Estradiol (a principal endogenous estrogen) is a steroidal estrogen.
Oral, transdermal, or topical estradiol is used for the management of moderate to severe vasomotor symptoms associated with menopause and for the management of vulvar and vaginal atrophy (atrophic vaginitis, kraurosis vulvae). Oral or transdermal estradiol is used for the treatment of female hypoestrogenism due to hypogonadism, castration, or primary ovarian failure. If estrogens are used solely for the management of vulvar and vaginal atrophy, use of topical vaginal preparations should be considered. Estradiol also may be administered intravaginally as a cream or tablet for the management of vulvar and vaginal atrophy. Estradiol vaginal ring is used for the management of urogenital symptoms associated with postmenopausal atrophy of the vagina (i.e., dryness, burning, pruritus, dyspareunia) and/or lower urinary tract (i.e., urinary urgency, dysuria).107
Oral or transdermal estradiol (Alora®, Climara®, Climara Pro®, Estraderm®, Menostar®, Vivelle®, Vivelle-Dot®) is used adjunctively with other therapeutic measures (e.g., diet, calcium, weight-bearing exercise [including walking, running], physical therapy) to retard further bone loss and the progression of osteoporosis associated with estrogen deficiency in postmenopausal women. While estrogen replacement therapy is effective for the prevention of osteoporosis in women and has been shown to reduce bone resorption and retard or halt bone loss in postmenopausal women, such therapy is associated with a number of adverse effects.114, 115 If prevention of postmenopausal osteoporosis is the sole indication for estrogen therapy, alternative therapy (e.g., alendronate, raloxifene, risedronate) also should be considered.114, 115
While results from earlier observational studies indicated that estrogen replacement therapy (ERT) or combined estrogen/progestin therapy (HRT) was associated with cardiovascular benefit in postmenopausal women, results from recent controlled studies indicate that hormone therapy does not decrease the incidence of cardiovascular disease.114, 115, 116 The American Heart Association (AHA), American College of Obstetricians and Gynecologists (ACOG), US Food and Drug Administration (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).115, 116
Oral estradiol is used for the palliative treatment of advanced, inoperable, metastatic carcinoma of the breast in postmenopausal women and in men. Estrogens are one of several second-line agents that can be used in certain postmenopausal women with metastatic breast cancer.
Oral estradiol is used for the palliative treatment of advanced carcinoma of the prostate in men; however, the risk of adverse cardiovascular effects of estrogens must be considered.
Oral estradiol acetate and estradiol acetate vaginal ring are used for management of moderate to severe vasomotor symptoms associated with menopause.117, 135 Estradiol acetate vaginal ring also is used for the management of moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause.117 If estradiol acetate vaginal ring is used solely for the management of vulvar and vaginal atrophy, use of an alternative topical vaginal preparation should be considered.117
Estradiol cypionate is used for the management of moderate to severe vasomotor symptoms associated with menopause.121 Estradiol cypionate also is used for the management of female hypogonadism.121
Estradiol cypionate in fixed combination with testosterone cypionate is used for the management of moderate to severe vasomotor symptoms associated with menopause.118 While estrogen/androgen combinations were found to be effective for this indication under a determination made by the US Food and Drug Administration (FDA) in 1976, formal administrative proceedings were initiated by the FDA in April 2003 to examine the effectiveness of estrogen/androgen combinations for the management of vasomotor symptoms associated with menopause.119, 120 FDA is undertaking this action because the agency does not believe there is substantial evidence available to establish the contribution of androgens to the effectiveness of estrogen/androgen combinations for the management of vasomotor symptoms in menopausal women who do not respond adequately to estrogen alone.119, 120 The FDA will allow continued marketing of combination estrogen/androgen products while the matter is under study.120
Estradiol cypionate in fixed combination with medroxyprogesterone acetate is used parenterally as a long-active contraceptive in women.109
In women, estradiol valerate is used for the management of moderate to severe vasomotor symptoms associated with menopause. Estradiol valerate also is used for the management of vulvar and vaginal atrophy, female hypogonadism and castration, and primary ovarian failure. If estrogens are used solely for the management of vulvar and vaginal atrophy, use of topical vaginal preparations should be considered.
Estradiol valerate is used for the palliative treatment of advanced carcinoma of the prostate in men; however, the risk of adverse cardiovascular effects of estrogens must be considered.
Although in the past estradiol valerate was used for the prevention of postpartum breast engorgement†, the FDA has withdrawn approval of estrogen-containing drugs for this indication since estrogens have not been shown to be safe for use in women with postpartum breast engorgement. Data from controlled studies indicate that the incidence of substantial painful engorgement is low in untreated women, and the condition usually responds to appropriate analgesic or other supportive therapy.
Ethinyl estradiol in fixed combination with norethindrone acetate is used for the management of moderate to severe vasomotor symptoms associated with menopause.133 Ethinyl estradiol in fixed combination with norethindrone acetate also is used adjunctively with other therapeutic measures (e.g., diet, calcium, weight-bearing exercise [including walking, running], physical therapy) to retard further bone loss and the progression of osteoporosis associated with estrogen deficiency in postmenopausal women. 133 While estrogen replacement therapy is effective for the prevention of osteoporosis in women and has been shown to reduce bone resorption and retard or halt bone loss in postmenopausal women, such therapy is associated with a number of adverse effects.114, 115 If prevention of postmenopausal osteoporosis is the sole indication for estrogen therapy, alternative therapy (e.g., alendronate, raloxifene, risedronate) also should be considered.133
Reconstitution and Administration
Estradiol is administered orally, intravaginally, percutaneously by topical application of a transdermal system, and by topical application of a gel, emulsion, or transdermal spray to the skin. Estradiol acetate is administered orally and intravaginally. Ethinyl estradiol is administered orally. Estradiol cypionate and estradiol valerate are administered IM.
