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    Estrogens, Excluding Hormonal Contraceptives

    BOXED WARNING

    Dementia, geriatric

    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 geriatric women 65 years and older. 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 a geriatric woman over 65 years of age. According to the Beers Criteria, oral and topical patch, or other systemic forms of 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 the potential for aggravation of incontinence. The Beers expert panel considers use of intra-vaginal preparations acceptable for the management of dyspareunia, lower urinary tract infections, and other vaginal/vulvar symptoms. In addition, evidence suggests that vaginal estrogens are safe and effective for the treatment of vaginal dryness; women with a history of breast cancer who do not respond to non-hormonal therapies are advised to discuss the risks and benefits of low-dose vaginal estrogen (estradiol less than 25 mcg twice weekly) with their healthcare provider. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to the OBRA guidelines, assessment of the underlying causes and identification of the type/category of urinary incontinence needs to be documented prior to or soon after initiating treatment with a medication to manage urinary incontinence (e.g., estrogen replacement agents). These medications have specific and limited indications based on the cause and categorization of incontinence. Patients should be assessed periodically for medication effects on urinary incontinence as well as lower urinary tract symptoms and treatment tolerability. The Guidelines caution that oral estrogen products may cause systemic side effects and increased risks (e.g., DVT, breast cancer), and topical agents may be preferred.

    Accidental exposure

    Estradiol is available in many topical dosage forms, including transdermal systems, topical emulsions, topical gels, and topical sprays. Estradiol topical gels and sprays are alcohol-based and thus are potentially flammable. Patients should be advised to avoid fire, flame, or smoking until the gel or spray has dried after application. Patients should be advised to carefully read and follow administration directions in order to avoid accidental exposure of estradiol hormone to others, including children and pets. In July 2010, the FDA released an advisory notice warning of inadvertent exposure to Evamist brand topical spray through skin contact with patients using the product. Adverse events including premature puberty, nipple swelling and breast development in females, and breast enlargement in males were reported. Reports of pet exposure were also reported; signs of exposure in pets may include mammary/nipple enlargement and vulvar swelling. To reduce the risk of exposure, patients applying this product should avoid contact of the treated area to children and pets. If direct contact cannot be avoided, the treated area should be covered with a garment. If inadvertent exposure occurs, the skin of the child or pet should be washed immediately with soap and water. Patients should be aware that if a child under their care shows signs of exposure including breast development or other sexual changes, the child should be examined by a healthcare professional. Once exposure is removed, symptoms of exposure should resolve.

    DEA CLASS

    Rx

    DESCRIPTION

    Estradiol is the principal human estrogen
    Multiple dosage forms are available: oral, topical, transdermal, vaginal, and parenteral
    Used primarily to treat vasomotor and genitourinary symptoms associated with natural or surgical menopause, to prevent osteoporosis, for female hypogonadism and other conditions associated with estrogen deficiency

    COMMON BRAND NAMES

    Alora, Climara, Delestrogen, Depo-Estradiol, Divigel, Elestrin, Estrace, Estraderm, Estring, EstroGel, Evamist, FemPatch, Femring, Gynodiol, Gynogen LA, Imvexxy, Menostar, Minivelle, Vagifem, Vivelle, Vivelle-Dot, Yuvafem

    HOW SUPPLIED

    Alora Topical Film ER: 0.025mg, 24h
    Alora/Climara/Estraderm/Estradiol/FemPatch/Menostar/Minivelle/Vivelle/Vivelle-Dot Transdermal Film ER: 0.025mg, 0.0375mg, 0.05mg, 0.06mg, 0.075mg, 0.1mg, 14mcg, 24h
    Delestrogen/Depo-Estradiol/Estradiol Valerate/Gynogen LA Intramuscular Inj Sol: 1mL, 5mg, 10mg, 20mg, 40mg
    Divigel/Elestrin/Estradiol/EstroGel Transdermal Gel: 0.06%, 0.1%
    Estrace/Estradiol Vaginal Cream: 0.01%
    Estrace/Estradiol/Gynodiol Oral Tab: 0.5mg, 1mg, 2mg
    Estradiol Acetate/Estring/Femring Vaginal Insert ER: 0.05mg, 0.1mg, 2mg, 24h
    Estradiol/Imvexxy/Vagifem/Yuvafem Vaginal Insert: 4mcg, 10mcg
    Evamist Transdermal Spray Met: 1actuation, 1.53mg

    DOSAGE & INDICATIONS

    For treatment of moderate to severe vasomotor symptoms (hot flashes) of menopause and/or related genitourinary symptoms including atrophic vaginitis, vulvar atrophy (kraurosis vulvae), whether menopause is natural or surgical (e.g., due to oophorectomy).
    For systemic treatment of the vasomotor symptoms (hot flashes) and genitourinary symptoms of menopause.
    Oral dosage
    Adult menopausal and postmenopausal females

    0.5 mg to 2 mg PO once daily. Usual initial dose: 1 or 2 mg PO once daily. Less than 1 mg/day PO may suffice for vaginal/vulvar symptoms only; however, in such patients, consider vaginal therapy alone. Use the lowest effective dose. Administration should be cyclic (e.g., 3 weeks on and 1 week off). In women with an intact uterus, estrogen may be given cyclically or combined with a progestin for at least 10 to 14 days per month to minimize the risk of endometrial hyperplasia. However, taking estrogens with progestins may have additional health risks for the patient; risk must be determined individually. Continuous, unopposed estrogen administration is acceptable in women without a uterus. Reevaluate periodically as clinically indicated to determine if use is still appropriate. 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. 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.  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.

    Transdermal dosage (bi-weekly estradiol patch, e.g., Alora, Minivelle, or Vivelle-Dot)
    Adult menopausal and postmenopausal females

    1 patch (delivering 0.025 mg, 0.0375 mg, 0.05 mg, 0.075 mg, or 0.1 mg per day); replace twice weekly (every 3 to 4 days). Usual initial dose is 0.0375 mg/day or 0.05 mg/day; see individual patch recommendations. Use the lowest effective dose. A switch between transdermal system types can be done immediately; if on oral therapy, begin a week after oral treatment stopped or when symptoms reappear. Generally, when used in a postmenopausal woman with an intact uterus, a progestin should also be considered to reduce the risk of endometrial hyperplasia. Reevaluate periodically as clinically indicated to determine if use is still appropriate. 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. 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. 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.

    Transdermal dosage (estradiol weekly patch, e.g., Climara)
    Adult menopausal and postmenopausal females

    1 patch (delivering 0.025 mg, 0.0375 mg, 0.05 mg, 0.06 mg, 0.075 mg, or 0.1 mg per day) applied and replaced every 7 days. Usual initial dose is 0.0375 mg/day or 0.05 mg/day. Use lowest effective dose. A switch between transdermal system types can be done immediately; if on oral therapy, begin 1 week after oral treatment is discontinued or when symptoms reappear. Generally, when used in a postmenopausal woman with an intact uterus, a progestin should also be considered to reduce the risk of endometrial hyperplasia. Reevaluate periodically as clinically indicated to determine if use is still appropriate. 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. 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. 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.

    Topical dosage (Divigel topical gel only)
    Adult menopausal and postmenopausal females

    Initially, one 0.25 gram/day packet once daily; apply the entire contents of a unit-dose packet topically to an approximate 5-inch by 7-inch area on the skin of the upper thigh once daily; alternate between the right and left upper thigh each day. Subsequent dosage adjustments may be made based upon the individual patient response; 0.5 gram/day, 0.75 gram/day, and 1 gram/day unit-dose packets are also available. Use lowest effective dose. Generally, when used in a postmenopausal woman with an intact uterus, a progestin should also be considered to reduce the risk of endometrial hyperplasia. Reevaluate periodically as clinically indicated to determine if use is still appropriate. 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. 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. 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.

    Topical dosage (Elestrin topical gel only)
    Adult menopausal and postmenopausal females

    Initially, apply 1 actuation of the pump (0.87 grams estradiol gel containing 0.52 mg of estradiol and delivering 12.5 mcg/day of estradiol systemically) once daily to the upper arm. Adjust based upon the individual patient response. Usual dose range is 1 to 2 pump actuations per day. Use the lowest effective dose. Generally, when used in a postmenopausal woman with an intact uterus, a progestin should also be considered to reduce the risk of endometrial hyperplasia. Reevaluate periodically as clinically indicated to determine if use is still appropriate. 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. 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. 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.

    Topical dosage (EstroGel topical gel only)
    Adult menopausal and postmenopausal females

    Apply 1 complete actuation of the pump (1.25 grams of 0.06% estradiol gel that contains 0.75 mg of estradiol) topically to 1 arm once daily; applied in a thin layer over the entire arm on the inside and outside from wrist to shoulder. Generally, when used in a postmenopausal woman with an intact uterus, a progestin should also be considered to reduce the risk of endometrial hyperplasia. Reevaluate periodically as clinically indicated to determine if use is still appropriate. 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. 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. 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.

    Topical dosage (Evamist topical spray only)
    Adult menopausal and postmenopausal females

    Initially, apply 1 spray (pump actuation, which supplies 1.53 mg estradiol) to the inner surface of the forearm once daily in the morning; if needed and based on clinical response, the dose may be increased to 2 to 3 sprays once daily in the morning. Each spray should be administered to adjacent, but non-overlapping sections of the inner surface of the forearm, starting near the elbow. Use lowest effective dose. Generally, when used in a postmenopausal woman with an intact uterus, a progestin should also be considered to reduce the risk of endometrial hyperplasia. Reevaluate periodically as clinically indicated to determine if use is still appropriate. 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. 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. 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.

    Vaginal dosage (estradiol acetate vaginal ring; Femring only)
    Adult menopausal and postmenopausal females

    Insert 1 vaginal ring (delivering either 50 or 100 mcg per 24 hours) vaginally into the upper third of the vaginal vault; keep in place continuously for 3 months, then remove. If appropriate, insert a new ring. Use lowest effective dose. While Femring may be used to treat isolated genitourinary symptoms, consider other vaginal products of lower estradiol dosage first. Generally, when used in a postmenopausal woman with an intact uterus, a progestin should also be considered to reduce the risk of endometrial hyperplasia. Reevaluate periodically as clinically indicated to determine if use is still appropriate. 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. 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. 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.

    Intramuscular dosage (estradiol valerate in oil)
    Adult menopausal and postmenopausal females

    Usual dosage is 10 to 20 mg IM once every 4 weeks.

    Intramuscular dosage (estradiol cypionate in oil)
    Adult menopausal and postmenopausal females

    Usual dosage is 1 mg to 5 mg IM once every 3 to 4 weeks as necessary.

    For the treatment of isolated vaginal and/or urogenital symptoms of menopause.
    Vaginal dosage (estradiol vaginal cream)
    Adult menopausal and postmenopausal females

    Initially, 2 grams to 4 grams (200 mcg to 400 mcg of estradiol) vaginally once daily for 1 to 2 weeks; then gradually reduce over 1 to 2 weeks. Usual maintenance: 1 gram (estradiol 100 mcg) vaginally 1 to 3 times per week. Treatment is cyclic (3 weeks on, then 1 week off). When isolated genitourinary symptoms caused by menopause are present, treatment guidelines recommend low-dose vaginal estrogens over systemic estrogens as first-line therapy.

