English

ThisiscontentfromElsevier'sDrugInformation

TRANSFORM HOW YOU USE DRUG INFORMATION

Learn more about Elsevier's Drug Information today! Get the drug data and decision support you need, including TRUE Daily Updates™ including every day including weekends and holidays.

Dec.13.2021

Conjugated Estrogens

Indications/Dosage

Labeled

  • atrophic vaginitis
  • dysfunctional uterine bleeding
  • dyspareunia
  • hot flashes
  • hypogonadism
  • menopause
  • oophorectomy
  • osteoporosis prophylaxis
  • ovarian failure
  • palliative treatment of breast cancer
  • prostate cancer

Off-Label

    † Off-label indication

    Oral dosage

    Adult menopausal and postmenopausal females

    Initially, 0.3 mg PO once daily. May titrate if needed. Use lowest effective dose. Few patients need up to 1.25 mg/day PO. Doses of less than 0.45 mg/day may be appropriate for patients with vaginal/vulvar symptoms only. Continuous, unopposed estrogen administration is acceptable in women without a uterus. In women with an intact uterus, estrogen may be given cyclically (e.g., 25 days of month then 5 days off) 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. In patients with an intact uterus, therapy is initiated arbitrarily if the patient has not menstruated for 2 months or more. If the patient is menstruating, the dose is initiated on day 5 of a cycle. Reassess every 3 to 6-months to determine if continued systemic hormone therapy is appropriate.[40617] [59299] [60224] In patients with only vaginal or urogenital symptoms, consider vaginal treatment alone.[40617] [59299] [60224] [50638] The North American Menopause Society (NAMS) Guidelines support the initiation of hormone replacement therapy (HRT) around the time of menopause if no contraindications to use exist and use is acceptable to the individual patient, as hormone therapy is the most effective treatment for vasomotor and genitourinary symptoms and has been shown to prevent bone loss and fracture.[50638] Early initiation of HRT and continuation of use at until the median age of menopause (52 years) is recommended in women with premature natural or surgically induced menopause. HRT for vasomotor symptoms and/or increased risk for bone loss around the time of menopause may be considered in those women aged younger than 60 years or who are fewer than 10 years from menopause onset.[50638] [52408] For women who initiate HRT more than 10 or 20 years from menopause onset or are aged 60 years or older, the benefit-risk ratio is less favorable due to known risks for HRT (e.g., stroke, myocardial infarction, venous thromboembolism, dementia, urinary incontinence), and guidelines generally recommend against use in these women. Decisions regarding whether to continue systemic HRT in women aged older than 60 years should be made on an individual basis for quality of life, persistent vasomotor symptoms, or prevention of bone loss and fracture, with consideration given to alternative treatments for prevention of bone loss and other health issues.[50638] [52408] Some women receiving oophorectomy for cancer-related concerns may be able to pursue hormone replacement to improve menopause-like symptoms following surgery. Some data suggest that the short-term treatment of vasomotor and menopause-symptoms in women receiving prophylactic oophorectomy due to BRCA 1/2 gene mutation-related cancer risks does not increase the risk for other cancers, particularly in women less than 45 years of age at time of surgery; larger studies are needed to confirm these findings and optimal treatment guidelines.[60229]

    for isolated vaginal and/or urogenital symptoms of menopause

    Vaginal dosage (vaginal cream)

    Adult menopausal and postmenopausal females

    Initially, 0.5 grams vaginally once daily for 21 days; then, no treatment for 7 days. May titrate up to 2 grams/day vaginally depending on response. Repeat cyclically. Use the lowest effective dose. Reassess need for hormonal treatment every 3 to 6-months.[43845] For moderate to severe dyspareunia, 0.5 grams vaginally twice weekly (e.g., every Monday and Thursday) may be sufficient in some patients; otherwise, consider the usual vaginal dose.[43845] When isolated genitourinary symptoms caused by menopause are present, treatment guidelines recommend low-dose vaginal estrogens over systemic estrogens as first-line therapy.[50638]

