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Estradiol (Systemic)

Pronunciation

Pronunciation

(es tra DYE ole)

Index Terms

  • Estradiol
  • Estradiol Acetate
  • Estradiol Transdermal
  • Estradiol Valerate
  • Gynodiol
  • Vivelle Dot

Dosage Forms

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

Emulsion, Transdermal, as hemihydrate:

Estrasorb: 4.35 mg/1.74 g (1.74 g [DSC]) [contains polysorbate 80, soybean oil]

Gel, Transdermal:

Divigel: 0.25 mg/0.25 g (1 ea); 0.5 mg/0.5 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)

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]

Generic: 10 mg/mL (5 mL [DSC]); 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 (8 ea); 0.0375 mg/24 hr (8 ea); 0.05 mg/24 hr (8 ea); 0.075 mg/24 hr (8 ea); 0.1 mg/24 hr (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 (8 ea); 0.0375 mg/24 hr (8 ea); 0.05 mg/24 hr (1 ea, 8 ea); 0.075 mg/24 hr (8 ea); 0.1 mg/24 hr (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 (4 ea); 0.0375 mg/24 hr (4 ea); 0.05 mg/24 hr (4 ea); 0.06 mg/24 hr (4 ea); 0.075 mg/24 hr (4 ea); 0.1 mg/24 hr (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

Brand Names: U.S.

  • Alora
  • Climara
  • Delestrogen
  • Depo - Estradiol
  • Divigel
  • Elestrin
  • Estrace
  • Estrasorb [DSC]
  • Estrogel
  • Evamist
  • Femring
  • Menostar
  • Minivelle
  • Vivelle - Dot

Pharmacologic Category

  • Estrogen Derivative

Pharmacology

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.

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

Estrasorb: Mean serum concentration on day 22 of therapy: ~35 to 65 pg/mL; Exposure increased by ~38% with application of sunscreen 10 minutes prior to estradiol 8.7 mg and exposure increased by ~46% when sunscreen was applied 25 minutes after estradiol application.

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

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)

Protein Binding

Bound to sex hormone-binding globulin and albumin

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.

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.

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.

Dosing: Adult

Note: Estrasorb has been discontinued in the US for more than 1 year.

General dosing guidelines: When treating postmenopausal women, use estrogens for the shortest duration possible at the lowest effective dose consistent with treatment goals. Reevaluate patients as clinically appropriate to determine if treatment is still necessary. Consider use of an estrogen with a progestin in postmenopausal women with a uterus. Women who have had a hysterectomy generally do not need a progestin; however, one may be needed if there is a history of endometriosis. Dosage needs to be adjusted based upon the patient's 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)

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 0.5 mg/day in a cyclic regimen for 23 days of a 28-day cycle were used in clinical studies

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 associated with menopause: Note: Attempt to taper or discontinue at 3- to 6-month intervals

Oral (Estrace): 1 to 2 mg daily, adjusted as necessary to limit symptoms; administration should be cyclic (3 weeks on, 1 week off)

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

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

Topical emulsion (Estrasorb): 3.48 g applied once daily in the morning

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 associated with menopause:

IM: Valerate (Delestrogen): 10 to 20 mg every 4 weeks. Attempt to taper or discontinue at 3- to 6-month intervals.

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. Attempt to taper or discontinue at 3- to 6-month intervals.

Oral (Estrace): 1 to 2 mg/day; administration should be cyclic (3 weeks on, 1 week off). Attempt to taper or discontinue at 3- to 6-month intervals

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.

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, bone mineral density (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. Attempt to taper or discontinue at 3- to 6-month intervals.

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 associated with menopause: Note: Adjust dose as necessary. Attempt to taper or discontinue at 3- to 6-month intervals.

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

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

Dosing: Hepatic Impairment

Use is contraindicated with hepatic dysfunction or disease

Administration

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

Injection formulation: 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).

