Estradiol (Systemic) (Lexi-Drugs)

ALERT: US Boxed Warning
  Endometrial cancer:
  Cardiovascular disease:
  Breast cancer:
  Dementia:
  Risk vs benefits:
  Secondary exposure (Evamist):
Drug Shortages

One or more forms of this drug may be in short supply or unavailable. Refer to the following for additional information:

ASHP: http://www.ashp.org/menu/DrugShortages

Pronunciation

(es tra DYE ole)

Brand Names: US

Alora; Climara; Delestrogen; Depo-Estradiol; Divigel; Elestrin; Estrace; Estrogel; Evamist; Femring; Menostar; Minivelle; Vivelle-Dot

Brand Names: Canada

Climara 100 [DSC]; Climara 25; Climara 50; Climara 75; Divigel; Estrace; Estradot 100; Estradot 25; Estradot 37.5; Estradot 50; Estradot 75; Estrogel; Lupin-Estradiol; Oesclim; PMS-Estradiol Valerate [DSC]; SANDOZ Estradiol Derm 100; SANDOZ Estradiol Derm 50; SANDOZ Estradiol Derm 75

Pharmacologic Category

Estrogen Derivative

Dosing: Adult

General dosing guidelines: When treating symptoms of menopause, hormone therapy should be evaluated routinely for appropriate dose, duration, and route of administration for each individual patient based on treatment goals, risk factors, and overall health (NAMS 2017). Combined estrogen/progestin therapy is indicated for postmenopausal persons with a uterus to decrease the risk of endometrial cancer. Individuals who have had a hysterectomy generally do not need a progestin; however, one may be needed if there is a history of endometriosis. Adjust dose based on patient response.

Breast cancer, metastatic: Oral (Estrace): Males and postmenopausal females: 10 mg 3 times/day or (off-label dosing) postmenopausal women: 2 mg 3 times/day (Ellis 2009)

Hormone therapy for transgender females (male-to-female), monotherapy or combination therapy (off-label use) (ES [Hembree 2017]):

IM:

Cypionate: 2 to 10 mg every week

Valerate: 5 to 30 mg every 2 weeks

Oral: 2 to 6 mg/day

Transdermal: Apply 0.025 to 0.2 mg/day patch every 3 to 5 days. Note: Apply two 0.1 mg patches to create a 0.2 mg/day dose.

Note: Adjust dose with a goal of elevating serum estradiol levels and suppressing serum testosterone levels into the normal range for females.

Hypoestrogenism (female) due to hypogonadism, castration, or primary ovarian failure:

Oral (Estrace): 1 to 2 mg/day; titrate as necessary to control symptoms using minimal effective dose for maintenance therapy

IM: Valerate (Delestrogen): 10 to 20 mg every 4 weeks

Transdermal (Alora, Climara, Vivelle-Dot): Refer to transdermal product-specific dosing (below).

Hypoestrogenism (female) due to hypogonadism: IM: Cypionate (Depo-Estradiol): 1.5 to 2 mg monthly

Osteoporosis prevention (females):

Oral (Estrace): Lowest effective dose has not been determined; doses of at least 0.5 mg/day were used in clinical studies evaluating bone mineral density (NAMS 2017).

Transdermal (Alora, Climara, Menostar, Minivelle, Vivelle-Dot): Refer to transdermal product-specific dosing (below).

Prostate cancer, advanced:

IM: Valerate (Delestrogen): 30 mg or more every 1 to 2 weeks

Oral (Estrace): 1 to 2 mg 3 times/day

Vasomotor symptoms (moderate to severe) associated with menopause:

Oral (Estrace): 0.5 to 1 mg once daily (AACE [Goodman 2011]; ACOG 141 2014). Dosage range: 0.5 to 2 mg/day (ES [Stuenkel 2015]).

IM: Cypionate (Depo-Estradiol): 1 to 5 mg every 3 to 4 weeks

IM: Valerate (Delestrogen): 10 to 20 mg every 4 weeks

Topical gel:

Divigel: Initial: 0.25 g/day; adjust dose based on patient response

Elestrin: Initial: 0.87 g/day applied at the same time each day; adjust dose based on patient response.

EstroGel: 1.25 g/day applied at the same time each day

Topical spray (Evamist): Initial: One spray (1.53 mg) per day. Adjust dose based on patient response. Dosing range: 1 to 3 sprays per day.

Transdermal (Alora, Climara, Minivelle, Vivelle-Dot): Refer to transdermal product-specific dosing (below).

Vaginal ring (Femring): Initial: 0.05 mg intravaginally; following insertion, dose is released daily for 3 months. Usual dose: 0.05 mg to 0.1 mg intravaginally every 3 months.

Vulvar and vaginal atrophy (moderate to severe) associated with menopause:

IM: Valerate (Delestrogen): 10 to 20 mg every 4 weeks

Intravaginal: Vaginal ring (Femring): Initial: 0.05 mg intravaginally; following insertion, dose is released daily for 3 months. Usual dose: 0.05 mg to 0.1 mg intravaginally every 3 months.

Oral (Estrace): 0.5 to 1 mg/day (ACOG 141 2014)

Topical gel (EstroGel): 1.25 g/day applied at the same time each day

Transdermal (Alora, Climara, Vivelle-Dot): Refer to transdermal product-specific dosing (below).

Transdermal product-specific dosing:

Note: Indicated dose may be used continuously in patients without a uterus. Continuous or cyclic schedules (3 weeks on, 1 week off) may be used in women with a uterus (indication and product specific; refer to manufacturers labeling). When changing patients from oral to transdermal therapy, start transdermal patch 1 week after discontinuing oral hormone (may begin sooner if symptoms reappear within 1 week):

Hypoestrogenism (female) due to hypogonadism, castration, or primary ovarian failure: Adjust dose as necessary to control symptoms.

Alora: Initial: Initial: Apply 0.05 mg/day patch twice weekly.

Climara: Initial: Apply 0.025 mg/day patch once weekly.

Vivelle-Dot: Initial: Apply 0.025 mg/day patch twice weekly.

Functional hypothalamic amenorrhea with low bone density (adolescent and young adult female; off-label use): The Endocrine Society guidelines are unable to recommend an optimal dose due to insufficient data (Gordon 2017). Application of 0.1 mg/day patch twice weekly (with cyclic progesterone for endometrial protection) improved spine and hip bone mineral density (BMD) in adolescent girls (bone age ≥15 years) with anorexia nervosa-associated low BMD (Misra 2011).

Osteoporosis prevention (female):

Alora, Minivelle, Vivelle-Dot: Initial: Apply 0.025 mg/day patch twice weekly. Adjust dose as necessary.

Climara: Initial: Apply 0.025 mg/day patch once weekly; adjust dosage based on response to therapy.

Estradot [Canadian product]: There are no specific initial dosage recommendations provided in the manufacturer’s labeling; individualize dose per clinical status, BMD status and 17-beta estradiol levels (maintain levels at 50 picogram/mL).

Menostar: Apply 0.014 mg/day patch once weekly. In women with a uterus, also administer a progestin for 14 days every 6 to 12 months.

Vasomotor symptoms associated with menopause: Note: Adjust dose as necessary.

Alora, Estradot [Canadian product]: Initial: Apply 0.05 mg/day patch twice weekly.

Climara: Initial: Apply 0.025 mg/day patch once weekly.

Minivelle, Vivelle-Dot: Initial: Apply 0.0375 mg/day patch twice weekly.

Oesclim [Canadian product]: Initial: Apply 0.025 to 0.05 mg/day patch twice weekly.

Vulvar and vaginal atrophy (moderate to severe) associated with menopause: Note: Adjust dose as necessary.

Alora: Initial: Apply 0.05 mg/day patch twice weekly.

Climara: Initial: Apply 0.025 mg/day patch once weekly.

Vivelle-Dot: Initial: Apply 0.0375 mg/day patch twice weekly.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment: Adult

For most products, there are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment: Adult

Use is contraindicated with hepatic dysfunction or disease

Dosing: Pediatric

Note: Estrasorb has been discontinued in the US for more than 1 year. Use lowest effective dose for shortest duration possible that is consistent with an individual’s treatment goals and risks; all dosage needs to be adjusted based upon the patient’s response.

Constitutional delay of growth and puberty (CDGP) (females): Limited data available: Children ≥12 years and Adolescents: Note: Begin with the lowest available dose and gradually increase. Obtain bone age every 6 months to avoid premature epiphyseal closure. If treatment continues beyond 1 year or breast growth is significant and has plateaued or breakthrough bleeding occurs, add cyclic progesterone. Continue until menstruation has been established, or longer if clinically indicated (Palmert 2012; Santos 2014; Sperling 2014).

Oral (micronized, Estrace): Initial dose: 5 mcg/kg once daily; after 6 to 12 months of therapy, may increase to 10 mcg/kg once daily (Palmert 2012). Using currently available dosage forms, some have recommended starting at a fixed dose of 0.25 mg once daily (1/2 of the 0.5 mg tablet) and increasing to 0.5 mg once daily after 6 to 12 months.

Transdermal: Initial dose: 3.1 to 6.2 mcg/day patch (eg, 1/8 to 1/4 of a 25 mcg/day patch), apply at night, remove in the morning. Increase by 3.1 to 6.2 mcg/day patch every 6 months (Palmert 2012). Note: The practice of cutting patches to achieve low doses is cited frequently in the literature (Ankarberg-Lindgren 2001; Davenport 2010; Hindmarsh 2009; Palmert 2012); however, product specific data may not be available for all transdermal products due to product availability/manufacturing changes.

Hypogonadism (females): Limited data available: Children ≥12 years and Adolescents: Note: Begin with the lowest available dose and gradually increase. Obtain bone age every 6 months to avoid premature epiphyseal closure. Once breast growth is significant and has plateaued or breakthrough bleeding occurs, add cyclic progesterone. Continue until menstruation has been established, or longer if clinically indicated (Palmert 2012; Sperling 2014).

Oral (micronized): Initial dose: 5 mcg/kg once daily for 6 to 12 months; may then increase to 10 mcg/kg/day for 6 to 12 months; dose may be increased at every 6 to 12 month intervals by 5 mcg/kg/day, up to 20 mcg/kg/day. Do not exceed adult dose of 2 mg daily (Palmert 2012).

Transdermal: Initial dose: 3.1 to 6.2 mcg/day patch (eg, 1/8 to 1/4 of a 25 mcg/day patch), apply at night, remove in the morning. Increase by 3.1 to 6.2 mcg/day patch every 6 months; Do not exceed adult dose of 50 to 100 mcg/24 hours (Palmert 2012). Note: The practice of cutting patches to achieve low doses is cited frequently in the literature (Ankarberg-Lindgren 2001; Davenport 2010; Hindmarsh 2009; Palmert 2012); however, product specific data may not be available for all transdermal products due to product availability/manufacturing changes.

Turner syndrome (females): Limited data available: Children ≥12 years and Adolescents: Begin at ~12 years of age using a low dose and gradually increase dose over 2 to 4 years to full adult dose. After 2 years of estrogen or when breakthrough bleeding occurs, add cyclic progesterone. Note: Full dose estrogen will be needed until at least age 30 years (Bondy 2007).

IM: Cypionate (Depot-Estradiol): Initial: 0.2 to 0.4 mg every 4 weeks, slowly increase dose over about 2 years to the goal adult dose: 3 mg/month; one trial started at 0.2 mg/dose, then increased dose at 6 month intervals in 0.2 mg/dose increments until dose of 1 mg reached and then increased in 0.5 mg/dose increments thereafter to a final dose of 3 mg (Bondy 2007; Rosenfield 2005)

Oral (micronized, Estrace): Initial dose: 5 mcg/kg once daily for the first 2 years, followed by 7.5 mcg/kg for the 3rd year, then 10 mcg/kg thereafter; once final height is attained, increase to adult dose of 1 to 2 mg/day (Bannink 2009). A fixed dose of 0.25 mg once daily; increasing to the adult dose of 2 to 4 mg/day over the course of 2 years has also been suggested (Bondy 2007). Note: Due to extensive first-pass metabolism, other routes of administration may be preferable.