    For postmenopausal osteoporosis prophylaxis

    Oral dosage

    Adult postmenopausal females

    Initiate at 0.3 mg PO once daily, given continuously, with no interruption in therapy, or cyclically. Use the lowest effective dose based on clinical and bone mineral density response. Few patients require 1.25 mg/day PO or more. Continuous unopposed estrogen administration is acceptable for women without a uterus. In women with an intact uterus, consider adding a progestin to reduce the risk of endometrial hyperplasia. Supplement calcium and vitamin D if dietary intake is inadequate. Reassess the appropriateness of hormone therapy every 3 to 6-months; carefully consider non-estrogen medication.[40617] In postmenopausal women with low bone mineral density, there is good evidence that standard-dose estrogen therapy reduces the risk for osteoporotic fractures, including hip, spine, and all non-spine fractures; however, estrogens are not generally recommended as a first-line prevention tactic due to the known risks of estrogen treatment (e.g., thromboembolism, cerebrovascular events) relative to other treatments. Women who need osteoporosis prophylaxis who are younger than 60 years or who are within 10 years of menopause onset may be given consideration for estrogen therapy, based on individual assessment of risk vs. benefit. Beyond the age of 60 years, other agents are preferred due to the known risks associated with hormonal therapy. Consider each woman's net balance of individual benefits and harms. If estrogen with or without a progestin is prescribed, use the lowest effective dose for the shortest duration that is consistent with an individual's treatment goals and risks. Estrogens can be used in conjunction with other medications for osteoporosis (e.g., bisphosphonates, denosumab, or teriparatide) based on clinical needs and judgment, when necessary. Estrogen therapy should not be used in patients with known osteoporosis; the risks outweigh the moderate benefit seen in postmenopausal women with established osteoporosis.[52408] [62806] [66837] [67122] [67125]

    For treatment of premenopausal females with estrogen deficiency due to hypogonadism

    Oral dosage

    Adult and Adolescent premenopausal females

    0.3 mg or 0.625 mg PO once daily, administered cyclically (e.g., 3 weeks on and 1 week off). Adjust dose based on the severity of symptoms and responsiveness of the endometrium. In clinical studies, doses as low as 0.15 mg/day PO have induced breast development in patients with delayed puberty. The dosage may be gradually titrated upward at 6- to 12-month intervals as needed to achieve appropriate bone age advancement and eventual epiphyseal closure. The number of estrogen cycles needed to produce cyclical monthly bleeding will depend on the responsiveness of the patient's endometrium. Dosage cycles are often repeated for 3- to 6- months to establish a normal menstruation cycle. A 2-month hiatus often follows establishment of menses to assess if the patient can maintain normal menstrual cycles without further hormonal therapy. If menses does not resume, medication cycles may be repeated. Data suggest that chronic dosing with 0.625 mg/day PO of conjugated estrogens is sufficient to induce cyclic menses with sequential progestin treatment and to maintain bone mineral density after skeletal maturity is achieved.[40617]

    For treatment of hypoestrogenism due to primary ovarian failure

    Oral dosage

    Adult and Adolescent females

    1.25 mg PO once daily, administered cyclically (e.g., 3 weeks on and 1 week off). Adjust dosage, upward or downward, according to severity of symptoms and response of the patient. For maintenance, use lowest effective dose cycle that provides symptom control.[40617] Estrogen replacement therapy is considered standard of care to reduce chronic health risks and to improve quality of life.[60230] In women with an intact uterus, the addition of progestin therapy to the estrogen helps prevent endometrial hyperplasia; hormone replacement may induce cyclic vaginal bleeding again, but won't restore ovarian function, and infertility is treated with other means. Maintenance treatment can continue until the average age of natural menopause, if the patient desires.

