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Dec.12.2021

Conjugated Estrogens; Bazedoxifene

Indications/Dosage

Labeled

  • atrophic vaginitis
  • hot flashes
  • menopause
  • osteoporosis prophylaxis

Off-Label

  • dyspareunia
† Off-label indication

For the treatment of moderate to severe vasomotor symptoms (i.e., hot flashes) and associated genitourinary symptoms, such as atrophic vaginitis, vulvar atrophy (kraurosis vulvae), and dyspareunia† in women with an intact uterus

Oral dosage

Adult menopausal and postmenopausal females

1 tablet PO once daily (conjugated estrogens 0.45 mg and bazedoxifene 20 mg per tablet). Reevaluate every 3 to 6 months to determine if the dose and continued hormone replacement are appropriate. The estrogen agonist/antagonist component (bazedoxifene) reduces the risk of endometrial hyperplasia that can occur with conjugated estrogens therapy and women taking this product should not take progestins, additional estrogens, or additional estrogen agonist/antagonists.[56074] This combination has been noted to relieve dyspareunia and improve vaginal/vulvar atrophy. However, in patients with only vaginal or urogenital symptoms, consider vaginal treatment alone.[50638] The North American Menopause Society (NAMS) Guidelines support the initiation of hormone replacement therapy (HRT) around the time of menopause if no contraindications to use exist and use is acceptable to the individual patient, as hormone therapy is the most effective treatment for vasomotor and genitourinary symptoms and has been shown to prevent bone loss and fracture.[50638] Early initiation of HRT and continuation of use at until the median age of menopause (52 years) is recommended in women with premature natural or surgically induced menopause. HRT for vasomotor symptoms and/or increased risk for bone loss around the time of menopause may be considered in those women aged younger than 60 years or who are fewer than 10 years from menopause onset.[50638] [52408] For women who initiate HRT more than 10 or 20 years from menopause onset or are aged 60 years or older, the benefit-risk ratio is less favorable due to known risks for HRT (e.g., stroke, myocardial infarction, venous thromboembolism, dementia, urinary incontinence), and guidelines generally recommend against use in these women. Decisions regarding whether to continue systemic HRT in women aged older than 60 years should be made on an individual basis for quality of life, persistent vasomotor symptoms, or prevention of bone loss and fracture, with consideration given to alternative treatments for prevention of bone loss and other health issues.[50638] [52408]

For postmenopausal osteoporosis prophylaxis in women with an intact uterus

Oral dosage

Adult postmenopausal females

1 tablet (conjugated estrogens 0.45 mg; bazedoxifene 20 mg) PO once daily. Consider only for women at significant risk of osteoporosis; carefully consider non-estrogen medication before using estrogen-based treatment. Supplement calcium and vitamin D if dietary intake inadequate. Reassess periodically to determine if hormone treatment is still necessary and clinically appropriate. The estrogen agonist/antagonist component (bazedoxifene) reduces the risk of endometrial hyperplasia. Women taking this product should not take progestins, additional estrogens, or additional estrogen agonist/antagonists.[56074] The combination of bazedoxifene and estrogen significantly reduced new vertebral fractures during clinical trials in postmenopausal women with osteoporosis. However, a reduction in nonvertebral fractures was not demonstrated.[66837] In postmenopausal women with low bone mineral density, there is good evidence that standard-dose estrogen therapy reduces the risk for osteoporotic fractures, including hip, spine, and all non-spine fractures; however, estrogens are not generally recommended as a first-line prevention tactic due to the known risks of estrogen treatment (e.g., thromboembolism, cerebrovascular events) relative to other treatments. Women who need osteoporosis prophylaxis who are younger than 60 years or who are within 10 years of menopause onset may be given consideration for estrogen therapy, based on individual assessment of risk vs. benefit. Beyond the age of 60 years, other agents are preferred due to the known risks associated with hormonal therapy. Consider each woman's net balance of individual benefits and harms. If estrogen with or without a progestin is prescribed, use the lowest effective dose for the shortest duration that is consistent with an individual's treatment goals and risks. Estrogen therapy should not be used in patients with known osteoporosis; the risks outweigh the moderate benefit seen in postmenopausal women with established osteoporosis. The effect of bazedoxifene-estrogen treatment on breast cancer risk is unknown.[52408] [62806] [66837] [67122] [67125]

Therapeutic Drug Monitoring

Maximum Dosage Limits

  • Adults

    1 tablet/day PO (conjugated estrogens 0.45 mg; bazedoxifene 20 mg).

  • Geriatric

    1 tablet/day PO (conjugated estrogens 0.45 mg; bazedoxifene 20 mg).

  • Adolescents

    Not indicated in premenopausal females.

  • Children

    Not indicated.

  • Infants

    Not indicated.

  • Neonates

    Not indicated.

Patients with Hepatic Impairment Dosing

Conjugated estrogens; bazedoxifene is contraindicated in hepatic impairment.[56074]

Patients with Renal Impairment Dosing

Conjugated estrogens; bazedoxifene is not recommended for use in patients with renal impairment due to a lack of pharmacokinetic, safety and efficacy data.[56074]

† Off-label indication
Revision Date: 12/12/2021, 04:08:24 PM

References

50638 - The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022 July. [Epub aheadof print]52408 - Gartlehner G, Patel SV, Feltner C, et al. Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Women: Evidence Report and Systematic Review for the US Preventive Services Task Force (USPSTF). JAMA. 2017;318:2234-2249. Review.56074 - Duavee (conjugated estrogens and bazedoxifene) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2022 Dec.62806 - Qaseem A, Forciea MA, McLean RM, et al; Clinical Guidelines Committee of the 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. Ann Intern Med. 2017;166:818-839. Epub 2017 May 9. Erratum in: Ann Intern Med. 2017;167:448.66837 - Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists/American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis-2020 update. Endocr Pract 2020;26(Suppl 1):1-46.67122 - Management of osteoporosis in postmenopausal women: the 2021 position statement of The North American Menopause Society. Menopause. 2021;28:973-997.67125 - Eastell R, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2019;104:1595-1622.

How Supplied

Conjugated Estrogens, Bazedoxifene Oral tablet

Duavee 0.45mg-20mg Tablet (00008-1123) (Wyeth Pharmaceuticals Inc, a subsidiary of Pfizer Inc) nullDuavee 0.45mg-20mg Tablet package photo

Description/Classification

Description

Conjugated estrogens; bazedoxifene is the combination of natural estrogens derived from the urine of pregnant mares combined with a third generation selective estrogen receptor modulator (SERM). The addition of the SERM to the estrogen helps prevent endometrial hyperplasia. The combination product is used in women with an intact uterus to treat vasomotor and genitourinary symptoms of menopause and to prevent osteoporosis. The combination was FDA approved in October 2013.

Classifications

  • Genito-urinary System and Sex Hormones
    • Sex Hormones and Modulators of the Genital System
      • Estrogens, Excluding Hormonal Contraceptives
      • Selective Estrogen Receptor Modulators/SERMS
Revision Date: 07/05/2017, 02:22:54 PM

References

Administration Information

General Administration Information

For storage information, see the specific product information within the How Supplied section.

Hazardous Drugs Classification

  • NIOSH 2016 List: Group 2 [63664]
  • NIOSH (Draft) 2020 List: Table 1
  • Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
  • Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Eye/face and respiratory protection may be needed during preparation and administration.[63664][67506][67507]

Route-Specific Administration

Oral Administration

Oral Solid Formulations

  • Administer once daily, without regard to meals. Tablets should be swallowed whole.
  • If a dose is missed, instruct patients to take it as soon as remembered unless it is almost time for the next scheduled dose. They should not take two doses at the same time.[56074]

Clinical Pharmaceutics Information

From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database
    Revision Date: 04/28/2022, 12:58:43 PM

    References

    56074 - Duavee (conjugated estrogens and bazedoxifene) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2022 Dec.63664 - CDC National Institute for Occupational Safety and Health (NIOSH). NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2016. DHHS (NIOSH) Publication Number 2016-161, September 2016. Available on the World Wide Web at https://www.cdc.gov/niosh/docs/2016-161/pdfs/2016-161.pdf?id=10.26616/NIOSHPUB201616167506 - American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2018; 75:1996-2031.67507 - NIOSH [2016]. NIOSH Alert: Preventing Occupational Exposures to Antineoplastics and Other Hazardous Drugs in Health Care Settings. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2016-161.

    Adverse Reactions

    Mild

    • abdominal pain
    • acne vulgaris
    • acneiform rash
    • alopecia
    • amenorrhea
    • anxiety
    • asthenia
    • breakthrough bleeding
    • breast discharge
    • breast enlargement
    • diarrhea
    • diplopia
    • dizziness
    • dysmenorrhea
    • dyspepsia
    • emotional lability
    • fatigue
    • gingivitis
    • gynecomastia
    • headache
    • hirsutism
    • insomnia
    • irritability
    • leukorrhea
    • libido decrease
    • libido increase
    • mastalgia
    • melasma
    • muscle cramps
    • musculoskeletal pain
    • nausea
    • paresthesias
    • pelvic pain
    • pruritus
    • rash
    • urticaria
    • vaginal discharge
    • weight gain

    Moderate

    • candidiasis
    • cervicitis
    • cholelithiasis
    • cholestasis
    • colitis
    • depression
    • edema
    • elevated hepatic enzymes
    • endometrial hyperplasia
    • fluid retention
    • galactorrhea
    • hepatitis
    • hyperglycemia
    • hypertension
    • hypertriglyceridemia
    • impaired cognition
    • jaundice
    • migraine
    • peliosis hepatis
    • peripheral vasodilation
    • urinary incontinence
    • vaginal bleeding
    • vaginitis

    Severe

    • anaphylactoid reactions
    • angioedema
    • biliary obstruction
    • bowel ischemia
    • breast cancer
    • bronchospasm
    • cholecystitis
    • dementia
    • endometrial cancer
    • erythema multiforme
    • erythema nodosum
    • myocardial infarction
    • new primary malignancy
    • ovarian cancer
    • pancreatitis
    • papilledema
    • pulmonary embolism
    • retinal thrombosis
    • stroke
    • teratogenesis
    • thromboembolism
    • thrombosis
    • visual impairment

    The use of estrogens in postmenopausal women, with or without a progestin, carries a risk for thromboembolism, and cardiovascular events such as myocardial infarction (MI) or stroke. Detailed information regarding what is known about thromboembolic and cardiovascular risk in postmenopausal women is available in the boxed warnings and precautions section of the product labeling for the products, as these risks must be considered prior to use of HRT in women, and with consideration to age and other risk factors for these events. Risks vary with the use of estrogen-alone vs. use of estrogen with progestin therapy. Similar risk data are not available for the use of estrogens with bazedoxifene. Estrogen agonist/antagonists, including bazedoxifene, are individually known to increase the risk of thromboembolism and thrombus formation. Serious cardiovascular adverse reactions to therapy may include myocardial infarction (MI), superificial or deep venous thrombosis (DVT), pulmonary embolism (PE), or stroke. Should any of these events occur or be suspected, discontinue conjugated estrogens; bazedoxifene HRT immediately.[56074]

    Although not specifically reported during clinical evaluation of conjugated estrogens; bazedoxifene, conjugated estrogens can cause sodium and fluid retention and peripheral vasodilation, resulting in edema or mild weight gain. They should be prescribed cautiously to patients in whom edema formation would be detrimental. Estrogens also can slightly increase blood pressure, occasionally causing hypertension. Data indicate in most patients the change is not clinically significant. In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In the PEPI trial, postmenopausal women 45—65 years of age randomized to any hormone therapy regimen containing conjugated estrogens experienced increases in both systolic and diastolic blood pressure of 3—5% after the first year of treatment, but the increases were not statistically different from placebo.[24010]

    Although the effects appear to be minimal in most patients receiving hormone therapy with estrogens, altered glucose tolerance secondary to decreased insulin sensitivity has been reported. In the PEPI trial, fasting glucose levels were lower, and mean 2-hour glucose levels were 8% higher, in combined HRT treated women versus placebo in all treatment arms. The effects appeared to be consistent across demographic, clinical, and lifestyle variables.[24010] Limited clinical studies of estrogen regimens have not noted significant alterations in glucose metabolism in healthy post-menopausal women. However, altered glucose tolerance secondary to decreased insulin sensitivity may be important for patients with hyperglycemia or diabetes mellitus. They should be observed for changes in glucose tolerance when initiating or discontinuing conjugated estrogens therapy.[56074]

    Numerous epidemiologic studies have examined the effects of estrogen and estrogen-progestin hormone replacement therapy (HRT) on the development of new primary malignancy (e.g., breast cancer, endometrial cancer, ovarian cancer) in postmenopausal women. Detailed clinical study information regarding what is known about cancer risk in postmenopausal women is available in the boxed warnings and precautions section of the product labeling for the products, as these risks must be considered prior to use of HRT in women, and with consideration to age and other risk factors for these events. There is an association of unopposed estrogen therapy and endometrial hyperplasia in women with an intact uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Adding a progestin or a selective estrogen modifier (SERM) like bazedoxifene to estrogen therapy has been shown to reduce, but not eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. By endometrial biopsy, the incidence of endometrial hyperplasia or malignancy for conjugated estrogens; bazedoxifene was below 1% during clinical studies in postmenopausal women.[56074] Clinical surveillance of all women using conjugated estrogens; bazedoxifene is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal vaginal bleeding. The Women's Health Initiative (WHI) estrogen plus progestin study reported increased risks of invasive breast cancer in patients taking combined estrogen-progestin HRT vs. placebo. The potential risk of breast cancer may increase with longer duration of use. The effect of bazedoxifene, when added to an estrogen, on the risk for breast cancer vs. estrogen-progestin therapy is not known. Women who used hormonal therapy for menopausal symptoms also had an increased risk for ovarian cancer, but data are still uncertain if risk is associated with a specific duration of use. The effect of bazedoxifene, when added to an estrogen, on the risk for ovarian cancer vs. estrogen-progestin therapy is not known.[23505] [27272] [32125] [27273] [50638] [56074]

    Hormone replacement therapy (HRT), both estrogen/progestin combination therapy and estrogen alone therapy, fails to prevent mild impaired cognition (memory loss) and is positively associated with the risk of developing dementia in women 65 years and older; do not use HRT to prevent or treat dementia or preserve cognition (memory).[56074] When data from the 2 populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI 1.19 to 2.60, p = 0.005). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women.[27451] [32126] [50638] In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to conjugated estrogens (CE 0.625 mg/day)-alone or placebo. After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95% CI, 0.83 to 2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 vs. 25 cases per 10,000 women-years.[56074] [27451] [32126]