Topical gel (Divigel): Initial: 0.1 mg of estradiol once daily for the first year, 0.2 mg of estradiol once daily for the second year, 0.5 mg of estradiol once daily for the third year, 1 mg of estradiol once daily for the fourth year, and 1.5 mg of estradiol once daily for the fifth year. Dosing based on a trial of 23 girls that followed development for 5 years; long-term dose is unknown. Due to lack of commercially available product for lower doses, individual sachets of 0.1 mg estradiol were prepared (Piippo 2004).

Transdermal patch: Initial: 6.25 mcg/day patch; slowly increase over about 2 years to the goal adult dose: 100 to 200 mcg/day patch (Bondy 2007)

Note: The lowest-dose commercially available patches deliver 14 and 25 μg daily; preferred dose fractionation method has not been established (eg, administering a partial patch, limiting to overnight use, or administering whole patches for 7 to 10 days per month). Product specific data may not be available for splitting/cutting some transdermal patches; one center has used the following titration method using Vivelle-Dot product (Davenport 2010):

Treatment month:

0 to <6 months of treatment: 3.125 mcg to 4.17 mcg/dose (equals 1/8 to 1/6 of a 25 mcg/day patch), apply at night, remove in the morning (not continuous)

6 to <12 months of treatment: 3.125 mcg to 4.17 mcg/dose (equals 1/8 to 1/6 of a 25 mcg/day patch) apply twice weekly (continuous)

12 to <18 months of treatment: 6.25 mcg to 8.33 mcg/dose (equals 1/4 to 1/3 of a 25 mcg/day patch), apply twice weekly (continuous)

18 to <24 months of treatment: 12.5 mcg/dose (equals 1/2 of a 25 mcg/day patch), apply twice weekly (continuous)

≥24 months of treatment: 25 mcg/day patch, apply twice weekly (continuous); then increase by one patch strength every 6 months to a final goal of 100 mcg/day continuously

Dosing: Renal Impairment: Pediatric

For most products, there are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment: Pediatric

For most products, there are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use is contraindicated with hepatic dysfunction or disease.

Use: Labeled Indications

Breast cancer, metastatic: Treatment of metastatic breast cancer (palliation) in appropriately selected men and postmenopausal women.

Hypoestrogenism (female): Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure

Osteoporosis prevention (female): Prevention of postmenopausal osteoporosis

Limitations of use: For use only in women at significant risk of postmenopausal osteoporosis; consider use of nonestrogen medications.

Prostate cancer, advanced: Treatment of androgen dependent advanced prostatic cancer (palliation)

Vasomotor symptoms associated with menopause: Treatment of moderate to severe vasomotor symptoms associated with menopause.

Vulvar and vaginal atrophy associated with menopause: Treatment of moderate to severe vulvar and vaginal atrophy associated with menopause.

Limitations of use: When used solely for the treatment of vulvar and vaginal atrophy, topical vaginal products should be considered.

Note: The International Society for the Study of Women’s Sexual Health and The North American Menopause Society have endorsed the term genitourinary syndrome of menopause (GSM) as new terminology for vulvovaginal atrophy. The term GSM encompasses all genital and urinary signs and symptoms associated with a loss of estrogen due to menopause Ref.

Use: Off-Label: Adult

  Functional hypothalamic amenorrhea with low bone density (young adult females)Level of Evidence [G]

Based on the Endocrine Society clinical practice guideline for the diagnosis and treatment of functional hypothalamic amenorrhea (FHA), short-term hormone replacement with transdermal estradiol (with cyclic oral progestin) is a suggested therapy in adolescents and women with low bone density and/or evidence of skeletal fragility who have not had a resumption of menses after 6 to 12 months of nutritional (calorie optimization; calcium, vitamin D, other nutrient supplementation), psychological, and/or modified exercise interventions. However, if nutritional deficits persist, hormone replacement may not protect bone health.

  Hormone therapy for transgender females (male-to-female)Level of Evidence [G]

Based on the Endocrine Society guidelines for the endocrine treatment of gender dysphoric/gender incongruent persons, estradiol as monotherapy or combination therapy, is effective for elevating serum estradiol levels and suppressing serum testosterone levels into the normal range for females, resulting in decreased hair growth, muscle mass, sexual desire, sperm production, spontaneous erections, and testicular volume, as well as breast growth, male sexual dysfunction, redistribution of body fat, and skin and voice changes. In many cases, estrogen therapy will need to be augmented with a second compound to suppress androgen secretion, such as spironolactone or a gonadotropin hormone-releasing agonist Ref.

Level of Evidence Definitions
  Level of Evidence Scale
Clinical Practice Guidelines

Functional Hypothalamic Amenorrhea:

“Functional Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice Guideline,” 2017

Hormone Therapy for Menopause:

American Association of Clinical Endocrinologists (AACE), Diagnosis and treatment of menopause, 2011

Endocrine Society (ES), Treatment of Symptoms of the Menopause, 2015

North American Menopause Society (NAMS), Hormone Therapy, 2017

North American Menopause Society (NAMS), Management of Symptomatic Vulvovaginal Atrophy, 2013

US Preventive Services Task Force (USPSTF), Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Women, 2017

Hormone Therapy for Transgender Females:

Endocrine Society, “Endocrine treatment of gender-dysphoric/gender-incongruent persons: An Endocrine Society clinical practice guideline,” December 2017

The World Professional Association for Transgender Health, “Standards of care for the health of transsexual, transgender and gender nonconforming people, Version 7,” 2011

Hypopituitarism:

Endocrine Society, “Hormonal Replacement in Hypopituitarism in Adults,” 2016

Oncology:

National Comprehensive Cancer Network (NCCN), Clinical Practice Guidelines in Oncology, Breast Cancer

National Comprehensive Cancer Network (NCCN), Clinical Practice Guidelines in Oncology, Prostate Cancer

Osteoporosis:

American Association of Clinical Endocrinologists and American College of Endocrinology, “Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis,” 2016

American College of Physicians, “Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update from the American College of Physicians,” 2017

National Osteoporosis Foundation, “Clinician’s Guide to Prevention and Treatment of Osteoporosis,” 2014

Administration: IM

Injection formulation: For intramuscular use only.

Estradiol cypionate: Shake or gently warm vial to redissolve crystals that may have formed during storage

Estradiol valerate: Should be injected into the upper outer quadrant of the gluteal muscle; administer with a dry needle (solution may become cloudy with wet needle).

The use of a progestin should be considered when administering estrogens to postmenopausal women with a uterus.

Administration: Topical

The use of a progestin should be considered when administering estrogens to postmenopausal women with a uterus.

Gel: Apply to clean, dry, unbroken skin at the same time each day. Wash hands after application. Gel is flammable; avoid fire or flame until skin is dry.

Divigel: Do not apply to face, breasts, vaginal area or irritated skin. The entire contents of packet should be applied to right or left upper thigh each day (alternate sites). Apply over an area ~5 x 7 inches. Do not wash application site for 1 hour. Allow gel to dry before dressing.

Elestrin: Do not apply to breasts or vaginal area. The entire dose should be applied to upper arm and shoulder area using two fingers to spread gel. Allow skin to dry for ≥5 minutes prior to dressing. Prior to first use, pump must be primed. After priming, the pump contains 30 metered doses; discard pump after 30 doses even though container may not be empty. If >1 dose is needed, wait 5 seconds before pumping next dose. To avoid secondary exposure, do not allow others to contact the application site for 2 hours after gel is applied. Allow at least 2 hours between applying gel and going swimming. Wait at least 25 minutes before applying sunscreen to application area. When sunscreen and gel are applied to the same site for >7 consecutive days, the absorption of estradiol is increased; do not apply sunscreen to an area where the gel was applied for ≥7 consecutive days.

EstroGel: Do not apply to breasts or vaginal area. Apply dose into the palm of hand and then apply gel to the other arm, from the wrist to the shoulder. Spread gel as thinly as possible over one arm but do not massage or rub in gel. Allow skin to dry for 5 minutes before dressing. Prior to first use, pump must be primed. After priming, the pump contains 32 daily doses (50 g canister) or 14 daily doses (25 g canister). Discard pump after allotted doses even though container may not be empty. To avoid secondary exposure, do not allow others to contact the application site for ≥1 hour after gel is applied. Wait as long as possible between applying gel and going swimming. When sunscreen was applied 1 hour after the gel to the same site for >7 consecutive days, the absorption of estradiol was decreased; when moisturizing lotion was applied 1 hour after the gel to the same site for >7 consecutive days, the absorption of estradiol was increased. The effect of applying sunscreen or lotion prior to the gel has not been studied.

Spray: Evamist: Prior to first use, prime pump by spraying 3 sprays with the cover on. To administer dose, hold container upright and vertical and rest the plastic cone flat against the skin while spraying. Spray to the inner surface of the forearm, starting near the elbow. If more than one spray is needed, apply to adjacent but not overlapping areas. Apply at the same time each day. Allow spray to dry for ~2 minutes; do not rub into skin; do not cover with clothing until dry. Do not wash application site for at least 60 minutes. Apply to clean, dry, unbroken skin. Do not apply to skin other than that of the forearm. Make sure that children do not come in contact with any skin area where the drug was applied. If contact with children is unavoidable, wear a garment with long sleeves that covers the site of application. If direct exposure should occur, wash the child in the area of exposure with soap and water as soon as possible. Solution contained in the spray is flammable; avoid fire, flame, or smoking until spray has dried. If needed, sunscreen should be applied ~1 hour prior to application of Evamist.

Transdermal patch: General administration instructions (also refer to product labeling): Apply patch immediately after removing from protective pouch to lower abdomen or buttocks. Apply to clean, dry, healthy skin that is free of oil, powder, or lotion. Avoid waistline or other areas where tight clothing may rub the patch off; do not apply to breasts. After application, hold patch in place using palm of hand for 10 seconds. Rotate application sites allowing a 1-week interval between applications at a particular site. In general, if patch falls off, the same patch may be reapplied or a new system may be used for the remainder of the dosing interval. When replacing patch, reapply to a new site. Remove patch slowly after use to avoid skin irritation. If any adhesive remains on the skin after removal, first allow skin to dry for 15 minutes, then gently rub area with an oil-based cream or lotion. Dispose of any used or unused patches by folding adhesive ends together, replace in pouch or sealed container and discard properly in trash away from children and pets.

Climara, Menostar: Swimming, bathing, or wearing patch while in a sauna have not been studied

Administration: Intravaginal

The use of a progestin should be considered when administering estrogens to postmenopausal women with a uterus.

Vaginal ring: Exact positioning is not critical for efficacy; however, patient should not feel anything once inserted. In case of discomfort, ring should be pushed further into vagina. If ring is expelled prior to 90 days, it may be rinsed off with warm water and reinserted. Ensure proper vaginal placement of the ring to avoid inadvertent urinary bladder insertion. If vaginal infection develops, Femring may remain in place during local treatment of a vaginal infection.

Administration: Pediatric

Oral: May administer with food or after a meal to reduce GI upset

Parenteral: Injection for IM use only

Cypionate: Inspect for any particulate (particularly crystals); warming and shaking the vial should redissolve any crystals

Transdermal: Note: See package insert for administration related to postmenopausal symptoms, prevention of osteoporosis in postmenopausal women, and palliative treatment of breast cancer or androgen-dependent prostate cancer in adults.

Gel (Divigel): Apply to clean, dry, unbroken skin at the same time each day. Apply entire contents of packet to right or left upper thigh each day (alternate sites). Do not apply to face, breasts, vaginal area, or irritated skin. Apply over an area ~5×7 inches. Do not wash application site for 1 hour. Allow to dry for 5 minutes prior to dressing. Gel is flammable; avoid fire or flame until dry. After application, wash hands with soap and water. Prior to the first use, pump must be primed.