Patients receiving a transdermal estradiol system should be carefully instructed in the use of the transdermal system.100, 101, 102, 105, 106, 108, 110, 111, 112, 123, 125, 136 To obtain optimum results, patients should also be given a copy of the patient instructions provided by the manufacturer.102, 105, 106, 108, 110, 111, 112, 123, 125, 136 To expose the adhesive surface of the system, the protective strip should be peeled and discarded prior to administration.100, 102, 105, 106, 108, 110, 111, 112, 123, 125, 136 The transdermal system is applied topically to a clean, dry, and not excessively hairy area of intact skin on the trunk of the body, preferably the abdomen or buttocks, by firmly pressing the system with the adhesive side touching the skin.100, 101, 102, 105, 106, 108, 110, 111, 112, 123, 125, 136 The system should be applied immediately after removal from its protective pouch and removal of the protective liner.100, 102, 105, 106, 108, 110, 111, 112, 123, 125, 136 The system should be pressed firmly in place with the palm of the hand for about 10 seconds, ensuring good contact, particularly around the edges.100, 101, 102, 105, 106, 108, 110, 111, 112, 123, 125, 136 The application site should not be oily, damaged, or irritated.100, 101, 102, 105, 106, 108, 110, 111, 112, 123, 125, 136 The transdermal system should not be applied to the breasts, and application at the waistline should be avoided, since tight clothing may cause the system to be rubbed off.100, 102, 105, 106, 108, 110, 111, 112, 123, 125, 136 If the system should inadvertently come off during the period of use, it may be reapplied or, if necessary, a new system may be applied; in either case, the application schedule employed should be continued.100, 102, 105, 106, 108, 110, 111, 112, 123, 125, 136 To minimize and/or prevent potential skin irritation, each transdermal system should be applied at a different site, with an interval of at least 1 week allowed between applications to a particular site.100, 101, 102, 105, 106, 108, 110, 111, 112, 123, 125, 136 Estradiol transdermal systems are applied once (Climara®, Climara Pro®, Estradiol Transdermal System [Mylan], Menostar®) or twice (Alora®, Combipatch®, Estraderm®, Vivelle®, Vivelle-Dot®) weekly; the system in use is removed and discarded and a new system is applied.100, 101, 102, 105, 106, 108, 110, 111, 112, 123, 125, 136 The transdermal systems for application twice weekly are commercially available in a dispensing package that is designed to aid the user in complying with the prescribed dosage regimen (the same 2 days each week).100, 101, 102, 108, 110, 111, 112 If a system is not changed on a designated day, it should be replaced as soon as possible.100, 102, 105, 106, 108, 110, 111, 112, 136
Patients receiving estradiol topical gel (Elestrin®, EstroGel®) should be instructed in use of the gel and given a copy of the patient instructions provided by the manufacturer.122, 124, 137 Estradiol topical gel should be applied topically once daily at the same time each day to clean, dry, intact skin.122, 124, 137 To apply a dose of Elestrin®, the pump should be held with the tip facing the arm and the pump should be firmly and fully depressed.137 Elestrin® gel is applied to the upper arm and shoulder using 2 fingers.137 To apply a dose of EstroGel®, the gel should be collected in the palm of the hand by pressing the pump firmly and fully.124 EstroGel® gel is applied to one arm from shoulder to wrist using the hand.124 The topical gel should not be applied to the breasts124, 137 or in or around the vagina.137 The application site should be allowed to dry for up for 5 minutes before dressing.124, 137 Hands should be washed with soap and water after application of the gel.124, 137 It is not known how long bathing and swimming should be delayed after application of the gel.122, 124, 137 Therefore, estradiol topical gel should be applied after bathing; the time allowed between application of the gel and swimming should be as long as possible (at least 2 hours).124, 137 Application of sunscreen 10 minutes prior to application of Elestrin® increases exposure to estradiol by 55%, and application of sunscreen 25 minutes after application of Elestrin® does not alter exposure to estradiol.137 Application of sunscreen for 7 days to the site of application of Elestrin® increased estradiol exposure twofold; this effect was noted when sunscreen was applied before and after application of Elestrin®.137 Concomitant application of EstroGel® and sunscreen preparations has not been evaluated.122
Patients receiving estradiol topical emulsion (Estrasorb®) should be instructed in use of the emulsion and given a copy of the patient instructions provided by the manufacturer.126 Estradiol topical emulsion should be applied topically once daily every morning to clean, dry, intact skin.126 To apply a dose, the contents of one pouch should be placed on the left thigh.126 The emulsion should be rubbed into the entire left thigh and calf for 3 minutes using one or both hands.126 Any excess emulsion remaining on the hands can be rubbed onto the buttocks.126 The contents of another pouch should be placed on the right thigh.126 The emulsion should be rubbed into the entire right thigh and calf for 3 minutes using one or both hands.126 Any excess emulsion remaining on the hands can be rubbed onto the buttocks.126 The emulsion should be applied immediately after opening the pouch.126 The application site should be allowed to dry before dressing.126 Hands should be washed with soap and water after application of the emulsion.126 Estradiol topical emulsion should not be applied in close proximity to application of sunscreen.126 Application of sunscreen 10 minutes prior to application of estradiol topical emulsion increases exposure to estradiol by 35%, and application of sunscreen 25 minutes after application of estradiol topical emulsion increases exposure to estradiol by 15%.126