    Vaginal dosage (Estring vaginal ring only)
    Adult menopausal and postmenopausal females

    Insert 1 vaginal ring (delivering estradiol 7.5 mcg/24 hours) deep into the upper third of the vaginal vault. Keep in place continuously for 3 months, then remove. If appropriate, insert a new ring. The dosage of Estring vaginal ring is not effective at treating vasomotor symptoms. Generally, when used in a postmenopausal woman with an intact uterus, a progestin should also be considered to reduce the risk of endometrial hyperplasia. Reevaluate periodically as clinically indicated to determine if use is still appropriate. When isolated genitourinary symptoms caused by menopause are present, treatment guidelines recommend low-dose vaginal estrogens over systemic estrogens as first-line therapy.

    Vaginal dosage (Vagifem, Yuvafem vaginal tablets only)
    Adult menopausal and postmenopausal females

    Insert 1 tablet (10 mcg) vaginally once daily for 2 weeks into the upper third of the vaginal vault using the supplied applicator. After 2 weeks, give a maintenance dose of 1 tablet vaginally twice weekly (e.g., every Tuesday and Friday). Generally, when used in a postmenopausal woman with an intact uterus, a progestin should also be considered to reduce the risk of endometrial hyperplasia. Reevaluate periodically as clinically indicated to determine if use is still appropriate. While doses as high as 25 mcg/dose have been used, the 25 mcg dosage strength is no longer marketed. When isolated genitourinary symptoms caused by menopause are present, treatment guidelines recommend low-dose vaginal estrogens over systemic estrogens as first-line therapy.

    For the treatment of moderate to severe dyspareunia, a symptom of atrophic vaginitis due to menopause.
    Vaginal dosage (Imvexxy vaginal insert only)
    Adult menopausal and postmenopausal females

    Place 1 insert vaginally once daily at approximately the same time of day for 2 weeks, followed by 1 insert twice weekly (e.g., Monday and Thursday). Generally, initiate with the 4 mcg insert. Max: 10 mcg/dose vaginally. Use the lowest effective dose. Generally, when used in a postmenopausal woman with an intact uterus, a progestin should also be considered to reduce the risk of endometrial hyperplasia. Reevaluate periodically as clinically indicated to determine if use is still appropriate. When isolated genitourinary symptoms caused by menopause are present, treatment guidelines recommend low-dose vaginal estrogens over systemic estrogens as first-line therapy.

    For osteoporosis prophylaxis in women due to menopause (either natural or surgical).
    Oral dosage
    Adult females

    Dosage range is 0.5 mg to 2 mg PO once daily. Only consider for women at significant risk for osteoporosis and for whom non-estrogen medications are not considered to be appropriate. Use the lowest effective dose. Continuous unopposed estrogen administration is acceptable in those without a uterus. In women with an intact uterus, consider a progestin to reduce the risk of endometrial hyperplasia. Re-evaluate the need and appropriateness of therapy at 3 to 6 month intervals. In postmenopausal women with low bone mineral density, there is good evidence that standard-dose estrogen therapy reduces 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.

    Transdermal dosage (estradiol biweekly transdermal patch, e.g., Alora, Minivelle, or Vivelle-Dot)
    Adult females

    Initially, 1 patch (0.025 mg/day) applied transdermally applied twice weekly (every 3 to 4 days) as directed in product label. For women at significant risk of osteoporosis after careful consideration of non-estrogen medications. May adjust dose to therapeutic goals. Use lowest effective dose. Continuous unopposed estrogen administration is acceptable in those without a uterus. For women with an intact uterus, consider a progestin to reduce the risk of endometrial hyperplasia. Alternatively, a cyclic schedule of 3 weeks on drug and 1 week off drug may be used. Reevaluate the need for the current dose and the appropriateness of therapy at 3 to 6 month intervals. In postmenopausal women with low bone mineral density, there is good evidence that standard-dose estrogen therapy reduces 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.

    Transdermal dosage (estradiol weekly transdermal patch, e.g., Menostar, Climara)
    Adult females

    Initially, 1 patch (0.014 mg/day or 0.025 mg/day, depending on brand chosen) applied transdermally once weekly (every 7 days) as directed in specific product label. Menostar is only indicated for osteoporosis prophylaxis and only comes in 0.014 mg/day strength. For women at significant risk of osteoporosis after careful consideration of non-estrogen medications. May adjust dose to achieve therapeutic goals. Use lowest effective dose. Continuous unopposed estrogen is acceptable in those without a uterus. Consider a progestin to reduce the risk of endometrial hyperplasia in women with an intact uterus. Alternatively, a cyclic schedule of 3 weeks on drug and 1 week off drug may be used. Re-evaluate the need for the current dose and the appropriateness of therapy at 3 to 6 month intervals. In postmenopausal women with low bone mineral density, there is good evidence that standard-dose estrogen therapy reduces 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.

    For estrogen replacement for premenopausal women with primary ovarian failure or female hypogonadism.
    Oral dosage
    Adult females

    0.5 mg to 2 mg PO once daily continuously; or in cycles of 21 days on and 7 days off. For hypogonadism, women are treated for the period of reproductive life until the time of natural menopause, which maintains feminization and prevents bone loss.

    Adolescent females 12 years and older

    Begin at a low dose (e.g., 0.25 mg PO once daily); dose is then increased over time to meet the goals of the individual patient based on age, sexual development, bone age and height, and other treatment goals. Replacement is usually begun at one-tenth to one-eighth of the usual adult dose and then increased to the usual adult dose gradually over a period of about 2 years. Usual range: 0.5 to 2 mg PO once daily. Use lowest effective dose. To allow for normal breast and uterine development, guidelines advise the delay of the addition of progestin (given for 1 week per month) at least 1 to 2 years after starting estrogen or when breakthrough bleeding occurs. Treatment continues for reproductive life.

    Transdermal dosage (estradiol bi-weekly patch, e.g., Alora or Vivelle-Dot)
    Adult females

    1 patch (delivering 0.025 mg, 0.0375 mg, 0.05 mg, 0.075 mg, or 0.1 mg per day) replaced twice weekly (every 3 to 4 days); start therapy with 0.025 mg/day dose and adjust as needed. Apply transdermally as directed; replace patch twice weekly (every 3 to 4 days); give cyclically or continuously. Use lowest effective dose. For hypogonadism, women are treated for the period of reproductive life until the time of natural menopause, which maintains feminization and prevents bone loss.

    Adolescent females 12 years and older

    Begin with a low dose patch (e.g., 14 mcg/day estradiol delivery) applied twice-weekly (every 3 to 4 days). Dose is increased over time to meet the goals of the individual patient based on age, sexual development, bone age and height, and other treatment goals. Gradually increase dose over about 2 years (e.g. 25, 37.5, 50, 75, 100 mcg/day estradiol delivered via patch) to adult dose for female hypogonadism. Use lowest effective dose. Pubertal induction can be accomplished with transdermal estradiol at an off-label dose as low as 3.1 to 6.2 mcg/24 hours; however, such dosage forms are not commercially available. To allow for normal breast and uterine development, guidelines advise the delay of the addition of progestin (given for 1 week per month) at least 1 to 2 years after starting estrogen or when breakthrough bleeding occurs. Treatment continues for reproductive life.

    Transdermal dosage (estradiol weekly patch, e.g., Climara)
    Adult females

    Initially, 0.025 mg/day patch applied to the skin once weekly. Adjust as needed, dose is 1 patch (delivering 0.025 mg, 0.0375 mg, 0.05 mg, 0.06 mg, 0.075 mg, or 0.1 mg per day) on trunk or buttocks and replaced every 7 days; give cyclically or continuously. Use the lowest effective dose. For hypogonadism, women are treated for the period of reproductive life until the time of natural menopause, which maintains feminization and prevents bone loss.

    Adolescent females 12 years and older

    Begin with a low dose patch (e.g., 14 mcg/day estradiol delivery) applied weekly (every 7 days). Dose is then increased over time to meet the goals of the individual patient based on age, sexual development, bone age and height, and other treatment goals. Gradually increase dose over about 2 years (e.g. 25, 37.5, 50, 60, 75, 100 mcg/day estradiol delivered via patch) to adult dose for female hypogonadism. Use lowest effective dose. Pubertal induction can be accomplished with transdermal estradiol at an off-label dose as low as 3.1 to 6.2 mcg/day; however, such dosage forms are not commercially available. To allow for normal breast and uterine development, guidelines advise the delay of the addition of progestin (given for 1 week per month) at least 1 to 2 years after starting estrogen or when breakthrough bleeding occurs. Treatment continues for reproductive life.

    Intramuscular dosage (estradiol cypionate in oil)
    Adult females

    For female hypogonadism, the usual dose is estradiol cypionate 1.5 to 2 mg IM every 4 weeks. For women with hypogonadism, estrogen treatment continues for reproductive life up until natural menopausal age to maintain feminization and prevent bone loss, but choices of treatment often change from IM depot dosing to other dosage forms.

    Adolescent females 12 years and older

    Begin with a low dose (e.g., 0.2 mg estradiol cypionate) IM every 4 weeks. Dose is then increased over time to meet the goals of the individual patient based on age, sexual development, bone age and height, and other treatment goals. Gradually increase dose over about 2 years to usual adult maintenance dose for female hypogonadism, i.e., estradiol cypionate 1.5 mg to 2 mg IM every 4 weeks. Use lowest effective dose. To allow for normal breast and uterine development, guidelines advise the delay of the addition of progestin (given for 1 week per month) at least 1 to 2 years after starting estrogen or when breakthrough bleeding occurs. Treatment continues for reproductive life, but choices of treatment often change from IM depot dosing to other dosage forms as the adolescent matures.

    Intramuscular dosage (estradiol valerate in oil)
    Adult females

    The usual dose is estradiol valerate 10 mg to 20 mg IM every 4 weeks. For women with hypogonadism, estrogen treatment continues for reproductive life up until the time of menopause to maintain feminization and prevent bone loss, but choices of treatment often change from IM depot dosing to other dosage forms.

    Adolescent females 12 years and older

    Not commonly used. Begin with a low dose (e.g., 2.5 mg estradiol valerate) IM every 4 weeks. Dose is then increased over time to meet the goals of the individual patient based on age, sexual development, bone age and height, and other treatment goals. Gradually increase dose over about 2 years to usual adult maintenance dose for female hypogonadism, i.e, estradiol valerate 10 mg to 20 mg IM every 4 weeks. Use lowest effective dose. To allow for normal breast and uterine development, guidelines advise the delay of the addition of progestin (given for 1 week per month) at least 1 to 2 years after starting estrogen or when breakthrough bleeding occurs. Treatment continues for reproductive life, but choices of treatment often change from intramuscular depot dosing to other dosage forms as the adolescent matures.

    For the palliative treatment of advanced inoperable prostate cancer.
    Oral dosage
    Adult males

    Suggested dosage is 1 to 2 mg 3 times daily. The effectiveness of therapy can be judged by specific prostate antigen (PSA) determinations as well as by symptomatic improvement of the patient.

    Intramuscular dosage (estradiol valerate injection)
    Adult males

    30 mg IM administered every 1 to 2 weeks. Efficacy is evaluated according to patient clinical response and serial prostate specific antigen (PSA) levels. A response to estrogen treatment, if it will occur, will usually be noted within 3 months. Continued until a significant advancement of the disease occurs.