Transdermal patch: Do not apply transdermal system to breasts, but place on trunk of body (preferably abdomen). Rotate application sites allowing a 1-week interval between applications at a particular site. Do not apply to oily, damaged or irritated skin; avoid waistline or other areas where tight clothing may rub the patch off. Apply patch immediately after removing from protective pouch. In general, if patch falls off, the same patch may be reapplied or a new system may be used for the remainder of the dosing interval (not recommended with all products) When replacing patch, reapply to a new site. Swimming, bathing, or showering are not expected to affect use of the patch. Note the following exceptions:

Climara, Menostar, Minivelle: Swimming, bathing, or wearing patch while in a sauna have not been studied; adhesion of patch may be decreased or delivery of estradiol may be affected. Showering is not expected to cause the Minivelle patch to fall off. Remove patch slowly after use to avoid skin irritation. If any adhesive remains on the skin after removal, first allow skin to dry for 15 minutes, then gently rub area with an oil-based cream or lotion. If patch falls off, a new patch should be applied for the remainder of the dosing interval.

Dietary Considerations

Ensure adequate calcium and vitamin D intake when used for the prevention of osteoporosis.

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 2]).

Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.

NIOSH recommends single gloving for administration of intact tablets or capsules. For IM preparation, NIOSH recommends double gloving, a protective gown, and ventilated engineering controls (a class II biological safety cabinet or a compounding aseptic containment isolator). Double gloving and a gown are required during IM administration. NIOSH recommends double gloving, a protective gown, and (if liquid that could splash) eye/face protection for administration of a topical product; if there is potential for inhalation, respiratory protection is recommended (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).

Storage/Stability

Store all products at controlled room temperature. In addition:

Depo-Estradiol: Protect from light.

Evamist: Do not freeze.

Femring: Store in pouch.

Transdermal patch (all products): Store in protective pouch.

Climara, Menostar: Do not store >30°C (>86°F).

Medication Patient Education with HCAHPS Considerations

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience hair loss, nausea, vomiting, cramps, bloating, enlarged breasts, painful periods, common cold symptoms, rhinitis, or pharyngitis. Have patient report immediately to prescriber signs of high calcium (weakness, confusion, fatigue, headache, nausea and vomiting, constipation, or bone pain), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of gallstones (pain in the upper right abdominal area, right shoulder area, or between the shoulder blades; jaundice; or fever with chills), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of blood clots (numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; angina; shortness of breath; tachycardia; or coughing up blood), severe headache, severe dizziness, passing out, severe abdominal pain, back pain, bulging eyes, contact lens discomfort, blindness, vision changes, lump in breast, breast soreness or pain, nipple discharge, vaginitis, abnormal vaginal bleeding, depression, mood changes, memory impairment, urinary retention, change in amount of urine passed, painful urination, edema, severe application site irritation, or signs of toxic shock syndrome (diarrhea, dizziness, passing out, severe muscle pain, nausea, vomiting, or sunburn like rash) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Medication Safety Issues
  Sound-alike/look-alike issues:
  Geriatric Patients: High-Risk Medication:
  Other safety issues:
  International issues:
Contraindications

Angioedema, anaphylactic reaction, or hypersensitivity to estradiol or any component of the formulation; undiagnosed abnormal genital bleeding; DVT or PE (current or history of); active or history of arterial thromboembolic disease (eg, stroke, MI); breast cancer (known, suspected or history of), except in appropriately selected patients being treated for metastatic disease; estrogen-dependent tumor (known or suspected); hepatic impairment or disease; known protein C, protein S, antithrombin deficiency or other known thrombophilic disorders; pregnancy (Note: Products approved for use only in postmenopausal women are not appropriate for use in pregnancy; use of some products is specifically contraindicated in the manufacturer’s labeling).

Documentation of allergenic cross-reactivity for estrogens is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Canadian labeling: Additional contraindications (not in US labeling): Note: May be dosage form dependent (consult product labeling): Breastfeeding; endometrial hyperplasia; active thrombophlebitis; partial or complete loss of vision or diplopia due to ophthalmic vascular disease; presence or history of hepatic tumors (benign or malignant); porphyria; classical migraine.

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylaxis: Anaphylaxis requiring emergency medical management has been reported and may develop at any time during therapy. Angioedema involving the face, feet, hands, larynx, and tongue has also been reported.

• Breast cancer: [US Boxed Warning]: Based on data from the Women’s Health Initiative (WHI) studies, an increased risk of invasive breast cancer was observed in postmenopausal women using conjugated estrogens (CE) in combination with medroxyprogesterone acetate (MPA). Observational studies noted this risk declines once therapy is discontinued. The WHI study did not observe an increased risk of invasive breast cancer in women with a hysterectomy using CE alone. The risk of breast cancer in postmenopausal patients on hormone therapy may depend upon type of estrogen and/or progestin, dose, timing of therapy initiation, duration of therapy, route of administration, and individual patient characteristics (AACE/ACE [Cobin 2017]; NAMS 2017). Hormone therapy may be associated with increased breast density (NAMS 2017); an increase in abnormal mammogram findings requiring further evaluation has been reported with estrogen alone or in combination with progestin therapy. Estrogen use may lead to severe hypercalcemia in patients with breast cancer and bone metastases; discontinue estrogen if hypercalcemia occurs.

• Dementia: [US Boxed Warning]: Estrogens with or without progestin should not be used to prevent dementia. In the Women’s Health Initiative Memory Study (WHIMS), an increased incidence of probable dementia was observed in women ≥65 years of age taking CE alone or in combination with MPA. Because the WHI memory studies were conducted in women ≥65 years of age, it is unknown if these findings apply to younger postmenopausal women. However, hormone therapy is not recommended at any age to prevent or treat cognitive decline or dementia (AACE [Goodman 2011]; NAMS 2017).

• Endometrial cancer: [US Boxed Warning]: The use of unopposed estrogen in women with a uterus is associated with an increased risk of endometrial cancer. The addition of a progestin to estrogen therapy may decrease the risk of endometrial hyperplasia, a precursor to endometrial cancer. Adequate diagnostic measures, including endometrial sampling if indicated, should be performed to rule out malignancy in postmenopausal women with undiagnosed abnormal vaginal bleeding.There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses. The risk of endometrial cancer appears to be dose and duration dependent, greatest with use ≥5 years, and may persist following discontinuation of therapy. The use of a progestin is not generally required when low doses of estrogen are used locally for vaginal atrophy, although long term data (>1 year) supporting this recommendation are lacking (NAMS 2013; NAMS 2017).

• Endometriosis: Estrogens may exacerbate endometriosis. Malignant transformation of residual endometrial implants has been reported posthysterectomy with unopposed estrogen therapy. Consider adding a progestin in women with residual endometriosis posthysterectomy.

• Lipid effects: Estrogen compounds are generally associated with lipid effects such as increased HDL-cholesterol and decreased LDL-cholesterol. Triglycerides may also be increased in women with preexisting hypertriglyceridemia; discontinue if pancreatitis occurs.

• Ovarian cancer: Available information related to the use of menopausal estrogen or estrogen/progestin therapy and risk of ovarian cancer is inconsistent. If an association is present, the absolute risk is likely rare and may be influenced by duration of therapy (AACE [Goodman 2011]; ES [Stuenkel 2015]; NAMS 2017).

• Retinal vascular thrombosis: Estrogens may cause retinal vascular thrombosis; discontinue if migraine, loss of vision, proptosis, diplopia, or other visual disturbances occur; discontinue permanently if papilledema or retinal vascular lesions are observed on examination.

Disease-related concerns:

• Asthma: Use caution with asthma; may exacerbate disease.

• Carbohydrate intolerance: May impair glucose tolerance; use caution in patients with diabetes. Prior to therapy, consider age, cardiovascular and metabolic risk factors in patients previously diagnosed with diabetes (AACE/ACE [Cobin 2017]).

• Cardiovascular disease: [US Boxed Warning]: Estrogens with or without progestin should not be used to prevent cardiovascular disease. Using data from the Women’s Health Initiative (WHI) studies, an increased risk of deep vein thrombosis (DVT) and stroke has been reported with CE and an increased risk of DVT, stroke, pulmonary emboli (PE) and myocardial infarction (MI) has been reported with CE with MPA in postmenopausal women 50 to 79 years of age. Additional risk factors include diabetes mellitus, hypercholesterolemia, hypertension, SLE, obesity, tobacco use, and/or history of venous thromboembolism (VTE). Adverse cardiovascular events have also been reported in males taking estrogens for prostate cancer. Risk factors should be managed appropriately; discontinue use immediately if adverse cardiovascular events occur or are suspected. Due to possible lower risk of thrombotic events, transdermal administration may be preferred for treating vasomotor symptoms of menopause in patients with risk factors for cardiovascular disease (AACE/ACE [Cobin 2017]; ACOG 556 2013; ES [Stuenkel 2015]). Use is contraindicated in women with active DVT, PE, arterial thromboembolic disease (stroke and MI), or a history of these conditions.

• Diseases exacerbated by fluid retention: Use caution with diseases which may be exacerbated by fluid retention, including cardiac or renal dysfunction.

• Epilepsy: Use caution with epilepsy; may exacerbate disease.

• Gallbladder disease: Use of postmenopausal estrogen may be associated with an increased risk of gallbladder disease requiring surgery.

• Hepatic dysfunction: Estrogens are poorly metabolized in patients with hepatic dysfunction. Use caution with a history of cholestatic jaundice associated with prior estrogen use or pregnancy. Discontinue if jaundice develops or if acute or chronic hepatic disturbances occur. Use is contraindicated with hepatic impairment or disease.

• Hepatic hemangiomas: Use caution with hepatic hemangiomas; may exacerbate disease.

• Hereditary angioedema: Exogenous estrogens may exacerbate angioedema symptoms in women with hereditary angioedema.

• Hypoparathyroidism: Use caution with hypoparathyroidism; estrogen-induced hypocalcemia may occur.

• Migraine: Use caution with migraine; may exacerbate disease.

• Porphyria: Use caution with porphyria; may exacerbate disease.

• SLE: Use caution with SLE; may exacerbate disease.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Thyroid replacement therapy: Estrogens may increase thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels. Women on thyroid replacement therapy may require higher doses of thyroid hormone while receiving estrogens.

Special populations:

• Pediatric: Prior to puberty, estrogens may cause premature closure of the epiphyses. Premature breast development, vaginal bleeding, and vaginal cornification may be induced in girls. Modification of the normal puberty process may occur in boys.

• Surgical patients: Whenever possible, estrogens should be discontinued at least 4 to 6 weeks prior to elective surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP [“Inactive” 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.

• Chlorobutanol: Some products may contain chlorobutanol (a chloral derivative) as a preservative, which may be habit forming.

• Tartrazine: Some products may contain tartrazine.

• Topical gel: Absorption of the topical gel (Elestrin) is increased by application of sunscreen; do not apply sunscreen within close proximity of estradiol. Application of sunscreen after EstroGel decreases absorption of estradiol while application of moisturizer lotion after EstroGel increases the absorption of estradiol; the effect of applying sunscreen or lotion prior to Estrogel has not been studied. Application of Divigel with sunscreen has not been evaluated.

• Topical spray: When sunscreen is applied ~1 hour prior to the topical spray (Evamist), no change in absorption was observed (estradiol absorption was decreased when sunscreen is applied 1 hour after Evamist).

• Transdermal patch: May contain conducting metal (eg, aluminum); remove patch prior to MRI.

• Vaginal ring: Use may not be appropriate in women with narrow vagina, vaginal stenosis, vaginal infections, cervical prolapse, rectoceles, cystoceles, or other conditions which may increase the risk of vaginal irritation, ulceration, or increase the risk of expulsion. Ring should be removed in case of ulceration, erosion, or adherence to vaginal wall; do not reinsert until healing is complete. Ensure proper vaginal placement of the ring to avoid inadvertent urinary bladder insertion.

Other warnings/precautions:

• Duration of use: Extended use of menopausal hormone therapy may be considered for persistent vasomotor symptoms, issues related to quality of life, or for osteoporosis prevention in women at increased risk of fracture. Menopausal hormonal therapy does not need to be routinely discontinued in women >60 years of age and may continue in women >65 years of age after clinical evaluation and discussion of benefits and risks of treatment. Annual exams should be performed with a review of comorbidities; possible adjustments to safer lower-dose and/or route of administration should be discussed (ACOG 565 2013; NAMS 2017).