Patients receiving estradiol transdermal spray (Evamist®) should be instructed in use of the spray and given a copy of the patient instructions provided by the manufacturer.139, 140 Estradiol transdermal spray should be applied topically 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 Prior to initial use, estradiol transdermal spray pump must be primed; it is not necessary to prime the pump before each daily dose.139 To prime the pump, the applicator is held upright with the cover on and the pump depressed three times.139 To apply a dose of estradiol transdermal spray, the cover should be removed, the applicator held upright and the cone section of the applicator placed flat against the skin; the pump should then be depressed.139 One, two, or three sprays may be applied to non-overlapping areas of the inner forearm, starting near the elbow.139 Estradiol transdermal spray should not be applied to any area other than the inner forearm; the spray should not be applied to the breasts or around the vagina.139 The application site should be allowed to dry for up for 2 minutes before dressing and 30 minutes before washing the area.139 The application site should not be massaged or rubbed.139 Other individuals should not be allowed to have direct contact with the skin at the site of spray application for at least 30 minutes following administration.139, 141 Patients receiving estradiol transdermal spray should ensure that children and pets avoid contact with the skin at the application site to prevent inadvertent exposure to the drug.140 (See Cautions.) If a child comes in direct contact with the patient's forearm where Evamist® was applied, the general area of contact should be washed with soap and water as soon as possible.140 Patients who cannot avoid such contact with children should wear clothing with long sleeves to cover the application site.140 Application of sunscreen 1 hour after application of estradiol transdermal spray decreases exposure to estradiol by 11%; application of sunscreen 1 hour prior to application of estradiol transdermal spray does not alter exposure to estradiol.139
Dosage of estradiol, estradiol acetate, estradiol cypionate, estradiol valerate, and ethinyl estradiol must be individualized according to the condition being treated and the tolerance and therapeutic response of the patient. To minimize the risk of adverse effects, the lowest possible effective dosage should be used. When short-term estrogen therapy is indicated (e.g., for the management of vasomotor symptoms associated with menopause; vulvar and vaginal atrophy), therapy should be discontinued as soon as possible; attempts to reduce dosage or discontinue the drug should be made at 3- to 6-month intervals. Because of the potential increased risk of cardiovascular events, breast cancer, and venous thromboembolic events, estrogen and estrogen/progestin therapy should be limited to the lowest effective doses and shortest duration of therapy consistent with treatment goals and risks for the individual woman.101, 107 Estrogen and estrogen/progestin therapy should be periodically reevaluated.101, 107
Estrogen therapy is administered continuously or cyclically. While estrogen therapy alone may be appropriate in women who have undergone a hysterectomy, many clinicians currently recommend that a progestin be added to estrogen therapy in women with an intact uterus. Addition of progestin therapy for 10 or more days of a cycle of estrogen administration or daily with estrogen in a continuous regimen reduces the incidence of endometrial hyperplasia and the attendant risk of endometrial carcinoma in women with an intact uterus. Morphologic and biochemical studies of the endometrium suggest that 10-13 days of progestin are needed to provide maximum maturation of the endometrium and to eliminate any hyperplastic changes. The manufacturer of Menostar® recommends that women with an intact uterus receive a progestin for 14 days every 6-12 months.125 When a progestin is used in conjunction with an estrogen, the usual precautions associated with progestin therapy should be observed. Clinicians prescribing progestins should be aware of the risks associated with these drugs and the manufacturers' labeling should be consulted. The choice and dosage of a progestin may be important factors in minimizing adverse effects.
When long-acting parenteral preparations are used in the management of conditions associated with estrogen deficiency, the drugs are usually administered once every 3-4 weeks.
For the management of moderate to severe vasomotor symptoms associated with menopause or for the management of vulvar and vaginal atrophy, the usual initial oral dosage of estradiol is 1 or 2 mg daily in a cyclic regimen.106 For replacement therapy in female hypogonadism, female castration, or primary ovarian failure, the usual initial oral dosage of estradiol is 1 or 2 mg daily.106 Subsequent dosage should be adjusted according to the patient's therapeutic response, using the lowest possible effective maintenance dosage.
For the prevention of osteoporosis, an oral dosage of estradiol 0.5 mg daily in a cyclic regimen has been used.106 The lowest effective dosage of estradiol for this indication has not been determined.106
When estradiol is used in fixed combination with norethindrone acetate (Activella®) for the management of moderate to severe vasomotor symptoms associated with menopause, the management of vulvar and vaginal atrophy associated with menopause, or prevention of postmenopausal osteoporosis, the usual dosage is 1 mg of estradiol combined with 0.5 mg of norethindrone acetate daily.128
When estradiol is used in fixed combination with drospirenone (Angeliq®) for the management of moderate to severe vasomotor symptoms associated with menopause or for the management of vulvar and vaginal atrophy associated with menopause, the usual dosage is 1 mg of estradiol combined with 0.5 mg of drospirenone daily.127
When estradiol is used with norgestimate (Prefest®) for the management of moderate to severe vasomotor symptoms associated with menopause, the management of vulvar and vaginal atrophy associated with menopause, or prevention of postmenopausal osteoporosis, the usual dosage is 1 mg of estradiol daily for 3 days followed by 1 mg of estradiol with 0.09 mg of norgestimate daily for 3 days; the regimen is continued without interruption.129
For the palliative treatment of advanced, metastatic carcinoma of the breast in appropriately selected men and postmenopausal women, the usual oral dosage of estradiol is 10 mg 3 times daily. Estrogen therapy is usually continued in these patients for at least 3 months.