    Uterine bleeding pattern changes and other genitourinary effects occur commonly during chronic, systemic conjugated estrogens therapy in postmenopausal women. Amenorrhea is expected with the continued use of conjugated estrogens; bazedoxifene treatment; in clinical studies, 83% to 88% of menopausal women reported cumulative amenorrhea at year 1 of therapy. Changes in uterine and vaginal bleeding patterns and breakthrough bleeding or spotting have been noted with estrogens with or without progestins and are commonly reported. Non-cyclic vaginal breakthrough bleeding is reported in 2% to 14% of patients. Changes in uterine bleeding patterns will usually taper and stabilize within 3 to 6 months. Metrorrhagia, pelvic pain, and dysmenorrhea are infrequent. Other genitourinary effects reported during estrogen/progestin therapy include vaginitis, vaginal discharge (leukorrhea), vaginitis or vaginal candidiasis and libido increase or libido decrease. Unusual vaginal bleeding or other pelvic symptoms that persist beyond 6 months should be evaluated by a healthcare professional. For example, continued and unexpected changes in bleeding patterns may indicate a change in uterine leiomyomatas (fibroids) or cervicitis if present. Women should report unusual symptoms to their healthcare professionals and follow advice for annual pelvic examinations and periodic Papanicolaou smears as indicated.[56074]

    Although not specifically reported during clinical evaluation of conjugated estrogens; bazedoxifene, breast changes that may occur with conjugated estrogen therapy include mastalgia and breast tenderness, which occur in approximately 8% to 12% of women on chronic estrogen hormone replacement therapy (HRT). Breast enlargement, breast discharge, galactorrhea, and fibrocystic breast changes have been reported with estrogens and/or progestin therapy. Gynecomastia may occur in men taking estrogen therapy. Patients should report breast changes, lumps, or breast discharge to their health care professionals. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.[56074]

    The safety of conjugated estrogens; bazedoxifene was evaluated in four Phase 3 clinical trials ranging from 12 weeks to 24 months in duration and enrolling 6210 postmenopausal women age 40—75 years (mean age 55 years). A total of 1224 patients were treated with conjugated estrogens; bazedoxifene and 1069 patients received placebo; abdominal pain upper (7% vs. 5%) and nausea (8% vs. 5%) were listed among the most common adverse reactions leading to discontinuation. Other gastrointestinal adverse events reported during evaluation include diarrhea (8% vs. 5%) and dyspepsia (7% vs. 6%).[56074] In general, gastrointestinal effects from conjugated estrogens administration are typically mild and relatively limited. With chronic use, abdominal pain can indicate biliary obstruction, and result in cholestatic jaundice. Estrogens enhance hepatic lipoprotein uptake and inhibit bile acid synthesis, resulting in increased concentration of cholesterol in the bile which can lead to cholelithiasis. Gallbladder disease and cholecystitis are 2- to 4-fold as frequent in women taking hormone replacement therapy (HRT) compared with controls.[25473] [56074] Rare adverse reactions reported with estrogen therapy include hepatitis (and elevated hepatic enzymes), enlargement of hepatic hemangiomas, ischemic colitis (bowel ischemia, no incidence reported), or pancreatitis. Patients with familial hyperlipoproteinemia may be at greater risk of pancreatitis while on estrogen therapy, which may greatly increase their serum triglycerides and cause hypertriglyceridemia in these susceptible individuals. Estrogens may induce peliosis hepatis, a very rare consequence of taking estrogens and combined oral contraceptives that is characterized by the presence of blood-filled spaces.[51257] Persistent or severe abdominal symptoms should be evaluated by a medical professional. Conjugated estrogens; bazedoxifene should be discontinued in any patient developing jaundice, cholestasis, or severe abdominal pain, and the patient should be evaluated.[56074]

    The safety of conjugated estrogens; bazedoxifene was evaluated in four Phase 3 clinical trials ranging from 12 weeks to 24 months in duration and enrolling 6210 postmenopausal women age 40—75 years (mean age 55 years). A total of 1224 patients were treated with conjugated estrogens; bazedoxifene and 1069 patients received placebo. Adverse reactions reported in > 5% of patients relative to placebo include: muscle cramps (9% vs. 6%), musculoskeletal pain/neck pain (5% vs. 4%), and oropharyngeal pain (7% vs. 6%).[56074]

    Although not specifically reported during clinical evaluation of conjugated estrogens; bazedoxifene, headache has been reported in greater than 5% of patients receiving conjugated estrogens by any route, and has been reported in patients receiving chronic HT. In some women, headache patterns are hormonally influenced. A number of changes can occur when a woman initiates HRT and include 1) migraines can appear for the first time, 2) a change in frequency, severity and duration of migraine headaches may be seen, or 3) an improvement or decrease in the occurrence of migraine headaches. When initiating therapy an individual's headache pattern should be observed and if migraines worsen consider discontinuing therapy. A severe headache may be a warning sign of a serious adverse event such as a stroke or retinal thrombosis.[56074] Retinal thrombosis has been reported in patients receiving estrogens such as conjugated estrogens. Discontinue medication pending examination if there is sudden visual impairment either partial or complete or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema, visual loss, or retinal vascular lesions, permanently discontinue estrogens. Exogenous estrogen use can cause a conical cornea to develop from steepening or increased curvature of the cornea, caused by thinning of the stroma. Patients with contact lenses may develop intolerance to their lenses.

    The safety of conjugated estrogens; bazedoxifene was evaluated in four Phase 3 clinical trials ranging from 12 weeks to 24 months in duration and enrolling 6210 postmenopausal women age 40—75 years (mean age 55 years). A total of 1224 patients were treated with conjugated estrogens; bazedoxifene and 1069 patients received placebo. Adverse reactions reported in >= 5% of patients relative to placebo included dizziness (5% vs. 3%).[56074] Although not specifically reported during clinical evaluation of conjugated estrogens; bazedoxifene, nervous system and mood disturbances occur in some women taking conjugated estrogens for hormonal therapy. These changes can include mental depression, fatigue, asthenia, nervousness, anxiety, or insomnia. Paresthesias have also been reported. Less common central nervous system events include chorea, emotional lability, irritability, exacerbation of epilepsy, and dementia. Possible growth potentiation of a benign meningioma may occur.

    Although not specifically reported during clinical evaluation of conjugated estrogens; bazedoxifene, conjugated estrogens and other estrogens used for hormone therapy can cause a variety of dermatological reactions. Melasma and chloasma, in the form of tan or brown patches, may develop on the forehead, cheeks, temples and upper lip. These patches may persist after the drug is discontinued. Other infrequent reactions include urticaria, erythema nodosum, alopecia, hirsutism, or rash (unspecified). Erythematous eruptions, with or without pruritus, may also occur. In some cases estrogens may induce or aggravate an existing acne vulgaris or cause an acneiform rash.[56074]

    Cases of anaphylactoid reactions with or without angioedema, requiring emergency medical treatment, have been reported during post marketing use of conjugated estrogen oral tablets. Reported symptoms include hives, pruritis, swollen lips-tongue-face, bronchospasm, abdominal pain, or vomiting. Angioedema involving the tongue, larynx, face, hands, and feet requiring medical intervention has occurred post marketing. Patients who develop these symptoms following treatment should discontinue use not be re-challenged with oral conjugated estrogen. Other potential events related to hypersensitivity can include erythema multiforme, urticaria and other rashes.[56074]

    Some women taking conjugated estrogens or other estrogens notice tenderness, swelling, or minor bleeding of their gums, which may lead to gingivitis. Proper attention to oral care and regular dental visits are recommended.

    In women with a history of cardiovascular disease, the use of estrogen and progestin combination therapy increases the risk of developing urinary incontinence. Patients in the HERS study who did not have urinary incontinence prior to the studies initiation were observed to determine if hormone replacement therapy was helpful in preventing urinary incontinence. The study found that women who received estrogen/progestin therapy were almost twice as likely as patients receiving placebo to develop urge incontinence and 3 times as likely to develop stress incontinence after 1 year of treatment. At 4 years, the effect of hormone replacement therapy became even more pronounced, increasing the risk to 3.23 for urge incontinence and to 4.81 for stress incontinence. The applicability of these findings to women who use conjugated estrogen; bazedoxifene is unclear.[27457]

    Conjugated estrogens are known to cause teratogenesis during pregnancy and are in FDA category X. Increased risk of a wide variety of fetal abnormalities, including modified development of sexual organs, cardiovascular anomalies and limb defects, have been reported following the use of estrogens in pregnant women.[56074] The use of diethylstilbestrol, DES is well known for creating disturbances in the reproductive systems of both male and female offspring; similar disturbances are reported to occur in female offspring of rats exposed to other estrogens during gestation. In any patient in whom pregnancy is suspected, pregnancy should be ruled out before continuing the use of conjugated estrogens.

    Revision Date: 12/08/2022, 03:22:02 PM

    References

    23505 - Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016-37.24010 - The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA 1995;273:199-208.25473 - The Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-13.27272 - Rossouw JE, Anderson GL, Prentice RL, et al. The Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333.27273 - Lacey JV, Mink PJ, Lubin JH, et al. Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 2002;288:334-341.27451 - 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 (WHIMS). JAMA 2003;289:2651-62.27457 - Steiner JE, Subak L, Grady D, et al. Hormone therapy for prevention of urinary incontinence: the HERS Study. Obstet Gynecol 2003;101(Suppl):S10.32125 - Stefanick ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 2006;295:1647-57.32126 - Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's health initiative memory study. JAMA 2004;291:2947-58.50638 - The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022 July. [Epub aheadof print]51257 - Radzikowska E, Maciejewski R, Janicki K, et al. The relationship between estrogen and the development of liver vascular disorders. Ann Univ Mariae Curie Sklodowska Med. 2001;56:189-93.56074 - Duavee (conjugated estrogens and bazedoxifene) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2022 Dec.

    Contraindications/Precautions

    Absolute contraindications are italicized.

    • breast cancer
    • cervical cancer
    • endometrial cancer
    • hepatic disease
    • hepatocellular cancer
    • history of angioedema
    • myocardial infarction
    • new primary malignancy
    • ovarian cancer
    • pregnancy
    • protein C deficiency
    • protein S deficiency
    • stroke
    • thromboembolic disease
    • thromboembolism
    • thrombophlebitis
    • uterine cancer
    • vaginal bleeding
    • vaginal cancer
    • asthma
    • breast-feeding
    • cardiac disease
    • cerebrovascular disease
    • children
    • contact lenses
    • coronary artery disease
    • dementia
    • depression
    • diabetes mellitus
    • endometrial hyperplasia
    • endometriosis
    • gallbladder disease
    • geriatric
    • hereditary angioedema
    • hypercalcemia
    • hypercholesterolemia
    • hypertriglyceridemia
    • hypocalcemia
    • hypoparathyroidism
    • hypothyroidism
    • infants
    • jaundice
    • migraine
    • obesity
    • pancreatitis
    • porphyria
    • renal disease
    • renal impairment
    • seizure disorder
    • surgery
    • systemic lupus erythematosus (SLE)
    • thyroid disease
    • tobacco smoking
    • uterine leiomyomata
    • visual disturbance

    Do not use conjugated estrogens; bazedoxifene in patients with a known hypersensitivity to the hormones or any of the specific product ingredients; conjugated estrogens are contraindicated in patients with known anaphylactic reactions or history of angioedema to the drug. Cases of both anaphylactic reactions and angioedema have been reported in patients taking estrogens, including conjugated estrogens. Events have developed in minutes and have required emergency medical treatment. Exogenous estrogens may also induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema, which can be hormonally sensitive.[56074]

    Conjugated estrogens; bazedoxifene products are contraindicated in patients with a known or suspected estrogen-dependent neoplasm, including breast cancer. The effect of treatment with conjugated estrogens; bazedoxifene on the risk of breast cancer is unknown. The data available are derived for studies of estrogen-alone or estrogen plus progestin hormonal replacement therapy (HRT). Since the 1970's, numerous epidemiological studies have examined the association of exogenous estrogen and breast cancer (new primary malignancy). The most important randomized clinical study providing information about breast cancer in estrogen-alone users is the Women's Health Initative (WHI) substudy of daily conjugated estrogens (0.625 mg)-alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, conjugated estrogen (0.625 mg/day)-alone was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80). The use of estrogen-alone has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.[23505] [27272] [27530] [27531] [32125] [56074] Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.[56074]

    Conjugated estrogens; bazedoxifene is contraindicated in women with estrogen-responsive tumors, including ovarian cancer. The effect of conjugated estrogens; bazedoxifene therapy on the risk of ovarian cancer is unknown. What is known about the risk of ovarian cancer due to hormonal therapy is derived from data available for estrogen-alone and estrogen plus progestin products; studies are not available for estrogen plus selective estrogen receptor modifier combinations. The Women's Health Initiative (WHI) estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for estrogen plus progestin versus placebo was 1.58 (95% CI 0.77 to 3.24). The absolute risk for estrogen plus progestin versus placebo was 4 versus 3 cases per 10,000 women-years.[17829] A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risk associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.5); there was no difference in the risk estimates by duration of the exposure (less than 5 years [median of 3 years] vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI 1.27 to 1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.[56074]

    Conjugated estrogens; bazedoxifene therapy is contraindicated in patients with known estrogen-dependent malignancies. There is an association of unopposed estrogen therapy and endometrial cancer in women with an intact uterus. Adding a progestin to estrogen therapy has been shown to reduce, but not eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Bazedoxifene, an estrogen agonist/antagonist, reduces the risk of endometrial hyperplasia that can occur with estrogen therapy in a manner similar to progestins. Clinical surveillance of all women using conjugated estrogens; bazedoxifene is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal vaginal bleeding.[56074] The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15-to 24-fold for 5 to 10 years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. With concurrent progestin use (cyclically or continuously), the incidence of endometrial hyperplasia due to conjugated estrogens is estimated to be 1% or less.[23505] [27272] [56074] Women taking conjugated estrogens; bazedoxifene should not take additional estrogens as this may increase the risk of endometrial hyperplasia. Use caution when prescribing conjugated estrogens; bazedoxifene in the overweight patient. Obesity (BMI greater than 27 kg/m2) may be associated with a reduction in bazedoxifene exposure; reduced drug exposure may be associated with an increased risk of endometrial hyperplasia.[56074]