    For the short-term treatment of abnormal or dysfunctional uterine bleeding caused by hormonal imbalance in the absence of organic pathology

    Intravenous or Intramuscular dosage (conjugated estrogens, equine injection, i.e., Premarin)

    Adult females

    25 mg IV or IM as a single dose. May repeat this dose in 6 to 12 hours, if necessary. The intravenous route is preferred for a more rapid response; inject IV slowly to reduce flushing. The use of conjugated estrogens parenterally does not preclude the use of other appropriate measures.[43846] [60233]

    Adolescent† females

    Use the same dosing as for adult patients: 25 mg IV or IM as a single dose. May repeat this dose in 6 to 12 hours, if necessary. The intravenous route is preferred for a more rapid response; inject IV slowly to reduce flushing. The use of conjugated estrogens parenterally does not preclude the use of other appropriate measures.[43846] While FDA-approval for use in adolescents has not been specifically established, adolescent females have been included in clinical trials and use is part of standard medical management options in this population when acute care is needed.[60233] [60234]

    For the palliative treatment of breast cancer that has metastasized, in appropriately selected men or women

    Oral dosage

    Adult males or females

    10 mg PO 3 times per day for at least 3 months. Estrogens have been used historically for this indication; in modern medicine, some estrogens are used as salvage endocrine therapy for metastatic disease.[40617] [60235]

    For the palliative treatment of advanced inoperable prostate cancer

    Oral dosage

    Adult males

    1.25 mg to 2.5 mg PO 3 times per day, usually for 3 months. The effectiveness of therapy can be judged by serial PSA determinations as well as by symptomatic improvement of the patient. A response to estrogen treatment, if it will occur, will usually be noted within 3 months. If the patient responds, estrogen therapy is continued until a significant advancement of the disease occurs.[40617] [60236]

    Therapeutic Drug Monitoring

    Maximum Dosage Limits

    • Adults

      Dependent on indication for therapy.

    • Elderly

      Dependent on indication for therapy.

    • Adolescents

      Dependent on indication for therapy.

    • Children

      Not indicated in prepubescent females.

    Patients with Hepatic Impairment Dosing

    Contraindicated in the presence of known liver dysfunction or hepatic disease of any type.

    Patients with Renal Impairment Dosing

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

    † Off-label indication
    Revision Date: 12/13/2021, 12:57:32 PM

    References

    40617 - Premarin tablets (conjugated estrogens, equine) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2017 Nov.43845 - Premarin Vaginal Cream (conjugated estrogens, equine vaginal cream) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2017 Nov.43846 - Premarin I.V. (conjugated estrogens, equine injection) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2017 Nov.50638 - The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022 July. [Epub aheadof print]52408 - Gartlehner G, Patel SV, Feltner C, et al. Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Women: Evidence Report and Systematic Review for the US Preventive Services Task Force (USPSTF). JAMA. 2017;318:2234-2249. Review.59299 - Cenestin tablets (synthetic conjugated estrogens) package insert. North Wales, PA: Teva Women's Health; 2017 Nov.60224 - Enjuvia tablets (synthetic conjugated estrogens, B) tablets package insert. North Wales, PA: Teva Women's Health, Inc.; 2017 Nov.60229 - Marchetti C, Iadarola R, Palaia I, et al. Hormone therapy in oophorectomized BRCA1/2 mutation carriers. Menopause. 2014;21:763-768.60230 - Shelling AN. Premature ovarian failure. Reproduction. 2010;140:633-641.60233 - DeVore GR, Owens O, Kase N. Use of intravenous Premarin in the treatment of dysfunctional uterine bleeding - a double-blind randomized control study. Obstet Gynecol. 1982;59:285-291.60234 - Cirilli AR, Cipot SJ. Emergency evaluation and management of vaginal bleeding in the nonpregnant patient. Emerg Med Clin North Am. 2012;30:991-1006.60235 - Iwase H, Yamamoto Y. Clinical benefit of sequential use of endocrine therapies for metastatic breast cancer. Int J Clin Oncol. 2015;20:253-261. Epub 2015 Feb 12.60236 - Pomerantz M, Manola J, Taplin ME, et al. Phase II study of low dose and high dose conjugated estrogen for androgen independent prostate cancer. J Urol. 2007;177:2146-2150.62806 - Qaseem A, Forciea MA, McLean RM, et al; Clinical Guidelines Committee of the American College of Physicians. Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update From the American College of Physicians. Ann Intern Med. 2017;166:818-839. Epub 2017 May 9. Erratum in: Ann Intern Med. 2017;167:448.66837 - Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists/American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis-2020 update. Endocr Pract 2020;26(Suppl 1):1-46.67122 - Management of osteoporosis in postmenopausal women: the 2021 position statement of The North American Menopause Society. Menopause. 2021;28:973-997.67125 - Eastell R, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2019;104:1595-1622.