    For the palliative treatment of breast cancer that is inoperable and progressive in selected men and postmenopausal women.
    Oral dosage (estradiol)
    Adults

    10 mg PO 3 times per day for at least 3 months.

    MAXIMUM DOSAGE

    Adults

    Dependent on indication for therapy.

    Elderly

    Dependent on indication for therapy.

    Adolescents

    Dependent on indication for therapy.

    Children

    Not indicated in prepubescent females.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Estradiol is contraindicated in the presence of jaundice or known hepatic impairment or disease of any type.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment patients who do not have end-stage renal disease (ESRD) are not available; it appears that no dosage adjustments are needed for initial dosing. Dosages should be chosen in accordance with expected clinical response and tolerance.
     
    Intermittent hemodialysis
    In postmenopausal women with end-stage renal disease (ESRD) receiving maintenance hemodialysis, total estradiol serum levels are higher than in normal subjects at baseline and following oral doses of estradiol. Therefore, conventional oral or transdermal estradiol doses used in individuals with normal renal function may be excessive for postmenopausal women with ESRD receiving maintenance hemodialysis.

    ADMINISTRATION

    Oral Administration

    Administer at approximately the same time each day.
    May administer with or without food.

    Injectable Administration

    Estradiol cypionate and estradiol valerate are administered intramuscularly. These products are NOT for intravenous or subcutaneous administration.
    Injections are oil based. No reconstitution is necessary.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intramuscular Administration

    Estradiol cypionate, estradiol valerate: Roll vial and syringe between the palms to ensure even dispersion prior to withdrawal and administration of the injection. For these oil-based products, a needle of at least 21 gauge is recommended; a dry, sterile syringe should be used.
    All intramuscular injections: Inject deeply into the upper, outer quadrant of the gluteal muscle.

    Topical Administration

    Administer topically via a topical emulsion, gel, spray, or as a transdermal patch.
    Wash hands before and after application.

    Transdermal Patch Formulations

    Administer topically to the skin using the chosen transdermal patch system.
    Wash hands before and after application.
    Instruct patient on proper application and dosage regimen of patch prescribed.
    Each patch brand provides instructions regarding where the patch may be applied. Apply to an area of clean, dry intact skin on an appropriate area of the body for the patch chosen. Do not apply to the breasts. Do not apply to the waistline or other areas where the patch may not adhere properly.
    The transdermal system should not be exposed to the sun for prolonged periods of time.
    Patients may bathe while wearing some systems. Swimming or using a sauna while using the patches has not been studied, and these activities, including bathing or showering, may decrease the adhesion of the system and the delivery of the estrogen.
    If a system should fall off, the same system may be reapplied to another area. If necessary, a new system may be applied, in which case, the original treatment schedule should continue.
    Always remove the old patch/system before applying a new patch/system.
    The sites of application must be rotated, with an interval of at least 1 week allowed between applications to the same site.

    Other Topical Formulations

    Topical gel, Divigel:
    Instruct patient on proper application.
    Apply the gel to clean, dry, unbroken skin. In a thin layer, spread the entire contents of a unit dose package to the right or left upper thigh over an area of approximately 5 inches by 7 inches. To minimize skin irritation, alternate between the left and right upper thigh each day.
    The application site should be allowed to completely dry before dressing or swimming.
    The application site should not be washed for at least 1 hour after application.
    Other people should not come in contact with the area of skin where the gel was applied until it is completely dried.
    Patients should be instructed to avoid fire, flames, or smoking until the gel has completely dried; Divigel is alcohol based and thus flammable.
    Divigel is available in 4 dose strengths of 0.25, 0.5, 0.75, and 1 gram for topical application (corresponding to 0.25, 0.5, 0.75, and 1 mg estradiol, respectively).
     
    Topical gel, Elestrin:
    Instruct patient on proper application.
    Prior to the first use, the pump must be primed by depressing the pump 10 times. Discard any of the unused gel that is released during priming.
    Apply the gel to clean, dry, unbroken skin on the upper arm. Patients should not swim for at least 2 hours after application of the gel.
    To apply the dose, depress the pump with the tip of the pump facing the area of the arm where the gel will be applied. Apply the gel to the entire upper arm and shoulder using 2 fingers.
    The area should be allowed to dry for at least 5 minutes prior to dressing.
    Other people should not come in contact with the skin for at least 2 hours after the gel is applied.
    Patients should be instructed to avoid fire, flames, or smoking until the gel has completely dried; the Elestrin gel is alcohol based and thus flammable.
    Sunscreen should not be applied to the upper arm for at least 25 minutes after gel application. In addition, sunscreen should not be applied to the area of gel application for 7 or more consecutive days.
    One pump actuation (0.87 gram dose) delivers 0.52 mg of estradiol equivalent to a systemic delivery of estradiol 0.0125 mg/day. Two pump actuations (1.7 grams dose) provides systemic delivery of estradiol 0.0375 mg/day.
     
    Topical gel, EstroGel:
    Instruct patient on proper application.
    Prior to the first use, the pump must be primed by fully depressing the pump 2 times for the 93-grams size pump or 3 times for the 50-grams or 25-grams size pumps. Discard the unused gel that is expelled during the priming process by thoroughly rinsing down the sink or placing in the household trash.
    The usual dosage is 1 complete actuation (pump depression) of the metered dose pump daily.
    Apply the gel to clean, dry, unbroken skin on the arm.
    To apply the dose, depress the pump and collect the gel into the palm of the hand. Apply the gel to 1 entire arm, covering the area from the shoulder to the wrist. The gel should be applied as thinly as possible.
    The arm should be allowed to dry for up to 5 minutes prior to dressing.
    Patients should not shower or swim for as long as possible after application of the gel.
    Other people should not come in contact with the skin for at least 1 hour after the gel is applied.
    Patients should be instructed to avoid fire, flames, or smoking until the gel has completely dried; the Estrogel is flammable.
    An EstroGel unit dose of 1.25 grams contains 0.75 mg of estradiol.
     
    Topical skin emulsion, Estrasorb:
    Instruct patient on proper application.
    Patients should be sitting in a comfortable position prior to emulsion application. Apply the emulsion to clean, dry skin on both legs each morning. Do not apply the emulsion to skin that is red or irritated.
    Each dose requires 2 foil packages. Each package should be opened separately. They should not be opened until just before the dose is applied.
    To apply the dose, open the first foil packet and expel the entire contents to the top of the left thigh. Using one or both hands, rub the emulsion into the entire left thigh and the left calf for 3 minutes and until thoroughly absorbed. Rub any excess material from the hands onto the buttocks. Repeat this process with the second foil packet using the right thigh and calf. Absorption of the topical emulsion has only been studied on the thighs, calves, and buttocks.
    The areas to which the topical emulsion has been applied should be allowed to dry completely before covering with clothing to avoid transfer to other individuals.
    Sunscreen and the topical emulsion should not be applied at the same time because sunscreen may increase the amount of emulsion absorbed.
    Daily topical application of the contents of 2 foil pouches provides systemic delivery of 0.05 mg of estradiol per day.
     
    Topical spray, Evamist:
    Instruct patient on proper application.
    Prior to the first use, prime the pump by spraying 3 sprays with the lid in place. The pump should be held vertical and upright for spraying.
    Apply each spray to the inner surface of the forearm. When applying more than 1 spray, apply each spray to adjacent, but non-overlapping skin of the inner forerarm starting at the elbow. Do not apply Evamist to other skin surfaces; other skin surfaces have not been studied.
    Allow spray to dry for approximately 2 minutes.
    Do not wash the site for 1 hour after application.
    Patients should cover the application site with clothing, after the 2 minute drying period, if another person may come in contact with that area of skin.
    Others should not be allowed to make contact with the area of skin where the spray has been applied. If direct contact occurs, the contact area should be washed thoroughly with soap and water.
    Patients should be instructed to avoid fire, flames, or smoking until the spray has dried; the Evamist is alcohol based and thus flammable.
    Each spray provides 90 microL containing 1.53 mg of estradiol.

    Intravaginal Administration

    Vaginal cream (Estrace):
    Wash and dry hands before handling. Screw the threaded end of the applicator with plunger onto the opened tube until secure. Squeeze from the bottom of the tube to expel the prescribed amount of cream into the applicator. Patients should be instructed to lie on their back with their knees drawn up, gently insert the applicator deeply into the vagina, and, once inserted, press the plunger downward to its original position. The applicator can be cleansed by removing the plunger from the barrel and washing with mild soap and water. Although not specifically recommended by the manufacturer, it may be prudent to advise patients to administer the vaginal cream just prior to bedtime in order to maximize absorption. Wash hands after use.
     
    Vaginal ring inserts (Estring, Femring):
    Wash and dry hands before handling. The ring insert may be placed by the patient or a health care provider. The opposite sides of the insert should be pressed together and inserted into the vagina compressed. The ring insert is placed as deeply as possible in the upper third of the vagina and is worn continuously for 90 days. After 90 days, the ring should be removed and a new insert is applied. The insert may be removed by hooking a finger through the ring and pulling it out. The patient should not feel the ring, nor should it interfere with sexual intercourse. In addition, if the ring moves into the lower part of the vagina, the patient can push the ring back into place using a finger. Alternatively, within the 90-day dosage period, if the insert is removed or expelled, rinse it with lukewarm (not hot or boiling) water, and re-insert the ring as needed. Wash hands after use. Remove the old ring insert before inserting a new one.
     
    Vaginal tablet (Vagifem):
    Wash and dry hands before handling. Use a new applicator containing an estradiol vaginal tablet each day, preferably at the same time each day; if the tablet has fallen out of the applicator, but is still contained in the packaging, carefully place it back into the applicator with clean dry hands. If the tablet has inadvertently fallen out of the applicator prior to insertion, the applicator should be thrown out and a new one containing a tablet used. Keep hands clean and dry while handling the tablet. Insert the applicator as far as comfortably possible into the vagina (without force), or until half of the applicator is inside the vagina, whichever is less. Then, gently press the plunger until the plunger is fully depressed. This will eject the tablet inside the vagina where it will dissolve slowly over several hours. After depressing the plunger, gently remove the applicator and dispose of it similarly to a plastic tampon applicator. Wash hands after use.
     
    Vaginal insert (Imvexxy):
    Wash and dry hands before handling the insert. Push the insert through the foil of the blister package. Hold the insert with the larger end between the fingers. The patient should select the best position for vaginal insertion that is most comfortable, either lying down or standing. With the smaller end up, place the insert about 2 inches into the vagina using the finger. Wash hands after use. The patient should write down the days of insertion. Wash hands after use.

    STORAGE

    Generic:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Alora:
    - Do not store outside of the sealed pouch
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Climara:
    - Store below 86 degrees F
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in carton
    - Store in original unopened pouch
    Delestrogen:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton until time of use
    Depo-Estradiol:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Divigel:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Elestrin:
    - Flammable, keep away from heat and flame
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Estrace:
    - Avoid excessive heat (above 104 degrees F)
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Estraderm:
    - Do not store outside of the sealed pouch
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Estrasorb:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Estring:
    - Store at room temperature (between 59 to 86 degrees F)
    EstroGel:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Evamist:
    - Do not freeze
    - Flammable, keep away from heat and flame
    - Store at room temperature (between 59 to 86 degrees F)
    FemPatch:
    - Do not store outside of the sealed pouch
    - Store below 86 degrees F
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Femring:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Femtrace:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Gynodiol :
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Gynogen LA:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton until time of use
    Imvexxy:
    - Do not refrigerate
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Menostar:
    - Store below 86 degrees F
    - Store in original container
    Minivelle:
    - Do not store outside of the sealed pouch
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Vagifem:
    - Do not refrigerate
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Vivelle:
    - Do not store outside of the sealed pouch
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Vivelle-Dot:
    - Do not store outside of the sealed pouch
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Yuvafem:
    - Do not refrigerate
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Hereditary angioedema, history of angioedema

    Do not use estradiol products in patients with a known hypersensitivity to any of the specific product ingredients; estradiol is 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 estradiol. 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.