    Conjugated estrogens; bazedoxifene is contraindicated in the presence of vaginal cancer, cervical cancer, uterine cancer, or other estrogen-responsive tumors. Clinical surveillance of all women using estrogen plus bazedoxifene therapy is important; all women receiving estrogen treatment should have an annual pelvic examination and other diagnostic or screening tests, such as cervical cytology, as clinically indicated or as generally recommended based on age, risk factors, and other individual needs. Because estrogens influence the growth of endometrial tissues, use conjugated estrogens cautiously in women with endometriosis or uterine leiomyomata (uterine fibroids).[56074] Bazedoxifene, an estrogen agonist/antagonist, reduces the risk of endometrial tissue growth that can occur with estrogen therapy, in a manner similar to use of progestins. Women taking conjugated estrogens; bazedoxifene should not take progestins, additional estrogens, or additional estrogen agonist/antagonists.[56074]

    Conjugated estrogens; bazedoxifene products are contraindicated in patients with an active or past history of stroke, thrombophlebitis, thromboembolism, thromboembolic disease, or myocardial infarction (MI). An increased risk of cerebrovascular disease (stroke) and deep venous thrombosis (DVT) has been reported with unopposed estrogen therapy; selective estrogen receptor modifiers (SERMS), like bazedoxifene, are also known to increase the risk for DVT. An increased risk of thromboembolism, including pulmonary embolism (PE), DVT, stroke and myocardial infarction (MI) has been reported with estrogen-containing hormone replacement therapy (HRT). Should any of these events occur or be suspected, discontinue conjugated estrogens; bazedoxifene immediately.[56074] Estrogens are also contraindicated for patients with known protein C deficiency, protein S deficiency, or antithrombin deficiency or other known thrombophilic disorders associated with increased risk of venous thrombosis. Other risk factors for arterial vascular disease (e.g., hypertension, diabetes, tobacco smoking, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) [e.g., personal history or family history of VTE, obesity, or systemic lupus (SLE)] should be monitored and managed appropriately.[56074] A positive relationship between estrogen use and an increased risk for thromboembolism has been demonstrated. In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) was increased for women receiving daily unopposed estrogen compared to placebo (30 vs. 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 vs. 15 per 10,000 women years). The increase in VTE risk was demonstrated during the first 2 years.[17825] [27272] Estrogens with or without a SERM or progestin should not be used for the prevention of cardiac disease or cardiovascular disease (e.g., coronary artery disease). In the Women's Health Initiative (WHI) estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as non-fatal MI, silent MI, or CHD death) was reported in women receiving conjugated estrogen-alone compared to placebo. Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE-alone vs. placebo) in women with less than 10 years since menopause (8 vs. 16 per 10,000 women-years).[27272] [17808] Studies have also shown no cardiovascular benefit to the use of estrogens for secondary prevention in women with documented cardiac disease or CHD.[25473] [27270] Estrogens also increase the risk for stroke. In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen-alone compared to women in the same age group receiving placebo (45 vs. 33 per 10,000 women-years). The increase in risk was demonstrated in the first year and persisted. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving estrogen-alone versus those receiving placebo (18 vs. 21 per 10,000 women-years). Only a daily oral conjugated estrogens dose of 0.625 mg was studied in the WHI estrogen-alone substudy; therefore, the relevance of the findings regarding adverse cardiovascular events to lower doses, routes of administration, or other estrogen products is not known.[38488] [27272] Patients with hypertension should be monitored closely for increases in blood pressure if estrogens are administered. In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogen therapy. In a large, randomized, placebo controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. Estrogens may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as a cardiac disease, warrant careful observation when estrogens are prescribed.[56074]

    If feasible, conjugated estrogens; bazedoxifene therapy should be discontinued at least 4 to 6 weeks before any surgery associated with an increased risk of thromboembolism, or during any periods of prolonged immobilization. The decision on when to resume estrogens after such procedures or conditions would be based on the perceived additional thromboembolic risk from estrogen use and the need for estrogen therapy; resume only after the patient is fully ambulatory. In addition, women taking conjugated estrogens; bazedoxifene should be advised to move about periodically during travel involving prolonged immobilization.[56074]

    Conjugated estrogens; bazedoxifene is contraindicated for use during pregnancy.[56074] There appears to be little or no increased risk of birth defects in children born to women who have used estrogens as an oral contraceptive inadvertently during early pregnancy.[40617] However, an increased risk of a wide variety of fetal abnormalities, including modified development of sexual organs, cardiovascular anomalies and limb defects, have been reported following the chronic use of estrogens alone in pregnant women. Data are not available for bazedoxifene use in human pregnancy and conjugated estrogens; bazedoxifene products have no FDA-approved indication for use during pregnancy.[56074] Administration of bazedoxifene to rats at maternally toxic dosages of 1 mg/kg/day or more (0.3 times or more of the human area under the curve (AUC) at the 20 mg dose) resulted in reduced numbers of live fetuses and/or reductions in fetal body weights; no fetal developmental anomalies were observed. In studies conducted with pregnant rabbits treated with bazedoxifene, abortion and an increased incidence of heart (ventricular septal defect) and skeletal system (ossification delays, misshapen or misaligned bones, primarily of the spine and skull) anomalies in the fetuses were present at maternally toxic dosages of 0.5 mg/kg/day or more (2 times the human AUC at the 20 mg dose). In any patient in whom pregnancy is suspected, pregnancy should be ruled out before continuing estrogen use.[56074]

    Conjugated estrogens; bazedoxifene should not be used during breast-feeding.[56074] It is not known if bazedoxifene is excreted in breat milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving conjugated estrogens. Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk.[56074]

    Conjugated estrogens; bazedoxifene products are contraindicated in the presence of hepatocellular cancer, hepatic adenoma, or in severe hepatic disease of any type. Estrogens and bazedoxifene may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, estrogens should be discontinued. Estrogens should also be used cautiously in patients with acute intermittent, or variegate hepatic porphyria, which can be exacerbated. Estrogens have been reported during trials to increase the risk of gallbladder disease (e.g., cholestasis, cholelithiasis and cholecystitis) by roughly 2- to 4-fold in postmenopausal women; use with caution in patients with a history of gallbladder disease.[56074]

    Patients with systemic lupus erythematosus (SLE) may have increased risk for thromboembolism and should be managed appropriately when estrogen therapy is considered.[56074] Approximately 85% of patients diagnosed with systemic lupus erythematosus (SLE) are females, giving support to the notion that hormonal influences, especially estrogen, contribute to the pathophysiology of SLE. Accordingly, hormone replacement therapy (HRT) has been reported to induce, unmask, and exacerbate lupus; case reports, anecdotal data, and the prospective Nurses Health Study indicate that a temporal relationship between HRT and lupus exist. However, several retrospective studies dispute a relationship between estrogens and lupus, and the SELENA trial, a large prospective, randomized clinical trial evaluating the safety of estrogen therapy (both as oral contraceptives and HRT in postmenopausal women) in patients with SLE has been completed and is being analyzed. Determining the risk of estrogen therapy in SLE patients is important as postmenopausal women with lupus can benefit from HRT; not only does it offer relief from postmenopausal symptoms (vasomotor symptoms, genital symptoms, and emotional lability), but it has the additional benefit of protecting patients from bone fracture and postmenopausal or drug-induced (i.e., chronic corticosteroid or cyclophosphamide therapy) osteoporosis. Women with hypercoagulable states are at increased risk of venous thromboembolism when taking HRT; given the increased prevalence of hypercoagulable states in patients with SLE (in particular antiphospholipid antibodies), the use of HRT in this population may be even more risky as the incidence of strokes, heart attacks, and blood clots is increased in general in women taking HRT. Unfortunately, definitive recommendations regarding the use of HRT in patients with SLE are not available. The results of the SELENA trial should provide evidence regarding the use of HRT in this population.[31435] [31436]

    In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of conjugated estrogens; bazedoxifene treatment if pancreatitis occurs.[56074]

    Retinal vascular thrombosis has been reported in women receiving estrogens. Any visual disturbance occurring during conjugated estrogens; bazedoxifene therapy should be examined by an ophthalmologist. Discontinue the product pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine with visual changes. If examination reveals papilledema or retinal vascular lesions, conjugated estrogens; bazedoxifene therapy should be permanently discontinued.[56074] Estrogen therapy may cause an exacerbation of migraine or a change in headache patterns and should be used with caution in women with migraine. Patients who complain of migraine with focal neurologic visual changes should be evaluated, and in some patients, such changes may indicate cerebrovascular events. Estrogens can increase the curvature of the cornea and may lead to intolerance of contact lenses.

    Patients with risk factors for arterial vascular disease (e.g., diabetes mellitus), which may increase the risk for thromboembolism, should be monitored and managed appropriately during conjugated estrogens; bazedoxifene therapy. Patients with diabetes mellitus should be observed for changes in glucose tolerance when initiating or discontinuing estrogen therapy, since estrogen therapy may exacerbate diabetes. Altered glucose tolerance secondary to decreased insulin sensitivity has been reported.[56074]

    Use conjugated estrogens; bazedoxifene therapy with caution in patients with thyroid disease, particularly hypothyroidism. Estrogens can increase thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.[56074]

    Conjugated estrogens; bazedoxifene therapy is not recommended for use in patients with renal impairment since data on the safety and efficacy in these patients is not available. Because estrogens may cause fluid retention, conditions that might be affected by fluid retention, such as heart disease or renal disease, require careful observation. Estrogen therapy may also cause an exacerbation of asthma, seizure disorder, and hepatic hemangiomas in some patients and should be used with caution in women with these conditions.[56074]

    Mood disorders, like depression, may be aggravated in women taking exogenous estrogens. Women with a history of depression may need special monitoring. If significant depression occurs, the hormone therapy should be discontinued.

    Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.[56074]

    Conjugated estrogens; bazedoxifene is not recommended for use in geriatric women greater than 75 years of age. Administration of HRT should generally be avoided in women 65 years of age and older, and HRT should not be used to prevent or treat dementia or preserve cognition (memory). Overall risk vs. benefit should be considered along with the goals of use of HRT for the individual patient when considering whether to continue HRT in those over 65 years of age.[27451] [32126] [50638] Hormone replacement therapy (HRT), both estrogen/progestin combination therapy and estrogen alone therapy, has been found to fail to prevent mild cognitive impairment (memory loss) and to increase the risk of dementia in women 65 years and older. In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to conjugated estrogens (CE 0.625 mg/day)-alone or placebo. After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95% CI, 0.83 to 2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 vs. 25 cases per 10,000 women-years.[56074] According to the Beers Criteria, systemic estrogens (with or without progestins), are considered potentially inappropriate medications (PIMs) for use in geriatric patients and should be avoided due to evidence of carcinogenic potential (i.e., breast and endometrium) and lack of cardiovascular or cognitive protective effects in older women. Additionally, the Beers expert panel recommends avoiding oral or transdermal estrogen in elderly women with any type of urinary incontinence due to lack of efficacy. The Beers expert panel considers use of vaginal estrogens acceptable for the management of dyspareunia, recurrent lower urinary tract infections, and other vaginal/vulvar symptoms.[63923]

    Conjugated estrogens; bazedoxifene is not indicated for use in pediatric patients; the products have no known use in infants, children, or premenopausal females.[56074] Large and repeated doses of estrogen over an extended time period have been shown to accelerate epiphyseal closure, which could result in short stature if treatment is initiated before the completion of physiologic puberty in normally developing children.[40617]

    Revision Date: 12/08/2022, 03:16:23 PM

    References

    17808 - Hsia J, Langer RD, Manson JE, et al. Conjugated equine estrogens and coronary heart disease. The Women's Health Initiative. Arch Intern Med. 2006;166:357-365.17825 - Cushman M, Kuller LH, Prentice R, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA. 2004;292:1573-1580.17829 - Anderson GL, Judd HL, Kaunitz AM, et al. Women's Health Initiative Investigators. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial. JAMA 2003;290:1739-1748.23505 - Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016-37.25473 - The Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-13.27270 - Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:49-57.27272 - Rossouw JE, Anderson GL, Prentice RL, et al. The Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333.27451 - 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 (WHIMS). JAMA 2003;289:2651-62.27530 - Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women: The Women's Health Initiative Randomized Trial. JAMA 2003;289:3243-53.27531 - Li CI, Malone KE, Porter PL, et al. Relationship between long durations and different regimens of hormone therapy and risk of breast cancer. JAMA 2003;289:3254-63.31435 - Askanase AD. Estrogen therapy in systemic lupus erythematosus. Treat Endocrinol 2004;3:19-26.31436 - Petri M. Exogenous estrogen in systemic lupus erythematosus: oral contraceptives and hormone replacement therapy. Lupus 2001;10:222-632125 - Stefanick ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 2006;295:1647-57.32126 - Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's health initiative memory study. JAMA 2004;291:2947-58.38488 - Rossoun JE, Prentice RL, Manson JE. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465-1477.40617 - Premarin tablets (conjugated estrogens, equine) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2017 Nov.50638 - The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022 July. [Epub aheadof print]56074 - Duavee (conjugated estrogens and bazedoxifene) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2022 Dec.63923 - The American Geriatrics Society 2019 Beers Criteria Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 2019;00:1-21.

    Mechanism of Action

    Conjugated estrogens and bazedoxifene function by binding to and activating estrogen receptors (ER) alpha and beta, which vary in proportion from tissue to tissue. The pairing of conjugated estrogens with bazedoxifene produces a composite effect that is specific to each target tissue. The bazedoxifene component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component.[56074]

    • Conjugated estrogens: Conjugated estrogens are composed of multiple estrogens from the urine of pregnant mares and are agonists of ER- alpha and beta. Exogenous estrogens elicit all of the actions of endogenous estrogens. Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estrogens also help prevent osteoporosis associated with the onset of menopause; they generally do not reverse bone density loss that has already developed.
    • Bazedoxifene: Bazedoxifene is a selective estrogen receptor modifier (SERM) The drug is an estrogen agonist/antagonist that acts as an agonist in some estrogen-sensitive tissues and an antagonist in others (e.g., uterus). In postmenopausal women taking estrogens, bazedoxifene helps reduce endometrial overgrowth.[56074]
    Revision Date: 10/08/2013, 10:04:57 AM

    References

    56074 - Duavee (conjugated estrogens and bazedoxifene) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2022 Dec.

