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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. The WHIMS study, an ancillary study of the WHI trial to assess the effects of HRT on cognitive function in women (65 years of age or older), found that patients receiving either active treatment or placebo had similar rates of developing mild cognitive impairment. Also, patients receiving combination or estrogen only HRT were more likely than patients receiving placebo to be diagnosed with dementia (pooled hazard ratio 1.76, 95% CI 1.19 to 2.60, p=0.005). In the population of patients taking combination HRT, ninety percent of the cases of dementia occurred in women older than 70 years with Alzheimer's disease being the most common classification; differences between the 2 treatment groups (combination HRT vs. placebo) were apparent after one year of treatment. When analyzed separately, the risk of dementia was increased in patients taking estrogen only therapy (hazard ratio 1.49, 95% CI 0.83 to 2.66) and in patients taking combination HRT (hazard ratio 2.05, 95% CI 1.21 to 3.48); however, this finding did not reach statistical significance in patients receiving estrogen only. An explanation for this may be because statistical power of the study was diminished as it was stopped early and fewer patients were enrolled than originally planned due to the early discontinuation of the WHI trial. Regardless, a protective effect of HRT was not found. Administration of HRT, including estradiol, should 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). The applicability of this finding to the typical user of HRT (i.e., younger, symptomatic women taking hormone replacement therapy to relieve menopausal symptoms) is unclear. According to the Beers Criteria, oral and topical patch 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. 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. Within the span of three years, the FDA received 8 post-marketing cases of accidental exposure to children between 3 and 5 years of age. Related adverse events including premature puberty, nipple swelling and breast development in females, and breast enlargement in males were reported. In addition, 2 cases of accidental exposure occurring in dogs were reported to the FDA's Center for Veterinary Medicine. 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. Pets also should not be allowed to lick or touch the application site. 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, signs should resolve.

    DEA CLASS

    Rx

    DESCRIPTION

    Estradiol is the principal human estrogen; it is substantially more active than its metabolites, estrone and estriol, at the cellular level
    Multiple dosage forms are available: oral, topical, transdermal, vaginal, and parenteral
    Used primarily to treat vasomotor and genitourinary symptoms associated with menopause, to prevent osteoporosis, for female hypogonadism and various 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, 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/EstroGel Transdermal Gel: 0.06%, 0.1%
    Estrace 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/Vagifem/Yuvafem Vaginal Tab: 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).
    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 every 3 to 6 months to determine if the dose and continued systemic hormone replacement are appropriate. The North American Menopause Society (NAMS) Guidelines support the initiation of hormone therapy 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.

    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 estrogen is prescribed in a woman with a uterus, a progestin should be considered to reduce the risk of endometrial hyperplasia. Reevaluate every 3 to 6 months to determine if the dose and continued systemic hormone replacement is appropriate. The North American Menopause Society (NAMS) Guidelines support the initiation of hormone therapy 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.

    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 every 3 to 6 months to determine if the dose and continued systemic hormone replacement is appropriate. The North American Menopause Society (NAMS) Guidelines support the initiation of hormone therapy 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.

    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 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 every 3 to 6 months to determine if the dose and continued systemic hormone replacement is appropriate. The North American Menopause Society (NAMS) Guidelines support the initiation of hormone therapy 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.

    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 every 3 to 6 months to determine if the dose and continued systemic hormone replacement is appropriate. The North American Menopause Society (NAMS) Guidelines support the initiation of hormone therapy 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.

    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 every 3 to 6 months to determine if the dose and continued systemic hormone replacement is appropriate. The North American Menopause Society (NAMS) Guidelines support the initiation of hormone therapy 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.

    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 every 3 to 6 months to determine if the dose and continued systemic hormone replacement is appropriate. The North American Menopause Society (NAMS) Guidelines support the initiation of hormone therapy 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.

    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 every 3 to 6 months to determine if the dose and continued systemic hormone replacement is appropriate. The North American Menopause Society (NAMS) Guidelines support the initiation of hormone therapy 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.