    How Supplied

    Conjugated Estrogens Lyophilisate for solution for injection

    Premarin 25mg Powder for Injection (00046-0749) (Wyeth Pharmaceuticals Inc, a subsidiary of Pfizer Inc) null

    Conjugated Estrogens Oral tablet

    Premarin 0.3mg Tablet (55289-0123) (PD-Rx Pharmaceuticals, Inc.) (off market)

    Conjugated Estrogens Oral tablet

    Premarin 0.3mg Tablet (00046-1100) (Wyeth Pharmaceuticals Inc, a subsidiary of Pfizer Inc) null

    Conjugated Estrogens Oral tablet

    Premarin 0.3mg Tablet (00046-0868) (Wyeth Pharmaceuticals Inc, a subsidiary of Pfizer Inc) (off market)

    Conjugated Estrogens Oral tablet

    Premarin 0.45mg Tablet (00046-0936) (Wyeth Pharmaceuticals Inc, a subsidiary of Pfizer Inc) (off market)

    Conjugated Estrogens Oral tablet

    Premarin 0.45mg Tablet (00046-1101) (Wyeth Pharmaceuticals Inc, a subsidiary of Pfizer Inc) null

    Conjugated Estrogens Oral tablet

    Premarin 0.625mg Tablet (55289-0943) (PD-Rx Pharmaceuticals, Inc.) (off market)

    Conjugated Estrogens Oral tablet

    Premarin 0.625mg Tablet (58864-0422) (PD-Rx Pharmaceuticals, Inc.) (off market)

    Conjugated Estrogens Oral tablet

    Premarin 0.625mg Tablet (00046-1102) (Wyeth Pharmaceuticals Inc, a subsidiary of Pfizer Inc) null

    Conjugated Estrogens Oral tablet

    Premarin 0.625mg Tablet (00046-0867) (Wyeth Pharmaceuticals Inc, a subsidiary of Pfizer Inc) (off market)

    Conjugated Estrogens Oral tablet

    Premarin 0.9mg Tablet (00046-1103) (Wyeth Pharmaceuticals Inc, a subsidiary of Pfizer Inc) null

    Conjugated Estrogens Oral tablet

    Premarin 0.9mg Tablet (00046-0864) (Wyeth Pharmaceuticals Inc, a subsidiary of Pfizer Inc) (off market)

    Conjugated Estrogens Oral tablet

    Premarin 1.25mg Tablet (55289-0047) (PD-Rx Pharmaceuticals, Inc.) (off market)

    Conjugated Estrogens Oral tablet

    Premarin 1.25mg Tablet (00046-0866) (Wyeth Pharmaceuticals Inc, a subsidiary of Pfizer Inc) (off market)

    Conjugated Estrogens Oral tablet

    Premarin 1.25mg Tablet (00046-1104) (Wyeth Pharmaceuticals Inc, a subsidiary of Pfizer Inc) null

    Conjugated Estrogens Oral tablet

    Premarin 2.5mg Tablet (00046-0865) (Wyeth Pharmaceuticals Inc, a subsidiary of Pfizer Inc) (off market)

    Conjugated Estrogens Vaginal cream

    Premarin 0.625mg Vaginal Cream (00046-0872) (Wyeth Pharmaceuticals Inc, a subsidiary of Pfizer Inc) nullPremarin 0.625mg Vaginal Cream package photo

    Conjugated Estrogens Vaginal cream

    Premarin 0.625mg Vaginal Cream (Refill Tube) (00046-0872) (Wyeth Pharmaceuticals Inc, a subsidiary of Pfizer Inc) (off market)

    Synthetic Conjugated Estrogens Oral tablet

    Cenestin 0.3mg Tablet (51285-0441) (Teva Pharmaceuticals USA) (off market)

    Synthetic Conjugated Estrogens Oral tablet

    Enjuvia 0.3mg Tablet (51285-0406) (Teva Pharmaceuticals USA) (off market)