• Genitourinary syndrome of menopause: Low-dose vaginal estrogen is preferred over systemic therapy for genitourinary syndrome of menopause (GSM) in the absence of vasomotor symptoms due to increased efficacy and decreased systemic effects (eg, cardiovascular effects, cancer risk) (Crandall 2018; NAMS 2013; NAMS 2017).

• Laboratory changes: The use of estrogens and/or progestins may change the results of some laboratory tests (eg, coagulation factors, lipids, glucose tolerance, binding proteins). The dose, route, and the specific estrogen/progestin influence these changes.

• Osteoporosis use: In women with premature menopause, hormone therapy to prevent bone loss may be used unless otherwise contraindicated; therapy should be reassessed when the average age of menopause is reached. It is also an appropriate bone-active therapy for women with vasomotor symptoms who are <60 years of age or within 10 years of menopause onset. Use may be considered for women at high risk of fractures who are not candidates for other osteoporosis therapies (NAMS 2017).

• Risks vs benefits: When used for the relief of menopausal symptoms or increased risk of bone fracture/loss, the benefit-risk of hormone therapy is most favorable if started in patients who have no contraindications to therapy, are <60 years of age, within 10 years of menopause onset, have a favorable lipid profile, and do not have the factor V Leiden genotype or metabolic syndrome. Risk factors for cardiovascular disease should also be considered when evaluating therapy and route of administration (AACE/ACE [Cobin 2017]; NAMS 2017). [US Boxed Warning]: Estrogens with or without progestin should be used for the shortest duration possible at the lowest effective dose consistent with treatment goals and risks for the individual woman. Patients should be reevaluated as clinically appropriate to determine if treatment is still necessary. Available data related to treatment risks are from Women’s Health Initiative (WHI) studies, which evaluated oral CE 0.625 mg with or without MPA 2.5 mg relative to placebo in postmenopausal women. Other combinations and dosage forms of estrogens and progestins were not studied. Outcomes reported from clinical trials using CE with or without MPA should be assumed to be similar for other doses and other dosage forms of estrogens and progestins until comparable data becomes available.

• Secondary exposure: Estradiol may be transferred to another person following skin-to-skin contact with the application site. [US Boxed Warning]: Breast budding and breast masses in prepubertal females and gynecomastia and breast masses in prepubertal males have been reported following unintentional contact with application sites of women using topical estradiol (Evamist). Patients should strictly adhere to instructions for use in order to prevent secondary exposure. In most cases, conditions resolved with removal of estradiol exposure. If unexpected changes in sexual development occur in prepubertal children, the possibility of unintentional estradiol exposure should be evaluated by a health care provider. Discontinue if conditions for the safe use of the topical spray cannot be met.

Geriatric Considerations

Before prescribing estrogen therapy to postmenopausal women, the risks and benefits must be weighed for each patient. Women should be informed of these risks and benefits, as well as possible side effects and the return of menstrual bleeding (when cycled with a progestin), and be involved in the decision to prescribe.

Warnings: Additional Pediatric Considerations

Some dosage forms may contain propylene glycol; in neonates large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP, 1997; Shehab, 2009).

Pregnancy Considerations

Products approved for use only in postmenopausal women are not appropriate for use in pregnancy; use of some products is specifically contraindicated in the manufacturer’s labeling.

In general, the use of estrogen and progestin as in combination hormonal contraceptives has not been associated with teratogenic effects when inadvertently taken early in pregnancy.

Breast-Feeding Considerations

Estrogens are present in breast milk.

Estrogens have been shown to decrease the quantity and quality of human milk. The manufacturers recommend caution be used if administered to breastfeeding women. Monitor the growth of the infant closely.

Briggs’ Drugs in Pregnancy & Lactation
Adverse Reactions

Frequency not always defined. Some adverse reactions observed with estrogen and/or progestin combination therapy.

Cardiovascular: Edema (10% to 13%), hypertension (3% to 7%), cerebrovascular accident, deep vein thrombosis, local thrombophlebitis, myocardial infarction, pulmonary thromboembolism, retinal thrombosis, thrombophlebitis, venous thromboembolism

Central nervous system: Headache (9% to 50%), pain (6% to 13%), depression (1% to 11%), anxiety (4% to 10%), dizziness (≤8%), migraine (7%), nipple pain (1% to 7%), hypoesthesia (3%), chorea, dementia, exacerbation of epilepsy, irritability, mood disorder, nervousness

Dermatologic: Skin rash (7% to 9%), pruritus (4% to 7%), chloasma, erythema multiforme, erythema nodosum, localized erythema (transdermal patch), loss of scalp hair, skin discoloration (melasma), urticaria

Endocrine & metabolic: Weight gain (4% to 9%), hot flash (6%), hirsutism (≤5%), change in libido, change in menstrual flow (alterations in frequency and flow of bleeding patterns), exacerbation of diabetes mellitus, exacerbation of porphyria, fibrocystic breast changes, fluid retention, galactorrhea, hypocalcemia, increased serum triglycerides, weight loss

Gastrointestinal: Abdominal pain (6% to 16%), dyspepsia (3% to 9%), constipation (4% to 7%), flatulence (3% to 7%), nausea (3% to 7%), gastroenteritis (3% to 4%), diarrhea (3%), abdominal cramps, bloating, carbohydrate intolerance, gallbladder disease, pancreatitis, vomiting

Genitourinary: Mastalgia (5% to 35%), vaginal hemorrhage (33%), breast tenderness (3% to 17%), endometrium disease (15%), breakthrough bleeding (6% to 11%), leukorrhea (2% to 11%), abnormal uterine bleeding (4% to 10%), breast hypertrophy (7%), dysmenorrhea (7%), cervical polyp (6%), vulvovaginal candidiasis (6%), urinary tract infection (4% to 6%), change in cervical ectropion, change in cervical secretions, endometrial hyperplasia, nipple discharge, spotting, uterine fibroids (size increased), uterine pain, vaginal discomfort (vaginal ring; burning, irritation, itching), vaginitis

Hematologic & oncologic: Hemorrhagic eruption, hypercoagulability state, malignant neoplasm of breast, ovarian cancer

Hepatic: Cholestatic jaundice, exacerbation of hepatic hemangioma

Hypersensitivity: Hypersensitivity reaction (4% to 5%), anaphylactoid reaction, anaphylaxis, angioedema

Infection: Infection (3% to 12%), fungal infection (3% to 10%)

Local: Application site reaction (gel, spray, transdermal patch ≤1%)

Neuromuscular & skeletal: Arthralgia (4% to 12%), back pain (3% to 11%), weakness (8%), limb pain (7% to 8%), myalgia (5% to 6%), neck pain (3% to 6%), arthropathy (4% to 5%), exacerbation of systemic lupus erythematosus, leg cramps

Ophthalmic: Conjunctivitis (3%), change in corneal curvature (steepening), contact lens intolerance

Otic: Otitis media (3%)

Respiratory: Nasopharyngitis (4% to 20%), upper respiratory tract infection (6% to 17%), flu-like symptoms (8% to 13%), sinusitis (4% to 13%), sinus headache (9% to 11%), bronchitis (6% to 8%), sinus congestion (7%), pharyngitis (2% to 7%), rhinitis (2% to 6%), cough (3% to 4%), asthma (3%), exacerbation of asthma

Miscellaneous: Accidental injury (7% to 14%), cyst (7%)

Postmarketing and/or case reports: Abnormal gait, abnormal hepatic function tests, aphasia, blindness, bowel obstruction (vaginal ring), chest pain, cholecystitis, cholelithiasis, cognitive dysfunction, dyspnea, emotional lability, fatigue, genitourinary complaint (inadvertent ring insertion into the bladder should be considered with unexplained urinary complaints), hemorrhage, hepatitis, hyperhidrosis, hypermenorrhea, ischemic heart disease, lip swelling, local irritation (transdermal patch), localized erythema (transdermal patch), malaise, mechanical complication of genitourinary device (ring adherence to vaginal or bladder wall), meningioma, muscle spasm, myoclonus, night sweats, oral paresthesia, ovarian cyst, palpitations, paresthesia, peripheral edema, pharyngeal edema, phlebitis, portal vein thrombosis, purpura, retinal vein occlusion, soft tissue sarcoma (malignant mesenchymoma), swollen tongue, tachyphylaxis, toxic shock syndrome (vaginal ring), transient ischemic attacks, unstable angina pectoris, uterine enlargement, uterine neoplasm, vaginal discharge

Allergy and Idiosyncratic Reactions
Metabolism/Transport Effects

Substrate of CYP1A2 (major), CYP2A6 (minor), CYP2B6 (minor), CYP2C19 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP2E1 (minor), CYP3A4 (major), P-glycoprotein/ABCB1; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP1A2 (weak)

Drug Interactions 

Ajmaline: Estrogen Derivatives may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Risk C: Monitor therapy

Anastrozole: Estrogen Derivatives may diminish the therapeutic effect of Anastrozole. Risk X: Avoid combination

Anthrax Immune Globulin (Human): Estrogen Derivatives may enhance the thrombogenic effect of Anthrax Immune Globulin (Human). Risk C: Monitor therapy

Anticoagulants: Estrogen Derivatives may diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Risk D: Consider therapy modification

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Ascorbic Acid: May increase the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Broccoli: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy

C1 inhibitors: Estrogen Derivatives may enhance the thrombogenic effect of C1 inhibitors. Risk C: Monitor therapy

Cannabis: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy

Chenodiol: Estrogen Derivatives may diminish the therapeutic effect of Chenodiol. Management: Monitor clinical response to chenodiol closely when used together with any estrogen derivative. Risk C: Monitor therapy

CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Risk C: Monitor therapy

Corticosteroids (Systemic): Estrogen Derivatives may increase the serum concentration of Corticosteroids (Systemic). Risk C: Monitor therapy

Cosyntropin: Estrogen Derivatives may diminish the diagnostic effect of Cosyntropin. Management: Discontinue estrogen containing drugs 4 to 6 weeks prior to cosyntropin (ACTH) testing. Risk D: Consider therapy modification

CYP1A2 Inducers (Moderate): May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Risk D: Consider therapy modification

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Risk D: Consider therapy modification

Dantrolene: Estrogen Derivatives may enhance the hepatotoxic effect of Dantrolene. Risk C: Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Dehydroepiandrosterone: May enhance the adverse/toxic effect of Estrogen Derivatives. Risk X: Avoid combination

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Risk D: Consider therapy modification

Exemestane: Estrogen Derivatives may diminish the therapeutic effect of Exemestane. Risk X: Avoid combination

Hemin: Estrogen Derivatives may diminish the therapeutic effect of Hemin. Risk X: Avoid combination

Herbs (Estrogenic Properties): May enhance the adverse/toxic effect of Estrogen Derivatives. Risk C: Monitor therapy

Hyaluronidase: Estrogen Derivatives may diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving estrogens (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Risk D: Consider therapy modification

Immune Globulin: Estrogen Derivatives may enhance the thrombogenic effect of Immune Globulin. Risk C: Monitor therapy

Indium 111 Capromab Pendetide: Estrogen Derivatives may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Risk X: Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

LamoTRIgine: Estrogen Derivatives may decrease the serum concentration of LamoTRIgine. Risk C: Monitor therapy

Lenalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Lenalidomide. Risk C: Monitor therapy

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Risk D: Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Risk D: Consider therapy modification

Mivacurium: Estrogen Derivatives may increase the serum concentration of Mivacurium. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the thrombogenic effect of Estrogen Derivatives. Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may increase the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy

Ospemifene: Estrogen Derivatives may enhance the adverse/toxic effect of Ospemifene. Estrogen Derivatives may diminish the therapeutic effect of Ospemifene. Risk X: Avoid combination

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Risk D: Consider therapy modification

Pomalidomide: May enhance the thrombogenic effect of Estrogen Derivatives. Management: Canadian pomalidomide labeling recommends caution with use of hormone replacement therapy and states that hormonal contraceptives are not recommended. US pomalidomide labeling does not contain these specific recommendations. Risk D: Consider therapy modification

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Risk C: Monitor therapy

ROPINIRole: Estrogen Derivatives may increase the serum concentration of ROPINIRole. Risk C: Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Somatropin: Estrogen Derivatives may diminish the therapeutic effect of Somatropin. Shown to be a concern with oral hormone replacement therapy in postmenopausal women. Management: Monitor for reduced growth hormone efficacy. A larger somatropin dose may be required to reach treatment goal. This interaction does not appear to apply to non-orally administered estrogens (e.g., transdermal, vaginal ring). Risk D: Consider therapy modification

St John’s Wort: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Risk D: Consider therapy modification

Succinylcholine: Estrogen Derivatives may increase the serum concentration of Succinylcholine. Risk C: Monitor therapy

Teriflunomide: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy

Thalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Thalidomide. Risk C: Monitor therapy

Theophylline Derivatives: Estrogen Derivatives may increase the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline. Risk C: Monitor therapy

Thyroid Products: Estrogen Derivatives may diminish the therapeutic effect of Thyroid Products. Risk C: Monitor therapy

Tipranavir: Estrogen Derivatives may enhance the dermatologic adverse effect of Tipranavir. The combination of tipranavir/ritonavir and ethinyl estradiol/norethindrone was associated with a high incidence of skin rash. Tipranavir may decrease the serum concentration of Estrogen Derivatives. Management: Women using hormonal contraceptives should consider alternative, non-hormonal forms of contraception. Risk D: Consider therapy modification

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions.Risk D: Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Ursodiol: Estrogen Derivatives may diminish the therapeutic effect of Ursodiol. Risk C: Monitor therapy

Food Interactions

Folic acid absorption may be decreased. Routine use of ethanol increases estrogen level and risk of breast cancer; may also increase the risk of osteoporosis. Management: Avoid ethanol.