For the palliative treatment of advanced carcinoma of the prostate, the usual oral dosage of estradiol is 1-2 mg 3 times daily.
Transdermal estradiol is commercially available as systems that are applied once or twice weekly.100, 105, 108, 110, 111, 125 Estradiol transdermal systems that are applied twice weekly include Alora® (available as a system delivering 0.025 mg/24 hours, 0.05 mg/24 hours, 0.075 mg/24 hours, or 0.1 mg/24 hours),108 Estraderm® (available as a system delivering 0.05 mg/24 hours or 0.1 mg/24 hours),100 and Vivelle® and Vivelle-Dot® (available as a system delivering 0.025 mg/24 hours, 0.0375 mg/24 hours, 0.05 mg/24 hours, 0.075 mg/24 hours, or 0.1 mg/24 hours).110, 111 Estradiol transdermal systems that are applied once weekly include Climara® (available as a system delivering 0.025 mg/24 hours, 0.0375 mg/24 hours, 0.05 mg/24 hours, 0.06 mg/24 hours, 0.075 mg/24 hours, or 0.1 mg/24 hours)105 and Menostar® (available as a system delivering 0.014 mg/24 hours).125 In addition, transdermal estradiol/norethindrone (CombiPatch®) is commercially available as a system delivering 0.05 mg/24 hours of estradiol and 0.14 mg/24 hours of norethindrone acetate and as a system delivering 0.05 mg/24 hours of estradiol and 0.25 mg/24 hours of norethindrone acetate.112 Transdermal estradiol/levonorgestrel (Climara Pro®) is commercially available as a system delivering 0.045 mg/24 hours of estradiol and 0.015 mg/24 hours of levonorgestrel.123
When Alora® or Estraderm® is used for the management of moderate to severe vasomotor symptoms associated with menopause or for the management of vulvar and vaginal atrophy, the usual initial dosage of transdermal estradiol is one system delivering 0.05 mg/24 hours applied twice weekly in a continuous regimen in women who have undergone a hysterectomy or a cyclic regimen (3 weeks on drug followed by 1 week without the drug, and then the regimen is repeated as necessary) in women with an intact uterus.100, 108
When Climara® is used for the management of moderate to severe vasomotor symptoms associated with menopause, the usual initial dosage of transdermal estradiol is one system delivering 0.025 mg/24 hours applied once weekly in a continuous regimen.105 Subsequent dosage should be adjusted according to the severity of the symptoms and the patient's therapeutic response, using the lowest possible effective maintenance dosage.105
When Vivelle® or Vivelle-Dot® is used for the management of moderate to severe vasomotor symptoms associated with menopause or for the management of vulvar and vaginal atrophy, the usual initial dosage of transdermal estradiol is one system delivering 0.0375 mg/24 hours applied twice weekly in a cyclic or continuous regimen.110, 111 Subsequent dosage should be adjusted according to the patient's therapeutic response, using the lowest possible effective maintenance dosage.100, 108 In women who have undergone hysterectomy, transdermal estradiol Vivelle-Dot® may be applied twice a week in a continuous regimen.111
When estradiol/levonorgestrel (Climara Pro®) is used for the management of moderate to severe vasomotor symptoms associated with menopause in women with an intact uterus, one system delivering 0.045 mg/24 hours of estradiol and 0.015 mg/24 hours of levonorgestrel is applied once weekly in a continuous regimen.123
When estradiol/norethindrone acetate (CombiPatch®) is used for the management of moderate to severe vasomotor systems associated with menopause, for the management of vulvar and vaginal atrophy, or for the treatment of hypoestrogenism secondary to hypogonadism, castration, or primary ovarian failure, CombiPatch® may be administered as a continuous combined regimen or as a continuous sequential regimen.112 In the continuous combined regimen, one CombiPatch® system delivering 0.05 mg/24 hours of estradiol and 0.14 mg/24 hours of norethindrone acetate is applied twice weekly in a continuous regimen.112 If necessary, the dosage of norethindrone acetate may be increased by using the dosage system that delivers 0.25 mg/24 hours of norethindrone acetate.112 In the continuous sequential regimen, one system of transdermal estradiol delivering 0.05 mg/24 hours (i.e., Vivelle®) is applied twice weekly for the first 14 days of a 28-day cycle then one estradiol/norethindrone acetate (CombiPatch®) system delivering 0.05 mg/24 hours of estradiol and 0.14 mg/24 hours of norethindrone acetate is applied twice weekly for the remaining 14 days of the cycle.112 If necessary, the dosage of norethindrone acetate may be increased by using the dosage system that delivers 0.25 mg/24 hours of norethindrone acetate.112
When Alora® is used for the prevention of postmenopausal osteoporosis, the minimum dose that has been shown to be effective is one system delivering 0.025 mg/24 hours applied twice weekly in a continuous regimen.108
When Climara® is used for the prevention of postmenopausal osteoporosis, the minimum dose that has been shown to be effective is one system delivering 0.025 mg/24 hours applied once weekly in a continuous regimen.105
For the prevention of osteoporosis, the usual initial dosage of transdermal estradiol (Estraderm®) is one system delivering 0.05 mg/24 hours applied twice weekly in a cyclic regimen in women with an intact uterus.100 In women who have undergone hysterectomy, one Estraderm® system is applied twice weekly in a continuous regimen.100 Subsequent dosage can be adjusted according to the patient's response.100
