescribing information. Kalamazoo, MI; 2000 Oct.

119. Food and Drug Administration. Certain estrogen-androgen combinations drugs; drugs for human use; drug efficacy study implementation; amendment and opportunity for hearing. [Docket nos. 78N-0377 and 98P-1041; DESI 7661] Fed Regist. 2003; 68:17953-7.

120. Food and Drug Administration. FDA revises finding on estrogen/androgen combination products in the treatment of hot flashes. FDA Talk Paper. Rockville, MD; 2003 Apr 10 . Correction April 11 2003. From the FDA web site. Accessed Jun 9 2003.

121. Pfizer. Depo-Estradiol (estradiol cypionate) injection prescribing information. New York, NY; 2004 Dec..

122. Asend Therapeutics. EstroGel 0.06% (estradiol gel) prescribing information. Herndon, VA; 2006 Apr.

123. Berlex. Climara Pro (estradiol/levonorgestrel transdermal system) prescribing information. Montville, NJ; 2006 May.

124. Ascend Therapeutics. EstroGel patient information. Herndon, VA; 2006 Apr.

125. Berlex. Menostar (estradiol transdermal system) prescribing information. Montville, NJ; 2006 Feb.

126. Espirit. Estrasorb (estradiol topical emulsion) prescribing information. East Brunswick, NJ; 2006 Jan.

127. Berlex. Angeliq (drospirenone/estradiol) tablets prescribing information. Montville, NJ; 2005 Sept.

128. Novo Nordisk. Activella (estradiol/norethindrone acetate) tablets prescribing information. Princeton, NJ; 2006 Jun.

129. Monarch Pharmaceuticals. Prefest (estradiol/norgestimate) tablets prescribing information. Bristol, TN; 2003 Feb 7.

130. Drug Enforcement Administration (DEA), Department of Justice. Implementation of the Anabolic Steroid Control Act of 2004. Fed Regist. 2005; 241:74653-8.

131. Drug Enforcement Administration (DEA), Office of Diversion Control. Exempt Anabolic Steorids (December 31, 2003). From the DEA website.

132. Monarch Pharmaceuticals. Delestrogen(estradiol valerate) injection prescribing information. Bristol, TN; 2004 Jun 23.

133. Warner Chilcott. Femhrt (norethindrone acetate/ethinyl estradiol) tablets prescribing information. Rockaway, NJ; 2005 Jan.

134. Warner Chilcott. Estrace (estradiol) vaginal cream prescribing information. Rockaway, NJ; 2005 Oct.

135. Warner Chilcott. Femtrace (estradiol acetate) tablets prescribing information. Rockaway, NJ; 2004 Aug.

136. Mylan. Estradiol transdermal system continuous delivery (once weekly) prescribing information. Morgantown, WV; 2005 Jul.

137. Kenwood Therapeutics. Elestrin (estradiol) gel prescribing information. Fairfield, NJ; 2006 Dec.

138. Musel AL, Warshaw EM. Cutaneous reactions to transdermal therapeutic systems. Dermatitis. 2006; 17:109-22. [PubMed 16956462]

139. Ther-Rx. Evamist (estradiol transdermal spray) prescribing information. St. Louis, MO; 2008 Apr.

140. Food and Drug Administration. FDA drug safety communication: Ongoing safety review of Evamist (estradiol transdermal spray) and unintended exposure of children and pets to topical estrogen. Available from: . Accessed 2010 Sep 8.

141. Ther-Rx. Evamist (estradiol transdermal spray) prescribing information. St. Louis, MO; 2009 Jul.

a. AHFS drug information 2007. McEvoy GK, ed. Estradiol. Bethesda, MD: American Society of Health-System Pharmacists; 2007;3099-103..

b. AHFS drug information 2004. McEvoy GK, ed. Estrogens General Statement. Bethesda, MD: American Society of Health-System Pharmacists; 2004:2949-57.

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