    Breast cancer, hypercalcemia, new primary malignancy

    Estradiol products are contraindicated in patients with a known or suspected estrogen-dependent neoplasm, including breast cancer. The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms, requiring further evaluation. All women taking estrogen with or without a progestin should receive an annual clinical breast examination, perform monthly self-examinations, and have regular mammograms as recommended by their health care professional based on patient age, risk factors, and prior mammogram results. Since the 1970's, numerous epidemiological studies have examined the association of estrogens or combined hormone replacement therapy (HRT) and breast cancer (new primary malignancy). The data available are derived from studies of estrogen-alone or estrogen plus progestin hormonal replacement therapy (HRT). The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the Womens Health Initiative (WHI) substudy of estrogen-alone therapy. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily estrogen monotherapy was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80]. The most important randomized clinical trial providing information about breast cancer in patients taking combined estrogen-progestin HRT regimens is the WHI substudy of estrogen plus a progestin. After a mean follow-up of 5.6 years, the WHI estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily estrogen plus progestin vs. placebo. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for estrogen-progestin compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years for estrogen-progestin compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years for estrogen-progestin compared with placebo. In the same WHI substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the combined HRT group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the 2 groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the 2 groups. Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with combined HRT as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration. While estrogen therapy may be used rarely for the palliative treatment of advanced breast cancer in men and women, 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.

    Ovarian cancer

    Estradiol products are contraindicated in women with estrogen-dependent neoplasms, including ovarian cancer. What is known about the risk of ovarian cancer due to estrogen-containing hormonal replacement therapy (HRT) regimens is derived from data available for estrogen-alone and estrogen plus progestin products. 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. 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.

    Endometrial cancer, endometrial hyperplasia, vaginal bleeding

    Estrogen 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 the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy 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 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 estrogen therapy is estimated to be 1% or less.

    Cervical cancer, endometriosis, uterine cancer, uterine leiomyomata, vaginal cancer

    Estrogens are contraindicated in the presence of vaginal cancer, cervical cancer, uterine cancer, or other estrogen-responsive tumors. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin 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 estradiol products cautiously in women with endometriosis or uterine leiomyomata (uterine fibroids). A few cases of malignant transformation of residual endometrial growths have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of a progestin should be considered to reduce the risk of endometrial tissue growth.

    Cardiac disease, cerebrovascular disease, coronary artery disease, hypercholesterolemia, hypertension, myocardial infarction, obesity, protein C deficiency, protein S deficiency, stroke, thromboembolic disease, thromboembolism, thrombophlebitis, tobacco smoking

    Estrogens are contraindicated in patients with an active or past history of thrombophlebitis, thromboembolism, thromboembolic disease, stroke, or myocardial infarction (MI). An increased risk of cerebrovascular disease (stroke) and deep venous thrombosis (DVT) has been reported with unopposed estrogen therapy. An increased risk of thromboembolism, including pulmonary embolism (PE), DVT, stroke and myocardial infarction (MI) has been reported with estrogen plus progestin hormone replacement therapy (HRT). Should any of these events occur or be suspected, discontinue estradiol immediately. 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. 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. In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving estrogen plus progestin HRT compared to women receiving placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted. Estrogens with or without progestins 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 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). In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily estrogen plus progestin compared to women receiving placebo (41 vs. 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5. Studies have also shown no cardiovascular benefit to the use of estrogens or estrogen-progestin therapy for secondary prevention in women with documented cardiac disease or CHD. 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). In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen plus progestin HRT compared to women in the same age group receiving placebo (33 vs. 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. Women over the age of 65 years were at increased risk for non-fatal stroke. 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. In men treated with estrogens for palliation of prostate or breast cancer, estrogens have increased the risk of nonfatal MI, PE, and thrombophlebitis.

    Surgery

    If feasible, estradiol 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 estradiol should be advised to move about periodically during travel involving prolonged immobilization.

    Pregnancy

    Estrogens are contraindicated during pregnancy. There is no known approved indication for the use of estrogens during pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy. Estradiol and other estrogens freely cross the placenta to the fetus. 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 continued use of estrogens in pregnant women. In any patient in whom pregnancy is suspected, pregnancy should be ruled out before continuing estrogen use. In select instances estradiol has been used off-label as an adjuvant to clomiphene treatment of infertility, or in donor oocyte program procedures in assisted reproduction technology (ART) under the direction of ART specialists; however, treatment is discontinued when pregnancy ensues.

    Breast-feeding

    Caution should be used if a breast-feeding mother is receiving estradiol for hormone replacement. Estrogen administration to nursing women is generally avoided during lactation as estrogens have been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving estradiol and other estrogens. Estrogens are not approved by the FDA for the treatment of postpartum breast engorgement.

    Gallbladder disease, hepatic disease, hepatocellular cancer, jaundice, porphyria

    Estrogens are contraindicated in the presence of hepatocellular cancer, hepatic adenoma, or in severe hepatic disease of any type. Estrogens 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.

    Systemic lupus erythematosus (SLE)

    Patients with systemic lupus erythematosus (SLE) may have increased risk for thromboembolism and should be managed appropriately when estrogen therapy is considered. 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, including estradiol, 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.

    Hypertriglyceridemia, pancreatitis

    In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of estradiol treatment if pancreatitis occurs.

    Contact lenses, migraine, visual disturbance

    Retinal vascular thrombosis has been reported in women receiving estrogens. Any visual disturbance should be examined by an ophthalmologist. Discontinue the estrogen 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, estrogens should be permanently discontinued. 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.

    Diabetes mellitus

    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 estradiol 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.

    Hypothyroidism, thyroid disease

    Use estradiol 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.

    Asthma, renal disease, seizure disorder

    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.

    Depression

    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, estradiol should be discontinued.

    Hypocalcemia, hypoparathyroidism

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

    Dementia, geriatric

    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 geriatric women 65 years and older. 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 a geriatric woman over 65 years of age. According to the Beers Criteria, oral and topical patch, or other systemic forms of 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 the potential for aggravation of incontinence. The Beers expert panel considers use of intra-vaginal preparations acceptable for the management of dyspareunia, lower urinary tract infections, and other vaginal/vulvar symptoms. In addition, evidence suggests that vaginal estrogens are safe and effective for the treatment of vaginal dryness; women with a history of breast cancer who do not respond to non-hormonal therapies are advised to discuss the risks and benefits of low-dose vaginal estrogen (estradiol less than 25 mcg twice weekly) with their healthcare provider. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to the OBRA guidelines, assessment of the underlying causes and identification of the type/category of urinary incontinence needs to be documented prior to or soon after initiating treatment with a medication to manage urinary incontinence (e.g., estrogen replacement agents). These medications have specific and limited indications based on the cause and categorization of incontinence. Patients should be assessed periodically for medication effects on urinary incontinence as well as lower urinary tract symptoms and treatment tolerability. The Guidelines caution that oral estrogen products may cause systemic side effects and increased risks (e.g., DVT, breast cancer), and topical agents may be preferred.

    Children, infants, neonates

    The safety and efficacy of estrogens have not been established in neonates, infants or children. Estrogens are not indicated in children because estrogens promote epiphysial closure. In young children, overdose of estrogens have not been reported to cause serious ill effects. However, nausea is common. Vaginal withdrawal bleeding may occur in female children exposed to estrogens in large doses. Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay; however, if estrogen is administered to adolescent patients whose bone growth is not complete, these patients should be monitored periodically for bone maturation and effects on epiphyseal centers.

    Intravenous administration

    Estradiol cypionate and estradiol valerate are esterified estrogens that are in oil-based injections; intravenous administration should be avoided as injection by this route may result in serious adverse effects. These injections are to be administered by the intramuscular route only.

    Accidental exposure

    Estradiol is available in many topical dosage forms, including transdermal systems, topical emulsions, topical gels, and topical sprays. Estradiol topical gels and sprays are alcohol-based and thus are potentially flammable. Patients should be advised to avoid fire, flame, or smoking until the gel or spray has dried after application. Patients should be advised to carefully read and follow administration directions in order to avoid accidental exposure of estradiol hormone to others, including children and pets. In July 2010, the FDA released an advisory notice warning of inadvertent exposure to Evamist brand topical spray through skin contact with patients using the product. Adverse events including premature puberty, nipple swelling and breast development in females, and breast enlargement in males were reported. Reports of pet exposure were also reported; signs of exposure in pets may include mammary/nipple enlargement and vulvar swelling. To reduce the risk of exposure, patients applying this product should avoid contact of the treated area to children and pets. If direct contact cannot be avoided, the treated area should be covered with a garment. If inadvertent exposure occurs, the skin of the child or pet should be washed immediately with soap and water. Patients should be aware that if a child under their care shows signs of exposure including breast development or other sexual changes, the child should be examined by a healthcare professional. Once exposure is removed, symptoms of exposure should resolve.

    ADVERSE REACTIONS

    Severe

    biliary obstruction / Delayed / Incidence not known
    GI obstruction / Delayed / Incidence not known
    cholecystitis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    stroke / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    thromboembolism / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    erythema nodosum / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    papilledema / Delayed / Incidence not known
    retinal thrombosis / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    dementia / Delayed / Incidence not known
    toxic-shock syndrome / Delayed / Incidence not known
    endometrial cancer / Delayed / Incidence not known
    ovarian cancer / Delayed / Incidence not known
    breast cancer / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    pulmonary oil microembolism / Rapid / Incidence not known
    teratogenesis / Delayed / Incidence not known

    Moderate

    fluid retention / Delayed / 1.0-10.0
    endometrial hyperplasia / Delayed / 1.0-10.0
    candidiasis / Delayed / 0-8.0
    vaginal bleeding / Delayed / Incidence not known
    cervical dysplasia / Delayed / Incidence not known
    vaginitis / Delayed / Incidence not known
    cervicitis / Delayed / Incidence not known
    galactorrhea / Delayed / Incidence not known
    peliosis hepatis / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    cholelithiasis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    hypertension / Early / Incidence not known
    migraine / Early / Incidence not known
    depression / Delayed / Incidence not known
    hematoma / Early / Incidence not known
    erythema / Early / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    hypocalcemia / Delayed / Incidence not known
    impaired cognition / Early / Incidence not known
    urinary incontinence / Early / Incidence not known
    vaginal pain / Early / Incidence not known
    hypercalcemia / Delayed / Incidence not known