For the prevention of osteoporosis, the usual dosage of transdermal estradiol (Menostar®) is one system delivering 0.014 mg/24 hours applied once weekly in a continuous regimen.125
When Vivelle® or Vivelle-Dot® is used for the prevention of postmenopausal osteoporosis, the usual dosage is one system delivering 0.025 mg/24 hours applied twice weekly.110, 111
When estradiol/levonorgestrel (Climara Pro®) is used for the prevention of postmenopausal osteoporosis in women with an intact uterus, one system delivering 0.045 mg/24 hours of estradiol and 0.015 mg/24 hours of levonorgestrel is applied once weekly in a continuous regimen.123
In women who are currently not receiving an oral estrogen, transdermal estradiol therapy can be initiated immediately.100, 105, 108, 110, 111 In women who are currently receiving an oral estrogen, transdermal estradiol therapy can be initiated 1 week after discontinuance of oral therapy or sooner if symptoms reappear before the week has passed.100, 105, 108, 110, 111
Commercially available estradiol 0.06% topical gel (Elestrin®) is supplied in a non-aerosol metered-dose pump.137 Each depression of the pump delivers 0.87 g of gel containing 0.52 mg of estradiol.137 When estradiol gel (Elestrin®) is used for the management of moderate to severe vasomotor symptoms associated with menopause, the usual initial dosage is 0.87 g of gel (0.52 mg of estradiol) applied topically once daily.137 Prior to using the pump for the first time, the pump must be primed by fully depressing the pump 10 times; this gel should be discarded in a manner that avoids accidental exposure or ingestion by household members or pets.137
Commercially available estradiol 0.06% topical gel (EstroGel®) is supplied in a non-aerosol metered-dose pump.122 Each depression of the pump delivers 1.25 g of gel containing 0.75 mg of estradiol.122 When estradiol gel (EstroGel®) is used for the management of moderate to severe vasomotor symptoms associated with menopause or the treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause, 1.25 g of gel (0.75 mg of estradiol) is applied topically once daily.122 Prior to using the pump for the first time, the pump must be primed by fully depressing the 93-g pump twice or depressing the 25-g pump 3 times; this gel should be discarded in a manner that avoids accidental exposure or ingestion by household members or pets.124
Commercially available estradiol hemihydrate 0.25% topical emulsion (Estrasorb®) is supplied in foil-laminated pouches.126 Each pouch contains 1.74 g of emulsion.126 When estradiol topical emulsion (Estrasorb®) is used for the management of moderate to severe vasomotor symptoms associated with menopause, the contents of 2 pouches (delivering a total of 0.05 mg of estradiol/24 hours) are applied topically once daily.126
Commercially available estradiol transdermal spray (Evamist®) is supplied in a metered-dose pump.139 The metered pump delivers a metered 90-mcL spray that contains 1.53 mg of estradiol per actuation.139 When estradiol transdermal spray is used for the management of moderate to severe vasomotor symptoms associated with menopause, the recommended initial dose is one spray to the inner forearm once daily.139 Subsequent dosage is based on clinical response.139 One, two, or three sprays may be administered each morning to adjacent, non-overlapping areas of the inner forearm.139
For the management of symptoms of vulvar and vaginal atrophy associated with menopause, 2-4 g of estradiol vaginal cream may be administered intravaginally once daily for 1-2 weeks, then gradually reduced to one-half the initial dosage for a similar period.134 Maintenance dosages of 1 g of estradiol vaginal cream administered intravaginally 1-3 times weekly may be used after restoration of the vaginal mucosa has occurred.134
When estradiol vaginal ring (Estring®) is used for the management of postmenopausal urogenital symptoms, one ring (delivering estradiol 0.0075 mg/24 hours) is inserted into the upper third of the vaginal vault; the ring is to remain in place for 3 months.107 After 3 months, the ring should be removed and, if appropriate, replaced with a new ring.107 If the ring is expelled, the ring should be rinsed in lukewarm water and reinserted.107
For the management of atrophic vaginitis, one vaginal tablet containing 25 mcg of estradiol (Vagifem®) is inserted intravaginally once daily (preferably at the same time each day) for 2 weeks (initial dosage).113 For maintenance therapy for this condition, one vaginal tablet containing 25 mcg of the drug is inserted intravaginally twice weekly.113
Estradiol acetate (Femtrace®) is commercially available for oral administration as tablets containing 0.45, 0.9, or 1.8 mg of estradiol acetate; the tablets are administered once daily.135 When estradiol acetate tablets are used for the management of moderate to severe vasomotor symptoms associated with menopause, therapy should be initiated with the lowest dose.135
Estradiol acetate vaginal ring (Femring®) is commercially available as a ring delivering estradiol 0.05 mg/24 hours or 0.1 mg/24 hours.117 When estradiol acetate vaginal ring (Femring®) is used for the management of moderate to severe vasomotor symptoms or symptoms of vulvar and vaginal atrophy associated with menopause, therapy should be initiated with the lowest dose.117 To initiate therapy, one ring delivering estradiol 0.05 mg/24 hours is inserted into the vaginal vault; the ring remains in place for 3 months.117 After 3 months, the ring should be removed and, if appropriate, replaced with a new ring.117