    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. 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). 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 osteoporosis prophylaxis secondary to estrogen deficiency, due to either natural or surgical menopause.
    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, which has not been determined. 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 cancer. Reevaluate the need and appropriateness of therapy at 3 to 6 month intervals. For the primary prevention of chronic conditions in postmenopausal women (except for those less than 50 years who have had surgical menopause), the US Preventive Services Task Force (USPSTF) recommends against the use of combined estrogen and progestin in women with an intact uterus and against the use of estrogen in women who have had a hysterectomy. Estrogen with or without progestin is of moderate benefit in reducing the incidence of fractures. However, in most postmenopausal women, the USPSTF concludes with high certainty that the chronic disease prevention benefits of combined estrogen and progestin do NOT outweigh the harms such as the risk for stroke, deep venous thrombosis, pulmonary embolism, gallbladder disease, dementia, invasive breast cancer, and urinary incontinence. The USPSTF concludes with moderate certainty among women with a hysterectomy that the chronic disease prevention benefits of estrogen are unlikely to outweigh the harms such as the risk for stroke, deep venous thrombosis, gallbladder disease, and urinary incontinence. However, the recommendation is for an average-risk population; consider each woman's net balance of 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.

    Transdermal dosage (estradiol biweekly transdermal patch, e.g., Alora, Minivelle, or Vivelle-Dot)
    Adult menopausal and postmenopausal 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. If needed, increase dose based on bone mineral density measurements. 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 cancer. Alternatively, a cyclic schedule of 3 weeks on drug and 1 week off drug may be used. Use lowest effective dose. Reevaluate the need for the current dose and the appropriateness of therapy at 3 to 6 month intervals. For the primary prevention of chronic conditions in postmenopausal women (except for those less than 50 years who have had surgical menopause), the US Preventive Services Task Force (USPSTF) recommends against the use of combined estrogen and progestin in women with an intact uterus and against the use of estrogen in women who have had a hysterectomy. Estrogen with or without progestin is of moderate benefit in reducing the incidence of fractures. However, in most postmenopausal women, the USPSTF concludes with high certainty that the chronic disease prevention benefits of combined estrogen and progestin do NOT outweigh the harms such as the risk for stroke, deep venous thrombosis, pulmonary embolism, gallbladder disease, dementia, invasive breast cancer, and urinary incontinence. The USPSTF concludes with moderate certainty among women with a hysterectomy that the chronic disease prevention benefits of estrogen are unlikely to outweigh the harms such as the risk for stroke, deep venous thrombosis, gallbladder disease, and urinary incontinence. However, the recommendation is for an average-risk population; consider each woman's net balance of 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.

    Transdermal dosage (estradiol weekly transdermal patch, e.g., Menostar, Climara)
    Adult menopausal and postmenopausal 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. Use lowest effective dose. Use for women at significant risk of osteoporosis after careful consideration of non-estrogen medications. If needed, increase dose based on bone mineral density measurements. Continuous unopposed estrogen administration is acceptable in those without a uterus. If female with an intact uterus, consider a progestin to reduce the risk of endometrial cancer. 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. For the primary prevention of chronic conditions in postmenopausal women (except for those less than 50 years who have had surgical menopause), the US Preventive Services Task Force (USPSTF) recommends against the use of combined estrogen and progestin in women with an intact uterus and against the use of estrogen in women who have had a hysterectomy. Estrogen with or without progestin is of moderate benefit in reducing the incidence of fractures. However, in most postmenopausal women, the USPSTF concludes with high certainty that the chronic disease prevention benefits of combined estrogen and progestin do NOT outweigh the harms such as the risk for stroke, deep venous thrombosis, pulmonary embolism, gallbladder disease, dementia, invasive breast cancer, and urinary incontinence. The USPSTF concludes with moderate certainty among women with a hysterectomy that the chronic disease prevention benefits of estrogen are unlikely to outweigh the harms such as the risk for stroke, deep venous thrombosis, gallbladder disease, and urinary incontinence. However, the recommendation is for an average-risk population; consider each woman's net balance of 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.

    For estrogen replacement for those with oophorectomy, 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.

    Intramuscular dosage (estradiol valerate in oil)
    Adult females

    The usual dose is estradiol valerate 10 mg to 20 mg IM every 4 weeks.

    Intramuscular dosage (estradiol cypionate in oil)
    Adult females

    For female hypogonadism, usual dose is 1.5 to 2 mg IM every 4 weeks.

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

    1 patch (delivering 0.0375 mg, 0.05 mg, 0.075 mg, or 0.1 mg per day) applied transdermally as directed; replace patch twice weekly (every 3 to 4 days); give cyclically or continuously. Usual initial dose is 0.0375 mg/day or 0.05 mg/day.

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

    1 patch (delivering 0.0375 mg, 0.05 mg, 0.06 mg, 0.075 mg, or 0.1 mg per day) on trunk or buttocks; replace every 7 days; give cyclically or continuously. Usual initial dose is 0.0375 mg/day or 0.05 mg/day.