    Synthetic Conjugated Estrogens Oral tablet

    Cenestin 0.45mg Tablet (51285-0446) (Teva Women's Health, Inc.) (off market)

    Synthetic Conjugated Estrogens Oral tablet

    Enjuvia 0.45mg Tablet (51285-0407) (Teva Pharmaceuticals USA) (off market)

    Synthetic Conjugated Estrogens Oral tablet

    Cenestin 0.625mg Tablet (51285-0442) (Teva Women's Health, Inc.) (off market)

    Synthetic Conjugated Estrogens Oral tablet

    Enjuvia 0.625mg Tablet (51285-0408) (Teva Pharmaceuticals USA) (off market)

    Synthetic Conjugated Estrogens Oral tablet

    Cenestin 0.9mg Tablet (51285-0443) (Teva Women's Health, Inc.) (off market)

    Synthetic Conjugated Estrogens Oral tablet

    Enjuvia 0.9mg Tablet (51285-0409) (Teva Pharmaceuticals USA) (off market)

    Synthetic Conjugated Estrogens Oral tablet

    Cenestin 1.25mg Tablet (51285-0444) (Teva Women's Health, Inc.) (off market)

    Synthetic Conjugated Estrogens Oral tablet

    Enjuvia 1.25mg Tablet (51285-0410) (Teva Pharmaceuticals USA) (off market)

    Description/Classification

    Description

    Conjugated estrogens are traditionally a mixture of the water soluble salts of sulfate esters from estrone, equilin, 17 alpha-dihydroequilin, and other related steroids. Traditionally conjugated estrogens are derived from pregnant equine urine (e.g., Premarin). The estrogens include the sodium salts of estrone sulfate, equilin sulfate, 17alpha- and 17beta-dihydroequilin sulfate, 17alpha- and 17beta-estradiol sulfate, 17alpha- and 17beta-dihydroequilenin sulfate, and equilenin sulfate; the exact composition of the equine urine-derived mixture is uncertain. The synthetic conjugated estrogens, A product (e.g., Cenestin) is derived from yam and soy plants and contains 9 synthetic estrogenic substances. The synthetic conjugated estrogens, B product (e.g., Enjuvia), is plant-derived, and includes the active estrogenic component delta 8,9-dyhydroestrone sulfate. The different conjugated estrogens products are not considered to be bioequivalent at this time. However, there is no evidence that 'natural' estrogens are more or less efficacious or safe than 'synthetic' estrogens given at equiestrogenic doses.[50638] Conjugated estrogens are used primarily as hormone replacement therapy (HRT) to treat moderate to severe vasomotor symptoms and genitourinary symptoms associated with menopause, and for the prevention of osteoporosis. Conjugated estrogens are also used for numerous abnormalities related to gonadotropin hormone dysfunction. Conjugated estrogens were first marketed in 1938; parenteral, oral and vaginal dose forms are available. Conjugated estrogens, A was approved by the FDA in March 1999. Conjugated estrogens, B was approved by the FDA in May 2004. In December 2008, the FDA approved synthetic conjugated estrogens A vaginal cream.

    Classifications

    • Genito-urinary System and Sex Hormones
      • Sex Hormones and Modulators of the Genital System
        • Estrogens, Excluding Hormonal Contraceptives
    Revision Date: 07/05/2017, 02:06:15 PM

    References

    50638 - The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022 July. [Epub aheadof print]

    Administration Information

    General Administration Information

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

    Hazardous Drugs Classification

    • NIOSH 2016 List: Group 2 [63664]
    • NIOSH (Draft) 2020 List: Table 1
    • Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
    • INJECTABLE: Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
    • ORAL TABLETS/CAPSULES/ORAL LIQUID: Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Eye/face and respiratory protection may be needed during preparation and administration.
    • Topical/Transdermal/Vaginal: Use double chemotherapy gloves and protective gown. Eye/face and respiratory protection may be needed during preparation and administration.[63664][67506] [67507]

    Route-Specific Administration

    Oral Administration

    • May administer without regard to meals.[40617]

    Injectable Administration

    • Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    • The intravenous route provides a more rapid onset of response compared to intramuscular administration. Inject slowly to reduce flushing.[43846]

