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
Estrogens increase the risk of endometrial cancer in postmenopausal women.100 105 106 107 108 110 111 112 113 117 118 121 122 123 125 126 128 129 132 134 135 136 137 139 (See Endometrial Cancer under Cautions.)
Do not use estrogens with or without progestins for prevention of cardiovascular disease (see Cardiovascular Risk Reduction under Uses and Cardiovascular Disorders under Cautions) or dementia (see Alzheimer’s Disease under Uses).100 105 106 108 110 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139
The Women’s Health Initiative (WHI) study of estrogen alone reported increased risks of stroke and DVT in postmenopausal women receiving approximately 7 years of therapy with conjugated estrogens 0.625 mg daily.122 137 139
The WHI study of estrogen plus progestin reported increased risks of MI, stroke, invasive breast cancer, pulmonary embolism, and DVT in postmenopausal women receiving >5 years of therapy with conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily.100 105 106 108 110 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139
The WHI Memory Study (WHIMS) reported increased risk of developing probable dementia in postmenopausal women ≥65 years of age receiving long-term therapy (4–5 years) with conjugated estrogens in conjunction with medroxyprogesterone acetate or conjugated estrogen alone.100 105 106 108 110 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139 Not known whether this finding also applies to younger postmenopausal women.100 105 106 108 110 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139
Other dosages of conjugated estrogens with medroxyprogesterone and other combinations or dosage forms of estrogens with progestin not studied in WHI trials; in absence of comparable data, assume risks are similar.100 105 106 108 110 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139
Prescribe estrogens (with or without progestins) at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman.100 105 106 108 110 112 117 121 122 123 125 126 127 128 129 132 133 134 135 136 137 139
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
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
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