    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 marked hepatic disease of any type.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    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. Aspirate prior to injection to avoid injection into a blood vessel.

    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 three dose strengths of 0.25, 0.5, and 1 gram for topical application (corresponding to 0.25, 0.5, 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 one 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 two 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): 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 before and after use.
    Vaginal ring insert (Estring, Femring): 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 before and after use.
    Vaginal tablet (Vagifem): The patient should be instructed to 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. Patients should 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 before and after use.

    STORAGE

    Generic:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Alora:
    - Store at 77 degrees F
    Climara:
    - Do not store outside the pouch provided
    - Store below 86 degrees F
    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:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Estrace:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Estraderm:
    - Store at 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 the pouch provided
    - Store below 86 degrees F
    Femring:
    - Do not store outside the pouch provided
    - 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
    Menostar:
    - Store below 86 degrees F
    - Store in original container
    Minivelle:
    - Store at 77 degrees F
    Vagifem:
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Vivelle:
    - Store at 77 degrees F
    Vivelle-Dot:
    - Store at 77 degrees F
    Yuvafem:
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Estradiol topical gels and sprays (e.g., Divigel, Elestrin, Estrogel, and Evamist) are alcohol-based. Alcohol-based gels and sprays are potentially flammable. Patients should be advised to avoid fire, flame, or smoking until the gel or spray has dried.

    Intravenous administration

    Estradiol cypionate and estradiol valerate are esterified estrogens that are in oil-based injections and are not recommended for intravenous administration. They are to be administered by the intramuscular route only.

    Breast cancer

    Estrogens, including estradiol, are contraindicated in patients with known, suspected, or history of breast cancer. Estrogen and estrogen/progestin therapy in postmenopausal women has been associated with an increased risk of breast cancer. In the past, high-dose estrogen therapy was used in selected men and postmenopausal women with inoperable, progressive cancer of the breast, but this therapy is rarely used today. Since 1970, numerous epidemiological studies have examined the association of exogenous estrogen and breast cancer. Epidemiologic studies have reported an increased risk of breast cancer in association with increasing duration of postmenopausal treatment with estrogens, with or without progestin. This association was reanalyzed in original data from 51 studies that involved treatment with various doses and types of estrogens, with and without progestin. In the reanalysis, an increased risk of having breast cancer diagnosed became apparent after about 5 years of continued treatment, and subsided after treatment had been discontinued for about 5 years. Some later studies have suggested that treatment with estrogen and progestin increases the risk of breast cancer more than treatment with estrogen alone. In the estrogen-progestin sub-study of the WHI trial , there were more diagnoses of breast cancer in the HRT group compared to the placebo group, with a hazard ratio of 1.24. The breast cancers diagnosed in the HRT group had similar histology and grade to those found in the placebo group, but the women receiving HRT were more likely to be diagnosed with a more invasive cancer (hazard ratio 1.24) that was larger in size (1.7 cm HRT vs. 1.5 cm placebo), node positive (25.9% HRT vs. 15.8% placebo), and diagnosed at a more advanced stage (regional/metastatic 25.4% HRT vs. 16% placebo) compared to those who received placebo. The increased risk of breast cancer became apparent after 4 years on combined HRT. Women reporting prior postmenopausal use of estrogen and/or estrogen with progestin had a higher relative risk for breast cancer associated with combined HRT than those who had never used these hormones. In the estrogen-only sub-study of WHI, NO increased risk of breast cancer in estrogen-treated women compared to placebo was found, even in women who used estrogen replacement therapy for 25 years or longer. Furthermore, the hazards ratio for invasive breast cancer in women taking estrogen only versus placebo after a mean follow-up of 7.1 years was 0.8 (95% CI 0.62—1.04, p = 0.09) in favor of estrogen therapy. In addition to the associated increase risk of breast cancer, at least 1 abnormal mammogram was discovered in a total of 31.5% of women in the combined HRT group compared to 21.2% of placebo patients, with an absolute increase in abnormal mammograms of about 4% per year in women receiving combined HRT; similarly, in women receiving estrogen only, 36.2% of women had mammograms with abnormalities during the trial, compared to only 28.1% of women receiving placebo (p < 0.001). Accordingly, after a thorough review of the available data, the World Health Organization International Agency for Research on Cancer (WHO IARC) has classified combined menopausal HRT as carcinogenic to humans; the agency indicates that the risk of breast cancer which is confined mostly to current or recent users increases with duration of use and is higher than the risk in women taking estrogen-only regimens. 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.

