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Estradiol (Topical)

Pronunciation

Pronunciation

(es tra DYE ole)

Index Terms

  • 17β-estradiol

Dosage Forms

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

Cream, Vaginal:

Estrace: 0.1 mg/g (42.5 g)

Ring, Vaginal, as base:

Estring: 2 mg (1 ea)

Tablet, Vaginal, as base:

Vagifem: 10 mcg

Brand Names: U.S.

  • Estrace
  • Estring
  • Vagifem

Pharmacologic Category

  • Estrogen Derivative

Pharmacology

In studies for vulvar and vaginal atrophy in postmenopausal women, local estrogens have been shown to reduce vaginal pH levels and mature the vaginal and urethral mucosa after 12 weeks of therapy, thereby improving vaginal dryness and mucosal atrophy.

Absorption

Average serum estradiol concentrations (Cavg) vary by product

Vaginal: Vaginal absorption is typically low; any contribution to circulating estradiol concentrations via systemic absorption does not exceed normal postmenopausal ranges (Ulrich 2010; Weisberg 2005).

Estring: Average steady state serum concentrations decrease from 11.2 pg/mL at 48 hours to 8 pg/mL at 12 weeks

Vagifem: Cavg: 10.9 pg/mL on day 1, 5.5 pg/mL on day 83

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. Sulfate conjugates are the primary form found in postmenopausal women.

Excretion

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

Time to Peak

Estring: 0.5 to 1 hour

Protein Binding

Bound to sex hormone-binding globulin and albumin

Use: Labeled Indications

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

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); estrogen-dependent tumor (known or suspected); hepatic impairment or disease; known protein C, protein S, antithrombin deficiency, or other known thrombophilic disorders; pregnancy.

Canadian labeling: Additional contraindications (not in US labeling): Endometrial hyperplasia; partial or complete loss of vision due to ophthalmic vascular disease; breastfeeding; porphyria.

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.

Dosing: Adult

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

Vulvar and vaginal atrophy associated with menopause: Intravaginal:

Vaginal cream (Estrace): Insert 2 to 4 g daily intravaginally for 1 to 2 weeks, then gradually reduce to 1/2 the initial dose for 1 to 2 weeks, followed by a maintenance dose of 1 g 1 to 3 times per week. Attempt to taper or discontinue at 3- to 6-month intervals.

Vaginal ring (Estring): 2 mg intravaginally; following insertion, ring should remain in place for 90 days

Vaginal tablet (Vagifem): Initial: Insert 1 tablet (10 mcg) once daily for 2 weeks; Maintenance: Insert 1 tablet twice weekly

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use is contraindicated with hepatic impairment or disease.

Administration

Vaginal cream: Gently insert applicator filled with vaginal cream deeply into vagina. Cleanse applicator after use with warm water and mild soap (do not boil or use hot water).

Vaginal ring: Insert as deeply as possible into the upper one-third of the vagina; exact positioning is not critical for efficacy; however, patient should not feel anything once inserted. In case of discomfort, ring should be gently pushed further into vagina. Straining at defecation may make the ring move down in the lower part of the vagina; if this occurs, push up ring with finger. If ring is expelled prior to 90 days, it may be rinsed in lukewarm water and reinserted. Ensure proper vaginal placement of the ring to avoid inadvertent urinary bladder insertion. If vaginal infection, ulceration, erosion, or adherence to vaginal wall develops, remove ring and reinsert only after healing is complete.

Vaginal tablet: Insert tablet with supplied applicator at the same time each day. Once inserted, press plunger until fully depressed, then remove applicator and discard. If tablet comes out of applicator prior to insertion, do not replace; use a new tablet filled applicator instead. (If the tablet has fallen out of applicator but still remains in the package, it can be reinserted in the applicator for use.)

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

Storage

Vaginal cream: Store at room temperature; protect from temperatures in excess of 40°C (104°F).

Vaginal ring: Store at 15°C to 25°C (59°F to 77°F).

Vaginal tablet: Store at 25°C (77°F); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF). Do not refrigerate.

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 always defined.