Test Interactions

Reduced response to metyrapone test.

Monitoring Parameters

Females: Prior to therapy, baseline risk for breast cancer and CVD. During therapy, age appropriate breast and pelvic exams; blood pressure; unscheduled bleeding lasting >6 months for endometrial pathology (sooner in patients who are obese, diabetic, or have a history of endometrial cancer); serum triglycerides (2 weeks after starting therapy in patients with baseline level >200 mg/dL); TSH (6 to 12 weeks after starting oral therapy in patients taking thyroid replacement) (ES [Stuenkel 2015]).

Menopausal symptoms: Efficacy beginning 1 to 3 months after starting therapy, then every 6 to 12 months as appropriate. Duration of treatment should be evaluated at least annually (ES [Stuenkel 2015]).

Note: Monitoring of FSH and serum estradiol is not useful when managing vasomotor symptoms or GSM

Prevention of osteoporosis: Bone density measurement

Menostar: When used in a woman with a uterus, endometrial sampling is recommended at yearly intervals or when clinically indicated.

Transgender hormone therapy: Serum estradiol levels (goal: ≤100 to 200 pg/mL) and serum testosterone levels (goal: <50 ng/dL) every 3 months during the first year and then annually or biannually; prolactin levels (as appropriate); routine cancer and laboratory screening as in non-transgender individuals for all tissues present (ES [Hembree 2017]).

Advanced Practitioners Physical Assessment/Monitoring

Assess results of annual gynecological exam. Monitor for thromboembolism, hypertension, edema, and CNS changes on a regular basis during therapy. Before prescribing estrogen therapy to postmenopausal women, the risks and benefits must be weighed for each patient. Women should be informed of these risks and benefits. as well as possible effects of progestin when added to estrogen therapy. Estrogens with or without progestin should be used for shortest duration possible consistent with treatment goals and periodic assessment of risk: benefit should be made. Caution patients with diabetes to monitor glucose levels closely (may impair glucose tolerance). Remind patient about the importance of frequent self-breast exams and the need for annual gynecological exam. If used for prostate cancer or breast cancer in men, follow appropriate monitoring guidelines. Monitor thyroid function and lipids during treatment.

Nursing Physical Assessment/Monitoring

Monitor for CNS changes, hypertension, thromboembolism, fluid retention, edema, CHF, and respiratory changes on a regular basis during therapy. Caution patients with diabetes to monitor glucose levels closely (may impair glucose tolerance). Remind patient about the importance of frequent self-breast exams and the need for annual gynecological exam.

Dosage Forms Considerations

EC-RX Estradiol is a compounding kit. Refer to manufacturer’s labeling for compounding instructions.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Gel, Transdermal:

Divigel: 0.25 mg/0.25 g (1 ea); 0.5 mg/0.5 g (1 ea); 0.75 mg/0.75 g (1 ea); 1 mg/g (1 g) [contains propylene glycol, trolamine (triethanolamine)]

Elestrin: 0.06% (26 g) [contains edetate disodium, propylene glycol, trolamine (triethanolamine)]

Estrogel: 0.06% (50 g) [contains alcohol, usp, trolamine (triethanolamine)]

Oil, Intramuscular, as cypionate:

Depo-Estradiol: 5 mg/mL (5 mL) [contains chlorobutanol (chlorobutol)]

Oil, Intramuscular, as valerate:

Delestrogen: 10 mg/mL (5 mL) [contains chlorobutanol (chlorobutol), sesame oil]

Delestrogen: 20 mg/mL (5 mL); 40 mg/mL (5 mL) [contains benzyl alcohol, benzyl benzoate, castor oil (ricine oil)]

Generic: 20 mg/mL (5 mL); 40 mg/mL (5 mL)

Patch Twice Weekly, Transdermal:

Alora: 0.025 mg/24 hr (1 ea, 8 ea); 0.05 mg/24 hr (1 ea, 8 ea); 0.075 mg/24 hr (1 ea, 8 ea); 0.1 mg/24 hr (1 ea, 8 ea)

Minivelle: 0.025 mg/24 hr (1 ea, 8 ea); 0.0375 mg/24 hr (1 ea, 8 ea); 0.05 mg/24 hr (1 ea, 8 ea); 0.075 mg/24 hr (1 ea, 8 ea); 0.1 mg/24 hr (1 ea, 8 ea)

Vivelle-Dot: 0.025 mg/24 hr (1 ea, 8 ea); 0.0375 mg/24 hr (1 ea, 8 ea); 0.05 mg/24 hr (1 ea, 8 ea); 0.075 mg/24 hr (1 ea, 8 ea); 0.1 mg/24 hr (1 ea, 8 ea)

Generic: 0.025 mg/24 hr (1 ea, 8 ea); 0.0375 mg/24 hr (1 ea, 8 ea); 0.05 mg/24 hr (1 ea, 8 ea); 0.075 mg/24 hr (1 ea, 8 ea); 0.1 mg/24 hr (1 ea, 8 ea)

Patch Weekly, Transdermal:

Climara: 0.025 mg/24 hr (4 ea); 0.0375 mg/24 hr (4 ea); 0.05 mg/24 hr (1 ea, 4 ea); 0.06 mg/24 hr (4 ea); 0.075 mg/24 hr (4 ea); 0.1 mg/24 hr (1 ea, 4 ea)

Menostar: 14 mcg/24 hr (4 ea)

Generic: 0.025 mg/24 hr (1 ea, 4 ea); 0.0375 mg/24 hr (1 ea, 4 ea); 0.05 mg/24 hr (1 ea, 4 ea); 0.06 mg/24 hr (1 ea, 4 ea); 0.075 mg/24 hr (1 ea, 4 ea); 0.1 mg/24 hr (1 ea, 4 ea)

Ring, Vaginal, as acetate:

Femring: 0.05 mg/24 hr (1 ea); 0.1 mg/24 hr (1 ea)

Solution, Transdermal:

Evamist: 1.53 mg/spray (8.1 mL)

Tablet, Oral:

Estrace: 0.5 mg, 1 mg, 2 mg [scored]

Generic: 0.5 mg, 1 mg, 2 mg

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Gel, Transdermal:

Divigel: 0.25 mg/0.25 g (1ea); 0.5 mg/0.5 g (1ea); 1 mg/g (1ea, 1gm) [contains PROPYLENE GLYCOL, TROLAMINE (TRIETHANOLAMINE)]

Divigel: 0.1% (0.25gm[DSC], 0.5gm[DSC], 1gm[DSC], 30ea[DSC]) [contains ALCOHOL, USP, PROPYLENE GLYCOL, TROLAMINE (TRIETHANOLAMINE)]

Estrogel: 0.06% (80gm) [contains ALCOHOL, USP, TROLAMINE (TRIETHANOLAMINE)]

Oil, Intramuscular, as valerate:

Generic: 10 mg/mL (10ml[DSC])

Patch Twice Weekly, Transdermal:

Estradot 25: 0.025 mg/24 hr (8ea)

Estradot 37.5: 0.0375 mg/24 hr (8ea)

Estradot 50: 0.05 mg/24 hr (8ea)

Estradot 75: 0.075 mg/24 hr (8ea)

Estradot 100: 0.1 mg/24 hr (8ea)

Oesclim: 0.025 mg/24 hr (8ea); 0.0375 mg/24 hr (8ea); 0.05 mg/24 hr (8ea); 0.075 mg/24 hr (8ea); 0.1 mg/24 hr (8ea)

Generic: 0.05 mg/24 hr (1ea); 0.075 mg/24 hr (1ea); 0.1 mg/24 hr (1ea)

Patch Weekly, Transdermal:

Climara 25: 0.025 mg/24 hr (4ea)

Climara 50: 0.05 mg/24 hr (4ea)

Climara 75: 0.075 mg/24 hr (4ea)

Climara 100: 0.1 mg/24 hr (4ea[DSC])

Tablet, Oral:

Estrace: 0.5 mg [contains TARTRAZINE (FD&C YELLOW #5)]

Estrace: 1 mg [contains BRILLIANT BLUE FCF (FD&C BLUE #1)]

Estrace: 2 mg [contains BRILLIANT BLUE FCF (FD&C BLUE #1), TARTRAZINE (FD&C YELLOW #5)]

Generic: 0.5 mg, 1 mg, 2 mg

Anatomic Therapeutic Chemical (ATC) Classification
  • G03CA03
Generic Available (US)

May be product dependent

Pricing: US

Gel (Divigel Transdermal)

0.25 mg/0.25gm (per each): $5.32

0.5 mg/0.5 g (per each): $5.32

0.75MG/0.75GM (per each): $5.32

1 mg/g (per gram): $5.32

Gel (Elestrin Transdermal)

0.52 MG/0.87 GM (0.06%) (per gram): $4.66

Gel (Estrogel Transdermal)

0.75 MG/1.25 GM (0.06%) (per gram): $2.91

Oil (Delestrogen Intramuscular)

10 mg/mL (per mL): $31.86

20 mg/mL (per mL): $44.90

40 mg/mL (per mL): $74.47

Oil (Depo-Estradiol Intramuscular)

5 mg/mL (per mL): $25.27

Oil (Estradiol Valerate Intramuscular)

20 mg/mL (per mL): $28.86

40 mg/mL (per mL): $47.88

Patch weekly (Climara Transdermal)

0.025 mg/24 hrs (per each): $39.54

0.0375 mg/24 hrs (per each): $39.54

0.05 mg/24 hrs (per each): $39.54

0.06 mg/24 hrs (per each): $39.54

0.075 mg/24 hrs (per each): $39.54

0.1 mg/24 hrs (per each): $39.54

Patch weekly (Estradiol Transdermal)

0.025 mg/24 hrs (per each): $22.10 – $23.21

0.0375 mg/24 hrs (per each): $22.10 – $23.21

0.05 mg/24 hrs (per each): $22.10 – $23.21

0.06 mg/24 hrs (per each): $22.10 – $23.21

0.075 mg/24 hrs (per each): $22.10 – $23.21

0.1 mg/24 hrs (per each): $22.10 – $23.21

Patch weekly (Menostar Transdermal)

14 mcg/24 hrs (per each): $48.68

Patch, twice-weekly (Alora Transdermal)

0.025 mg/24 hrs (per each): $15.48

0.05 mg/24 hrs (per each): $16.94

0.075 mg/24 hrs (per each): $17.29

0.1 mg/24 hrs (per each): $17.69

Patch, twice-weekly (Estradiol Transdermal)

0.025 mg/24 hrs (per each): $11.33 – $24.46

0.0375 mg/24 hrs (per each): $11.34 – $24.46

0.05 mg/24 hrs (per each): $11.34 – $24.46

0.075 mg/24 hrs (per each): $11.35 – $24.46

0.1 mg/24 hrs (per each): $11.35 – $24.46

Patch, twice-weekly (Minivelle Transdermal)

0.025 mg/24 hrs (per each): $27.21

0.0375 mg/24 hrs (per each): $27.21

0.05 mg/24 hrs (per each): $27.21

0.075 mg/24 hrs (per each): $27.21

0.1 mg/24 hrs (per each): $27.21

Patch, twice-weekly (Vivelle-Dot Transdermal)

0.025 mg/24 hrs (per each): $18.19

0.0375 mg/24 hrs (per each): $18.19

0.05 mg/24 hrs (per each): $18.20

0.075 mg/24 hrs (per each): $18.22

0.1 mg/24 hrs (per each): $18.23

Ring (Femring Vaginal)

0.05 mg/24 hrs (per each): $532.40

0.1 mg/24 hrs (per each): $567.35

Solution (Evamist Transdermal)

1.53 mg/spray (per mL): $18.34

Tablets (Estrace Oral)

0.5 mg (per each): $6.54

1 mg (per each): $6.54

2 mg (per each): $8.40

Tablets (Estradiol Oral)

0.5 mg (per each): $0.28 – $0.55

1 mg (per each): $0.38 – $0.68

2 mg (per each): $0.54 – $0.94

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer’s AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

Estrogens are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estradiol is the principle intracellular human estrogen and is more potent than estrone and estriol at the receptor level; it is the primary estrogen secreted prior to menopause. Following menopause, estrone and estrone sulfate are more highly produced. Estrogens modulate the pituitary secretion of gonadotropins, luteinizing hormone, and follicle-stimulating hormone through a negative feedback system; estrogen replacement reduces elevated levels of these hormones in postmenopausal women.