    Mild

    headache / Early / 5.0-21.0
    back pain / Delayed / 3.3-11.0
    weight gain / Delayed / 1.0-10.0
    skin irritation / Early / 1.0-10.0
    pruritus / Rapid / 1.0-10.0
    diarrhea / Early / 5.0-5.0
    dysmenorrhea / Delayed / 10.0
    breakthrough bleeding / Delayed / 10.0
    mastalgia / Delayed / 10.0
    nausea / Early / 10.0
    abdominal pain / Early / 10.0
    libido increase / Delayed / Incidence not known
    amenorrhea / Delayed / Incidence not known
    menorrhagia / Delayed / Incidence not known
    libido decrease / Delayed / Incidence not known
    breast discharge / Delayed / Incidence not known
    gynecomastia / Delayed / Incidence not known
    breast enlargement / Delayed / Incidence not known
    vomiting / Early / Incidence not known
    emotional lability / Early / Incidence not known
    irritability / Delayed / Incidence not known
    anxiety / Delayed / Incidence not known
    fatigue / Early / Incidence not known
    insomnia / Early / Incidence not known
    maculopapular rash / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    hirsutism / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    skin discoloration / Delayed / Incidence not known
    melasma / Delayed / Incidence not known
    rash / Early / Incidence not known
    acne vulgaris / Delayed / Incidence not known
    xerosis / Delayed / Incidence not known
    vesicular rash / Delayed / Incidence not known
    gingivitis / Delayed / Incidence not known
    diplopia / Early / Incidence not known
    muscle cramps / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known
    infection / Delayed / Incidence not known
    vaginal irritation / Early / Incidence not known
    vaginal discharge / Delayed / Incidence not known
    bladder discomfort / Early / Incidence not known
    injection site reaction / Rapid / Incidence not known