>10%: Central nervous system: Headache (13%)

1% to 10%:

Cardiovascular: Cerebrovascular accident, chest pain, edema, hypertension, local thrombophlebitis, lower extremity edema, myocardial infarction, pulmonary embolism, retinal vascular thrombosis, syncope, venous thrombosis

Central nervous system: Insomnia (4%), anxiety, migraine

Dermatologic: Chloasma, dermatitis, erythema multiforme, erythema nodosum, loss of scalp hair, pruritus, skin discoloration (melasma), skin hypertrophy, skin rash, urticaria

Endocrine & metabolic: Hot flash (2%), breast tenderness, change in libido, fibrocystic breast changes, galactorrhea, hirsutism, hypocalcemia, weight changes

Gastrointestinal: Diarrhea (5%), abdominal pain (4%), nausea (3%), carbohydrate intolerance, dyspepsia, flatulence, gastritis, hemorrhoids, toothache

Genitourinary: Leukorrhea (7%), genital candidiasis (6%), vaginitis (5%), vaginal discomfort (≤5%), vaginal pain (≤5%), bacterial vaginosis (4%; asymptomatic), vaginal hemorrhage (4%), urinary tract infection (2%), mastalgia (1%), abnormal vaginal hemorrhage (including abnormal flow, breakthrough bleeding, spotting), breast hypertrophy, change in cervical ectropion, change in cervical secretion, cystitis, dysmenorrhea, dysuria, endometrial hyperplasia, genital rash, nipple discharge, urinary incontinence

Hematologic & oncologic: Endometrial carcinoma, exacerbation of porphyria, hemorrhagic eruption, malignant neoplasm of breast, malignant neoplasm of ovary, uterine fibroids (change)

Hypersensitivity: Hypersensitivity (1%), anaphylactoid reaction, anaphylaxis, angioedema

Neuromuscular & skeletal: Back pain (6% to 7%), arthritis (4%), arthralgia (3%), musculoskeletal pain (2%), leg cramps

Ophthalmic: Contact lens intolerance

Otic: Otitis media

Respiratory: Respiratory tract infection (5%), sinusitis (4%), flu-like symptoms (3%), pharyngitis (1%), asthma exacerbation, bronchitis

Postmarketing and/or case reports: Intestinal obstruction (ring), mechanical complication of genitourinary device (ring adherence to vaginal wall), toxic shock syndrome (ring), vaginal disease (erosion), vaginal ulcer

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 (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 WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years or 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 WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age 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.

Warnings/Precautions

Concerns related to adverse effects:

• 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 also lead to severe hypercalcemia in patients with breast cancer and bone metastases; discontinue estrogen if hypercalcemia occurs. Use is contraindicated in patients with known or suspected breast cancer.

• 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 use 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 in patients 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 with caution in patients 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 impairment: 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 with caution in patients with hepatic hemangiomas; may exacerbate disease.

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

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

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

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

• SLE: Use with caution in patients 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: These products are only approved for use in postmenopausal women. 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:

• Vaginal ring: Use may not be appropriate in women with narrow or short vagina, vaginal stenosis, vaginal infections, prolapse, or other conditions that may increase the risk of vaginal irritation, ulceration, or increase the risk of expulsion. Ring should be removed in case of infection, 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.

• Vaginal tablet: Local applicator-induced abrasion may occur in women with severely atrophic vaginal mucosa.

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.

• 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. Systemic absorption occurs following vaginal use; warnings, precautions, and adverse events observed with oral therapy should be considered.

• Vulvar and vaginal atrophy use: Moderate-to-severe symptoms of vulvar and vaginal atrophy include vaginal dryness, dyspareunia, and atrophic vaginitis. Use caution applying topical products to severely atrophic vaginal mucosa. Local abrasion caused by the vaginal applicator has been reported in women with 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 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. Assess need for therapy at 3- to 6-month intervals.

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

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 alopecia, cramps, bloating, or dark patches on face. 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, severe vaginal irritation, vaginal bleeding, vaginitis, lump in breast, breast soreness or pain, nipple discharge, depression, mood changes, memory impairment, bulging eyes, contact lens discomfort, vision changes, edema, 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 healthcare 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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