    Hypercalcemia, hypocalcemia

    Estrogens are not recommended in patients with hypercalcemia associated with tumors or metabolic bone disease because estrogens influence the metabolism of calcium and phosphorus. In particular, severe hypercalcemia may occur in patients with breast cancer with bone metastases. If hypercalcemia occurs, estradiol should be discontinued and measures taken to reduce the serum calcium level. Estrogens should also be used with caution in individuals with severe hypocalcemia.

    Endometrial cancer, endometrial hyperplasia, vaginal bleeding

    Since 1970, at least 35 epidemiological studies have examined the association of exogenous estrogen and endometrial cancer in women with an intact uterus. These studies were summarized in a review published in 1992 of hormonal replacement therapy in postmenopausal women. The majority of these studies have shown an increased risk of endometrial cancer in women who have received exogenous estrogens without concomitant progestin. Histologic and clinical data, as well as limited epidemiologic data suggest that the addition of a progestin to estrogen therapy offsets the risk of endometrial carcinoma caused by exogenous estrogen. With concurrent progestin use, the incidence of endometrial hyperplasia due to estrogens is estimated to be 1% or less. The best available epidemiological evidence is from one case-control study that showed no increased risk for endometrial cancer when progestins were used with estrogen for at least 10 days/month. Accordingly, the WHO IARC has classified combined menopausal HRT as carcinogenic to humans when progestins are taken for < 10 days/month; the agency also indicates that when progestins are taken daily, the risk of endometrial cancer is similar to that in women who have never used hormonal therapy. Because of the risk of endometrial cancer, women taking exogenous estrogen who are experiencing persistent abnormal vaginal bleeding should receive adequate diagnostic tests to rule out malignancy. Estrogens, including estradiol, are contraindicated in patients with preexisting endometrial hyperplasia or endometrial cancer.

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

    Estrogens, including estradiol, should be used cautiously in patients with uterine leiomyomata (fibroids) or endometriosis since they can exacerbate fibroid or endometrial growth. They are contraindicated in the presence of vaginal cancer, cervical cancer, uterine cancer, or other estrogen-responsive tumors. Estrogens are contraindicated in women with undiagnosed abnormal vaginal bleeding. Women experiencing persistent abnormal vaginal bleeding should receive adequate diagnostic tests to rule out malignancy before being prescribed estrogens. All women receiving estrogen treatment should have an annual pelvic examination which includes a Papanicolaou smear to screen for cervical dysplasia.

    Ovarian cancer

    Estrogens, including estradiol, are contraindicated in the presence of estrogen-responsive tumors. Use of estrogen-only products, in particular for 10 or more years, has been associated with an increased risk of ovarian cancer in some epidemiological studies. Other studies did not show a significant association. Data are insufficient to determine whether there is an increased risk with combined estrogen/progestin therapy in postmenopausal women.

    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 is 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 has 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. Caution should be exercised when estradiol is administered to a nursing woman. The infant may need to be monitored for effects such as breast enlargement, poor appetite, and appropriate growth and weight gain. Estrogens are not approved by the FDA for the treatment of postpartum breast engorgement. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

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

    Estrogens should be used cautiously in patients with acute intermittent, or variegate hepatic porphyria, which can be exacerbated. Exogenous orally administered estrogens may increase the risk of gallbladder disease (e.g., cholestasis, cholelithiasis and cholecystitis) in postmenopausal women. Based on evidence from the HERS trial, the risk of gallbladder disease may be more prevalent in those postmenopausal women with established coronary heart disease who receive oral estrogens. Similar increases in gallbladder disease have not been reported with transdermally administered estradiol, perhaps due to the fact that estradiol does not appear to increase saturation of cholesterol in the bile when administered by this route. Patients with familial hyperlipoproteinemia may develop elevations in triglycerides while taking exogenous estrogens which may predispose them to pancreatitis; caution is warranted in these individuals. Estrogens are contraindicated in the presence of hepatocellular cancer, hepatic adenoma, or in severe hepatic disease of any type. Use caution in patients with a history of cholestatic jaundice.

    Asthma, edema, hypertension, migraine, renal disease, seizure disorder

    In some patients, blood pressure may increase during therapy with estrogen therapy. Patients with hypertension should be monitored closely for increases in blood pressure if estrogens are administered. Because estrogens, including estradiol, may cause fluid retention, conditions that might be affected by edema, such as asthma, heart disease, renal disease, migraine, or seizure disorder require careful observation. Discontinue estradiol pending examination if there is sudden onset of migraine, especially if accompanied by focal neurologic symptoms, as this may indicate a more serious condition.