Emulsion (Estrasorb): For topical use only; not for ophthalmic, oral, or vaginal use. Do not apply to face or breasts. Apply to clean, dry skin while in a sitting position. Contents of two pouches (total 3.48 g) are to be applied individually, once daily in the morning. Apply contents of first pouch to left thigh; massage into skin of left thigh and calf until thoroughly absorbed. Apply contents of second pouch to the right thigh; massage into skin of right thigh and calf until thoroughly absorbed. Wash hands with soap and water after application. Allow skin to dry before covering legs with clothing.

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.

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

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.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Dietary Considerations

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

Storage

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).

Drug Interactions

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

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

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

Anthrax Immune Globulin (Human): Estrogen Derivatives may enhance the thrombogenic effect of Anthrax Immune Globulin (Human). 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. Consider therapy modification

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

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

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Cannabis: May decrease the serum concentration of CYP1A2 Substrates. 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. Monitor therapy

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

CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. 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). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. 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. Consider therapy modification

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

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

Herbs (Estrogenic Properties): May enhance the adverse/toxic effect of Estrogen Derivatives. 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. Consider therapy modification

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

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

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

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

NSAID (COX-2 Inhibitor): May enhance the thrombogenic effect of Estrogen Derivatives. NSAID (COX-2 Inhibitor) may increase the serum concentration of Estrogen Derivatives. Monitor therapy

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

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit 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.). Monitor therapy

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.). Monitor therapy

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. Consider therapy modification

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

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

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. 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). Consider therapy modification

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Teriflunomide: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

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

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

Thyroid Products: Estrogen Derivatives may diminish the therapeutic effect of Thyroid Products. 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. Consider therapy modification

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Test Interactions

Reduced response to metyrapone test.

Adverse Reactions

Frequency not 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%)

<1% (Limited to important or life-threatening): Bowel obstruction (vaginal ring), genitourinary complaint (inadvertent ring insertion into the bladder should be considered with unexplained urinary complaints), hemorrhage, mechanical complication of genitourinary device (ring adherence to vaginal or bladder wall), portal vein thrombosis, toxic shock syndrome (vaginal ring), unstable angina pectoris

ALERT: U.S. Boxed Warning

Endometrial cancer:

There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Close clinical surveillance of all women taking estrogens is important. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be taken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal genital bleeding.

Cardiovascular disease:

Estrogen-alone therapy should not be used for the prevention of cardiovascular disease. The Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (0.625 mg) alone, relative to placebo.

Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease. The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism (PE), stroke, and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg), relative to placebo.

Breast cancer:

The Women's Health Initiative (WHI) estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer

Dementia:

Estrogen-alone therapy should not be used for the prevention of dementia. The WHI Memory Study (WHIMS) estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years and older during 5.2 years of treatment with daily conjugated estrogens (0.625 mg) alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.

Estrogen plus progestin therapy should not be used for the prevention of dementia. The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years or older during 4 years of treatment with daily conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.

Risk vs benefits:

In the absence of comparable data, these risks should be assumed to be similar for other doses of conjugated estrogens (with or without medroxyprogesterone acetate) and other dosage forms of estrogens (with or without progestins). Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

Secondary exposure (Evamist):

Breast budding and breast masses in prepubertal females and gynecomastia and breast masses in prepubertal males have been reported following unintentional secondary exposure to Evamist by women using this product. In most cases, the condition resolved with removal of Evamist exposure. Women should ensure that children do not come into contact with the site(s) where Evamist is applied. Advise patients to strictly adhere to recommended instructions for use.

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). This risk may be associated with duration of use and declines once combined therapy is discontinued (Chlebowski 2009). The risk of invasive breast cancer was decreased in postmenopausal women with a hysterectomy using CE only, regardless of weight. However, the risk was not significantly decreased in women at high risk for breast cancer (family history of breast cancer, personal history of benign breast disease) (Anderson 2012). An increase in abnormal mammogram findings has also 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.

• 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 is dose and duration dependent; risk appears to be 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 (NAMS 2012; NAMS 2013).

• 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.

• Inherited thrombophilia: Women with inherited thrombophilias (eg, protein C or S deficiency) may have increased risk of venous thromboembolism (DeSancho 2010; van Vlijmen 2011). Use is contraindicated in women with protein C, protein S, antithrombin deficiency, or other known thrombophilic disorders.