For the management of moderate to severe vasomotor symptoms associated with menopause, the usual dosage of estradiol cypionate is 1-5 mg administered IM once every 3-4 weeks.121
For replacement therapy in female hypogonadism, the usual dosage of estradiol cypionate is 1.5-2 mg once every month.121
When estradiol cypionate in fixed combination with testosterone cypionate is used for the management of moderate to severe vasomotor symptoms associated with menopause, the usual dosage of estradiol cypionate is 2 mg in combination with testosterone 50 mg administered IM every 4 weeks.118
For the management of moderate to severe vasomotor symptoms or for the management of vulvar and vaginal atrophy associated with menopause, and for replacement therapy in female hypogonadism, female castration, or primary ovarian failure, the usual dosage of estradiol valerate is 10-20 mg once every 4 weeks as necessary.132
For the palliative treatment of advanced carcinoma of the prostate, the usual dosage of estradiol valerate is 30 mg or more once every 1 or 2 weeks.132
Estrogen-Progestin Combination Therapy
Ethinyl estradiol in fixed combination with norethindrone acetate (Femhrt®) is commercially available for oral administration as tablets containing 2.5 mcg of ethinyl estradiol with 0.5 mg of norethindrone acetate and as tablets containing 5 mcg of ethinyl estradiol with 1 mg of norethindrone acetate; the tablets are administered once daily.133 When ethinyl estradiol is used in combination with norethindrone acetate for the management of moderate to severe vasomotor symptoms associated with menopause or the prevention of postmenopausal osteoporosis, therapy should be initiated with the lowest dose.133
Estradiol, estradiol acetate, estradiol cypionate, estradiol valerate, and ethinyl estradiol share the toxic potentials of other estrogens, and the usual cautions, precautions, and contraindications associated with estrogen therapy should be observed. In addition, when estradiol or ethinyl estradiol is used in conjunction with progestins, the cautions, precautions, and contraindications associated with progestins must be considered in addition to those associated with estrogens.112, 123, 127, 128, 129, 133
In clinical studies, the most common adverse effect reported with transdermal estradiol therapy was erythema and irritation at the application site.100 Dermatologic reactions have been reported in up to 97% of patients using transdermal systems.138 The irritation generally resolves completely within a day or so.101 Rash has been reported rarely in patients receiving transdermal estradiol therapy.100 Rotation of application sites minimizes and/or prevents potential skin irritation.101 If erythema persists or severe irritation or rash occurs, patients should contact their physician.101, 102
Estrace® 2-mg tablets contain the dye tartrazine (FD&C yellow No. 5), which may cause allergic reactions including bronchial asthma in susceptible individuals. Although the incidence of tartrazine sensitivity is low, it frequently occurs in patients who are sensitive to aspirin.
The US Food and Drug Administration (FDA) is reviewing reports of adverse effects associated with estradiol transdermal spray (Evamist®) in children and pets who may have been inadvertently exposed to the drug through skin contact with women receiving the drug.140 Children exposed to the drug may experience signs of premature puberty including nipple swelling and breast development in females and breast enlargement in males.140 If such a child shows signs of premature puberty (e.g., nipple or breast swelling, breast tenderness or enlargement), the parents should be advised to contact the child's clinician and to inform the clinician of the child's possible exposure to the drug.140
Some estradiol topical preparations (e.g., gel, solution) contain alcohol. Preparations containing alcohol are flammable; exposure to open flame or lighted cigarettes should be avoided until the applied product has dried.139
Estradiol is the principal and most active endogenous estrogen. Ethinyl estradiol is one of the most potent synthetic estrogens, and unlike estradiol, ethinyl estradiol has similar activity following oral or parenteral administration. Following subcutaneous administration, ethinyl estradiol is equal in potency to estradiol, but following oral administration, ethinyl estradiol is 15-20 times more active than estradiol. The principal pharmacologic effects of estradiol, estradiol cypionate or valerate, and ethinyl estradiol are similar to those of other natural and synthetic estrogens.
Estradiol valerate has a duration of action of 14-21 days, and estradiol cypionate has a duration of action of 14-28 days.
Estradiol is a naturally occurring steroidal estrogen. The drug may be obtained from natural sources or prepared synthetically. Estradiol is structurally similar to estrone but differs from estrone in the substitution of a secondary alcohol group for the keto group at the 17 position on ring D of the steroid nucleus.
Estradiol occurs as white or creamy white, small crystals or as a crystalline powder, is odorless and hygroscopic, and is practically insoluble in water and has a solubility of approximately 35.7 mg/mL in alcohol at 25°C.