     

    Reconstitution

    • Reconstitute with 5 mL of Sterile Water for Injection. Introduce the sterile diluent slowly against the side of the vial and gently agitate the vial to aid in dissolution; do not shake vigorously.
    • NOTE: Premarin IV is incompatible with protein hydrolysate, ascorbic acid, or any acid pH solution.
    • Use immediately after reconstitution.[43846]

    Intravenous Administration

    • Inject slowly into the distal port tubing of a freely-flowing IV infusion of 0.9% Sodium Chloride injection, 5% Dextrose injection, or Lactated Ringer's injection. To prevent flushing reaction, the rate of injection should not exceed 5 mg/minute.

    Intramuscular Administration

    • Inject deeply into a large muscle.

    Intravaginal Administration

    • Follow "Instructions for Use" supplied by the manufacturer. The proper dose is marked on the applicator.
    • Instruct patient on proper vaginal application.
    • After administration, wash applicator with mild soap and warm water. Do not boil or use hot water.[43845]

    Clinical Pharmaceutics Information

    From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database

    Estrogens conjugated

    pH Range
    Approximately pH 7.3
    ReferencesTrissel LA. Drug information - pH values. Data on file.
    Osmolality/Osmolarity
    Reconstituted conjugated estrogens is hypertonic having an osmolality exceeding 2000 mOsm/kg.
    ReferencesTrissel LA. Drug information- osmolalities. Data on file.
    Stability
    Although refrigerated storage is recommended for intact vials of conjugated estrogens to maximize the shelf life, the manufacturer indicates that the drug may be stored for up to 7 days at room temperature. Vogenberg and Souney reported that it was stable for up to 2 years at room temperature. Nguyen et al. evaluated the stability of estrogens conjugated in the dry state. Samples were stored at room temperature and elevated temperature of 38 degree C for 6 months. In the dry state, estrogens conjugated were fairly stable and did not change substantially at either storage temperature. The authors concluded that estrogens conjugated injection could be stored in the unreconstituted state in ambulances. The manufacturer states that the reconstituted solution should be used immediately after reconstitution. Nguyen et al. also evaluated the stability of estrogens conjugated after reconstitution. Samples were stored at room temperature and elevated temperature of 38 degree C for 6 months. Reconstituted estrogens conjugated were fairly stable initially but exhibited significant losses of 12 to 20% within 2 months especially at the higher storage temperature. The authors concluded that reconstituted estrogens conjugated injection should be stored under refrigeration and discarded at least monthly. Infusion Solutions: The manufacturer indicates that estrogens conjugated are compatible with dextrose, saline, or invert sugar solutions.
    ReferencesAnon. Manufacturer's information and labeling. (Package insert).
    ReferencesCohen V, Jellinek SP, Teperikidis L, et al. Room-temperature storage of medications labeled for refrigeration. Am J Health-Syst Pharm. 2007; 64
    ReferencesNguyen HP, Tedmon L, Li L, et al. Investigation of the temperature stability of premarin intravenous using liquid chromatography-mass spectrometry. J Pharm Biomed Anal. 2011; 55
    ReferencesVogenberg FR, Souney PF. Stability guidelines for routinely refrigerated drug products. Am J Hosp Pharm. 1983; 40
    pH Effects
    Conjugated estrogens are incompatible at low pH and should not be mixed with a drug or solution that results in acidic pH.
    ReferencesAnon. Manufacturer's information and labeling. (Package insert).
    ReferencesMcEvoy GK (ed). AHFS Drug Information (current edition). Bethesda, MD: American Society of Health-System Pharmacists.
    Other Information
    Conjugated estrogens is cited by NIOSH as a drug that should be handled as hazardous.
    ReferencesAnon. Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings. NIOSH Publication No. 2004-165. 2004; 165
      Revision Date: 04/28/2022, 12:57:47 PMCopyright 2004-2023 by Lawrence A. Trissel. All Rights Reserved.