Pharmacodynamics/Kinetics

Absorption: Well absorbed from the gastrointestinal tract, mucous membranes, and the skin. Average serum estradiol concentrations (Cavg) vary by product

Injection: Estradiol valerate and estradiol cypionate are absorbed over several weeks following IM injection

Topical:

Alora: Cavg: 41 to 98 pg/mL

Climara: Cavg: 22 to 106 pg/mL

Divigel: Cavg: 9.8 to 30.5 pg/mL

Elestrin: Cavg: 15.4 to 39.2 pg/mL; Exposure increased by 55% with application of sunscreen 10 minutes prior to dose

Estrogel: Cavg on day 14 of therapy: 28.3 pg/mL. Cmax of estradiol is altered by repeated daily application (for 7 days) of sunscreen (decreased by 16%) or lotion (increased by 73%) when applied 1 hour after the dose.

Evamist: Cavg: 19.6 to 30.9 pg/mL

Menostar: Cavg: 13.7 pg/mL

Vivelle-Dot: Cavg: 34 to 104 pg/mL

Vaginal: Femring: Rapid during the first hour following application, then declines to a steady rate over 3 months; Cavg: 40.6 to 76 pg/mL

Distribution: Widely distributed; high concentrations in the sex hormone target organs

Protein binding: Bound to sex hormone-binding globulin and albumin

Metabolism: Hepatic; partial metabolism via CYP3A4 enzymes; estradiol is reversibly converted to estrone and estriol; oral estradiol also undergoes enterohepatic recirculation by conjugation in the liver, followed by excretion of sulfate and glucuronide conjugates into the bile, then hydrolysis in the intestine and estrogen reabsorption. Sulfate conjugates are the primary form found in postmenopausal women. With transdermal application, less estradiol is metabolized leading to higher circulating concentrations of estradiol and lower concentrations of estrone and conjugates.

Excretion: Primarily urine (as estradiol, estrone, estriol and their glucuronide and sulfate conjugates)

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

No significant effects or complications reported

Effects on Bleeding

No information available to require special precautions

Index Terms

17-beta E2; 17-beta estradiol; E2; Estradiol; Estradiol Acetate; Estradiol Transdermal; Estradiol Valerate; Gynodiol; Vivelle Dot

References

<800> Hazardous Drugs—Handling in Healthcare Settings. United States Pharmacopeia and National Formulary (USP 40-NF 35). Rockville, MD: United States Pharmacopeia Convention; 2017:83-102.

American College of Obstetricians and Gynecologists. ACOG committee opinion no. 556: Postmenopausal estrogen therapy: route of administration and risk of venous thromboembolism. Obstet Gynecol. 2013;121:887-890.[PubMed 23635705]

American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 141: management of menopausal symptoms. Obstet Gynecol. 2014;123(1):202-216. doi: 10.1097/01.AOG.0000441353.20693.78. Erratum in: Obstet Gynecol. 2016;127(1):166.[PubMed 24463691]

ACOG Committee Opinion No. 565: Hormone therapy and heart disease. Obstet Gynecol. 2013;121:1407-1410.[PubMed 23812486]

Ahlfors CE. Benzyl alcohol, kernicterus, and unbound bilirubin. J Pediatr. 2001;139(2):317-319.[PubMed 11487763]

Alora (estradiol transdermal system) [prescribing information]. Madison, NJ: Allergan USA, Inc; November 2018.

American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American Geriatrics Society 2015 updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2015;63(11):2227-2246. doi:10.1111/jgs.13702.[PubMed 26446832]

Anderson GL, Limacher M, Assaf AR, et al, “Effects of Conjugated Equine Estrogen In Postmenopausal Women With Hysterectomy: The Women’s Health Initiative Randomized Controlled Trial.” JAMA, 2004, 291(14):1701-12.[PubMed 15082697]

Centers for Disease Control (CDC). Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep. 1982;31(22):290-291. http://www.cdc.gov/mmwr/preview/mmwrhtml/00001109.htm[PubMed 6810084]

Climara (estradiol transdermal system) [prescribing information]. Whippany, NJ: Bayer; November 2017.

Cobin RH, Goodman NF; AACE Reproductive Endocrinology Scientific Committee. American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) position statement on menopause-2017 update. Endocr Pract. 2017;23(7):869-880. doi: 10.4158/EP171828.PS.[PubMed 28703650]

Crandall CJ, Hovey KM, Andrews CA, et al. Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the Women’s Health Initiative Observational Study. Menopause. 2018;25(1):11-20. doi: 10.1097/GME.0000000000000956.[PubMed 28816933]

Delestrogen (estradiol valerate) [prescribing information]. Spring Valley, NY: Par Pharmaceutical; November 2017.

Depo-Estradiol (estradiol cypionate) [prescribing information]. New York, NY: Pharmacia & Upjohn Company; November 2016.

Divigel (estradiol gel) [prescribing information]. Bridgewater, NJ; Vertical Pharmaceuticals; August 2018.

Divigel (estradiol gel) [product monograph]. Montreal, Quebec, Canada: Searchlight Pharma Inc; March 2019.

Elestrin (estradiol gel) [prescribing information]. Somerset NJ; Meda Pharmaceuticals; November 2017.

Ellis MJ, Gao F, Dehdashti F, et al, “Lower-Dose vs High-Dose Oral Estradiol Therapy of Hormone Receptor-Positive, Aromatase Inhibitor-Resistant Advanced Breast Cancer: A Phase 2 Randomized Study,” JAMA, 2009, 302(7):774-80.[PubMed 19690310]

Estrace (estradiol) cream [prescribing information]. Madison, NJ: Allergan; June 2018.

Estrace (estradiol) tablets [prescribing information]. North Wales, PA: Teva Pharmaceuticals USA, Inc; May 2016.

Estrace (estradiol) [product monograph]. Mississauga, Ontario, Canada: Acerus Pharmaceuticals; August 2015.

Estraderm (estradiol) [prescribing information]. East Hanover, PA: Novartis Pharmaceuticals; November 2017.

Estradot (estradiol) [product monograph]. Dorval, Quebec, Canada: Novartis Pharmaceuticals Canada Inc; August 2017.

EstroGel (estradiol gel) [prescribing information]. Herndon, VA: ASCEND Therapeutics; November 2017.

Evamist (estradiol transdermal spray) [prescribing information]. Minneapolis, MN: Perrigo; November 2017.

Femring (estradiol acetate) [prescribing information]. Irvine, CA: Allergan; August 2018.

Femtrace (estradiol acetate) [prescribing information]. Irvine, CA: Allergan USA Inc; November 2017.

Goodman NF, Cobin RH, Ginzburg SB, et al; American Association of Clinical Endocrinologists (AACE). American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of menopause. Endocr Pract. 2011;17(suppl 6):1-25.[PubMed 22193047]

Gordon CM, Ackerman KE, Berga SL, et al. Functional hypothalamic amenorrhea: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2017;102(5):1413-1439. doi: 10.1210/jc.2017-00131.[PubMed 28368518]

Hembree WC, Cohen-Kettenis PT, Gooren L, et al. Endocrine treatment of gender-dysphoric/gender-incongruent persons: an Endocrine Society clinical practice guideline. Endocr Pract. 2017;23(12):1437. doi: 10.4158/1934-2403-23.12.1437.[PubMed 29320642]

Hsia J, Langer RD, Manson JE, et al, “Conjugated Equine Estrogens and Coronary Heart Disease: The Women’s Health Initiative,” Arch Intern Med, 2006, 166(3):357-65.[PubMed 16476878]

Hulley S, Grady D, Bush T, et al, “Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group,” JAMA, 1998, 280(7):605-13.[PubMed 9718051]

“Inactive” ingredients in pharmaceutical products: update (subject review). American Academy of Pediatrics (AAP) Committee on Drugs. Pediatrics. 1997;99(2):268-278.[PubMed 9024461]

Menostar (estradiol transdermal system) [prescribing information]. Whippany, NJ: Bayer HealthCare; August 2017.

Minivelle (estradiol transdermal system) [prescribing information]. Miami, FL: Noven Pharmaceuticals; November 2017.

Misra M, Katzman D, Miller KK, et al. Physiologic estrogen replacement increases bone density in adolescent girls with anorexia nervosa. J Bone Miner Res. 2011;26(10):2430-2438. doi:10.1002/jbmr.447.[PubMed 21698665]

North American Menopause Society (NAMS). The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017;24(7):728-753. doi: 10.1097/GME.0000000000000921.[PubMed 28650869]

North American Menopause Society [NAMS], Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society. Menopause. 2013 Sep;20(9):888-902; quiz 903-4. doi: 10.1097/GME.0b013e3182a122c2.[PubMed 23985562]

Oesclim (estradiol) [product monograph]. Montreal, Quebec, Canada: Searchlight Pharma Inc; February 2017.

Pharmacy Quality Alliance. Use of high-risk medications in the elderly (HRM). http://pqaalliance.org/images/uploads/files/HRM2015.pdf. Published 2015. Accessed October 26, 2015.

Portman DJ, Gass ML; Vulvovaginal Atrophy Terminology Consensus Conference Panel. Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women’s Sexual Health and the North American Menopause Society. Menopause. 2014;21(10):1063-8. doi: 10.1097/GME.0000000000000329.[PubMed 25160739]

Rossouw JE, Anderson GL, Prentice RL, et al, “Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principle Results From the Women’s Health Initiative Randomized Controlled Trial,” JAMA, 2002, 288(3):321-33.[PubMed 12117397]

Shumaker SA, Legault C, Rapp SR, et al, “Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women: The Women’s Health Initiative Memory Study: A Randomized Controlled Trial,” JAMA, 2003, 289(20):2651-62.[PubMed 12771112]

Stallard S, Litherland JC, Cordiner CM, et al, “Effect of Hormone Replacement Therapy on the Pathological Stage of Breast Cancer: Population Based, Cross Sectional Study,” BMJ, 2000, 320(7231):348-9.[PubMed 10657329]

Stuenkel CA, Davis SR, Gompel A, et al. Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline [published online ahead of print October 7, 2015]. J Clin Endocrinol Metab. 2015:jc20152236.[PubMed 26444994]

US Department of Health and Human Services; Centers for Disease Control and Prevention; National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2016. http://www.cdc.gov/niosh/topics/antineoplastic/pdf/hazardous-drugs-list_2016-161.pdf. Updated September 2016. Accessed October 5, 2016.