Transdermal estradiol (Alora®) is commercially available as a system that consists of an outer layer of polyethylene backing film and a drug reservoir consisting of estradiol and sorbitan monooleate dissolved in an acrylic adhesive matrix.108 A polyester overlapped release liner protects the adhesive matrix during storage and should be removed prior to application.108
Transdermal estradiol (Climara®) is commercially available as a system that consists of an outer layer of translucent polyethylene film and an acrylate adhesive matrix that contains estradiol; a siliconized or fluoropolymer-coated polyester film is attached to the adhesive surface and should be removed prior to application.105
Transdermal estradiol (Estraderm®) is commercially available as a system that consists of an outer layer of transparent polyester film; a drug reservoir of estradiol and alcohol gelled with hydroxypropyl cellulose; an ethylene-vinyl acetate copolymer membrane that controls the rate of diffusion of the drug; and a final adhesive layer consisting of light mineral oil and polyisobutylene.100 The adhesive layer is covered by a protective strip of siliconized polyester film which is removed prior to application.100
Transdermal estradiol (Menostar®) is commercially available as a system that consists of an outer layer of translucent polyethylene film and an acrylate adhesive matrix that contains estradiol; a siliconized or fluoropolymer-coated polyester film is attached to the adhesive surface and should be removed prior to application.126
Transdermal estradiol (Vivelle®, Vivelle-Dot®) is commercially available as a system that consists of an outer layer of translucent film and an adhesive formulation that contains estradiol; a polyester release liner is attached to the adhesive surface and should be removed prior to application.110, 111
Transdermal estradiol in fixed combination with levonorgestrel (Climara Pro®) is commercially available as a system that consists of an outer layer of translucent polyethylene film and an acrylate adhesive matrix that contains estradiol and levonorgestrel; a siliconized or fluoropolymer-coated polyester film is attached to the adhesive surface and should be removed prior to application.123
Transdermal estradiol in fixed combination with norethindrone acetate (CombiPatch®) is commercially available as a system that consists of an outer layer of polyolefin film and a silicone and acrylic-based multipolymeric adhesive matrix that contains estradiol and norethindrone acetate; a protective liner is attached to the adhesive surface and should be removed prior to application.112
Estradiol topical gel (Elestrin®) is commercially available as a hydroalcoholic gel containing estradiol 0.06%; the gel also contains purified water, alcohol, propylene glycol, diethylene glycol monoethyl ether, triethanolamine, carbomer 940, and edetate disodium.137 Elestrin® is supplied in a non-aerosol metered-dose pump.137 The pump contains 144 g of gel and delivers 100 metered doses of 0.87 g of gel.137
Estradiol topical gel (EstroGel®) is commercially available as a clear, colorless, hydroalcoholic gel containing estradiol 0.06%; the gel also contains purified water, alcohol, triethanolamine, and carbomer 934P and is formulated to provide controlled release of estradiol.122 EstroGel® is supplied in a non-aerosol metered-dose pump.122 The pump containing 93 g of gel delivers 64 metered doses of 1.25 g of gel, and the pump containing 25 g of gel delivers 14 metered doses of 1.25 g of gel.122
Estradiol topical emulsion (Estrasorb®) is commercially available as an emulsion containing estradiol hemihydrate 0.25%; estradiol is encapsulated using a micellar nanoparticle technology.126 The emulsion also contains soybean oil, water, polysorbate 80, and alcohol.126 Estradiol topical emulsion is supplied in foil-laminated pouches.126 Each pouch contains 1.74 g of emulsion and 4.35 mg of estradiol hemihydrate.126
Estradiol transdermal spray (Evamist®) delivers a metered 90-mcL spray that contains 1.53 mg of estradiol per actuation.139 The commercially available pump contains 8.1 mL of solution and delivers 75 metered doses.141 The solution is packaged in a glass vial fitted with a metered-dose pump; this unit is encased in a plastic housing with a conical bell opening that controls the distance, angle, and area of application of the spray.139
Estradiol also is commercially available as a vaginal tablet and as a vaginal ring that consists of estradiol, silicone polymers, and barium sulfate.107, 113
Estradiol acetate is commercially available as an oral tablet and as a vaginal ring that consists of estradiol acetate, silicone polymers, and barium sulfate.117, 135
Estradiol cypionate is formed by esterification of estradiol with cyclopentanepropionic acid at C 17 on ring D of the steroid nucleus. Estradiol cypionate occurs as a white to practically white, crystalline powder, is odorless or may have a slight odor, and has solubilities of less than 0.1 mg/mL in water and approximately 25 mg/mL in alcohol at 25°C. The drug is also sparingly soluble in vegetable oils. Estradiol cypionate is commercially available alone and in fixed combination with testosterone cypionate for parenteral use. Commercially available estradiol cypionate injection is a sterile solution of the drug in a suitable oil (e.g., cottonseed oil); the injection may also contain chlorobutanol as a preservative.
Estradiol valerate is formed by esterification of estradiol with valeric acid at C 17 on ring D of the steroid nucleus. Estradiol valerate occurs as a white, crystalline powder and is usually odorless but may have a faint, fatty odor. The drug is practically insoluble in water and sparingly soluble in sesame oil and in peanut oil. Estradiol valerate injection is a sterile solution of the drug in a suitable vegetable oil (e.g., sesame oil, castor oil); commercially available injections may also contain chlorobutanol or benzyl benzoate and benzyl alcohol as preservatives.
Ethinyl estradiol is a semisynthetic estrogen. The presence of the ethinyl group at C 17 on ring D of the steroid nucleus prevents enzymatic degradation of the estradiol molecule and results in an orally active compound.
Ethinyl estradiol occurs as a white to creamy white, odorless, crystalline powder and is insoluble in water and soluble in alcohol and vegetable oils.