• 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: Postmenopausal estrogens with or without progestins may increase the risk of ovarian cancer; however, the absolute risk to an individual woman is small. Although results from various studies are not consistent, risk does not appear to be significantly associated with the duration, route, or dose of therapy. In one study, the risk decreased after 2 years following discontinuation of therapy (Mørch 2009). Although the risk of ovarian cancer is rare, women who are at an increased risk (eg, family history) should be counseled about the association (NAMS 2012).

• 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 have adverse effects on glucose tolerance; use caution in women with diabetes.

• 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). Risk factors should be managed appropriately; discontinue use if adverse cardiovascular events occur or are suspected. Use is contraindicated in women with active DVT, PE, active arterial thromboembolic disease 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 emulsion, gel: Absorption of the topical emulsion (Estrasorb) and topical gel (Elestrin) is increased by application of sunscreen; do not apply sunscreen within close proximity of estradiol. Application of sunscreen or lotion after EstroGel decreases 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.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Other warnings/precautions:

• 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. In addition, personal risk factors (eg, cardiovascular disease, smoking, diabetes, age) also contribute to adverse events; use of specific products may be contraindicated in women with certain risk factors.

• Osteoporosis use: For use only in women at significant risk of osteoporosis and for who other nonestrogen medications are not considered appropriate.

• Risks vs benefits: [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. Women who are early in menopause, who are in good cardiovascular health, and who are at low risk for adverse cardiovascular events can be considered candidates for estrogen with or without progestin therapy for the relief of menopausal symptoms (ACOG 565 2013). Use of a transdermal product should be considered over an oral agent in women requiring systemic therapy who have risk factors for venous thromboembolism or coronary heart disease (ACOG 556 2013; Schenck-Gustafsson 2011; Tremollieres 2011).

• 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.

• Vulvar and vaginal atrophy use: Moderate-to-severe symptoms of vulvar and vaginal atrophy include vaginal dryness, dyspareunia, and atrophic vaginitis. When used solely for the treatment of vulvar and vaginal atrophy, topical vaginal products should be considered. Use caution applying topical products to severely atrophic vaginal mucosa. Use of a progestin is normally not required when low-dose estrogen is applied locally and only for this purpose (NAMS 2012; NAMS 2013).

Monitoring Parameters

Routine physical examination that includes blood pressure and Papanicolaou smear, breast exam, mammogram. Monitor for signs of endometrial cancer in female patients with a uterus. Adequate diagnostic measures, including endometrial sampling, if indicated, should be performed to rule out malignancy in all cases of undiagnosed abnormal genital bleeding. Monitor for loss of vision, sudden onset of proptosis, diplopia, migraine; signs and symptoms of thromboembolic disorders; glycemic control in patients with diabetes; lipid profiles in patients being treated for hyperlipidemias; thyroid function in patients on thyroid hormone replacement therapy.

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

Menopausal symptoms, vulvar and vaginal atrophy: Assess need for therapy at 3- to 6-month intervals

Prevention of osteoporosis: Bone density measurement

Note: Monitoring of FSH and serum estradiol is not useful when managing vasomotor symptoms associated with menopause or vulvar and vaginal atrophy.

Pregnancy Risk Factor

X

Pregnancy Considerations

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. These products are contraindicated for use during pregnancy.

Patient Education

• 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, dark patches on face, cramps, bloating, enlarged breasts, painful periods, or injection site irritation. Have patient report immediately to prescriber signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), angina, shortness of breath, coughing up blood, severe headache, severe dizziness, passing out, severe nausea, vomiting, severe abdominal pain, back pain, bulging eyes, contact lens discomfort, vision changes, lump in breast, breast soreness or pain, nipple discharge, vaginitis, vaginal bleeding, depression, mood changes, memory impairment, urinary retention, change in amount of urine passed, dysuria, severe skin irritation, or signs of toxic shock syndrome (diarrhea, dizziness, passing out, fevere, 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.

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