    Diabetes mellitus

    Although the effects appear to be minimal in most patients receiving hormone replacement therapy with estrogens or estrogen-progestin combinations; altered glucose tolerance secondary to decreased insulin sensitivity has been reported. Patients with hyperglycemia or diabetes mellitus should be observed for changes in glucose tolerance when initiating or discontinuing estrogen therapy with estradiol.

    Cardiac disease, cerebrovascular disease, coronary artery disease, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, myocardial infarction, obesity, stroke, thromboembolic disease, thrombophlebitis, tobacco smoking

    Estrogen therapies have been associated with an increased risk of cerebrovascular disease (i.e., stroke), venous thrombosis (venous thromboembolism or VTE) and pulmonary embolism, and the addition of a progestin to estrogen therapy adds an increased risk of cardiovascular events such as myocardial infarction. Estrogens, including estradiol, are contraindicated in patients with an active or past history of stroke, myocardial infarction, thrombophlebitis, or thromboembolic disease. Should any of these occur or be suspected, discontinue the estrogen immediately. A positive relationship between estrogen dosage and blood clotting has been demonstrated. Estrogens decrease levels of antithrombin-III and increase the production of blood clotting factors VII, VIII, IX and X. Because tobacco smoking increases the risk of DVT, myocardial infarction, and other thromboembolic disease, estrogen-containing treatment should be used cautiously in smokers. Risk is especially high for female cigarette smokers 35 years of age or older. Patients should be advised not to smoke. Risk factors for heart disease (e.g., hypertension, diabetes mellitus, tobacco use, hyperlipidemia, hypercholesterolemia and/or hypertriglyceridemia, obesity) should be managed appropriately. Because estrogens may cause fluid retention, patients with conditions that may be affected by this factor, such as a cardiac disease, should be carefully monitored when estrogens are prescribed. Furthermore, estrogens with or without progestins should not be used for the prevention of cardiac disease. In the estrogen sub-study of the WHI trial, estrogen alone did not affect (either increase or decrease) heart disease, although an increase in the number of strokes and VTE was observed in women receiving estrogen HRT compared to placebo. In the estrogen-progestin sub-study of WHI, an increased risk of coronary heart disease (CHD) events (defined as non-fatal MI and CHD death) and stroke, and a 2-fold greater rate of VTE, including DVT and PE, were observed with estrogen-progestin HRT compared to placebo. The increase in risk was observed in year one and persisted. In postmenopausal women with documented cardiac disease, a controlled clinical trial (i.e., HERS trial) demonstrated no cardiovascular benefit to using estrogen-progestin HRT as secondary prevention. During an average follow-up of 4.1 years, treatment did not reduce the overall rate of CHD events in postmenopausal women with established coronary artery disease. There were more CHD events in the HRT-treated group than in the placebo group in year 1, but not during the subsequent years. Over two thousand women from the original HERS trial agreed to participate in an open label extension of HERS, known as HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the estrogen-progestin HRT group and the placebo group in HERS, HERS II, and overall. In men treated with estrogen for palliation of prostate and breast cancer, estrogens have increased the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.

    Systemic lupus erythematosus (SLE)

    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.

    Surgery

    Because certain major surgical procedures are associated with prolonged immobilization or increased risk of thromboembolism, estrogens, including estradiol, should be discontinued several weeks (i.e., 4—6 weeks) prior to major surgery where feasible. The decision on when to resume estrogens after such procedures would be based on the perceived additional thromboembolic risk from estrogen use and the need for estrogen therapy.

    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.

    Hypothyroidism, thyroid disease

    Use estrogens, including 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.

    Contact lenses, visual disturbance

    Estrogens can increase the curvature of the cornea and may lead to intolerance of contact lenses. In addition, there have been clinical case reports of retinal vascular thrombosis. Hormonal agents, including estradiol, should be discontinued in patients with a sudden onset of migraine or unexplained visual disturbance (e.g., sudden partial or complete loss of vision, or a sudden onset of proptosis or diplopia), pending an ophthalmology exam. If papilledema or retinal vascular lesions become evident, estrogens should be permanently discontinued.