    DRUG INTERACTIONS

    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.
    Acebutolol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Acetaminophen; Propoxyphene: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as propoxyphene 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.
    Albiglutide: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as combined hormonal oral contraceptives (OCs). Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. atients 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.
    Aliskiren; Amlodipine: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Aliskiren; Valsartan: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Alogliptin; Metformin: (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.
    Alpha-blockers: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored to confirm that the desired antihypertensive effect is being obtained.
    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.
    Amiloride: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Amiloride; Hydrochlorothiazide, HCTZ: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Amiodarone: (Minor) Amiodarone inhibits CYP3A4, and may increase serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) if coadministered.
    Amlodipine: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Amlodipine; Atorvastatin: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Amlodipine; Benazepril: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Amlodipine; Olmesartan: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Amlodipine; Telmisartan: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Amlodipine; Valsartan: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Amoxicillin; Clarithromycin; Lansoprazole: (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 and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
    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 and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
    Amprenavir: (Severe) Amprenavir may interact with most estrogens and progestins. Oral contraceptives in particular should not be coadministered with amprenavir. Oral contraceptives have been shown to decrease the serum concentrations of amprenavir, which could lead to loss of virologic response and possible viral resistance to amprenavir. Alternative methods of non-hormonal contraception are recommended if amprenavir is prescribed.
    Anastrozole: (Severe) 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.
    Angiotensin II receptor antagonists: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Angiotensin-converting enzyme inhibitors: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    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 estradiol 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.
    Armodafinil: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    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.
    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.
    Atenolol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Atenolol; Chlorthalidone: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Atracurium: (Minor) Estrogens have been associated in rare cases with pseudocholinesterase deficiency. Since non-depolarizing neuromuscular blockers are metabolized by cholinesterase, prolonged neuromuscular blockade may occur in individuals on concurrent therapy with estrogens.
    Azelastine; Fluticasone: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Azilsartan: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Azilsartan; Chlorthalidone: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Barbiturates: (Major) Barbiturates can accelerate the hepatic clearance of estrogens and progestins. As a result, the effectiveness of oral contraceptives or other hormonal contraceptives can be lost. Pregnancy has been reported during therapy with both estrogen or progestin containing contraceptives in patients receiving barbiturates (e.g., phenobarbital). It may be prudent to use an additional contraceptive method to protect against unwanted pregnancy. For patients taking estrogens for other indications, like hormone replacement, a higher dose of estrogen may be required during barbiturate therapy.
    Beclomethasone: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Benazepril: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Benazepril; Hydrochlorothiazide, HCTZ: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Bendroflumethiazide; Nadolol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Beta-blockers: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Betamethasone: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Betaxolol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Bexarotene: (Moderate) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including estrogens. It is recommended that two reliable forms of contraception be used simultaneously, unless abstinence is the chosen method, during oral bexarotene therapy. Because of the potential interaction with hormonal contraceptives, it is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy. Patients receiving estrogens or progestins should report any breakthrough bleeding to their prescribers.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Bisoprolol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    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 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 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. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
    Brigatinib: (Major) Coadministration of brigatinib may reduce the efficacy of hormonal contraceptives. Because brigatinib can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use effective non-hormonal contraception during treatment with brigatinib and for at least 4 months after the final dose. Brigatinib induces CYP3A4 and estradiol valerate is a CYP3A4 substrate.
    Brimonidine; Timolol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    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.
    Budesonide: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Budesonide; Formoterol: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Bumetanide: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Calcium: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    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.
    Canagliflozin; Metformin: (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.
    Candesartan: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Candesartan; Hydrochlorothiazide, HCTZ: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Captopril: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Captopril; Hydrochlorothiazide, HCTZ: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Carbamazepine: (Major) Concurrent administration of estrogens with carbamazepine may reduce plasma estrogen concentrations and therefore reduce the clinical efficacy of estrogen products. If an estrogen-containing product is being used for contraception, consider an alternate or additional form of contraception; unintended pregnancy has occurred in women who relied on hormonal contraceptives and received carbamazepine. The alternative contraceptive agent may need to be continued for 1 month after discontinuation of carbamazepine. Women taking estrogen for hormone replacement may require a dosage adjustment. Women taking estrogen products for any indication and carbamazepine should report breakthrough bleeding to their prescriber. Estrogens are metabolized by CYP3A4, and carbamazepine is a potent CYP3A4 inducer. Additionally, patients taking both anticonvulsants and estrogen may be at higher risk of folate deficiency secondary to additive effects on folate metabolism. If contraceptive failure occurs, the additive effects could potentially heighten the risk of neural tube defects in the fetus.
    Carteolol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Carvedilol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Central-acting adrenergic agents: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    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.
    Chloramphenicol: (Moderate) 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. Also, anti-infectives that disrupt the normal GI flora, including chloramphenicol, may potentially decrease the effectiveness of estrogen-containing oral contraceptives.
    Chlorothiazide: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Chlorthalidone: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Chlorthalidone; Clonidine: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Ciclesonide: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Cimetidine: (Minor) Cimetidine has been reported to reduce the hepatic clearance of endogenous estradiol. The clinical significance of cimetidine's action on exogenous estrogens, like oral contraceptives, is uncertain. Patients who ingest cimetidine might experience an increase in certain estrogen-related side effects.
    Cisatracurium: (Minor) Estrogens have been associated in rare cases with pseudocholinesterase deficiency. Since non-depolarizing neuromuscular blockers are metabolized by cholinesterase, prolonged neuromuscular blockade may occur in individuals on concurrent therapy with estrogens.
    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 and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
    Clindamycin: (Moderate) Anti-infectives that disrupt the normal GI flora, clindamycin, lincomycin, may potentially decrease the effectiveness of estrogen-containing oral contraceptives. (Moderate) Anti-infectives which disrupt the normal GI flora, including lincomycin and clindamycin, may potentially decrease the effectiveness of estrogen containing oral contraceptives. Alternative or additional contraception may be advisable.
    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.
    Clonidine: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Cod Liver Oil: (Minor) Plasma levels of vitamin A have been reported to increase during concomitant use of oral contraceptives. However, the clinical significance of this finding is uncertain.
    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.
    Corticosteroids: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Corticotropin, ACTH: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Cortisone: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    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.
    Cyclosporine: (Moderate) Estrogens and/or progestins in oral contraceptives or non-oral combination contraceptives may inhibit the metabolism of cyclosporine. Delayed cyclosporine clearance and elevated cyclosporine concentrations can lead to seizures, nephrotoxicity and/or hepatotoxicity. Additionally, estrogens are metabolized by CYP3A4; cyclosporine may increase plasma concentrations of estrogens and cause estrogen-related side effects. If estrogens or progestins are initiated or discontinued, the patient's cyclosporine concentrations should be monitored closely. Additionally, patients should be monitored for estrogenic side effects if these drugs are used concomitantly.
    Danazol: (Minor) As danazol inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives, including oral contraceptives.
    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.
    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.
    Dapagliflozin; Metformin: (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.
    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.
    Darunavir: (Moderate) Darunavir is expected to increase the metabolism of estradiol. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
    Darunavir; Cobicistat: (Moderate) Darunavir is expected to increase the metabolism of estradiol. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Darunavir is expected to increase the metabolism of estradiol. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Ritonavir has been shown to increase the metabolism of ethinyl estradiol. Ritonavir is a substrate and inhibitor of CYP3A4. It is not known if the effects of protease inhibitors are similar on estradiol; however, estradiol is metabolized by CYP3A4, similar to ethinyl estradiol.
    Deflazacort: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Delavirdine: (Minor) As delavirdine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives, including oral contraceptives.
    Demeclocycline: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Dexamethasone: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Diltiazem: (Minor) As diltiazem inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    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.
    Dirithromycin: (Moderate) Anti-infectives which disrupt the normal GI flora, including dirithromycin, may potentially decrease the effectiveness of estrogen containing oral contraceptives. Alternative or additional contraception may be advisable.
    Dorzolamide; Timolol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Doxacurium: (Minor) Estrogens have been associated in rare cases with pseudocholinesterase deficiency. Since non-depolarizing neuromuscular blockers are metabolized by cholinesterase, prolonged neuromuscular blockade may occur in individuals on concurrent therapy with estrogens.
    Doxazosin: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored to confirm that the desired antihypertensive effect is being obtained.
    Doxycycline: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Dulaglutide: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as combined hormonal oral contraceptives (OCs). Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. atients 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.
    Duloxetine: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as duloxetine 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.
    Efavirenz: (Moderate) Estrogens are CYP3A4 substrates and efavirenz is a CYP3A4 inducer; concomitant use of efavirenz-containing products (including efavirenz; emtricitabine; tenofovir) may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., menopausal symptoms, breakthrough bleeding, reduced efficacy) if these drugs are used together.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Estrogens are CYP3A4 substrates and efavirenz is a CYP3A4 inducer; concomitant use of efavirenz-containing products (including efavirenz; emtricitabine; tenofovir) may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., menopausal symptoms, breakthrough bleeding, reduced efficacy) if these drugs are used together.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Estrogens are CYP3A4 substrates and efavirenz is a CYP3A4 inducer; concomitant use of efavirenz-containing products (including efavirenz; emtricitabine; tenofovir) may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., menopausal symptoms, breakthrough bleeding, reduced efficacy) if these drugs are used together.
    Elagolix: (Major) During use of elagolix, females of childbearing potential should use non-hormonal methods of contraception for the duration of treatment and for 1 week following the discontinuation of therapy. Estrogen-containing injectable, implantable, transdermal, vaginal or oral contraceptives are expected to reduce the efficacy of elagolix. The effect of progestin-only contraceptives on elagolix is not known. However, elagolix is a weak to moderate inducer of CYP3A4, and many estrogens and progestins are metabolized via this enzyme. Thus, elagolix may decrease plasma concentrations of hormonal contraceptives.
    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.
    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.
    Empagliflozin; Metformin: (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.
    Enalapril, Enalaprilat: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Enalapril; Felodipine: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Enalapril; Hydrochlorothiazide, HCTZ: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Eprosartan: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    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.
    Ertugliflozin; Metformin: (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.
    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.
    Erythromycin: (Minor) As erythromycin inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Erythromycin; Sulfisoxazole: (Moderate) Anti-infectives that disrupt the normal GI flora, including sulfonamides, may potentially decrease the effectiveness of estrogen-containing oral contraceptives. (Minor) As erythromycin inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Esmolol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Ethacrynic Acid: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Ethotoin: (Moderate) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins in patients receiving phenytoin (the active metabolite of fosphenytoin) concurrently. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on phenytoin or fosphenytoin, with dose adjustments made based on clinical efficacy.
    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.
    Exenatide: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as combined hormonal oral contraceptives (OCs). Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. atients 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.
    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.
    Felodipine: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Fluconazole: (Minor) As fluconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Fludrocortisone: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Flunisolide: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Fluoxetine: (Minor) As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Fluoxetine; Olanzapine: (Minor) As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Fluticasone: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Fluticasone; Salmeterol: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Fluticasone; Vilanterol: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Formoterol; Mometasone: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Fosamprenavir: (Major) Fosamprenavir should not be administered with oral contraceptives due to the risk of clinically significant hepatic transaminase elevations; a similar response could be expected with HRT. Additionally, hormonal contraceptives, estrogens, and progestins may decrease the serum concentrations of fosamprenavir's active metabolite, amprenavir, which could lead to loss of virologic response and possible viral resistance. If these drugs are used together, carefully monitor the patient for adverse hepatic effects, decreased virologic response, and viral resistance.
    Fosinopril: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Fosphenytoin: (Moderate) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins in patients receiving phenytoin (the active metabolite of fosphenytoin) concurrently. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on phenytoin or fosphenytoin, with dose adjustments made based on clinical efficacy.
    Furosemide: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Glipizide; Metformin: (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.
    Glyburide; Metformin: (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.
    Glycylcyclines: (Moderate) The manufacturer of tigecycline reports that concurrent use of antibacterial drugs with oral contraceptives may decrease the efficacy of oral contraceptives. However, the effect of tigecycline specifically on the efficacy of oral contraceptives is unknown. Alternative or additional contraception may be advisable.
    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.
    Griseofulvin: (Moderate) Concomitant use of griseofulvin and oral contraceptives has been reported to reduce the efficacy of the oral contraceptive and cause breakthrough bleeding. Patients who experience breakthrough bleeding while receiving these drugs together should notify their prescribers. An alternate or additional form of contraception should be used during concomitant treatment and should be continued for 1 month after griseofulvin discontinuation. Additionally, patients taking non-oral combination contraceptives, estrogens, or progestins for hormone replacement therapy may also experience reduced clinical efficacy; dosage adjustments may be necessary.
    Guanabenz: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Guanfacine: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Hemin: (Moderate) Hemin works by inhibiting aminolevulinic acid synthetase. Estrogens increase the activity of this enzyme should not be used with hemin.
    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.
    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.
    Hydantoins: (Moderate) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins in patients receiving phenytoin (the active metabolite of fosphenytoin) concurrently. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on phenytoin or fosphenytoin, with dose adjustments made based on clinical efficacy.
    Hydralazine: (Minor) The administration of estrogens can increase fluid retention, which increases blood pressure, thereby antagonizing the antihypertensive effects of hydralazine.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness. (Minor) The administration of estrogens can increase fluid retention, which increases blood pressure, thereby antagonizing the antihypertensive effects of hydralazine.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Minor) The administration of estrogens can increase fluid retention, which increases blood pressure, thereby antagonizing the antihypertensive effects of hydralazine.
    Hydrochlorothiazide, HCTZ: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Hydrochlorothiazide, HCTZ; Losartan: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Hydrochlorothiazide, HCTZ; Moexipril: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Hydrochlorothiazide, HCTZ; Propranolol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Hydrochlorothiazide, HCTZ; Quinapril: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Hydrochlorothiazide, HCTZ; Triamterene: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Hydrochlorothiazide, HCTZ; Valsartan: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Hydrocortisone: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Icosapent ethyl: (Moderate) Estrogens may exacerbate hypertriglyceridemia and should be discontinued or changed to alternate therapy, if possible, prior to initiation of icosapent ethyl.
    Imatinib: (Minor) As imatinib inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Incretin Mimetics: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as combined hormonal oral contraceptives (OCs). Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. atients 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.
    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.
    Insulin Degludec; Liraglutide: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as combined hormonal oral contraceptives (OCs). Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. atients 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.
    Insulin Glargine; Lixisenatide: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as combined hormonal oral contraceptives (OCs). Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. atients 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.
    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.
    Irbesartan: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Isradipine: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Itraconazole: (Minor) As itraconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Ivosidenib: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
    Ketoconazole: (Minor) As ketoconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Labetalol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    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.
    Letrozole: (Severe) 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.
    Levobetaxolol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Levobunolol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Levothyroxine: (Minor) The administration of estrogens can increase circulating concentrations of thyroxine-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.
    Levothyroxine; Liothyronine (Porcine): (Minor) The administration of estrogens can increase circulating concentrations of thyroxine-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.
    Levothyroxine; Liothyronine (Synthetic): (Minor) The administration of estrogens can increase circulating concentrations of thyroxine-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.
    Linagliptin; Metformin: (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.
    Lincomycin: (Moderate) Anti-infectives that disrupt the normal GI flora, clindamycin, lincomycin, may potentially decrease the effectiveness of estrogen-containing oral contraceptives. (Moderate) Anti-infectives which disrupt the normal GI flora, including lincomycin and clindamycin, may potentially decrease the effectiveness of estrogen containing oral contraceptives. Alternative or additional contraception may be advisable.