Vivelle (estradiol transdermal system) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; November 2017.

Vivelle-Dot (estradiol transdermal system) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; August 2017.

Brand Names: International

Aerodiol (AT, BE); Bedol (GB, IE); Climaderm (BR, VE); Climara (AT, AU, BB, BE, BG, CH, CZ, EE, FI, FR, IE, KR, LU, LV, NZ, PH, PL, RU, TH, ZA); Dermestril (BE, CZ, DE, FI, IT, PT); Dermestril Septem (FR); Divigel (CH, DK, EE, IE, IN, LV, MY, SE, SG, TH, TW, UA); Enadiol (CL, PY); Estra Gel (TW); Estrade (TW); Estraderm (CO, DK, ES, SE, VN); Estraderm MX (AU, IN, PT, SA, SG); Estraderm TTS (AE, AT, BF, BJ, CI, CO, CY, CZ, DE, EG, ET, FR, GB, GH, GM, GN, GR, IQ, IR, IT, JO, KE, KR, LB, LR, LY, MA, ML, MR, MU, MW, NE, NG, NZ, OM, PL, PY, SC, SD, SL, SN, SY, TN, TR, TZ, UG, YE, ZA, ZM); Estradiol Depot (KR); Estradot (AU, BR, CZ, DE, ES, FI, GB, GR, IE, NO, PT, SE, UY); Estramon (UA); Estrapatch (FR); Estreva (DE, HK, PE, PT, TR, VN); Estreva Gel (PE); Estrifam (DE); Estro-Pause (ZA); Estrofem (AR, AT, AU, BE, BR, CH, CN, CZ, DK, EE, EG, FI, FR, HK, HU, IL, IN, IS, JO, KR, LB, LT, LU, LV, NZ, PH, RU, SA, SG, SI, TH, UY); Estrofem Forte (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZM, ZW); Estrogel (VE); Estrozhel (UA); Evopad (ES); Evorel (AR, BB, BM, BS, DK, GY, IE, IL, JM, NL, NO, PR, SE, SR, TT, UY, ZA); Evorel Conti (BB, BM, BS, GY, JM, NL, PR, SR, TT); Fem (CN); Femanest (SE); Fematab (IE); Fematrix (GB, IE); Feminova (BE); Femsept (FR); Femseven (GB, IE); Femtran (AU, NZ); Ginoderm Gel (PY); Gynokadin (DE); Gynova (BD); GynPolar (DE); Kliovance (AU); Lindisc (AR, CO, CR, EC, GT, HN, NI, PA, SV); Linoladiol N (EE); Lumelin 2 (TW); Menodin-Retard (CO); Menorest (AU, DE, IT); Merimono (DE); Oesclim (FR); Oestrodose (IL); Postmenop (TH); Preda (KR); Primogyn Depot (ZA); Progyluton 21 (ZW); Progynon (CH, DE, DK, IT, SE); Progynon Depot (IN, TW); Progynova (AR, AT, AU, BE, BZ, CL, CN, CO, CR, DO, ES, FI, FR, GT, HN, ID, IN, KR, LK, MT, MY, NI, NZ, PA, PE, PH, PL, RU, SE, SG, SV, UA, UY, VE, ZA); Prosu 2 (TW); Provames (FR); Pyvihel (UA); Sandrena (BR, CH); Sandrena Gel (AU, DE); Sisare Gel (DE); Thais (FR); Tradelia (DE); Valiera (VN); Vivelle-Dot (BE, DK); Vivelledot (FR); Zumenon (AT, BE, GB)

Estradiol (Systemic) (Patient Education – Adult Medication)
You must carefully read the “Consumer Information Use and Disclaimer” below in order to understand and correctly use this information
Pronunciation

(es tra DYE ole)

Brand Names: US

Alora; Climara; Delestrogen; Depo-Estradiol; Divigel; Elestrin; Estrace; Estrogel; Evamist; Femring; Menostar; Minivelle; Vivelle-Dot

Brand Names: Canada

Climara; Depo-Estradiol; Divigel; Estrace; Estradot; EstroGel; Menostar; Oesclim

Warning
  • Estrogens may raise the chance of uterine cancer. Progestins may lower this chance. A warning sign for cancer of the uterus is vaginal bleeding. Report any vaginal bleeding to the doctor.
  • Do not use estrogens to prevent heart disease or dementia. Using estrogens may raise the chances of having a heart attack, a stroke, breast cancer, ovarian cancer, a blood clot, or dementia.
  • Use estrogens with or without progestin for the shortest time needed at the lowest useful dose.
What is this drug used for?
  • It is used to put off soft, brittle bones (osteoporosis) in women after change of life.
  • It is used to prevent or lower the signs of the change of life (menopause).
  • It is used to add estrogen to the body when the ovaries have been taken out or do not work the right way.
  • Rarely, it is used to treat breast or prostate cancers.
  • It may be given to you for other reasons. Talk with the doctor.
What do I need to tell my doctor BEFORE I take this drug?
  • All products:
  • If you have an allergy to estradiol or any other part of this drug.
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you have ever had a very bad or life-threatening reaction called angioedema. Signs may be swelling of the hands, face, lips, eyes, tongue, or throat; trouble breathing; trouble swallowing; unusual hoarseness.
  • If you have had any of these health problems: Bleeding disorder, blood clots, a higher risk of having a blood clot, breast cancer, liver problems or liver tumor, heart attack, stroke, or a tumor where estrogen makes it grow.
  • If you have eyesight problems like loss of eyesight from blood vessel problems in the eye.
  • If you have thickening of the endometrium (lining of the uterus).
  • If you have unexplained vaginal bleeding.
  • If you are pregnant or may be pregnant. Do not take this drug if you are pregnant.
  • Vaginal ring:
  • If you have any of these health problems: Some vaginal problems like narrow vagina or vaginal infection, uterus not in the normal spot, or other health problems that may raise the chance of vaginal irritation, vaginal ulcers, or make it more likely for the vaginal ring to come out. Ask your doctor if you are not sure.
  • This is not a list of all drugs or health problems that interact with this drug.
  • Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this drug with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.
What are some things I need to know or do while I take this drug?
  • All products:
  • Tell all of your health care providers that you take this drug. This includes your doctors, nurses, pharmacists, and dentists.
  • This drug may raise the chance of blood clots, a stroke, or a heart attack. Talk with the doctor.
  • Talk with your doctor if you will need to be still for long periods of time like long trips, bedrest after surgery, or illness. Not moving for long periods may raise your chance of blood clots.
  • If you are allergic to tartrazine, talk with your doctor. Some products have tartrazine.
  • If you have high blood sugar (diabetes), you will need to watch your blood sugar closely.
  • High blood pressure has happened with drugs like this one. Have your blood pressure checked as you have been told by your doctor.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • Have a bone density test as you have been told by your doctor. Talk with your doctor.
  • Be sure to have regular breast exams and gynecology check-ups. Your doctor will tell you how often to have these. You will also need to do breast self-exams as your doctor has told you. Talk with your doctor.
  • High calcium levels have happened with drugs like this one in some people with cancer. Call your doctor right away if you have signs of high calcium levels like weakness, confusion, feeling tired, headache, upset stomach or throwing up, constipation, or bone pain.
  • High triglyceride levels have happened with this drug. Tell your doctor if you have ever had high triglyceride levels.
  • This drug may cause dark patches of skin on your face. Avoid sun, sunlamps, and tanning beds. Use sunscreen and wear clothing and eyewear that protects you from the sun.
  • This drug may affect certain lab tests. Tell all of your health care providers and lab workers that you take this drug.
  • Do not smoke. Smoking raises the chance of heart disease. Talk with your doctor.
  • Limit your drinking of alcohol.
  • If you drink grapefruit juice or eat grapefruit often, talk with your doctor.
  • This drug may affect growth in children and teens in some cases. They may need regular growth checks. Talk with the doctor.
  • If you are 65 or older, use this drug with care. You could have more side effects.
  • Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.
  • Soft, brittle bones (osteoporosis):
  • This drug works best when used with calcium/vitamin D and weight-bearing workouts like walking or PT (physical therapy).
  • Follow the diet and workout plan that your doctor told you about.
  • All skin products:
  • Talk with your doctor before you use other drugs or products on your skin.
  • Skin gel:
  • Do not use sunscreen before using gel or soon after using gel.
  • Do not use sunscreen on gel part for 7 days in a row.
  • Skin spray:
  • Check with your doctor about how to use sunscreen with this drug.
  • If a child touches the spray, she/he needs to wash the skin with soap and water.
  • Vaginal ring:
  • Tell your doctor if you have trouble getting the ring out. Sometimes, the ring has gotten stuck to the vaginal wall and surgery was needed.
  • Contact with blood during use may cause the ring to change colors. This will not affect how well this drug works.
What are some side effects that I need to call my doctor about right away?
  • WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:
  • All products:
  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
  • Signs of gallbladder problems like pain in the upper right belly area, right shoulder area, or between the shoulder blades; yellow skin or eyes; fever with chills; bloating; or very upset stomach or throwing up.
  • Signs of high blood pressure like very bad headache or dizziness, passing out, or change in eyesight.
  • Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
  • Very bad belly pain.
  • Back pain.
  • Bulging eyes.
  • Change in how contact lenses feel in the eyes.
  • Loss of eyesight.
  • Change in eyesight.
  • A lump in the breast, breast soreness, or nipple discharge.
  • Breast pain.
  • Vaginal itching or discharge.
  • Vaginal bleeding that is not normal.
  • Low mood (depression).
  • Mood changes.
  • Memory problems or loss.
  • Fever.
  • Not able to pass urine or change in how much urine is passed.
  • Pain when passing urine.
  • Swelling.
  • Call your doctor right away if you have signs of a blood clot like chest pain or pressure; coughing up blood; shortness of breath; swelling, warmth, numbness, change of color, or pain in a leg or arm; or trouble speaking or swallowing.
  • Injection, patch, and vaginal ring:
  • Very bad irritation where this drug is used.
  • Vaginal ring:
  • Toxic shock syndrome (TSS) has happened in a few patients using vaginal rings. TSS is rare, but can be deadly. Tell your doctor right away if you have diarrhea, dizziness or light-headedness, passing out, fever, muscle pain, upset stomach, throwing up, or a sunburn-like rash.
What are some other side effects of this drug?
  • All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:
  • All products:
  • Headache.
  • Hair loss.
  • Upset stomach or throwing up.
  • Cramps.
  • Bloating.
  • Enlarged breasts.
  • Breast soreness.
  • Vaginal bleeding or spotting.
  • Painful periods.
  • Divigel®:
  • Signs of a common cold.
  • Nose and throat irritation.
  • Injection, patch, and vaginal ring:
  • Irritation where this drug is used.
  • These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.
  • You may report side effects to your national health agency.
How is this drug best taken?
  • Use this drug as ordered by your doctor. Read all information given to you. Follow all instructions closely.
  • Injection:
  • It is given as a shot into a muscle.
  • If you will be giving yourself the shot, your doctor or nurse will teach you how to give the shot.
  • Follow how to use as you have been told by the doctor or read the package insert.
  • Do not use if the solution is cloudy, leaking, or has particles.
  • This drug is colorless to a faint yellow. Do not use if the solution changes color.
  • Throw away needles in a needle/sharp disposal box. Do not reuse needles or other items. When the box is full, follow all local rules for getting rid of it. Talk with a doctor or pharmacist if you have any questions.
  • Tablets:
  • Take this drug at the same time of day.
  • There may be days when you will not take this drug.
  • Take with or without food. Take with food if it causes an upset stomach.
  • All skin products:
  • Do not take this drug by mouth. Use on your skin only. Keep out of your mouth, nose, and eyes (may burn).
  • Use this drug at the same time of day.
  • Do not use on skin that has any problems.
  • Do not put on the face, breast, or vagina.
  • Wash your hands before and after use.
  • Skin gel and spray:
  • Do not let any other person touch the gel, solution, or the treated part of your skin.
  • Avoid fire, flames, or smoking until dry.
  • Let dry before covering with clothing.
  • Divigel®:
  • Put on clean, dry, healthy skin on the thigh.
  • Move the site with each packet.
  • Put over 5 x 7 inches.
  • Do not bathe, shower, or swim right after putting on.
  • EstroGel®:
  • Prime pump before first use.
  • Put on clean, dry, healthy skin of 1 arm from the wrist to the shoulder.
  • Do not bathe, shower, or swim right after putting on.
  • Elestrin®:
  • Prime pump before first use.
  • Put on clean, dry, healthy skin of upper arm and shoulder.
  • Do not bathe, shower, or swim for 2 hours after putting on.
  • Skin spray:
  • Prime the pump by pressing 3 times before you use this the first time. Throw away any product that comes out.
  • Hold container upright and rest plastic cone flat on the skin while spraying.
  • Put on clean, dry, healthy skin of the inner forearm. Start near the elbow.
  • If your dose is more than 1 spray, move site with each spray as you have been told.
  • Do not rub into skin.
  • Do not wash the treated part for at least 1 hour after putting on.
  • Skin patch:
  • Put patch on clean, dry, healthy skin. Move the site with each new patch.
  • Put patch on a site without hair.
  • Do not place on breast. Place below waistline.
  • Do not put the patch on the waistline.
  • Do not use patches that are cut or do not look right.
  • If the patch falls off, put a new one on.
  • Wear only one patch at a time.
  • After you take off a skin patch, be sure to fold the sticky sides of the patch to each other. Throw away used patches where children and pets cannot get to them.
  • Vaginal ring:
  • Put into the vagina and leave in place for 90 days.
  • Follow how to use as you have been told by the doctor or read the package insert.
  • To use, wash your hands and take ring from the pouch.
  • Be sure your hands are dry before you touch this drug.
  • Press sides of ring at the same time between thumb and index finger and put folded ring into the vagina.
  • Perfect placement is not needed for the ring to work. The ring will not hurt.
  • To take out, hook your index finger around the rim or hold rim between index finger and middle finger and pull out.
  • Do not throw the vaginal ring in the toilet.
  • Wash hands after use.
What do I do if I miss a dose?
  • Injection and vaginal ring:
  • Call your doctor to find out what to do.
  • Skin patch:
  • Put on a missed patch as soon as you think about it after taking off the old one.
  • Skin gel and spray:
  • Use a missed dose as soon as you think about it.
  • If it is less than 12 hours until the next dose, skip the missed dose and go back to your normal time.
  • Do not use 2 doses at the same time or extra doses.
  • Tablets:
  • Take a missed dose as soon as you think about it.
  • If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.
How do I store and/or throw out this drug?
  • Injection:
  • If you need to store this drug at home, talk with your doctor, nurse, or pharmacist about how to store it.
  • All other products:
  • Store at room temperature.
  • Store in a dry place. Do not store in a bathroom.
  • Skin gel and spray:
  • Protect from heat or open flame.
  • If you are using a pump, throw away any part not used after labeled number of doses are used.
  • All products:
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.
General drug facts
  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else’s drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. If you have any questions about this drug, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.
Estradiol (Systemic) (Patient Education – Pediatric Medication)
You must carefully read the “Consumer Information Use and Disclaimer” below in order to understand and correctly use this information
Pronunciation