    Pharmacokinetics

    Conjugated estrogens; bazedoxifene is administered orally. The distribution and metabolism of combination conjugated estrogens; bazedoxifene has not been studied. Independently, the distribution and metabolism of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. 17-beta estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. In postmenopausal women, a significant proportion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 (CYP450) 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Following intravenous (IV) administration of a 3 mg dose of bazedoxifene, the volume of distribution is 14.7 +/- 3.9 l/kg. Bazedoxifene is highly bound (98—99%) to plasma proteins in vitro, but does not bind to SHBG. The metabolic disposition of bazedoxifene has been determined following oral administration of 20 mg of radiolabeled bazedoxifene. Bazedoxifene is extensively metabolized in women and glucuronidation is the major metabolic pathway; little or no CYP450-mediated metabolism of bazedoxifene is evident. Bazedoxifene-5-glucuronide is the major circulating metabolite. The concentrations of this glucuronide are approximately 10-fold higher than those of unchanged drug in plasma.[56074]

     

    After administration of a single dose of conjugated estrogens/bazedoxifene, baseline-adjusted total estrone (representing conjugated estrogens) is eliminated with a half-life of approximately 17 hours. Bazedoxifene is eliminated with a half-life of approximately 30 hours. Steady-state concentrations are achieved by the second week of once-daily administration.The conjugated estrogens components, 17-beta estradiol, estrone, and estriol are excreted in the urine, along with glucuronide and sulfate conjugates. The clearance of bazedoxifene is 0.4 +/- 0.1 L/h/kg based on intravenous administration. The major route of excretion after oral administration of 20 mg of radiolabeled bazedoxifene is via biliary excretion, followed by elimination in the feces (approx. 85%), with < 1% of the radioactive dose eliminated in the urine. Based on these results, it is expected that bazedoxifene undergoes enterohepatic recycling from the gut back to the systemic circulation, therefore, some drugs may potentially interfere with bazedoxifene recycling process in the gut by various mechanism resulting in a decrease in its systemic exposure.[56074]

     

    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: none

    Route-Specific Pharmacokinetics

    Oral Route

    Conjugated estrogens are soluble in water and are well-absorbed from the gastrointestinal tract after release from the drug formulation. Bazedoxifene exhibits a linear increase in plasma concentrations for single doses from 0.5—120 mg and multiple daily doses from 1—80 mg. The absolute bioavailability of bazedoxifene is approximately 6%. Following administration of multiple doses of conjugated estrogens 0.45 mg/bazedoxifene 20 mg to healthy women who were naturally postmenopausal or who had undergone bilateral oophorectomy, the mean steady state pharmacokinetic parameters at Day 10 for conjugated estrogens (baseline adjusted for total estrone) and bazedoxifene are as follows: Cmax (2.6 +/- 0.8 ng/mL and 6.9 +/- 3.9 ng/mL, respectively), Tmax (6.5 +/- 1.6 hours and 2.5 +/- 2.1 hours, respectively), and AUC (35 +/- 12 ng x hour/mL and 71 +/- 34 ng x hour/mL, respectively). In a single-dose, crossover study in 23 postmenopausal women given conjugated estrogens 0.625 mg/bazedoxifene 20 mg with a high fat/high calorie meal, food increased AUC of bazedoxifene by 25%; the Cmax of bazedoxifene was unchanged.[56074]

    Special Populations

    Hepatic Impairment

    Conjugated estrogens; bazedoxifene is contraindicated in hepatic impairment.[56074] The pharmacokinetics of conjugated estrogens; bazedoxifene tablets have not been studied in patients with hepatic impairment. A single dose of bazedoxifene 20 mg was given to fasted, healthy (n = 18) and hepatically impaired postmenopausal women. In six mild hepatic impairment patients (Child Pugh Class A), Cmax and AUC of bazedoxifene increased 67% and 143%, respectively, compared to healthy subjects. In six moderate hepatic impairment patients (Child Pugh Class B), Cmax and AUC of bazedoxifene increased 32% and 109%, respectively, compared to healthy subjects. In six severe hepatic impairment patients (Child Pugh Class C), Cmax and AUC of bazedoxifene increased 20% and 268%, respectively, compared to healthy subjects. The bazedoxifene half-life was prolonged from 32 to 50 hrs in patients with severe hepatic impairment, compared to healthy subjects.[56074]

    Renal Impairment

    The pharmacokinetics of conjugated estrogens; bazedoxifene tablets have not been studied in patients with renal impairment, and due to the lack of data, use of the combination is not recommended in these patients.[56074]

    Pediatrics

    The pharmacokinetics of conjugated estrogens; bazedoxifene tablets have not been evaluated in a pediatric population.[56074]

    Geriatric

    The pharmacokinetics of conjugated estrogens; bazedoxifene tablets have not been evaluated in a geriatric population. No pharmacokinetic studies with conjugated estrogens were conducted in specific populations, including women over 75 years of age. The pharmacokinetics of a 20 mg single-dose of bazedoxifene, were evaluated in postmenopausal women. On average, compared to women 51—64 years of age (n = 8), women 65—74 years of age (n = 8) showed a 1.5-fold increase in AUC, and women >= 75 years of age (n = 8) showed a 2.6-fold increase in AUC.[56074]

    Obesity

    A 17% reduction in bazedoxifene exposure was predicted in women with BMI > 27 kg/m2 (n = 144) compared to those with BMI <= 27 kg/m2 (n = 93) after administration of conjugated estrogens; bazedoxifene, based on a population pharmacokinetic model using data from four Phase 1 studies. A reduction in bazedoxifene exposure may be associated with an increased risk of endometrial hyperplasia.[56074]

    Revision Date: 07/20/2015, 03:28:48 PM

    References

    56074 - Duavee (conjugated estrogens and bazedoxifene) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2022 Dec.

    Pregnancy/Breast-feeding

    pregnancy

    Conjugated estrogens; bazedoxifene is contraindicated for use during pregnancy.[56074] There appears to be little or no increased risk of birth defects in children born to women who have used estrogens as an oral contraceptive inadvertently during early pregnancy.[40617] However, an increased risk of a wide variety of fetal abnormalities, including modified development of sexual organs, cardiovascular anomalies and limb defects, have been reported following the chronic use of estrogens alone in pregnant women. Data are not available for bazedoxifene use in human pregnancy and conjugated estrogens; bazedoxifene products have no FDA-approved indication for use during pregnancy.[56074] Administration of bazedoxifene to rats at maternally toxic dosages of 1 mg/kg/day or more (0.3 times or more of the human area under the curve (AUC) at the 20 mg dose) resulted in reduced numbers of live fetuses and/or reductions in fetal body weights; no fetal developmental anomalies were observed. In studies conducted with pregnant rabbits treated with bazedoxifene, abortion and an increased incidence of heart (ventricular septal defect) and skeletal system (ossification delays, misshapen or misaligned bones, primarily of the spine and skull) anomalies in the fetuses were present at maternally toxic dosages of 0.5 mg/kg/day or more (2 times the human AUC at the 20 mg dose). In any patient in whom pregnancy is suspected, pregnancy should be ruled out before continuing estrogen use.[56074]

    breast-feeding

    Conjugated estrogens; bazedoxifene should not be used during breast-feeding.[56074] It is not known if bazedoxifene is excreted in breat milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving conjugated estrogens. Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk.[56074]

    Revision Date: 12/01/2017, 06:27:29 PM

    References

    40617 - Premarin tablets (conjugated estrogens, equine) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2017 Nov.56074 - Duavee (conjugated estrogens and bazedoxifene) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2022 Dec.

    Interactions

    Level 1 (Severe)

    • Anastrozole
    • Delavirdine
    • Letrozole
    • Ribociclib; Letrozole
    • Testolactone
    • Tranexamic Acid

    Level 2 (Major)

    • Amobarbital
    • Apalutamide
    • Aprepitant, Fosaprepitant
    • Aspirin, ASA; Butalbital; Caffeine
    • Aspirin, ASA; Butalbital; Caffeine; Codeine
    • Barbiturates
    • Belzutifan
    • Bexarotene
    • Bosentan
    • Butabarbital
    • Butalbital; Acetaminophen
    • Butalbital; Acetaminophen; Caffeine
    • Butalbital; Acetaminophen; Caffeine; Codeine
    • Carbamazepine
    • Cenobamate
    • Enzalutamide
    • Etravirine
    • Exemestane
    • Felbamate
    • Fosamprenavir
    • Fosphenytoin
    • Griseofulvin
    • Isoniazid, INH; Pyrazinamide, PZA; Rifampin
    • Isoniazid, INH; Rifampin
    • Lamotrigine
    • Lorlatinib
    • Mavacamten
    • Methohexital
    • Metreleptin
    • Mitapivat
    • Mitotane
    • Mobocertinib
    • Omeprazole; Amoxicillin; Rifabutin
    • Ospemifene
    • Oxcarbazepine
    • Pentobarbital
    • Phenobarbital
    • Phenobarbital; Hyoscyamine; Atropine; Scopolamine
    • Phentermine; Topiramate
    • Phenytoin
    • Primidone
    • Raloxifene
    • Rifabutin
    • Rifampin
    • Rifamycins
    • Rifapentine
    • Secobarbital
    • Sotorasib
    • St. John's Wort, Hypericum perforatum
    • Tazemetostat
    • tobacco
    • Topiramate
    • Toremifene
    • Warfarin

    Level 3 (Moderate)

    • Atazanavir
    • Atazanavir; Cobicistat
    • Azelastine; Fluticasone
    • Azithromycin
    • Beclomethasone
    • Betamethasone
    • Budesonide
    • Budesonide; Formoterol
    • Budesonide; Glycopyrrolate; Formoterol
    • Chlorpheniramine; Ibuprofen; Pseudoephedrine
    • Ciclesonide
    • Clobazam
    • Corticosteroids
    • Cortisone
    • Cyclosporine
    • Dantrolene
    • Darunavir
    • Darunavir; Cobicistat
    • Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide
    • Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir
    • Deflazacort
    • Dexamethasone
    • Diphenhydramine; Ibuprofen
    • Efavirenz
    • Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate
    • Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate
    • Fludrocortisone
    • Flunisolide
    • Fluoxetine
    • Fluticasone
    • Fluticasone; Salmeterol
    • Fluticasone; Umeclidinium; Vilanterol
    • Fluticasone; Vilanterol
    • Formoterol; Mometasone
    • Hemin
    • Hydrocodone; Ibuprofen
    • Hydrocortisone
    • Ibuprofen
    • Ibuprofen; Famotidine
    • Ibuprofen; Oxycodone
    • Ibuprofen; Pseudoephedrine
    • Icosapent ethyl
    • Indinavir
    • Lenalidomide
    • Lonapegsomatropin
    • Lopinavir; Ritonavir
    • Methylprednisolone
    • Metyrapone
    • Modafinil
    • Mometasone
    • Nelfinavir
    • Nevirapine
    • Nirmatrelvir; Ritonavir
    • Olanzapine; Fluoxetine
    • Olopatadine; Mometasone
    • Ombitasvir; Paritaprevir; Ritonavir
    • Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements)
    • Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved)
    • Prednisolone
    • Prednisone
    • Ritonavir
    • Ropinirole
    • Saquinavir
    • Somatropin, rh-GH
    • Tipranavir
    • Triamcinolone
    • Valproic Acid, Divalproex Sodium

    Level 4 (Minor)