    Children, infants, neonates

    Estrogens, including estradiol, are not indicated in neonates, infants, or children because estrogens promote epiphysial closure and may be associated with other adverse events. Use with caution in those patients in whom bone growth is not complete. In young children, acute overdoses 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. In addition, the FDA is reviewing 8 post-marketing cases of inadvertent exposure to estradiol from contact with women using Evamist brand topical spray. Reported adverse events, occurring in children 3 to 5 years of age, include premature puberty, nipple swelling and breast development in females, and breast enlargement in males. Patients applying this product should avoid contact of the treated area to children. If direct contact cannot be avoided, the treated area should be covered with a garment. If inadvertent exposure occurs, the skin of the child should be washed immediately with soap and water.

    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. The WHIMS study, an ancillary study of the WHI trial to assess the effects of HRT on cognitive function in women (65 years of age or older), found that patients receiving either active treatment or placebo had similar rates of developing mild cognitive impairment. Also, patients receiving combination or estrogen only HRT were more likely than patients receiving placebo to be diagnosed with dementia (pooled hazard ratio 1.76, 95% CI 1.19 to 2.60, p=0.005). In the population of patients taking combination HRT, ninety percent of the cases of dementia occurred in women older than 70 years with Alzheimer's disease being the most common classification; differences between the 2 treatment groups (combination HRT vs. placebo) were apparent after one year of treatment. When analyzed separately, the risk of dementia was increased in patients taking estrogen only therapy (hazard ratio 1.49, 95% CI 0.83 to 2.66) and in patients taking combination HRT (hazard ratio 2.05, 95% CI 1.21 to 3.48); however, this finding did not reach statistical significance in patients receiving estrogen only. An explanation for this may be because statistical power of the study was diminished as it was stopped early and fewer patients were enrolled than originally planned due to the early discontinuation of the WHI trial. Regardless, a protective effect of HRT was not found. Administration of HRT, including estradiol, should 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). The applicability of this finding to the typical user of HRT (i.e., younger, symptomatic women taking hormone replacement therapy to relieve menopausal symptoms) is unclear. According to the Beers Criteria, oral and topical patch 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. 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. Within the span of three years, the FDA received 8 post-marketing cases of accidental exposure to children between 3 and 5 years of age. Related adverse events including premature puberty, nipple swelling and breast development in females, and breast enlargement in males were reported. In addition, 2 cases of accidental exposure occurring in dogs were reported to the FDA's Center for Veterinary Medicine. 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. Pets also should not be allowed to lick or touch the application site. 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, signs should resolve.

    Angioedema, hereditary angioedema

    Cases of both anaphylactic reactions and angioedema have been reported in patients taking exogenous estrogens. Events have developed in minutes and have required emergency medical treatment. Therefore, estradiol is contraindicated in patients with known anaphylactic reactions or angioedema to estradiol. Exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema, which may be hormonally sensitive.

    Protein C deficiency, protein S deficiency

    Estradiol, like other estrogens, is 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.

    ADVERSE REACTIONS

    Severe

    GI obstruction / Delayed / Incidence not known
    biliary obstruction / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    cholecystitis / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    thromboembolism / Delayed / Incidence not known
    stroke / Early / Incidence not known
    erythema nodosum / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    visual impairment / Early / Incidence not known
    retinal thrombosis / Delayed / Incidence not known
    papilledema / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known
    toxic-shock syndrome / Delayed / Incidence not known

    Moderate

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

    Mild

    weight gain / Delayed / 1.0-10.0
    headache / Early / 1.0-10.0
    pruritus / Rapid / 1.0-10.0
    skin irritation / Early / 1.0-10.0
    back pain / Delayed / 7.0-7.0
    diarrhea / Early / 5.0-5.0
    breakthrough bleeding / Delayed / 10.0
    dysmenorrhea / Delayed / 10.0
    mastalgia / Delayed / 10.0
    abdominal pain / Early / 10.0
    nausea / Early / 10.0
    amenorrhea / Delayed / Incidence not known
    menorrhagia / Delayed / Incidence not known
    libido increase / Delayed / Incidence not known
    libido decrease / Delayed / Incidence not known
    breast discharge / Delayed / Incidence not known
    breast enlargement / Delayed / Incidence not known
    gynecomastia / Delayed / Incidence not known
    vomiting / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    insomnia / Early / Incidence not known
    emotional lability / Early / Incidence not known
    irritability / Delayed / Incidence not known
    fatigue / Early / Incidence not known
    alopecia / Delayed / Incidence not known
    hirsutism / Delayed / Incidence not known
    rash (unspecified) / Early / Incidence not known
    vesicular rash / Delayed / Incidence not known
    acne vulgaris / Delayed / Incidence not known
    skin discoloration / Delayed / Incidence not known
    melasma / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    xerosis / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    gingivitis / Delayed / Incidence not known
    diplopia / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    muscle cramps / Delayed / Incidence not known
    infection / Delayed / Incidence not known
    vaginal irritation / Early / Incidence not known
    bladder discomfort / Early / Incidence not known
    injection site reaction / Rapid / Incidence not known