(es tra DYE ole)

Brand Names: US

Alora; Climara; Delestrogen; Depo-Estradiol; Divigel; Elestrin; Estrace; Estrogel; Evamist; Femring; Menostar; Minivelle; Vivelle-Dot

Brand Names: Canada

Climara; Depo-Estradiol; Divigel; Estrace; Estradot; EstroGel; Menostar; Oesclim

Warning
  • Estrogens may raise the chance of uterine cancer. Progestins may lower this chance. A warning sign for cancer of the uterus is vaginal bleeding. Report any vaginal bleeding to the doctor.
  • Do not use estrogens to prevent heart disease or dementia. Using estrogens may raise the chances of having a heart attack, a stroke, breast cancer, ovarian cancer, a blood clot, or dementia.
  • Use estrogens with or without progestin for the shortest time needed at the lowest useful dose.
What is this drug used for?
  • Tablets, injection, and patch:
  • It is used to add estrogen to the body when the ovaries have been taken out or do not work the right way.
  • It may be given to your child for other reasons. Talk with the doctor.
  • Emulsion, gel, spray, and vaginal ring:
  • If your child has been given this form of this drug, talk with the doctor for information about the benefits and risks. Talk with the doctor if you have questions or concerns about giving this drug to your child.
What do I need to tell the doctor BEFORE my child takes this drug?
  • If your child has an allergy to this drug or any part of this drug.
  • If your child is allergic to any drugs like this one or any other drugs, foods, or other substances. Tell the doctor about the allergy and what signs your child had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If your child has ever had a very bad or life-threatening reaction called angioedema. Signs may be swelling of the hands, face, lips, eyes, tongue, or throat; trouble breathing; trouble swallowing; unusual hoarseness.
  • If your child has had any of these health problems: Bleeding disorder, blood clots, a higher risk of having a blood clot, breast cancer, liver problems or liver tumor, heart attack, stroke, tumor where estrogen makes it grow, or vaginal bleeding where the cause is not known.
  • If your child has eyesight problems like loss of eyesight from blood vessel problems in the eye.
  • If your child has thickening of the endometrium (lining of the uterus).
  • If your child is pregnant:
  • Do not give this drug to your child if she is pregnant.
  • This is not a list of all drugs or health problems that interact with this drug.
  • Tell the doctor and pharmacist about all of your child’s drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for your child to take this drug with all of his/her drugs and health problems. Do not start, stop, or change the dose of any drug your child takes without checking with the doctor.
What are some things I need to know or do while my child takes this drug?
  • Tell all of your child’s health care providers that your child is taking this drug. This includes your child’s doctors, nurses, pharmacists, and dentists.
  • This drug may raise the chance of blood clots, a stroke, or a heart attack. Talk with the doctor.
  • Talk with the doctor if your child will need to be still for long periods of time like long trips, bedrest after surgery, or illness. Not moving for long periods may raise the chance of blood clots.
  • If your child is allergic to tartrazine, talk with your child’s doctor. Some products have tartrazine.
  • If your child has high blood sugar (diabetes), you will need to watch his/her blood sugar closely.
  • High blood pressure has happened with drugs like this one. Have your child’s blood pressure checked as you have been told by the doctor.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • Your child may need to have a bone density test. Talk with the doctor.
  • Be sure that your child has regular breast exams and gynecology check-ups. The doctor will tell you how often your child needs to have these. Your child will also need to do breast self-exams as the doctor has told you. Talk with the doctor.
  • High calcium levels have happened with drugs like this one in some people with cancer. Call your child’s doctor right away if your child has signs of high calcium levels like weakness, confusion, feeling tired, headache, upset stomach or throwing up, constipation, or bone pain.
  • High triglyceride levels have happened with this drug. Tell your child’s doctor if your child has ever had high triglyceride levels.
  • This drug may cause dark patches of skin on your child’s face. Avoid lots of sun, sunlamps, and tanning beds. Use sunscreen and dress your child in clothing and eyewear that protects him/her from the sun.
  • This drug may affect certain lab tests. Tell all of your child’s health care providers and lab workers that your child takes this drug.
  • Be sure your child does not smoke. Smoking raises the chance of heart disease. Talk with the doctor.
  • Alcohol may interact with this drug. Be sure your child does not drink alcohol.
  • If your child drinks grapefruit juice or eats grapefruit often, talk with your child’s doctor.
  • This drug may affect growth in children and teens in some cases. They may need regular growth checks. Talk with the doctor.
  • If your child is breast-feeding a baby:
  • Tell the doctor if your child is breast-feeding a baby. You will need to talk about any risks to the baby.
What are some side effects that I need to call my child’s doctor about right away?
  • WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your child’s doctor or get medical help right away if your child has any of the following signs or symptoms that may be related to a very bad side effect:
  • All products:
  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
  • Signs of gallbladder problems like pain in the upper right belly area, right shoulder area, or between the shoulder blades; yellow skin or eyes; fever with chills; bloating; or very upset stomach or throwing up.
  • Signs of high blood pressure like very bad headache or dizziness, passing out, or change in eyesight.
  • Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
  • Very bad belly pain.
  • Back pain.
  • Bulging eyes.
  • Change in how contact lenses feel in the eyes.
  • Loss of eyesight.
  • Change in eyesight.
  • A lump in the breast, breast soreness, or nipple discharge.
  • Breast pain.
  • Vaginal itching or discharge.
  • Vaginal bleeding that is not normal.
  • Low mood (depression).
  • Mood changes.
  • Memory problems or loss.
  • Fever.
  • Not able to pass urine or change in how much urine is passed.
  • Pain when passing urine.
  • Swelling.
  • Call the doctor right away if your child has signs of a blood clot like chest pain or pressure; coughing up blood; shortness of breath; swelling, warmth, numbness, change of color, or pain in a leg or arm; or trouble speaking or swallowing.
  • Injection and patch:
  • Very bad irritation where this drug is used.
What are some other side effects of this drug?
  • All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your child’s doctor or get medical help if any of these side effects or any other side effects bother your child or do not go away:
  • All products:
  • Headache.
  • Hair loss.
  • Upset stomach or throwing up.
  • Cramps.
  • Bloating.
  • Enlarged breasts.
  • Breast soreness.
  • Vaginal bleeding or spotting.
  • If your child has menstrual periods:
  • Painful periods.
  • Injection and patch:
  • Irritation where this drug is used.
  • These are not all of the side effects that may occur. If you have questions about side effects, call your child’s doctor. Call your child’s doctor for medical advice about side effects.
  • You may report side effects to your national health agency.
How is this drug best given?
  • Give this drug as ordered by your child’s doctor. Read all information given to you. Follow all instructions closely.
  • Injection:
  • It is given as a shot into a muscle.
  • If you will be giving your child the shot, your child’s doctor or nurse will teach you how to give the shot.
  • Follow how to give this drug as you have been told by your child’s doctor or read the package insert.
  • Do not use if the solution is cloudy, leaking, or has particles.
  • This drug is colorless to a faint yellow. Do not use if the solution changes color.
  • Throw away needles in a needle/sharp disposal box. Do not reuse needles or other items. When the box is full, follow all local rules for getting rid of it. Talk with a doctor or pharmacist if you have any questions.
  • Tablets:
  • Give this drug at the same time of day.
  • There may be days when your child will not take this drug.
  • Give this drug with or without food. Give with food if it causes an upset stomach.
  • Skin patch:
  • Do not give by mouth. Use on your child’s skin only. Keep out of your child’s mouth, nose, and eyes (may burn).
  • Give this drug at the same time of day.
  • Do not use on skin that has any problems.
  • Do not put on the face, breast, or vagina.
  • Wash your hands before and after use.
  • Put patch on clean, dry, healthy skin. Move the site with each new patch.
  • Put patch on a site without hair.
  • Do not place on breast. Place below waistline.
  • Do not put the patch on the waistline.
  • Do not use patches that are cut or do not look right.
  • If the patch falls off, put a new one on.
  • Do not put on more than 1 patch at a time.
  • After you take off a skin patch, be sure to fold the sticky sides of the patch to each other. Throw away used patches where children and pets cannot get to them.
What do I do if my child misses a dose?
  • Injection:
  • Call your child’s doctor to find out what to do.
  • Tablets:
  • Give a missed dose as soon as you think about it.
  • If it is close to the time for your child’s next dose, skip the missed dose and go back to your child’s normal time.
  • Do not give 2 doses at the same time or extra doses.
  • Skin patch:
  • Put on a missed patch as soon as you think about it after taking off the old one.
How do I store and/or throw out this drug?
  • Injection:
  • If you need to store this drug at home, talk with your child’s doctor, nurse, or pharmacist about how to store it.
  • All other products:
  • Store at room temperature.
  • Store in a dry place. Do not store in a bathroom.
  • All products:
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.
General drug facts
  • If your child’s symptoms or health problems do not get better or if they become worse, call your child’s doctor.
  • Do not share your child’s drug with others and do not give anyone else’s drug to your child.
  • Keep a list of all your child’s drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your child’s doctor.
  • Talk with your child’s doctor before giving your child any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. If you have any questions about this drug, please talk with your child’s doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.