    Lincosamides: (Moderate) Anti-infectives that disrupt the normal GI flora, clindamycin, lincomycin, may potentially decrease the effectiveness of estrogen-containing oral contraceptives. (Moderate) Anti-infectives which disrupt the normal GI flora, including lincomycin and clindamycin, may potentially decrease the effectiveness of estrogen containing oral contraceptives. Alternative or additional contraception may be advisable.
    Liothyronine: (Minor) The administration of estrogens can increase circulating concentrations of thyroxine-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.
    Liraglutide: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as combined hormonal oral contraceptives (OCs). Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. atients 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.
    Lisinopril: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Lixisenatide: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as combined hormonal oral contraceptives (OCs). Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. atients 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.
    Loop diuretics: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Lopinavir; Ritonavir: (Moderate) Lopinavir; ritonavir 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. (Moderate) Ritonavir has been shown to increase the metabolism of ethinyl estradiol. Ritonavir is a substrate and inhibitor of CYP3A4. It is not known if the effects of protease inhibitors are similar on estradiol; however, estradiol is metabolized by CYP3A4, similar to ethinyl estradiol.
    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. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
    Losartan: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    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.
    Melatonin: (Moderate) Caution should be exercised when using melatonin in patients taking estrogens (i.e., combined oral contraceptives, non-oral combination contraceptives or estrogen for hormone replacement therapy), which increase melatonin levels by inhibiting melatonin metabolism via CYP1A1 and CYP1A2.
    Metformin: (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.
    Metformin; Pioglitazone: (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.
    Metformin; Repaglinide: (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.
    Metformin; Rosiglitazone: (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.
    Metformin; 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.
    Metformin; 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.
    Methyclothiazide: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Methyldopa: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Methylprednisolone: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Metolazone: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Metoprolol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Metreleptin: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    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.
    Midazolam: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam.
    Mifepristone: (Severe) Mifepristone is a progesterone-receptor antagonist and will interfere with the effectiveness of hormonal contraceptives. Therefore, non-hormonal contraceptive methods should be used in Cushing's patients taking mifepristone.
    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.
    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.
    Minocycline: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Minoxidil: (Minor) Estrogens can cause fluid retention, increasing blood pressure and thereby antagonizing the antihypertensive effects of minoxidil.
    Mivacurium: (Minor) Estrogens have been associated in rare cases with pseudocholinesterase deficiency. Since non-depolarizing neuromuscular blockers are metabolized by cholinesterase, prolonged neuromuscular blockade may occur in individuals on concurrent therapy with estrogens.
    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.
    Moexipril: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Mometasone: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Nadolol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Nebivolol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Nebivolol; Valsartan: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Nefazodone: (Minor) Nefazodone inhibits the hepatic CYP3A4 isoenzyme. Estrogenic-related side effects, such as nausea and breast tenderness, may potentially increase when nefazodone is co-administered with either estrogens or combined hormonal contraceptives, including oral contraceptives. An interaction has been reported clinically, but more study is needed to determine the clinical significance of this interaction in the general population.
    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.
    Neomycin: (Moderate) Anti-infectives that disrupt the normal GI flora, including neomycin, may potentially decrease the effectiveness of estrogen-containing oral contraceptives. (Moderate) Anti-infectives which disrupt the normal GI flora, including neomycin, may potentially decrease the effectiveness of estrogen containing oral contraceptives. Alternative or additional contraception may be advisable.
    Neuromuscular blockers: (Minor) Estrogens have been associated in rare cases with pseudocholinesterase deficiency. Since non-depolarizing neuromuscular blockers are metabolized by cholinesterase, prolonged neuromuscular blockade may occur in individuals on concurrent therapy with estrogens.
    Nevirapine: (Moderate) Nevirapine may decrease plasma concentrations of oral contraceptives and non-oral combination contraceptives (i.e., ethinyl estradiol and norethindrone). 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. When these oral contraceptives are used for hormone replacement and given with nevirapine, the therapeutic effect of the hormonal therapy should be monitored.
    Nicardipine: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Nifedipine: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal therapy should be monitored for antihypertensive effectiveness.
    Nilotinib: (Moderate) Nilotinib is a competitive inhibitor of UGT1A1 and CYP3A4. Estradiol is a substrate of UGT1A1. Increased concentrations of estradiol may occur following coadministration with nilotinib.
    Nimodipine: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Nisoldipine: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Nitrofurantoin: (Moderate) Anti-infectives that disrupt the normal GI flora may potentially decrease the effectiveness of estrogen-containing oral contraceptives.
    Nitroprusside: (Minor) The administration of estrogens may increase blood pressure, and thereby antagonizing the antihypertensive effects of nitroprusside.
    Olmesartan: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Omadacycline: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Ritonavir has been shown to increase the metabolism of ethinyl estradiol. Ritonavir is a substrate and inhibitor of CYP3A4. It is not known if the effects of protease inhibitors are similar on estradiol; however, estradiol is metabolized by CYP3A4, similar to ethinyl estradiol.
    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.
    Oxcarbazepine: (Moderate) Estrogens are susceptible to drug interactions with hepatic enzyme inducing drugs such as oxcarbazepine. Concurrent administration of oxcarbazepine with estrogens, oral contraceptives, or non-oral combination contraceptives, progestins may increase the hormone's elimination. If used for contraception, an alternate or additional form of contraception should be considered. 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.
    Pancuronium: (Minor) Estrogens have been associated in rare cases with pseudocholinesterase deficiency. Since non-depolarizing neuromuscular blockers are metabolized by cholinesterase, prolonged neuromuscular blockade may occur in individuals on concurrent therapy with estrogens.
    Penbutolol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Perindopril: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Perindopril; Amlodipine: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Phenoxybenzamine: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored to confirm that the desired antihypertensive effect is being obtained.
    Phentermine; Topiramate: (Major) Topiramate can increase the clearance of estrogens and compromise the efficacy of estrogens used as hormone replacement therapies or contraceptives. Patients taking oral contraceptives, non-oral combination contraceptives, or progestions for contraception or patients taking estrogens or progestins for hormone replacement therapy should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of the products may need adjustment; the manufacturer of topiramate recommends that an oral contraceptive containing 50 mcg of ethinyl estradiol be used. Different or additional forms of contraception may also be needed.
    Phentolamine: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored to confirm that the desired antihypertensive effect is being obtained.
    Phenytoin: (Moderate) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins in patients receiving phenytoin (the active metabolite of fosphenytoin) concurrently. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on phenytoin or fosphenytoin, with dose adjustments made based on clinical efficacy.
    Pindolol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Posaconazole: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as systemic azole antifungals (fluconazole, itraconazole, ketoconazole, miconazole, posaconazole, and voriconazole) 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.
    Potassium-sparing diuretics: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    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.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Either additive or antagonistic effects could potentially occur if prasterone is combined with estrogen therapy.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Either additive or antagonistic effects could potentially occur if prasterone is combined with estrogen therapy.
    Prazosin: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored to confirm that the desired antihypertensive effect is being obtained.
    Prednisolone: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Prednisone: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Propoxyphene: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as propoxyphene 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.
    Propranolol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Pyrimethamine; Sulfadoxine: (Moderate) Anti-infectives that disrupt the normal GI flora, including sulfonamides, may potentially decrease the effectiveness of estrogen-containing oral contraceptives.
    Quinapril: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    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.
    Ramipril: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Rapacuronium: (Minor) Estrogens have been associated in rare cases with pseudocholinesterase deficiency. Since non-depolarizing neuromuscular blockers are metabolized by cholinesterase, prolonged neuromuscular blockade may occur in individuals on concurrent therapy with estrogens.
    Reserpine: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored to confirm that the desired antihypertensive effect is being obtained.
    Ribociclib; Letrozole: (Severe) 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.
    Rifamycins: (Major) Estrogens are susceptible to drug interactions with hepatic enzyme inducing drugs such as rifampin, rifabutin, or rifapentine. Concurrent administration of these drugs with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins may increase the hormone's elimination. In addition, free estrogen-hormone concentrations are decreased because rifampin increases estrogenic protein binding ability. Additionally, like other anti-infectives, rifampin indirectly inhibits the enterohepatic recirculation of estrogen through disruption of GI flora growth. Women taking both hormones and any of these drugs should report breakthrough bleeding to their prescribers; it is estimated that 70% of women taking oral contraceptives and rifampin experience menstrual abnormalities, and 6% become pregnant. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifampin, rifabutin, or rifapentine. 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 the interacting medication. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifampin, rifabutin, or rifapentine, with dose adjustments made based on clinical efficacy.
    Ritonavir: (Moderate) Ritonavir has been shown to increase the metabolism of ethinyl estradiol. Ritonavir is a substrate and inhibitor of CYP3A4. It is not known if the effects of protease inhibitors are similar on estradiol; however, estradiol is metabolized by CYP3A4, similar to ethinyl estradiol.
    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.
    Rocuronium: (Minor) Estrogens have been associated in rare cases with pseudocholinesterase deficiency. Since non-depolarizing neuromuscular blockers are metabolized by cholinesterase, prolonged neuromuscular blockade may occur in individuals on concurrent therapy with estrogens.
    Romidepsin: (Major) The concomitant use of romidepsin and estradiol cypionate may reduce the efficacy of estradiol cypionate. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies. (Major) The concomitant use of romidepsin and estradiol valerate may reduce the efficacy of estradiol valerate. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies.
    Ropinirole: (Minor) Estrogens reduce the oral clearance of ropinirole by 36 percent. Dosage adjustment may not be needed for ropinirole in patients on estrogen therapy because patients must be carefully titrated with ropinirole to tolerance or adequate effect. However, if estrogen therapy is stopped or started during treatment with ropinirole, then adjustment of the ropinirole dose may be required.
    Sacubitril; Valsartan: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    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.
    Selegiline: (Moderate) Selegiline concentrations may be increased by the co-administration of oral contraceptives containing estrogens and progestins. The metabolism of selegiline appears to be decreased by the presence of oral contraceptives. Dose reductions in selegiline may be necessary in patients on combined contraceptive agents in order to limit the risk of increased MAO type B inhibition. (Moderate) Selegiline concentrations may be increased by the coadministration of oral contraceptives containing estrogens and progestins. In one pharmacokinetic study, it was reported that both peak and total selegiline concentrations were increased 10- and 20-fold, respectively, in users of oral contraceptives versus non-users. The metabolism of selegiline appears to be decreased by the presence of oral contraceptives. Dose reductions in selegiline may be necessary in patients on ethinyl estradiol or hormonal combined contraceptive agents in order to limit the risk of increased MAO type B inhibition.
    Semaglutide: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as combined hormonal oral contraceptives (OCs). Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. atients 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.
    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.
    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.
    Sorafenib: (Moderate) Sorafenib inhibits glucuronidation by the UGT1A1 and UGT1A9 pathways. Although specific drug interaction studies have not been completed, systemic exposure to substrates of UGT1A1, like estradiol, and UGT1A9 may increase when coadministered with sorafenib.
    Sotalol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Soy Isoflavones: (Moderate) Theoretically, the soy isoflavones may compete with or have additive effects with, drugs that have estrogenic activity or which selectively modulate estrogen receptors. The soy isoflavones have a diphenolic structure similar to that of the potent synthetic and natural estrogens. All isoflavones are competitive ligands of in vitro estrogen receptor assays and appear to function as selective estrogen receptor modifiers (SERMs). However, the estrogenic potencies of the soy isoflavones genistein and daidzein are much weaker than that of native estradiol. Soy isoflavones should be used with caution in patients taking estrogens, including combined hormonal and oral contraceptives, since the effects of combining soy isoflavone dietary supplements with estrogens are not clear.
    Spironolactone: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    St. John's Wort, Hypericum perforatum: (Moderate) In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Inducers of CYP3A4, such as St. John's Wort (Hypericum perforatum) preparations, may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. One report noted intermenstrual bleeding after the concurrent use of St. John's wort in 8 premenstrual women who had been on oral contraceptives for long durations of time. Intermenstrual bleeding implies that there may be a loss of contraceptive or hormonal-replacement efficacy. The interaction has reportedly occurred within 1 week of beginning St. John's wort in five of the cases. In 3 patients for whom follow-up was available, the discontinuation of St. John's wort resolved the bleeding abnormalities. Women should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of these combinations is recommended.
    Succinylcholine: (Minor) Estrogens have been associated in rare cases with pseudocholinesterase deficiency. Since non-depolarizing neuromuscular blockers are metabolized by cholinesterase, prolonged neuromuscular blockade may occur in individuals on concurrent therapy with estrogens.
    Sulfadiazine: (Moderate) Anti-infectives that disrupt the normal GI flora, including sulfonamides, may potentially decrease the effectiveness of estrogen-containing oral contraceptives.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Anti-infectives that disrupt the normal GI flora, including sulfonamides, may potentially decrease the effectiveness of estrogen-containing oral contraceptives.
    Sulfasalazine: (Moderate) Anti-infectives that disrupt the normal GI flora, including sulfonamides, may potentially decrease the effectiveness of estrogen-containing oral contraceptives.
    Sulfisoxazole: (Moderate) Anti-infectives that disrupt the normal GI flora, including sulfonamides, may potentially decrease the effectiveness of estrogen-containing oral contraceptives.
    Sulfonamides: (Moderate) Anti-infectives that disrupt the normal GI flora, including sulfonamides, may potentially decrease the effectiveness of estrogen-containing oral contraceptives. (Moderate) Anti-infectives which disrupt the normal GI flora, including sulfonamides, may potentially decrease the effectiveness of estrogen containing oral contraceptives. Alternative or additional contraception may be advisable.
    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.
    Sunscreens: (Moderate) Application of sunscreen 10 minutes prior to the application of topical estradiol increases the exposure to estradiol by approximately 35 percent. Application of sunscreen 25 minutes after the application of topical estradiol increases the exposure to estradiol by approximately 15 percent. Patients should be advised to separate the application of topical estradiol and sunscreens as long as possible in order to avoid increased estradiol absorption.
    Tacrine: (Moderate) Estrogens have been reported to increase serum tacrine Cmax and AUC. Practitioners should monitor patients for signs of increased cholinergic-related side effects if postmenopausal hormone replacement therapy is used concurrently with tacrine.
    Telaprevir: (Moderate) Close clinical monitoring for signs of estrogen deficiency is advised when administering ethinyl estradiol in combination with telaprevir. When used concurrently, ethinyl estradiol plasma concentrations may be decreased, potentially resulting in impaired efficacy. If ethinyl estradiol dose adjustments are made during combination therapy, re-adjust the dose upon completion of telaprevir treatment. Telaprevir will also likely reduce estrogen levels when administered as mestranol, which is further metabolized to EE. Close clinical monitoring for contraception failure is advised when coadministering combined hormonal oral contraceptives or ethinyl estradiol; etonogestrel contraceptive vaginal ring with telaprevir. Two effective non-hormonal methods of contraception should be used during treatment with telaprevir.
    Telmisartan: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Terazosin: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored to confirm that the desired antihypertensive effect is being obtained.
    Testolactone: (Severe) 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.
    Tetracycline: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Tetracyclines: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Thiazide diuretics: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    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.
    Thyroid hormones: (Minor) The administration of estrogens can increase circulating concentrations of thyroxine-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.
    Timolol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Tipranavir: (Moderate) Tipranavir 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.
    Tobacco: (Major) Females receiving combined hormonal contraceptives should be advised not to smoke tobacco. Tobacco smoking appears to enhance the procoagulant effect of estrogens. Tobacco smoking and combined hormonal contraceptives may interact synergistically via a pharmacodynamic interaction to increase the risk of DVT, myocardial infarction, stroke and other thromboembolic disease. Risk is especially high for female smokers 35 years of age or older or those who smoke >= 15 cigarettes per day. (Major) Females receiving combined hormonal contraceptives should be advised not to smoke tobacco. Tobacco smoking appears to enhance the procoagulant effect of estrogens. Tobacco smoking pharmacodynamically increases the risk of DVT, myocardial infarction, stroke and other thromboembolic disease. Risk is especially high for female smokers 35 years of age or older and in those who smoke greater than or equal to 15 cigarettes per day.
    Topiramate: (Major) Topiramate can increase the clearance of estrogens and compromise the efficacy of estrogens used as hormone replacement therapies or contraceptives. Patients taking oral contraceptives, non-oral combination contraceptives, or progestions for contraception or patients taking estrogens or progestins for hormone replacement therapy should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of the products may need adjustment; the manufacturer of topiramate recommends that an oral contraceptive containing 50 mcg of ethinyl estradiol be used. Different or additional forms of contraception may also be needed.
    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.
    Torsemide: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Trandolapril: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Trandolapril; Verapamil: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. (Minor) Verapamil inhibits CYP3A4 activity. Serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when verapamil is coadministered with either estrogens or combined hormonal contraceptives.
    Tranexamic Acid: (Severe) 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.
    Triamcinolone: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Triamterene: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    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.
    Tubocurarine: (Minor) Estrogens have been associated in rare cases with pseudocholinesterase deficiency. Since non-depolarizing neuromuscular blockers are metabolized by cholinesterase, prolonged neuromuscular blockade may occur in individuals on concurrent therapy with estrogens.
    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.
    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.
    Valsartan: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Vecuronium: (Minor) Estrogens have been associated in rare cases with pseudocholinesterase deficiency. Since non-depolarizing neuromuscular blockers are metabolized by cholinesterase, prolonged neuromuscular blockade may occur in individuals on concurrent therapy with estrogens.
    Verapamil: (Minor) Verapamil inhibits CYP3A4 activity. Serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when verapamil is coadministered with either estrogens or combined hormonal contraceptives.
    Voriconazole: (Minor) As voriconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Warfarin: (Major) Estrogen-based hromone replacement therapies and cocntraceptive 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.
    Zafirlukast: (Minor) As zarfirlukast inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.