Estradiol tablets should be stored in tight, light-resistant containers at a temperature of 20-25°C.106 The commercially available transdermal systems of estradiol should be stored at a temperature of 30°C or lower; after removal from the protective pouch, a transdermal system should be applied immediately and should not be stored.100, 105, 110, 125 The commercially available transdermal systems of estradiol/norethindrone acetate should be refrigerated at 2-8°C until dispensed.112 Once dispensed, the transdermal systems may be stored at a temperature lower than 25°C for up to 6 months.112 The commercially available transdermal systems of estradiol/levonorgestrel should be stored at 20-25°C but may be exposed to temperatures ranging from 15-30°C.123 After removal from the protective pouch, the transdermal systems should be applied immediately and should not be stored.112, 123, 125 Estradiol vaginal ring should be stored at controlled room temperature (15-30°C).107 Estradiol topical gel, estradiol topical emulsion, estradiol transdermal spray, estradiol vaginal tablets, and estradiol acetate vaginal ring should be stored at a controlled room temperature of 25°C, but may be exposed to temperatures ranging from 15-30°C.113, 117, 122, 126, 137, 139 Estradiol cypionate and estradiol valerate injections should be stored at room temperature.121, 132 Estradiol acetate tablets should be stored at 25°C but may be exposed to temperatures ranging from 15-30°C.135
Additional Information
For further information on chemistry, pharmacology, pharmacokinetics, cautions, acute toxicity, drug interactions, laboratory test interferences, and dosage and administration of estradiol and estradiol esters, see the Estrogens General Statement 68:16.04. 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.
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Topical | Gel | 0.06% | ||
Solution | 1.53 mg/meter spray | |||
Transdermal System | 0.014 mg/24 hours (1 mg/3.25 cm2) | |||
0.025 mg/24 hours (0.77 mg/9 cm2) | ||||
0.025 mg/24 hours (2 mg/6.5 cm2) | Berlex | |||
0.025 mg/24 hours (0.97 mg/7.75 cm2)* | Estradiol Transdermal System (once weekly) | |||
0.025 mg/24 hours (2.17 mg/7.25 cm2) | ||||
0.025 mg/24 hours (0.39 mg/2.5 cm2) | 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) | |||
0.0375 mg/24 hours (3.28 mg/11 cm2) | Vivelle® | Novartis | ||
0.0375 mg/24 hours (0.585 mg/3.75 cm2) | Vivelle-Dot® | 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) | Novartis | |||
0.05 mg/24 hours (1.94 mg/15.5 cm2)* | Estradiol Transdermal System (once weekly) | |||
0.05 mg/24 hours (4.33 mg/14.5 cm2) | Vivelle® | Novartis | ||
0.05 mg/24 hours (0.78 mg/5 cm2) | Vivelle-Dot® | 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) | |||
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) | |||
0.075 mg/24 hours (6.57 mg/22 cm2) | Vivelle® | Novartis | ||
0.075 mg/24 hours (1.17 mg/7.5 cm2) | Vivelle-Dot® | 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® | Novartis | ||
0.1 mg/24 hours (3.88 mg/31 cm2)* | Estradiol Transdermal System (once weekly) | |||
0.1 mg/24 hours (8.66 mg/29 cm2) | Vivelle® | Novartis | ||
0.1 mg/24 hours (1.56 mg/10 cm2) | Vivelle-Dot® | Novartis | ||
Vaginal | Cream | 0.01% | ||
Ring | 2 mg/ring (0.0075 mg/24 hours) |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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) | ||
Tablets, film-coated | 1 mg with Norethindrone Acetate 0.5 mg | Activella® (28 tablets) | ||
1 mg with Drospirenone 0.5 mg | Angeliq® (28 tablets) | Berlex | ||
Topical | Transdermal System | 0.045 mg and 0.015 mg Levonorgestrel/24 hours (4.4 mg and 1.39 mg Levonorgestrel/22 cm2) | Berlex | |
0.05 mg and 0.14 mg Norethindrone Acetate/24 hours (0.62 mg and 2.7 mg Norethindrone Acetate/9 cm2) | 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 |
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® (scored) | Warner Chilcott |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 0.45 mg | ||
0.9 mg | Femtrace® | Warner Chillcott | ||
1.8 mg | Femtrace® | Warner Chilcott | ||
Vaginal | Ring | 12.4 mg/ring (0.05 mg estradiol/24 hours) | Warner Chilcott | |
24.8 mg/ring (0.1 mg estradiol/24 hours) | Femring® | Warner Chilcott |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection (in oil) | 5 mg/mL | Depo®-Estradiol | Pfizer |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection (in oil) | 2 mg/mL with Testosterone Cypionate 50 mg/mL | Pfizer |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection (in oil) | 10 mg/mL | ||
20 mg/mL | Delestrogen® | Monarch | ||
40 mg/mL | Delestrogen® | Monarch |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 2.5 mcg with Norethindrone Acetate 0.5 mg | Warner Chillcott | |
5 mcg with Norethindrone Acetate 1 mg | FemHRT® | Warner Chillcott |
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 FDA website. [Web]
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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. [Web]
116. American Heart Association. Q & A about hormone replacement therapy. November 20, 2002. From the American Heart Association web site. [Web]
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. [Web]
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. [Web]
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. Accessed 2010 Sep 8.
141. Ther-Rx. Evamist® (estradiol transdermal spray) prescribing information. St. Louis, MO; 2009 Jul.