    DRUG INTERACTIONS

    Acarbose: (Minor) Estrogens can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with any of these agents is instituted or discontinued.
    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. Additionally, estrogens can impair glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving greater than 50 mcg of ethinyl estradiol or equivalent estrogen per day. However, any patient with diabetes may need to monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    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: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Alogliptin; Metformin: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Alogliptin; Pioglitazone: (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    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) Estrogens can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with any of these agents is instituted or discontinued.
    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: (Severe) Bosentan is a significant inducer of CYP3A hepatic enzymes. Hormonal contraceptives, including oral 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. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. In addition, bosentan is teratogenic and is contraindicated during pregnancy. An interaction study has demonstrated that coadministration of bosentan and an oral contraceptive product (ethinyl estradiol; norethindrone) produced average decreases in norethindrone and ethinyl estradiol serum concentrations of 14% and 31%, respectively; however, decreases in drug exposure were are as high as 56% and 66%, respectively, in individual subjects.
    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) 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 of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Canagliflozin; Metformin: (Minor) 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 of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    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) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued.
    Dapagliflozin; Metformin: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued.
    Dapagliflozin; Saxagliptin: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued.
    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.
    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.
    Dasatinib: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as dasatinib 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.
    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.
    Desiccated Thyroid: (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.
    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.
    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. Additionally, estrogens can impair glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving greater than 50 mcg of ethinyl estradiol or equivalent estrogen per day. However, any patient with diabetes may need to monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    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.
    Empagliflozin: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued.
    Empagliflozin; Linagliptin: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Empagliflozin; Metformin: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued.
    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.
    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: (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.
    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. Additionally, estrogens can impair glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving greater than 50 mcg of ethinyl estradiol or equivalent estrogen per day. However, any patient with diabetes may need to monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    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.
    Glimepiride; Pioglitazone: (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Glimepiride; Rosiglitazone: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Glipizide; Metformin: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Glyburide; Metformin: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    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.
    Gonadotropin-Releasing Hormone Analogs: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    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. Additionally, estrogens can impair glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving greater than 50 mcg of ethinyl estradiol or equivalent estrogen per day. However, any patient with diabetes may need to monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    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. Additionally, estrogens can impair glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving greater than 50 mcg of ethinyl estradiol or equivalent estrogen per day. However, any patient with diabetes may need to monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    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. Additionally, estrogens can impair glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving greater than 50 mcg of ethinyl estradiol or equivalent estrogen per day. However, any patient with diabetes may need to monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Insulins: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect.
    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.
    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.
    Linagliptin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Linagliptin; Metformin: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    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.
    Liotrix: (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. Additionally, estrogens can impair glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving greater than 50 mcg of ethinyl estradiol or equivalent estrogen per day. However, any patient with diabetes may need to monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    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. Additionally, estrogens can impair glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving greater than 50 mcg of ethinyl estradiol or equivalent estrogen per day. However, any patient with diabetes may need to monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    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.
    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) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    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) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Metformin; Pioglitazone: (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Metformin; Repaglinide: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Metformin; Rosiglitazone: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Metformin; Saxagliptin: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued.
    Metformin; Sitagliptin: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued.
    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: (Severe) A subtherapeutic response to metyrapone can be seen in patients on estrogen therapy. It is generally advisable to discontinue estrogens prior to and during metyrapone administration.
    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, RU-486: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as mifepristone may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Miglitol: (Minor) Estrogens can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with any of these agents is instituted or discontinued.
    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.
    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.
    Pioglitazone: (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    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) Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    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.
    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.
    Rosiglitazone: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    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.
    Saxagliptin: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued.
    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.
    Simvastatin; Sitagliptin: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued.
    Sitagliptin: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued.
    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.
    Streptogramins: (Minor) As dalofopristin; quinupristin 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.
    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) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    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.
    Tamoxifen: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    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.
    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) Because of contraindications to the use of oral contraceptives in patients with active thromboembolism risks, concurrent use of combined hormonal contraceptives is generally avoided in patients taking warfarin. However, per ACOG guidelines, in select patients the benefits of such contraception may outweigh the risks, as long as appropriate anticoagulant therapy is utilized. Alternative anticoagulants to warfarin may be considered. Oral contraceptives may inhibit CYP3A4 and CYP1A2, which can influence warfarin pharmacokinetics and also alter the INR; dosage adjustment of warfarin should be based on the prothrombin time or INR value. Isolated case reports have noted an augmented response 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 estrogens to thromboembolic disease has been demonstrated, and the US FDA has suggested class labeling of estrogens for HRT, 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. The addition of certain progestins may also increase thromboembolic risks. 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 between hormone replacement therapy and the risk of thromboembolic disease has been demonstrated in the Women's Health Initiative Trials (WHI trials). The US FDA has suggested class labeling of HRT products in accordance with this data. HRT products are generally contraindicated in patients with a current history of stroke, cerebrovascular disease, coronary artery disease, coronary thrombosis, thrombophlebitis (including pulmonary embolism and DVT), thromboembolic disease or valvular heart disease with complications. Concurrent use of HRT in female patients receiving anticoagulation therapy with warfarin is generally avoided. If concurrent use of an estrogen or estrogen-progestin containing HRT cannot be avoided in a patient taking warfarin, carefully monitor for signs and symptoms of thromboembolic complications. If such occur, the estrogen or estrogen-progestin containing HRT regimen should be discontinued. HRT is not expected to significantly alter the INR or to affect the metabolism of warfarin. Dosage adjustment of warfarin 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 is 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 has 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. Caution should be exercised when estradiol is administered to a nursing woman. The infant may need to be monitored for effects such as breast enlargement, poor appetite, and appropriate growth and weight gain. Estrogens are not approved by the FDA for the treatment of postpartum breast engorgement. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    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, and topically.
     