    • Acarbose
    • Alogliptin; Metformin
    • Alpha-glucosidase Inhibitors
    • Aluminum Hydroxide
    • Aluminum Hydroxide; Magnesium Carbonate
    • Aluminum Hydroxide; Magnesium Hydroxide
    • Aluminum Hydroxide; Magnesium Hydroxide; Simethicone
    • Aluminum Hydroxide; Magnesium Trisilicate
    • Amlodipine; Atorvastatin
    • Amoxicillin; Clarithromycin; Omeprazole
    • Atorvastatin
    • Atorvastatin; Ezetimibe
    • Bromocriptine
    • Calcium
    • Canagliflozin
    • Canagliflozin; Metformin
    • Chenodiol
    • Chloramphenicol
    • Clarithromycin
    • Conivaptan
    • Cosyntropin
    • Dalfopristin; Quinupristin
    • Danazol
    • Dapagliflozin
    • Dapagliflozin; Metformin
    • Dapagliflozin; Saxagliptin
    • Daratumumab; Hyaluronidase
    • Diltiazem
    • Dipeptidyl Peptidase-4 Inhibitors
    • Empagliflozin
    • Empagliflozin; Linagliptin
    • Empagliflozin; Linagliptin; Metformin
    • Empagliflozin; Metformin
    • Ertugliflozin
    • Ertugliflozin; Metformin
    • Ertugliflozin; Sitagliptin
    • Erythromycin
    • Glipizide; Metformin
    • Glyburide; Metformin
    • grapefruit juice
    • Hyaluronidase
    • Hyaluronidase, Recombinant; Immune Globulin
    • Hydralazine
    • Hydralazine; Hydrochlorothiazide, HCTZ
    • Hydralazine; Isosorbide Dinitrate, ISDN
    • Imatinib
    • Insulins
    • Itraconazole
    • Ketoconazole
    • Lansoprazole; Amoxicillin; Clarithromycin
    • Levoketoconazole
    • Levothyroxine
    • Levothyroxine; Liothyronine (Porcine)
    • Levothyroxine; Liothyronine (Synthetic)
    • Linagliptin; Metformin
    • Liothyronine
    • Magnesium Hydroxide
    • Meglitinides
    • Metformin
    • Metformin; Repaglinide
    • Metformin; Rosiglitazone
    • Metformin; Saxagliptin
    • Metformin; Sitagliptin
    • Mifepristone
    • Miglitol
    • Mineral Oil
    • Minoxidil
    • Nitroprusside
    • Pertuzumab; Trastuzumab; Hyaluronidase
    • Pioglitazone; Metformin
    • Pramlintide
    • Rituximab; Hyaluronidase
    • SGLT2 Inhibitors
    • Streptogramins
    • Sulfonylureas
    • Thiazolidinediones
    • Thyroid hormones
    • Trandolapril; Verapamil
    • Trastuzumab; Hyaluronidase
    • Tricyclic antidepressants
    • Ursodeoxycholic Acid, Ursodiol
    • Verapamil
    • Vonoprazan; Amoxicillin; Clarithromycin
    • Zafirlukast
    Acarbose: (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [30585] [62853] Alogliptin; Metformin: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [28550] [30585] [62853] Alpha-glucosidase Inhibitors: (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [30585] [62853] Aluminum Hydroxide: (Minor) In clinical evaluation, a single dose of 460 mg aluminum hydroxide and 400 mg magnesium hydroxide was given with a bazedoxifene 40 mg tablet in 30 postmenopausal women after an overnight fast. Coadministration of aluminum/magnesium hydroxide and bazedoxifene decreased Cmax of bazedoxifene by 8% and increased AUC of bazedoxifene by 7%. The clinical effect of this change is not known, but appears to be clinically insignificant. Separating times of administration may help limit any possible interaction. [56074] Aluminum Hydroxide; Magnesium Carbonate: (Minor) In clinical evaluation, a single dose of 460 mg aluminum hydroxide and 400 mg magnesium hydroxide was given with a bazedoxifene 40 mg tablet in 30 postmenopausal women after an overnight fast. Coadministration of aluminum/magnesium hydroxide and bazedoxifene decreased Cmax of bazedoxifene by 8% and increased AUC of bazedoxifene by 7%. The clinical effect of this change is not known, but appears to be clinically insignificant. Separating times of administration may help limit any possible interaction. [56074] Aluminum Hydroxide; Magnesium Hydroxide: (Minor) In clinical evaluation, a single dose of 460 mg aluminum hydroxide and 400 mg magnesium hydroxide was given with a bazedoxifene 40 mg tablet in 30 postmenopausal women after an overnight fast. Coadministration of aluminum/magnesium hydroxide and bazedoxifene decreased Cmax of bazedoxifene by 8% and increased AUC of bazedoxifene by 7%. The clinical effect of this change is not known, but appears to be clinically insignificant. Separating times of administration may help limit any possible interaction. [56074] (Minor) In clinical evaluation, a single dose of 460 mg aluminum hydroxide and 400 mg magnesium hydroxide was given with a bazedoxifene 40 mg tablet in 30 postmenopausal women after an overnight fast. Coadministration of aluminum/magnesium hydroxide and bazedoxifene decreased Cmax of bazedoxifene by 8% and increased AUC of bazedoxifene by 7%. The clinical effect of this change is not known, but does not appear to be significant. Separating adminisration times may help limit any possible interaction. [56074] Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Minor) In clinical evaluation, a single dose of 460 mg aluminum hydroxide and 400 mg magnesium hydroxide was given with a bazedoxifene 40 mg tablet in 30 postmenopausal women after an overnight fast. Coadministration of aluminum/magnesium hydroxide and bazedoxifene decreased Cmax of bazedoxifene by 8% and increased AUC of bazedoxifene by 7%. The clinical effect of this change is not known, but appears to be clinically insignificant. Separating times of administration may help limit any possible interaction. [56074] (Minor) In clinical evaluation, a single dose of 460 mg aluminum hydroxide and 400 mg magnesium hydroxide was given with a bazedoxifene 40 mg tablet in 30 postmenopausal women after an overnight fast. Coadministration of aluminum/magnesium hydroxide and bazedoxifene decreased Cmax of bazedoxifene by 8% and increased AUC of bazedoxifene by 7%. The clinical effect of this change is not known, but does not appear to be significant. Separating adminisration times may help limit any possible interaction. [56074] Aluminum Hydroxide; Magnesium Trisilicate: (Minor) In clinical evaluation, a single dose of 460 mg aluminum hydroxide and 400 mg magnesium hydroxide was given with a bazedoxifene 40 mg tablet in 30 postmenopausal women after an overnight fast. Coadministration of aluminum/magnesium hydroxide and bazedoxifene decreased Cmax of bazedoxifene by 8% and increased AUC of bazedoxifene by 7%. The clinical effect of this change is not known, but appears to be clinically insignificant. Separating times of administration may help limit any possible interaction. [56074] Amlodipine; Atorvastatin: (Minor) In clinical evaluation, atorvastatin 20 mg was given once with bazedoxifene 40 mg in 30 postmenopausal women. Co-administration decreased the Cmax of bazedoxifene by 3% and increased AUC of bazedoxifene by 6%. The clinical effect of this change is not known. Monitor patients for loss of efficacy and increased side effects during conjugated estrogens; bazedoxifene therapy. In addition, bazedoxifene 40 mg was given for 8 consecutive days prior to co-administration of bazedoxifene 40 mg and atorvastatin 20 mg. Co-administration decreased the Cmax of atorvastatin by 14%. The AUC of atorvastatin was unchanged. The Cmax and AUC of 2-OH atorvastatin were decreased by 18% and 8%, respectively. The possibility of reduced anti-lipemic efficacy should be considered; however, the clinical relevance of this interaction has not been determined, since the AUC (exposure) of atorvastatin remained unchanged. [56074] Amobarbital: (Major) Women taking both estrogens and barbiturates should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed barbiturates. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of barbiturates. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on barbiturates, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and barbiturate are strong CYP3A4 inducers. Concurrent administration may increase estrogen elimination. [22005] [28200] [28502] [29653] [29821] [30858] [40617] [48201] [49996] [51268] [56579] [57271] Amoxicillin; Clarithromycin; Omeprazole: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea, breast tenderness, and endometrial hyperplasia. Patients receiving estrogens should be monitored for an increase in adverse events. In addition, when chronically coadministering clarithromycin (> 30 days) with conjugated estrogens; bazedoxifene, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. [28001] [28025] [56074] Anastrozole: (Contraindicated) Estrogen therapy is not recommended during aromatase inhibitor treatment, due to opposing pharmacologic actions. Estrogens, including those found in hormonal contraceptives, could interfere competitively with the pharmacologic action of the aromatase inhibitors such as Anastrozole. The goal of aromatase inhibitor therapy is to decrease circulating estrogen concentrations and inhibit the growth of hormonally-responsive cancers. Aromatase inhibitors exhibit their antiestrogenic effects by reducing the peripheral conversion of adrenally synthesized androgens (e.g., androstenedione) to estrogens through inhibition of the aromatase enzyme. [54612] Apalutamide: (Major) Women taking both estrogens and apalutamide should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed apalutamide. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on apalutamide, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination. [29653] [30858] [40617] [47343] [57085] [62874] Aprepitant, Fosaprepitant: (Major) If aprepitant, fosaprepitant is coadministered with hormonal contraceptives, including hormonal contraceptive devices (skin patches, implants, and hormonal IUDs), use an alternative or back-up non-hormonal method of contraception (e.g., condoms, spermicides) during treatment and for at least 1 month following the last dose of aprepitant, fosaprepitant. The efficacy of conjugated estrogens may be reduced when coadministered with aprepitant, fosaprepitant and for 28 days after the last dose. The exact mechanism for this interaction has not been described. Ethinyl estradiol is a CYP3A4 substrate and aprepitant, fosaprepitant is a CYP3A4 inducer; however, aprepitant, fosaprepitant is also a dose-dependent weak-to-moderate CYP3A4 inhibitor. When administered as an oral 3-day regimen (125mg/80mg/80mg) in combination with ondansetron and dexamethasone, aprepitant decreased trough concentrations of ethinyl estradiol and norethindrone by up to 64% for 3 weeks post-treatment. When ethinyl estradiol and norgestimate were administered on days 1 to 21 and aprepitant (40mg) give as a single dose on day 8, the AUC of ethinyl estradiol decreased by 4% on day 8 and by 29% on day 12; the AUC of norelgestromin increased by 18% on day 8, and decreased by 10% on day 12. Trough concentrations of both ethinyl estradiol and norelgestromin were generally lower after coadministration of aprepitant (40mg) on day 8 compared to administration without aprepitant. Specific studies have not been done with other hormonal contraceptives (e.g., progestins, non-oral combination contraceptives), an alternative or additional non-hormonal method of birth control during treatment and for 28 days after treatment is prudent to avoid potential for contraceptive failure. Additionally, although not specifically studied, because estrogens are CYP3A4 substrates, the efficacy of estrogens or progestins when used for hormone replacement may also be reduced. The clinical significance of this is not known since aprepitant, fosaprepitant is only used intermittently. [30676] [40617] [47343] [57085] Aspirin, ASA; Butalbital; Caffeine: (Major) Women taking both estrogens and barbiturates should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed barbiturates. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of barbiturates. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on barbiturates, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and barbiturate are strong CYP3A4 inducers. Concurrent administration may increase estrogen elimination. [22005] [28200] [28502] [29653] [29821] [30858] [40617] [48201] [49996] [51268] [56579] [57271] Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Women taking both estrogens and barbiturates should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed barbiturates. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of barbiturates. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on barbiturates, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and barbiturate are strong CYP3A4 inducers. Concurrent administration may increase estrogen elimination. [22005] [28200] [28502] [29653] [29821] [30858] [40617] [48201] [49996] [51268] [56579] [57271] Atazanavir: (Moderate) Atazanavir has been shown to decrease the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should be instructed to report any estrogen- related adverse events. [28142] Atazanavir; Cobicistat: (Moderate) Atazanavir has been shown to decrease the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should be instructed to report any estrogen- related adverse events. [28142] Atorvastatin: (Minor) In clinical evaluation, atorvastatin 20 mg was given once with bazedoxifene 40 mg in 30 postmenopausal women. Co-administration decreased the Cmax of bazedoxifene by 3% and increased AUC of bazedoxifene by 6%. The clinical effect of this change is not known. Monitor patients for loss of efficacy and increased side effects during conjugated estrogens; bazedoxifene therapy. In addition, bazedoxifene 40 mg was given for 8 consecutive days prior to co-administration of bazedoxifene 40 mg and atorvastatin 20 mg. Co-administration decreased the Cmax of atorvastatin by 14%. The AUC of atorvastatin was unchanged. The Cmax and AUC of 2-OH atorvastatin were decreased by 18% and 8%, respectively. The possibility of reduced anti-lipemic efficacy should be considered; however, the clinical relevance of this interaction has not been determined, since the AUC (exposure) of atorvastatin remained unchanged. [56074] Atorvastatin; Ezetimibe: (Minor) In clinical evaluation, atorvastatin 20 mg was given once with bazedoxifene 40 mg in 30 postmenopausal women. Co-administration decreased the Cmax of bazedoxifene by 3% and increased AUC of bazedoxifene by 6%. The clinical effect of this change is not known. Monitor patients for loss of efficacy and increased side effects during conjugated estrogens; bazedoxifene therapy. In addition, bazedoxifene 40 mg was given for 8 consecutive days prior to co-administration of bazedoxifene 40 mg and atorvastatin 20 mg. Co-administration decreased the Cmax of atorvastatin by 14%. The AUC of atorvastatin was unchanged. The Cmax and AUC of 2-OH atorvastatin were decreased by 18% and 8%, respectively. The possibility of reduced anti-lipemic efficacy should be considered; however, the clinical relevance of this interaction has not been determined, since the AUC (exposure) of atorvastatin remained unchanged. [56074] Azelastine; Fluticasone: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Azithromycin: (Moderate) Coadministration of azithromycin and bazedoxifene increased the Cmax of bazedoxifene by 6% and decreased AUC of bazedoxifene by 15%. The clinical effect of these changes is not described. [56074] Barbiturates: (Major) Women taking both estrogens and barbiturates should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed barbiturates. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of barbiturates. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on barbiturates, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and barbiturate are strong CYP3A4 inducers. Concurrent administration may increase estrogen elimination. [22005] [28200] [28502] [29653] [29821] [30858] [40617] [48201] [49996] [51268] [56579] [57271] Beclomethasone: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Belzutifan: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. [29653] [30858] [40617] [47343] [57085] [66875] Betamethasone: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Bexarotene: (Major) Women taking both estrogens and bexarotene should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed bexarotene. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of bexarotene. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on bexarotene, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and bexarotene is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. [29653] [30858] [40617] [47343] [57085] [59747] Bosentan: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use two acceptable contraception methods during treatment and for one month after discontinuation of bosentan therapy. The patient may choose one highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or two barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on bosentan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and bosentan is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. [28496] Bromocriptine: (Minor) Bromocriptine is used to restore ovulation and ovarian function in amenorrheic women. Estrogens and progestins can cause amenorrhea and, therefore, counteract the desired effects of bromocriptine. Concurrent use is not recommended; an alternate form of contraception is recommended during bromocriptine therapy. [5066] Budesonide: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Budesonide; Formoterol: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Budesonide; Glycopyrrolate; Formoterol: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Butabarbital: (Major) Women taking both estrogens and barbiturates should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed barbiturates. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of barbiturates. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on barbiturates, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and barbiturate are strong CYP3A4 inducers. Concurrent administration may increase estrogen elimination. [22005] [28200] [28502] [29653] [29821] [30858] [40617] [48201] [49996] [51268] [56579] [57271] Butalbital; Acetaminophen: (Major) Women taking both estrogens and barbiturates should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed barbiturates. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of barbiturates. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on barbiturates, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and barbiturate are strong CYP3A4 inducers. Concurrent administration may increase estrogen elimination. [22005] [28200] [28502] [29653] [29821] [30858] [40617] [48201] [49996] [51268] [56579] [57271] Butalbital; Acetaminophen; Caffeine: (Major) Women taking both estrogens and barbiturates should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed barbiturates. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of barbiturates. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on barbiturates, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and barbiturate are strong CYP3A4 inducers. Concurrent administration may increase estrogen elimination. [22005] [28200] [28502] [29653] [29821] [30858] [40617] [48201] [49996] [51268] [56579] [57271] Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Women taking both estrogens and barbiturates should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed barbiturates. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of barbiturates. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on barbiturates, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and barbiturate are strong CYP3A4 inducers. Concurrent administration may increase estrogen elimination. [22005] [28200] [28502] [29653] [29821] [30858] [40617] [48201] [49996] [51268] [56579] [57271] Calcium: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis. [6395] Canagliflozin: (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [30585] [62853] Canagliflozin; Metformin: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [28550] [30585] [62853] (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [30585] [62853] Carbamazepine: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month following discontinuation of carbamazepine. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on carbamazepine, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and carbamazepine is a strong CYP3A inducer. Concurrent administration may increase estrogen elimination. [28577] [29653] [30675] [30858] [40617] [41237] [47343] [48201] [57085] (Moderate) Bazedoxifene undergoes metabolism by UGT enzymes in the intestinal tract and liver. The metabolism of bazedoxifene may be increased by concomitant use of substances known to induce UGTs, such as carbamazepine. A reduction in bazedoxifene exposure may be associated with an increase risk of endometrial hyperplasia. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. In addition, in vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as carbamazepine, may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. [56074] Cenobamate: (Major) Women taking both estrogens and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. [29653] [30858] [40617] [47343] [57085] [64768] Chenodiol: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol. [37102] Chloramphenicol: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as chloramphenicol may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. [4718] [4744] Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) In clinical evaluation, a single dose of ibuprofen 600 mg was given with a bazedoxifene 20 mg capsule in 12 postmenopausal women after an overnight fast. Co-administration increased the Cmax and AUC of bazedoxifene by 18% and 7%, respectively. The Cmax of ibuprofen increased by 6%, the AUC was unchanged. The clinical effect of this change is not known. However, co-administration of ibuprofen and conjugated estrogens; bazedoxifene may increase bazedoxifene efficacy and/or side effects. Use caution during coadministration and monitor patient closely. [56074] Ciclesonide: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Clarithromycin: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea, breast tenderness, and endometrial hyperplasia. Patients receiving estrogens should be monitored for an increase in adverse events. In addition, when chronically coadministering clarithromycin (> 30 days) with conjugated estrogens; bazedoxifene, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. [28001] [28025] [56074] Clobazam: (Moderate) Concurrent administration of clobazam, a weak CYP3A4 inducer, with estrogens, may increase the elimination of these hormones. Patients may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy. [46370] [6300] Conivaptan: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. [4718] [4744] Corticosteroids: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Cortisone: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Cosyntropin: (Minor) Use cosyntropin cautiously in patients taking estrogens as these patients may exhibit abnormally high basal plasma cortisol concentrations and a decreased response to the test. [43709] Cyclosporine: (Moderate) Estrogens in oral contraceptives or non-oral combination contraceptives may inhibit the metabolism of cyclosporine. Delayed cyclosporine clearance can increase cyclosporine concentrations. Additionally, estrogens are metabolized by CYP3A4; cyclosporine inhibits CYP3A4 and may increase estrogen concentrations and estrogen-related side effects. The patient's cyclosporine concentrations should be monitored closely; monitor clinical status including blood pressure and renal and hepatic function. Be alert for complaints of estrogen-related side effects (e.g., nausea, fluid retention, breast tenderness). [28025] [29678] [29679] Dalfopristin; Quinupristin: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as dalfopristin; quinupristin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. [4744] [5221] Danazol: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as danazol may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. [4718] [4744] Dantrolene: (Moderate) Concomitant use of dantrolene and estrogens may increase the risk of developing hepatotoxicity. While a definite drug interaction with dantrolene and estrogen therapy has not yet been established, caution should be observed if the two drugs are to be given concomitantly. Hepatotoxicity has occurred more often, for example, in women over 35 years of age receiving concomitant estrogen therapy. [3486] [49509] Dapagliflozin: (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [30585] [62853] Dapagliflozin; Metformin: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [28550] [30585] [62853] (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [30585] [62853] Dapagliflozin; Saxagliptin: (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [30585] [62853] Daratumumab; Hyaluronidase: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect. [28946] [41365] [41366] Darunavir: (Moderate) Darunavir increases the metabolism of estrogens. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency. Patients should be instructed to report any breakthrough bleeding or adverse events to their prescribers. [28001] [32432] Darunavir; Cobicistat: (Moderate) Darunavir increases the metabolism of estrogens. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency. Patients should be instructed to report any breakthrough bleeding or adverse events to their prescribers. [28001] [32432] Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Darunavir increases the metabolism of estrogens. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency. Patients should be instructed to report any breakthrough bleeding or adverse events to their prescribers. [28001] [32432] Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) In vitro and in vivo studies have shown that estrogens are metabolized partially by CYP3A4. Inhibitors of CYP3A4, such as ritonavir, may increase the exposure of conjugated estrogens resulting in an increased risk of estrogen-related side effects or endometrial hyperplasia. Therefore, when chronically coadministering ritonavir (more than 30 days) with conjugated estrogens, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. Patients should report any breakthrough bleeding or adverse events to their prescribers. [28315] [56074] Deflazacort: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Delavirdine: (Contraindicated) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as delavirdine may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. [4718] [4744] Dexamethasone: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Diltiazem: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as diltiazem may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. [4718] [4744] Dipeptidyl Peptidase-4 Inhibitors: (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [30585] [62853] Diphenhydramine; Ibuprofen: (Moderate) In clinical evaluation, a single dose of ibuprofen 600 mg was given with a bazedoxifene 20 mg capsule in 12 postmenopausal women after an overnight fast. Co-administration increased the Cmax and AUC of bazedoxifene by 18% and 7%, respectively. The Cmax of ibuprofen increased by 6%, the AUC was unchanged. The clinical effect of this change is not known. However, co-administration of ibuprofen and conjugated estrogens; bazedoxifene may increase bazedoxifene efficacy and/or side effects. Use caution during coadministration and monitor patient closely. [56074] Efavirenz: (Moderate) Estrogens are partially metabolized by CYP3A4. Efavirenz induces CYP3A4 and, therefore, may decrease plasma concentrations of estrogens. Patients receiving estrogens should be monitored for a decrease in estrogen efficacy when coadministered with efavirenz. [4744] [5172] Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Estrogens are partially metabolized by CYP3A4. Efavirenz induces CYP3A4 and, therefore, may decrease plasma concentrations of estrogens. Patients receiving estrogens should be monitored for a decrease in estrogen efficacy when coadministered with efavirenz. [4744] [5172] Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Estrogens are partially metabolized by CYP3A4. Efavirenz induces CYP3A4 and, therefore, may decrease plasma concentrations of estrogens. Patients receiving estrogens should be monitored for a decrease in estrogen efficacy when coadministered with efavirenz. [4744] [5172] Empagliflozin: (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [30585] [62853] Empagliflozin; Linagliptin: (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [30585] [62853] Empagliflozin; Linagliptin; Metformin: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [28550] [30585] [62853] (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [30585] [62853] Empagliflozin; Metformin: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [28550] [30585] [62853] (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [30585] [62853] Enzalutamide: (Major) Women taking both estrogens and enzalutamide should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed enzalutamide. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and enzalutamide is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination. [29653] [30858] [40617] [47343] [51727] [57085] Ertugliflozin: (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [30585] [62853] Ertugliflozin; Metformin: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [28550] [30585] [62853] (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [30585] [62853] Ertugliflozin; Sitagliptin: (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [30585] [62853] Erythromycin: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as erythromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea, breast tenderness, and endometrial hyperplasia. Patients receiving estrogens should be monitored for an increase in adverse events. In addition, when chronically coadministering erythromycin ( > 30 days) with conjugated estrogens; bazedoxifene, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. [4744] [56074] Etravirine: (Major) Women taking both estrogens and etravirine should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed etravirine. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of etravirine. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on etravirine, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and etravirine is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. [29653] [30858] [33718] [40617] [47343] [57085] Exemestane: (Major) Estrogens, including hormonal contraceptives, could interfere competitively with the pharmacologic action of the aromatase inhibitors. The goal of aromatase inhibitor therapy is to decrease circulating estrogen concentrations and inhibit the growth of hormonally-responsive cancers. Estrogen therapy is not recommended during aromatase inhibitor treatment, due to opposing pharmacologic actions. Aromatase inhibitors (e.g., aminoglutethimide, anastrozole, exemestane, letrozole, testolactone, vorozole) exhibit their antiestrogenic effects by reducing the peripheral conversion of adrenally synthesized androgens (e.g., androstenedione) to estrogens through inhibition of the aromatase enzyme. [29110] Felbamate: (Major) Estrogens and progestins are both susceptible to drug interactions with hepatic enzyme inducing drugs. Estrogens are metabolized by CYP3A4. Anticonvulsants that stimulate the activity of this enzyme include: barbiturates (including primidone), carbamazepine, felbamate, oxcarbazepine, phenytoin or fosphenytoin (and possibly ethotoin), and topiramate. The anticonvulsants mentioned may cause oral contraceptive failure, especially when low-dose estrogen regimens (e.g., ethinyl estradiol is < 50 mcg/day) are used. Epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism and the higher risk for oral contraceptive failure. During oral contraceptive failure, the additive effects could potentially heighten the risk of neural tube defects in pregnancy. Women on OCs and enzyme-inducing anticonvulsant medications concurrently should report breakthrough bleeding to their prescribers. Oral contraceptive formulations containing higher dosages of ethinyl estradiol (i.e., 50 mcg ethinyl estradiol) may be needed to increase contraceptive efficacy. It may be prudent for some women who receive OCs concurrently with enzyme-inducing anticonvulsants to use an additional contraceptive method to protect against unwanted pregnancy. Higher dosages of oral contraceptives (e.g., ethinyl estradiol >= 50 mcg/day) or a second contraceptive method are typically suggested if women use an enzyme-inducing anti-epileptic drug or a barbiturate. Proper intake of folic acid should also be ensured. [4970] [4971] [5306] [5307] [7006] [7241] Fludrocortisone: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Flunisolide: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Fluoxetine: (Moderate) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as fluoxetine may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. [40617] Fluticasone: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Fluticasone; Salmeterol: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Fluticasone; Umeclidinium; Vilanterol: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Fluticasone; Vilanterol: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Formoterol; Mometasone: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Fosamprenavir: (Major) Avoid concurrent use of contraceptives and hormone replacement therapies (HRT) containing estrogens with fosamprenavir. Alternative methods of non-hormonal contraception are recommended. Concomitant use may decrease the efficacy of both the estrogen and fosamprenavir, which could lead to loss of virologic response and possible viral resistance. Additionally, there is an increased risk of transaminase elevations during concurrent use of estrogens and fosamprenavir boosted with ritonavir. [29012] [68183] Fosphenytoin: (Major) Women taking both estrogens and phenytoin/fosphenytoin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed phenytoin/fosphenytoin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of phenytoin/fosphenytoin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on phenytoin/fosphenytoin, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and phenytoin/fosphenytoin is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination. [28535] [28771] [29653] [30858] [40617] [55436] [57085] (Moderate) Bazedoxifene undergoes metabolism by UGT enzymes in the intestinal tract and liver. The metabolism of bazedoxifene may be increased by concomitant use of substances known to induce UGTs, such as phenytoin or fosphenytoin. A reduction in bazedoxifene exposure may be associated with an increase risk of endometrial hyperplasia. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. [56074] Glipizide; Metformin: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [28550] [30585] [62853] Glyburide; Metformin: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [28550] [30585] [62853] Grapefruit juice: (Minor) Grapefruit juice has been reported to decrease the metabolism of some estrogens. Grapefruit juice contains a compound that inhibits CYP3A4 in enterocytes. Estrogen levels may increase by up to 30 percent with chronic use. The clinical significance of the interaction is unknown. It is possible that estrogen induced side effects could be increased in some individuals. Patients should be advised to not significantly alter their grapefruit juice ingestion.When chronically ingesting any CYP3A4 inhibitor ( > 30 days) with estrogens, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. [56074] [6395] Griseofulvin: (Major) Women taking both estrogens and griseofulvin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed griseofulvin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of griseofulvin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on griseofulvin, with dose adjustments made based on clinical efficacy. Concurrent administration may increase estrogen elimination; the mechanism by which griseofulvin enhances estrogen elimination has not been fully elucidated. [28509] [29653] [29964] [30858] Hemin: (Moderate) Hemin works by inhibiting aminolevulinic acid synthetase. Estrogens increase the activity of this enzyme should not be used with hemin. [6702] Hyaluronidase, Recombinant; Immune Globulin: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect. [28946] [41365] [41366] Hyaluronidase: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect. [28946] [41365] [41366] Hydralazine: (Minor) The administration of estrogens can increase fluid retention, which increases blood pressure, thereby antagonizing the antihypertensive effects of hydralazine. [805] Hydralazine; Hydrochlorothiazide, HCTZ: (Minor) The administration of estrogens can increase fluid retention, which increases blood pressure, thereby antagonizing the antihypertensive effects of hydralazine. [805] Hydralazine; Isosorbide Dinitrate, ISDN: (Minor) The administration of estrogens can increase fluid retention, which increases blood pressure, thereby antagonizing the antihypertensive effects of hydralazine. [805] Hydrocodone; Ibuprofen: (Moderate) In clinical evaluation, a single dose of ibuprofen 600 mg was given with a bazedoxifene 20 mg capsule in 12 postmenopausal women after an overnight fast. Co-administration increased the Cmax and AUC of bazedoxifene by 18% and 7%, respectively. The Cmax of ibuprofen increased by 6%, the AUC was unchanged. The clinical effect of this change is not known. However, co-administration of ibuprofen and conjugated estrogens; bazedoxifene may increase bazedoxifene efficacy and/or side effects. Use caution during coadministration and monitor patient closely. [56074] Hydrocortisone: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Ibuprofen: (Moderate) In clinical evaluation, a single dose of ibuprofen 600 mg was given with a bazedoxifene 20 mg capsule in 12 postmenopausal women after an overnight fast. Co-administration increased the Cmax and AUC of bazedoxifene by 18% and 7%, respectively. The Cmax of ibuprofen increased by 6%, the AUC was unchanged. The clinical effect of this change is not known. However, co-administration of ibuprofen and conjugated estrogens; bazedoxifene may increase bazedoxifene efficacy and/or side effects. Use caution during coadministration and monitor patient closely. [56074] Ibuprofen; Famotidine: (Moderate) In clinical evaluation, a single dose of ibuprofen 600 mg was given with a bazedoxifene 20 mg capsule in 12 postmenopausal women after an overnight fast. Co-administration increased the Cmax and AUC of bazedoxifene by 18% and 7%, respectively. The Cmax of ibuprofen increased by 6%, the AUC was unchanged. The clinical effect of this change is not known. However, co-administration of ibuprofen and conjugated estrogens; bazedoxifene may increase bazedoxifene efficacy and/or side effects. Use caution during coadministration and monitor patient closely. [56074] Ibuprofen; Oxycodone: (Moderate) In clinical evaluation, a single dose of ibuprofen 600 mg was given with a bazedoxifene 20 mg capsule in 12 postmenopausal women after an overnight fast. Co-administration increased the Cmax and AUC of bazedoxifene by 18% and 7%, respectively. The Cmax of ibuprofen increased by 6%, the AUC was unchanged. The clinical effect of this change is not known. However, co-administration of ibuprofen and conjugated estrogens; bazedoxifene may increase bazedoxifene efficacy and/or side effects. Use caution during coadministration and monitor patient closely. [56074] Ibuprofen; Pseudoephedrine: (Moderate) In clinical evaluation, a single dose of ibuprofen 600 mg was given with a bazedoxifene 20 mg capsule in 12 postmenopausal women after an overnight fast. Co-administration increased the Cmax and AUC of bazedoxifene by 18% and 7%, respectively. The Cmax of ibuprofen increased by 6%, the AUC was unchanged. The clinical effect of this change is not known. However, co-administration of ibuprofen and conjugated estrogens; bazedoxifene may increase bazedoxifene efficacy and/or side effects. Use caution during coadministration and monitor patient closely. [56074] Icosapent ethyl: (Moderate) Estrogens may exacerbate hypertriglyceridemia and should be discontinued or changed to alternate therapy, if possible, prior to initiation of icosapent ethyl. [51323] Imatinib: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as imatinib, STI-571 may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. [4718] [4744] Indinavir: (Moderate) Indinavir has been shown to decrease the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should be instructed to report any estrogen- related adverse events. [28731] Insulins: (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [30585] [62853] Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Bazedoxifene undergoes metabolism by UGT enzymes in the intestinal tract and liver. The metabolism of bazedoxifene may be increased by concomitant use of substances known to induce UGTs, such as rifampin. A reduction in bazedoxifene exposure may be associated with an increase risk of endometrial hyperplasia. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. In addition, in vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as rifampin, may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Patients taking these hormones may need to be monitored for reduced clinical effect while on rifampin, with dose adjustments made based on clinical efficacy. [56074] (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. [28001] [28482] [28483] [28509] [29210] [30314] [32946] Isoniazid, INH; Rifampin: (Major) Bazedoxifene undergoes metabolism by UGT enzymes in the intestinal tract and liver. The metabolism of bazedoxifene may be increased by concomitant use of substances known to induce UGTs, such as rifampin. A reduction in bazedoxifene exposure may be associated with an increase risk of endometrial hyperplasia. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. In addition, in vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as rifampin, may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Patients taking these hormones may need to be monitored for reduced clinical effect while on rifampin, with dose adjustments made based on clinical efficacy. [56074] (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. [28001] [28482] [28483] [28509] [29210] [30314] [32946] Itraconazole: (Minor) In vitro and in vivo studies have shown that estrogens are metabolized partially by CYP3A4. Therefore, inhibitors of CYP3A4 may affect estrogen drug metabolism. Inhibitors of CYP3A4, such as itraconazole, may increase the exposure of conjugated estrogens resulting in an increased risk of endometrial hyperplasia. Therefore, for chronically administered CYP3A4 inhibitors ( > 30 days) concurrently administered with conjugated estrogens, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. [40617] [56074] Ketoconazole: (Minor) In vitro and in vivo studies have shown that estrogens are metabolized partially by CYP3A4. Therefore, inhibitors of CYP3A4 may affect estrogen drug metabolism. Inhibitors of CYP3A4, such as ketoconazole, may increase the exposure of conjugated estrogens resulting in an increased risk of endometrial hyperplasia. Therefore, for chronically administered CYP3A4 inhibitors ( > 30 days) concurrently administered with conjugated estrogens, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. [40617] [56074] Lamotrigine: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. [28451] Lansoprazole; Amoxicillin; Clarithromycin: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea, breast tenderness, and endometrial hyperplasia. Patients receiving estrogens should be monitored for an increase in adverse events. In addition, when chronically coadministering clarithromycin (> 30 days) with conjugated estrogens; bazedoxifene, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. [28001] [28025] [56074] Lenalidomide: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling. [49472] Letrozole: (Contraindicated) Estrogens, including hormonal contraceptives, could interfere competitively with the pharmacologic action of the aromatase inhibitors. The goal of aromatase inhibitor therapy is to decrease circulating estrogen concentrations and inhibit the growth of hormonally-responsive cancers. Estrogen therapy is not recommended during aromatase inhibitor treatment, due to opposing pharmacologic actions. Aromatase inhibitors (e.g., aminoglutethimide, anastrozole, exemestane, letrozole, testolactone, vorozole) exhibit their antiestrogenic effects by reducing the peripheral conversion of adrenally synthesized androgens (e.g., androstenedione) to estrogens through inhibition of the aromatase enzyme. [28123] [29101] [29110] [29360] Levoketoconazole: (Minor) In vitro and in vivo studies have shown that estrogens are metabolized partially by CYP3A4. Therefore, inhibitors of CYP3A4 may affect estrogen drug metabolism. Inhibitors of CYP3A4, such as ketoconazole, may increase the exposure of conjugated estrogens resulting in an increased risk of endometrial hyperplasia. Therefore, for chronically administered CYP3A4 inhibitors ( > 30 days) concurrently administered with conjugated estrogens, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. [40617] [56074] Levothyroxine: (Minor) The administration of estrogens can increase circulating concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. Increased amounts of thyroxine-binding globulin may result in a reduced clinical response to thyroid hormones. Some hypothyroid patients on estrogen may require larger doses of thyroid hormones. Monitor thyroid-stimulating hormone (TSH) level and follow the recommendation for thyroid hormone replacement. [29653] [43942] [53562] Levothyroxine; Liothyronine (Porcine): (Minor) The administration of estrogens can increase circulating concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. Increased amounts of thyroxine-binding globulin may result in a reduced clinical response to thyroid hormones. Some hypothyroid patients on estrogen may require larger doses of thyroid hormones. Monitor thyroid-stimulating hormone (TSH) level and follow the recommendation for thyroid hormone replacement. [29653] [43942] [53562] Levothyroxine; Liothyronine (Synthetic): (Minor) The administration of estrogens can increase circulating concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. Increased amounts of thyroxine-binding globulin may result in a reduced clinical response to thyroid hormones. Some hypothyroid patients on estrogen may require larger doses of thyroid hormones. Monitor thyroid-stimulating hormone (TSH) level and follow the recommendation for thyroid hormone replacement. [29653] [43942] [53562] Linagliptin; Metformin: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [28550] [30585] [62853] Liothyronine: (Minor) The administration of estrogens can increase circulating concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. Increased amounts of thyroxine-binding globulin may result in a reduced clinical response to thyroid hormones. Some hypothyroid patients on estrogen may require larger doses of thyroid hormones. Monitor thyroid-stimulating hormone (TSH) level and follow the recommendation for thyroid hormone replacement. [29653] [43942] [53562] Lonapegsomatropin: (Moderate) Somatropin can induce the activity of cytochrome-mediated metabolism of antipyrine clearance. Because estrogens are also metabolized in this way, somatropin may alter the metabolism of estrogens. In addition, growth-hormone deficient women also treated with estrogen replacement therapy require substantially more somatropin therapy to obtain comparable effects when compared to women not taking estrogen. Patients should be monitored for changes in efficacy of either drug when somatropin and estrogens are coadministered. [6807] Lopinavir; Ritonavir: (Moderate) In vitro and in vivo studies have shown that estrogens are metabolized partially by CYP3A4. Inhibitors of CYP3A4, such as ritonavir, may increase the exposure of conjugated estrogens resulting in an increased risk of estrogen-related side effects or endometrial hyperplasia. Therefore, when chronically coadministering ritonavir (more than 30 days) with conjugated estrogens, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. Patients should report any breakthrough bleeding or adverse events to their prescribers. [28315] [56074] Lorlatinib: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. [29653] [30858] [40617] [57085] [63732] Magnesium Hydroxide: (Minor) In clinical evaluation, a single dose of 460 mg aluminum hydroxide and 400 mg magnesium hydroxide was given with a bazedoxifene 40 mg tablet in 30 postmenopausal women after an overnight fast. Coadministration of aluminum/magnesium hydroxide and bazedoxifene decreased Cmax of bazedoxifene by 8% and increased AUC of bazedoxifene by 7%. The clinical effect of this change is not known, but does not appear to be significant. Separating adminisration times may help limit any possible interaction. [56074] Mavacamten: (Major) Patients taking both estrogens and mavacamten should report breakthrough vaginal bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed mavacamten. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 4 months after discontinuation of mavacamten. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on mavacamten, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and mavacamten is a moderate CYP3A inducer. Concurrent administration may increase estrogen elimination. [29653] [30858] [40617] [47343] [57085] [67543] Meglitinides: (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [30585] [62853] Metformin: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [28550] [30585] [62853] Metformin; Repaglinide: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [28550] [30585] [62853] Metformin; Rosiglitazone: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [28550] [30585] [62853] Metformin; Saxagliptin: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [28550] [30585] [62853] Metformin; Sitagliptin: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [28550] [30585] [62853] Methohexital: (Major) Women taking both estrogens and barbiturates should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed barbiturates. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of barbiturates. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on barbiturates, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and barbiturate are strong CYP3A4 inducers. Concurrent administration may increase estrogen elimination. [22005] [28200] [28502] [29653] [29821] [30858] [40617] [48201] [49996] [51268] [56579] [57271] Methylprednisolone: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Metreleptin: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination. [56753] Metyrapone: (Moderate) A subtherapeutic response to metyrapone can be seen in patients on estrogen therapy. When metapyrone is used as a diagnostic drug for testing hypothalamic-pituitary ACTH function, the effect of estrogen may need to be considered, or, another diagnostic test chosen. If possible, consider discontinuing the use of estrogen prior to and during testing. During use for Cushing's syndrome, estrogen therapy may increase cortisol levels, which may attenuate the response to metyrapone treatment. Monitor for evidence of clinical response to treatment, and adjust treatment as clinically indicated. [33528] [33675] Mifepristone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as mifepristone may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. [48697] Miglitol: (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [30585] [62853] Mineral Oil: (Minor) While information regarding this interaction is limited, it appears that the simultaneous oral administration of estrogens and mineral oil may decrease the oral absorption of the estrogens, resulting in lower estrogen plasma concentrations. This interaction may be more likely with the chronic administration of mineral oil, as opposed to a single dose of mineral oil used for occasional constipation. In order to avoid an interaction, it would be prudent to separate administration times, giving estrogens 1 hour before or 2 hours after the oral administration of mineral oil. [30487] Minoxidil: (Minor) Estrogens can cause fluid retention, increasing blood pressure and thereby antagonizing the antihypertensive effects of minoxidil. [805] Mitapivat: (Major) Women taking both estrogens and mitapivat should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed mitapivat. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of mitapivat. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on mitapivat, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and mitapivat is a CYP3A inducer. Concurrent administration may increase estrogen elimination. [29653] [30858] [40617] [47343] [57085] [67403] Mitotane: (Major) Women taking both estrogens and mitotane should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed mitotane. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of mitotane. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on mitotane, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and mitotane is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination. [29653] [30858] [40617] [41934] [57085] Mobocertinib: (Major) Women taking both estrogens and mobocertinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed mobocertinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of mobocertinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on mobocertinib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and mobocertinib is a weak CYP3A inducer. Concurrent administration may increase estrogen elimination. [29653] [30858] [40617] [47343] [57085] [66990] Modafinil: (Moderate) Modafinil is an inducer of CYP3A hepatic enzymes. Estrogens are metabolized by CYP3A4. A decrease in estrogen concentrations, and thus efficacy, may occur in patients taking estrogens for hormone replacement therapy. If these drugs are used together, monitor patients for a decrease in clinical effects. Dosage adjustments may be necessary. [41243] [4718] [4744] Mometasone: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Nelfinavir: (Moderate) Nelfinavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers. [28839] Nevirapine: (Moderate) Women taking both estrogens and nevirapine should report breakthrough bleeding to their prescribers. Nevirapine may decrease plasma concentrations of hormonal contraceptives. However, despite lower exposures, literature suggests that use of nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. Thus, the manufacturer states that no dose adjustments are needed when these drugs are used for contraception in combination with nevirapine. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on nevirapine, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and nevirapine is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. [42456] Nirmatrelvir; Ritonavir: (Moderate) In vitro and in vivo studies have shown that estrogens are metabolized partially by CYP3A4. Inhibitors of CYP3A4, such as ritonavir, may increase the exposure of conjugated estrogens resulting in an increased risk of estrogen-related side effects or endometrial hyperplasia. Therefore, when chronically coadministering ritonavir (more than 30 days) with conjugated estrogens, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. Patients should report any breakthrough bleeding or adverse events to their prescribers. [28315] [56074] Nitroprusside: (Minor) The administration of estrogens may increase blood pressure, and thereby antagonizing the antihypertensive effects of nitroprusside. [805] Olanzapine; Fluoxetine: (Moderate) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as fluoxetine may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. [40617] Olopatadine; Mometasone: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Ombitasvir; Paritaprevir; Ritonavir: (Moderate) In vitro and in vivo studies have shown that estrogens are metabolized partially by CYP3A4. Inhibitors of CYP3A4, such as ritonavir, may increase the exposure of conjugated estrogens resulting in an increased risk of estrogen-related side effects or endometrial hyperplasia. Therefore, when chronically coadministering ritonavir (more than 30 days) with conjugated estrogens, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. Patients should report any breakthrough bleeding or adverse events to their prescribers. [28315] [56074] Omeprazole; Amoxicillin; Rifabutin: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. [28001] [28482] [28483] [28509] [29210] [30314] [32946] Ospemifene: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied. [53344] Oxcarbazepine: (Major) Women taking both estrogens and oxcarbazepine should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed oxcarbazepine. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of oxcarbazepine. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on oxcarbazepine, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and oxcarbazepine is a CYP3A4 inducer. Concurrent administration has been shown to decrease the exposure of some estrogens by approximately 50%. [29014] Pentobarbital: (Major) Women taking both estrogens and barbiturates should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed barbiturates. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of barbiturates. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on barbiturates, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and barbiturate are strong CYP3A4 inducers. Concurrent administration may increase estrogen elimination. [22005] [28200] [28502] [29653] [29821] [30858] [40617] [48201] [49996] [51268] [56579] [57271] Pertuzumab; Trastuzumab; Hyaluronidase: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect. [28946] [41365] [41366] Phenobarbital: (Major) Women taking both estrogens and barbiturates should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed barbiturates. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of barbiturates. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on barbiturates, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and barbiturate are strong CYP3A4 inducers. Concurrent administration may increase estrogen elimination. [22005] [28200] [28502] [29653] [29821] [30858] [40617] [48201] [49996] [51268] [56579] [57271] (Moderate) Bazedoxifene undergoes metabolism by UGT enzymes in the intestinal tract and liver. The metabolism of bazedoxifene may be increased by concomitant use of substances known to induce UGTs, such as phenobarbital. A reduction in bazedoxifene exposure may be associated with an increase risk of endometrial hyperplasia. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. In addition, in vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as phenobarbital, may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. [56074] Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Women taking both estrogens and barbiturates should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed barbiturates. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of barbiturates. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on barbiturates, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and barbiturate are strong CYP3A4 inducers. Concurrent administration may increase estrogen elimination. [22005] [28200] [28502] [29653] [29821] [30858] [40617] [48201] [49996] [51268] [56579] [57271] (Moderate) Bazedoxifene undergoes metabolism by UGT enzymes in the intestinal tract and liver. The metabolism of bazedoxifene may be increased by concomitant use of substances known to induce UGTs, such as phenobarbital. A reduction in bazedoxifene exposure may be associated with an increase risk of endometrial hyperplasia. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. In addition, in vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as phenobarbital, may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. [56074] Phentermine; Topiramate: (Major) Women taking both estrogens and topiramate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed topiramate, especially for patients receiving topiramate doses greater than 200 mg per day. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of topiramate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on topiramate, with dose adjustments made based on clinical efficacy. Concurrent administration may increase estrogen elimination. [28378] Phenytoin: (Major) Women taking both estrogens and phenytoin/fosphenytoin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed phenytoin/fosphenytoin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of phenytoin/fosphenytoin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on phenytoin/fosphenytoin, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and phenytoin/fosphenytoin is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination. Additionally, epileptic women taking both anticonvulsants and hormonal contraceptives may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; if oral contraceptive failure occurs, the additive effects could potentially heighten the risk of neural tube defects in pregnancy. [28535] [28771] [29653] [30858] [40617] [55436] [57085] (Moderate) Bazedoxifene undergoes metabolism by UGT enzymes in the intestinal tract and liver. The metabolism of bazedoxifene may be increased by concomitant use of substances known to induce UGTs, such as phenytoin. A reduction in bazedoxifene exposure may be associated with an increase risk of endometrial hyperplasia. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. [56074] Pioglitazone; Metformin: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [28550] [30585] [62853] Pramlintide: (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [30585] [62853] Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Either additive or antagonistic effects could potentially occur if prasterone is combined with estrogen therapy. [2455] Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Either additive or antagonistic effects could potentially occur if prasterone is combined with estrogen therapy. [2455] Prednisolone: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Prednisone: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Primidone: (Major) Women taking both estrogens and barbiturates should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed barbiturates. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of barbiturates. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on barbiturates, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and barbiturate are strong CYP3A4 inducers. Concurrent administration may increase estrogen elimination. [22005] [28200] [28502] [29653] [29821] [30858] [40617] [48201] [49996] [51268] [56579] [57271] Raloxifene: (Major) The concurrent use of raloxifene and systemic estrogens or other hormone replacement therapy has not been studied in prospective clinical trials. Thus, concomitant use of raloxifene with systemic estrogens is not recommended. [29603] Ribociclib; Letrozole: (Contraindicated) Estrogens, including hormonal contraceptives, could interfere competitively with the pharmacologic action of the aromatase inhibitors. The goal of aromatase inhibitor therapy is to decrease circulating estrogen concentrations and inhibit the growth of hormonally-responsive cancers. Estrogen therapy is not recommended during aromatase inhibitor treatment, due to opposing pharmacologic actions. Aromatase inhibitors (e.g., aminoglutethimide, anastrozole, exemestane, letrozole, testolactone, vorozole) exhibit their antiestrogenic effects by reducing the peripheral conversion of adrenally synthesized androgens (e.g., androstenedione) to estrogens through inhibition of the aromatase enzyme. [28123] [29101] [29110] [29360] Rifabutin: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. [28001] [28482] [28483] [28509] [29210] [30314] [32946] Rifampin: (Major) Bazedoxifene undergoes metabolism by UGT enzymes in the intestinal tract and liver. The metabolism of bazedoxifene may be increased by concomitant use of substances known to induce UGTs, such as rifampin. A reduction in bazedoxifene exposure may be associated with an increase risk of endometrial hyperplasia. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. In addition, in vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as rifampin, may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Patients taking these hormones may need to be monitored for reduced clinical effect while on rifampin, with dose adjustments made based on clinical efficacy. [56074] (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. [28001] [28482] [28483] [28509] [29210] [30314] [32946] Rifamycins: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. [28001] [28482] [28483] [28509] [29210] [30314] [32946] Rifapentine: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination. [28001] [28482] [28483] [28509] [29210] [30314] [32946] Ritonavir: (Moderate) In vitro and in vivo studies have shown that estrogens are metabolized partially by CYP3A4. Inhibitors of CYP3A4, such as ritonavir, may increase the exposure of conjugated estrogens resulting in an increased risk of estrogen-related side effects or endometrial hyperplasia. Therefore, when chronically coadministering ritonavir (more than 30 days) with conjugated estrogens, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. Patients should report any breakthrough bleeding or adverse events to their prescribers. [28315] [56074] Rituximab; Hyaluronidase: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect. [28946] [41365] [41366] Ropinirole: (Moderate) Concomitant use of ropinirole and higher doses of estrogens may increase the exposure of ropinirole. A dose adjustment of ropinirole may be needed when estrogen therapy is initiated or discontinued. Some estrogens have reduced ropinirole oral clearance by 36%. [31241] Saquinavir: (Moderate) Saquinavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers. [28995] Secobarbital: (Major) Women taking both estrogens and barbiturates should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed barbiturates. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of barbiturates. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on barbiturates, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and barbiturate are strong CYP3A4 inducers. Concurrent administration may increase estrogen elimination. [22005] [28200] [28502] [29653] [29821] [30858] [40617] [48201] [49996] [51268] [56579] [57271] SGLT2 Inhibitors: (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [30585] [62853] Somatropin, rh-GH: (Moderate) Somatropin can induce the activity of cytochrome-mediated metabolism of antipyrine clearance. Because estrogens are also metabolized in this way, somatropin may alter the metabolism of estrogens. In addition, growth-hormone deficient women also treated with estrogen replacement therapy require substantially more somatropin therapy to obtain comparable effects when compared to women not taking estrogen. Patients should be monitored for changes in efficacy of either drug when somatropin and estrogens are coadministered. [6807] Sotorasib: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. [29653] [30858] [40617] [47343] [57085] [66700] St. John's Wort, Hypericum perforatum: (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination. [28211] [29653] [30858] [40617] [56579] [57085] [57202] Streptogramins: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as dalfopristin; quinupristin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. [4744] [5221] Sulfonylureas: (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [30585] [62853] Tazemetostat: (Major) Women taking both estrogens and tazemetostat should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed tazemetostat. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 6 months after discontinuation of tazemetostat. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on tazemetostat, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and tazemetostat is a CYP3A4 inducer. Concurrent administration may increase estrogen elimination. [64952] Testolactone: (Contraindicated) Estrogens could interfere competitively with the pharmacologic action of the aromatase inhibitors. The goal of aromatase inhibitor therapy is to decrease circulating estrogen concentrations and inhibit the growth of hormonally-responsive cancers. Estrogen therapy is not recommended during aromatase inhibitor treatment, due to opposing pharmacologic actions. Aromatase inhibitors (e.g., aminoglutethimide, anastrozole, exemestane, letrozole, testolactone, vorozole) exhibit their antiestrogenic effects by reducing the peripheral conversion of adrenally synthesized androgens (e.g., androstenedione) to estrogens through inhibition of the aromatase enzyme. In addition, in women receiving long-term aromatase inhibitor therapy, atrophic vaginitis due to estrogen suppression is common; atrophic vaginitis due to aromatase inhibitor therapy is sometimes treated with vaginal estrogen as the systemic exposure of estrogen from vaginal preparations is thought to be low. In a study of 7 women on aromatase inhibitor therapy, estrogen concentrations rose significantly after the addition of vaginally administered estrogen for atrophic vaginitis. Estrogen concentrations increased from a mean baseline level of < 5 pmol/l to 72 pmol/l after 2 weeks and to < 35 pmol/l at 4 weeks. Although the study was small, estrogen concentrations rose significantly in 6/7 patients. Clinicians should be aware that serum estrogen concentrations may increase with the use of vaginal estrogen preparations; alternative treatments for atrophic vaginitis in patients taking aromatase inhibitors should be considered. [4846] [5837] [5847] [6098] [8953] Thiazolidinediones: (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [30585] [62853] Thyroid hormones: (Minor) The administration of estrogens can increase circulating concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. Increased amounts of thyroxine-binding globulin may result in a reduced clinical response to thyroid hormones. Some hypothyroid patients on estrogen may require larger doses of thyroid hormones. Monitor thyroid-stimulating hormone (TSH) level and follow the recommendation for thyroid hormone replacement. [29653] [43942] [53562] Tipranavir: (Moderate) Tipranavir increases the metabolism of estrogens. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency. Patients should be instructed to report any breakthrough bleeding or adverse events to their prescribers. [31320] Tobacco: (Major) Advise patients to avoid cigarette smoking while taking estrogen hormones. Cigarette smoking increases the risk of serious cardiovascular events, such as myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism. Combined hormonal contraceptives are contraindicated in females who are over 35 years of age and smoke. [29653] [30858] [67846] Topiramate: (Major) Women taking both estrogens and topiramate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed topiramate, especially for patients receiving topiramate doses greater than 200 mg per day. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of topiramate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on topiramate, with dose adjustments made based on clinical efficacy. Concurrent administration may increase estrogen elimination. [28378] Toremifene: (Major) The use of estrogens, including oral contraceptives, with toremifene is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which toremifene is prescribed. Toremifene exerts its effects by blocking estrogen receptors. Since toremifene and estrogens are pharmacological opposites, they are not usually given concurrently. [2786] Trandolapril; Verapamil: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as verapamil may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. [4718] [4744] Tranexamic Acid: (Contraindicated) Tranexamic acid is contraindicated in women who are using combination hormonal contraception containing an estrogen and a progestin. Use with other estrogens is also not recommended. Estrogens increase the hepatic synthesis of prothrombin and factors VII, VIII, IX, and X and decrease antithrombin III; estrogens also increase norepinephrine-induced platelet aggregability. A positive relationship of estrogens to thromboembolic disease has been demonstrated, and the US FDA has suggested class labeling of combined OCs and non-oral combination contraceptives in accordance with this data. OC products containing >= 50-mcg ethinyl estradiol are associated with the greatest risk of thromboembolic complications. Therefore, do not coadminister estrogens, combined hormonal oral contraceptives, or non-oral combination contraceptives together with tranexamic acid. Tranexamic acid is an antifibrinolytic agent, and concomitant use can further exacerbate the thrombotic risk associated with these estrogen-containing hormonal products; in post-market use of tranexamic acid, cases of thromboembolic events have been reported, with cases occurring in those patients concomitantly receiving combined hormonal contraceptives containing both an estrogen and a progestin. [37613] [50666] [7622] Trastuzumab; Hyaluronidase: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect. [28946] [41365] [41366] Triamcinolone: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Tricyclic antidepressants: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction. [4718] Ursodeoxycholic Acid, Ursodiol: (Minor) Estrogens and combined hormonal and oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation, and hence may counteract the effectiveness of ursodeoxycholic acid, ursodiol. [28078] [28082] Valproic Acid, Divalproex Sodium: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency. [44735] Verapamil: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as verapamil may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. [4718] [4744] Vonoprazan; Amoxicillin; Clarithromycin: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea, breast tenderness, and endometrial hyperplasia. Patients receiving estrogens should be monitored for an increase in adverse events. In addition, when chronically coadministering clarithromycin (> 30 days) with conjugated estrogens; bazedoxifene, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. [28001] [28025] [56074] Warfarin: (Major) Estrogen-based hormone replacement therapies and contraceptive methods are generally contraindicated in patients with thromboembolic risk. However, per ACOG guidelines, in select patients the benefits of such contraception may outweigh the risks, as long as appropriate anticoagulant therapy is utilized. Combined oral contraceptives (COCs) may inhibit CYP3A4 and CYP1A2, which can rarely influence warfarin pharmacokinetics and the INR value. Isolated case reports have noted altered responses to warfarin in patients receiving combined hormonal contraceptives. Estrogens increase the hepatic synthesis of prothrombin and factors VII, VIII, IX, and X and decrease antithrombin III; estrogens also increase norepinephrine-induced platelet aggregability. A positive relationship of estrogen-containing OCs to thromboembolic disease has been demonstrated. OC products containing 50-mcg or more of ethinyl estradiol are associated with the greatest risk of thromboembolic complications. The addition of certain progestins may influence thromboembolic risks. A positive relationship between estrogen-based HRT and the risk of thromboembolic disease has also been demonstrated in the Women's Health Initiative Trials. Estrogen-based HRT products are generally contraindicated in patients with a current or past history of stroke, cerebrovascular disease, coronary artery disease, coronary thrombosis, thrombophlebitis, thromboembolic disease (including pulmonary embolism and DVT), or valvular heart disease with complications. If concurrent use of an estrogen-based product cannot be avoided, carefully monitor for signs and symptoms of thromboembolic complications. If thromboembolic events occur, discontinue the HRT regimen. Estrogen-based HRT is generally not expected to significantly alter the INR or to affect the metabolism of warfarin. Dosage adjustment of warfarin in a woman taking HRT should be based on the prothrombin time or INR value. [17825] [28549] [29140] [48201] [50666] [51295] [66564] Zafirlukast: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as zafirlukast may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. [4744] [4948]
    Revision Date: 11/23/2022, 02:26:00 AM

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    Monitoring Parameters

    • pap smear
    • pelvic exam

    US Drug Names

    • DUAVEE
    ;