    PREGNANCY AND LACTATION

    Pregnancy

    Estrogens are contraindicated during pregnancy. There is no known approved indication for the use of estrogens during pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy. Estradiol and other estrogens freely cross the placenta to the fetus. 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 continued use of estrogens in pregnant women. In any patient in whom pregnancy is suspected, pregnancy should be ruled out before continuing estrogen use. In select instances estradiol has been used off-label as an adjuvant to clomiphene treatment of infertility, or in donor oocyte program procedures in assisted reproduction technology (ART) under the direction of ART specialists; however, treatment is discontinued when pregnancy ensues.

    Caution should be used if a breast-feeding mother is receiving estradiol for hormone replacement. Estrogen administration to nursing women is generally avoided during lactation as estrogens have been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving estradiol and other estrogens. Estrogens are not approved by the FDA for the treatment of postpartum breast engorgement.

    MECHANISM OF ACTION

    The primary source of estrogens in premenopausal women is the ovary, which normally secretes 0.07 to 0.5 mg of estradiol daily, depending on the phase of the menstrual cycle. Once estrogens enter the cells of responsive tissues (e.g., female organs, breasts, hypothalamus, pituitary), they increase the rate of synthesis of DNA, RNA, and some proteins. The secretion of gonadotropin-releasing hormone by the hypothalamus is reduced during estrogen administration, causing reduction in follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary. Exogenous estrogens elicit all of the actions of endogenous estrogens. Estrogens are responsible for the growth and development of female sex organs and the maintenance of sex characteristics including growth of axillary and pubic hair and shaping of body contours and skeleton. At the cellular level, estrogens increase cervical secretions, cause proliferation of the endometrium, and increase uterine tone. Paradoxically, prolonged administration of estrogen can shrink the endometrium. During the preovulatory or nonovulatory phase of the menstrual cycle, withdrawal of estrogen can initiate menstruation; in the ovulatory phase, the decrease in progesterone secretion is the more significant factor causing menstruation. In post-menopausal use, amenorrhea occurs in most women within several months of oral estrogen use.
     
    Estrogens have a weak anabolic effect and also can affect bone calcium deposition and accelerate epiphysial closure. Estrogens appear to prevent osteoporosis associated with the onset of menopause. Estrogens generally have a favorable effect on blood lipids, reducing LDL- and increasing HDL-cholesterol concentrations on average, by 15%. Serum triglycerides increase with estrogen administration. Estrogens increase the rate of synthesis of many proteins, including thyroid binding globulin and several clotting factors. Estrogens reduce levels of antithrombin III, and increase platelet aggregation. Estrogens also enhance sodium and fluid retention.
     
    Unopposed estrogen has been associated with increased risk of endometrial cancer in menopausal women with an intact uterus; concomitant progestin therapy reduces, but does not eliminate, this risk. However, combination hormone replacement therapy (HRT) may add additional health risks for some women, as evidenced by the HERS trials , the Women's Health Initiative study , and other investigations. In particular, the Women's Health Initiative (WHI) study reported an increased risk of myocardial infarction, stroke, dementia, invasive breast cancer, and venous thromboembolism in patients taking combination HRT and an increased risk of stroke, dementia, and venous thromboembolism in patients taking estrogen only HRT; an increased risk of invasive breast cancer was not evident in women taking estrogen only. Because of these findings, patients should be prescribed estrogen HRT or estrogen-progestin HRT for the shortest duration consistent with the treatment goals. Estrogen HRT with or without a progestin is not indicated and should not be used to prevent coronary artery disease or other cardiovascular disease. The risks and benefits of HRT must be determined for a woman individually.
     
    In men with advanced prostate cancer, estrogens exert their effect by inhibition of the hypothalamic-pituitary axis through negative feedback. This results in decreased secretion of luteinizing hormone (LH). Decreased testosterone production from the Leydig cells in the testes occurs, which may decrease tumor growth and lower prostate specific antigen (PSA) levels. Improvement in bone metastasis may also occur. In the past, high-dose estrogen therapy was also used in selected men and postmenopausal women with inoperable, progressive breast cancer. Since the development of selective estrogen receptor modifiers (SERMs), high-dose estrogen therapy for the palliative treatment of breast cancer is rarely used today.

    PHARMACOKINETICS

    Estradiol products are administered orally, intramuscularly, vaginally, transdermally, and topically. The pharmacokinetics of estradiol differ with the formulation used for delivery and the route of administration. Following systemic absorption, estradiol is rapidly transformed by the liver to estrone and estriol, the major circulating forms in the serum, by 17-beta-hydroxysteroid dehydrogenase. The estrogens are widely distributed and are strongly protein-bound, primarily to albumin and sex hormone-binding globulin (SHBG). Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens are metabolized partially by CYP3A4 in the liver. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Estradiol, estrone, and estriol undergo glucuronide and sulfate conjugation to a variety of minor metabolites which are excreted primarily in the urine.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A4
    In vitro and in vivo studies indicate that estrogens are partially metabolized by CYP3A4. Interactions with drugs that are inhibitors or inducers of CYP3A4 are possible.

    Oral Route

    Estradiol is extensively metabolized in the gastrointestinal mucosa during oral absorption and in the liver. Micronization of oral estradiol tablets slows oral absorption and decreases the first-pass metabolizm in the liver and increases the normally poor oral bioavailability of estradiol. Absolute bioavailability of oral micronized estradiol is roughly 5% to 10% of an administered dose. The plasma half-life of orally administered estradiol is approximately 1 to 2 hours at steady state; but other circulating estrogens persist longer.

    Intramuscular Route

    Estradiol cypionate and Estradiol valerate: These forms of estradiol are given as a depot injection in oil, which slows absorption after intramuscular (IM) injection. Esterification of estradiol to estradiol cypionate or valerate significantly increases the parenteral duration of action compared to aqueous estradiol formulations. Intramuscular administration of the cypionate esters of estradiol have more prolonged actions (average, 3 to 6 weeks) than the valerate esters (average, 2 to 3 weeks), respectively. However, IM dosage intervals are usually every 4 weeks for both cypionate and valerate esters of estradiol for most indications; dosage and dosage intervals are adjusted to patient response.

    Topical Route

    Topical emulsions, gels, or sprays: Topical administration of estradiol avoids first-pass metabolism and allows for continuous delivery of the hormone. The formulas are designed to help deliver systemic estradiol levels through the skin. Estradiol is minimally metabolized in the skin, thus higher therapeutic estradiol serum levels are present, and more closely approximate natural premenopausal concentrations. Different formulations are not interchangeable and differ in amount of estradiol delivered systemically per day and other pharmacokinetic absorption parameters. Estradiol topical emulsion (Estrasorb), for example, utilizes micellar nanoparticle technology. Once in the serum, the distribution, metabolism and excretion of topically administered estradiol occurs through the same pathways as for oral administration.
     
    Transdermal patches: Transdermal systems are designed to help deliver systemic levels of estradiol through the skin. Transdermal administration of estradiol avoids first-pass metabolism and allows for continuous delivery of the hormone. Estradiol is minimally metabolized in the skin, thus higher therapeutic estradiol serum levels are present, and more closely approximate natural premenopausal concentrations. Transdermal systems differ in the amount of estradiol delivered per day, dosage interval of application, and other absorption pharmacokinetic parameters. Minimal fluctuations in estradiol concentrations are seen with transdermal application. Once in the serum, the distribution, metabolism and excretion of transdermally administered estradiol occurs through the same pathways as for oral administration. Transdermal estradiol has a short elimination half-life (approximately 2 hours); serum estradiol concentrations generally return to postmenopausal levels within 4 to 8 hours of patch removal.

    Other Route(s)

    Vaginal Route
    In general, estradiol is well absorbed through the vaginal mucous membranes. The vaginal dosage applied determines systemic hormone exposure; as a result, systemic as well as local tissue effects may occur. However, the systemic effects differ with specific vaginal products and many products are not acceptable for treating systemic or vasomotor symptoms or preventing osteoporosis.
     
    Vaginal Cream:  Specific pharmacokinetic data are not available; this dosage form is only acceptable to treat genitourinary symptoms.
     
    Vaginal Ring Inserts: Drug delivery from vaginal ring dosage forms is rapid; the time to maximum concentrations (Tmax) is usually less than 1 hour following insertion. Serum estradiol concentrations peak, then decrease rapidly such that by 24 to 48 hours following insertion of the dosage form, serum estradiol concentrations are relatively constant through the end of the 3-month dosing interval. Different vaginal ring devices are not interchangeable due to differences in dosage and efficacy in symptom control. For example, Estring dosages are not effective for addressing vasomotor symptoms; low dose systemic delivery of estradiol from Estring (estradiol) results in mean steady-state serum estradiol estimates of 7 to 8.1 pg/mL; with an estradiol delivery rate of roughly 7.5 mcg/24 hours. Following administration of Femring (estradiol acetate) 0.05 mg/day, the average serum estradiol concentration is 40.6 pg/mL; the corresponding apparent in vivo estradiol delivery rate is 0.052 mg/day. Following administration of Femring 0.10 mg/day, the average serum estradiol concentration is 76 pg/mL; the apparent in vivo delivery rate is 0.097 mg/day. Consistent with the avoidance of first-pass metabolism achieved by vaginal estradiol administration, serum estradiol concentrations are slightly higher than estrone concentrations. Once absorbed systemically, the distribution, metabolism and excretion of estradiol delivered via vaginal application occurs via the same pathways as for oral administration.
     
    Vaginal Tablets (e.g., Yuvefem, Vagifem): In an open-label, multiple-dose, parallel group study conducted in 58 patients, a mean estradiol (E2) average concentration at Day 83 of 5.5 pg/mL was measured after a regimen of 10 mcg vaginally daily for 2 weeks followed by a twice-weekly maintenance regimen for the remaining 10 weeks. When patients received a dose of 25 mcg daily for 2 weeks followed by a twice-weekly maintenance regimen, the average concentration at Day 83 was 11.59 pg/mL.
     
    Vaginal Insert (e.g., Imvexxy): The vaginal insert does not increase systemic estradiol concentrations significantly. At Day 84 of study, estradiol concentrations following a 2-week daily regimen followed by a twice-weekly maintenance regimen and compared to baseline concentrations were as follows: For the 4 mcg/dose regimen, mean 4.3 vs. 3.9 pg/mL; for the 10 mcg/dose regimen, mean 4.8 vs. 5 pg/mL; and a mean 4.4 vs. 4.5 pg/mL for placebo.