    Affected cytochrome P450 isoenzymes: 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: Estradiol is extensively metabolized in the GI mucosa during absorption and in the liver. Micronization of oral estradiol tablets slows oral absorption and decreases the first-pass effects in the liver and increases the normally poor bioavailability of estradiol. Absolute bioavailability of micronized estradiol is roughly 5—10% of an administered dose. Following oral administration, estradiol is rapidly transformed by the liver to estrone and estriol, the major circulating forms in the serum, by 17beta-hydroxysteroid dehydrogenase. The estrogens are widely distributed and are strongly protein-bound, primarily to albumin and sex hormone-binding globulin (SHBG). Estradiol, estrone, and estriol undergo glucuronide and sulfate conjugation to a variety of minor metabolites which are excreted primarily in the urine. In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Some biliary excretion and entero-hepatic recycling of estradiol and its metabolites occurs. The plasma half-life of orally administered estradiol is approximately 1—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 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 than the valerate esters, averaging 3—6 weeks and 2—3 weeks, respectively. However, IM dosage intervals are usually every 4 weeks for both cypionate and valerate esters of estradiol for most indications; dosage is adjusted to patient response.

    Topical Route

    Estradiol emulsions, gels, or sprays: Topical 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. Estradiol topical emulsion (Estrasorb) utilizes micellar nanoparticle technology for estradiol administration through the skin. Estradiol topical emulsion incorporates 17-beta-estradiol in a soy-based oil formulation, designed to deliver systemic levels of estrogen through the skin. Once in the serum, the distribution, metabolism and excretion of topically administered estradiol occurs through the same pathways as for oral administration.
    Estradiol transdermal patch: 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. Minimal fluctuations in estradiol concentrations are seen with transdermal application. Transdermal estradiol has a short elimination half-life (~2 hours); serum estradiol concentrations return to postmenopausal levels within 4—8 hours of patch removal. Once in the serum, the distribution, metabolism and excretion of transdermally administered estradiol occurs through the same pathways as for oral administration.

    Other Route(s)

    Vaginal Route
    Estradiol: Estradiol is well absorbed through the vaginal mucous membranes. Drug delivery from intravaginal ring dosage forms is rapid as evidenced by Tmax values for estradiol of less than 1 hour. Following Cmax, serum estradiol concentrations decrease rapidly such that by 24—48 hours post-application of the dosage form, serum estradiol concentrations are relatively constant through the end of the 3-month dosing interval. The vaginal dosage applied determines systemic hormone exposure; as a result, systemic as well as local tissue effects may occur. Different intravaginal 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 results in mean steady state serum estradiol estimates of 7—8.1 pg/mL; with an estradiol delivery rate of roughly 7.5 mcg/24 hours. Following administration of Femring 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.