      References

      40617 - Premarin tablets (conjugated estrogens, equine) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2017 Nov.43845 - Premarin Vaginal Cream (conjugated estrogens, equine vaginal cream) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2017 Nov.43846 - Premarin I.V. (conjugated estrogens, equine injection) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2017 Nov.63664 - CDC National Institute for Occupational Safety and Health (NIOSH). NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2016. DHHS (NIOSH) Publication Number 2016-161, September 2016. Available on the World Wide Web at https://www.cdc.gov/niosh/docs/2016-161/pdfs/2016-161.pdf?id=10.26616/NIOSHPUB201616167506 - American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2018; 75:1996-2031.67507 - NIOSH [2016]. NIOSH Alert: Preventing Occupational Exposures to Antineoplastics and Other Hazardous Drugs in Health Care Settings. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2016-161.

      Adverse Reactions

      Mild

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

      Moderate

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

      Severe

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

      Uterine bleeding pattern changes and other genitourinary effects occur commonly during chronic, systemic conjugated estrogens therapy in postmenopausal women and is most common with oral replacement therapy; non-cyclic vaginal breakthrough bleeding is reported in 2% to 14% of patients. Amenorrhea is common and desirable in many postmenopausal women with an intact uterus and is not considered an adverse effect when estrogens are given continuously with a progestin; however, continued amenorrhea in a premenopausal woman may signal a lack of therapeutic response to the estrogen. Withdrawal bleeding, similar to menstrual bleeding, occurs with cyclic progestin administration, and is usually of shorter duration than regular menses. Changes in vaginal bleeding pattern and breakthrough bleeding or spotting have been noted with estrogens with or without progestins and are commonly reported. Metrorrhagia (3% to 11%) and pelvic pain or dysmenorrhea (4% to 12%) are infrequent. Changes in uterine bleeding patterns will usually taper and stabilize within 3 to 6 months. Infrequent genitourinary effects reported with conjugated estrogens use include dysmenorrhea or pelvic pain (reported in 1% to 8% of postmenopausal women), vaginal discharge (leukorrhea, roughly 3% to 7%), vaginitis or vaginal candidiasis (5% to 7%) and libido increase (less than 5%). The vaginal cream may cause vaginal irritation, burning or genital pruritus on application in less than 5% of patients. Less frequent (1% or less) adverse reactions to conjugated estrogens include changes in cervical ectropion, cervical secretion changes, cervical dysplasia, or libido decrease. Unusual vaginal bleeding or other pelvic symptoms that persist beyond 6 months should be evaluated by a health care professional. For example, continued and unexpected changes in bleeding patterns may indicate a change in uterine leiomyomatas (fibroids) or cervicitis, if present. Women should report unusual symptoms to their healthcare professionals, and follow advice for annual pelvic examinations and periodic Papanicolaou smears.[40617]

      Breast changes that may occur with conjugated estrogen therapy include mastalgia (breast pain) and breast tenderness, which occur in 8% to 12% of women on chronic estrogen HRT. Breast enlargement, breast discharge, galactorrhea, and fibrocystic breast changes have been reported with estrogens and/or progestin therapy. Gynecomastia may occur in men on estrogen therapy. Patients should report breast changes, lumps, or breast discharge to their health care professionals. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.[40617]

      Gastrointestinal effects from conjugated estrogens administration are typically mild and relatively limited. Common side effects with conjugated estrogen use include diarrhea (0—7%), dyspepsia (9—11%), flatulence (4—7%) and nausea (6—12%). Some GI complaints may attenuate with continued administration. In larger doses, estrogens may cause vomiting and nausea may be significant. Other reported effects in < 5% of patients include abdominal pain, cramps or bloating, hypertriglyceridemia, and an increased incidence of gallbladder disease. With chronic use, abdominal pain can indicate biliary obstruction, and result in cholestatic jaundice. Estrogens enhance hepatic lipoprotein uptake and inhibit bile acid synthesis, resulting in increased concentration of cholesterol in the bile which can lead to cholelithiasis. Gallbladder disease and cholecystitis are 2- to 4-fold as frequent in women taking hormone replacement therapy (HRT) compared with controls.[25473] Rare adverse reactions (< 1%) include hepatitis (and elevated hepatic enzymes), enlargement of hepatic hemangiomas, ischemic colitis (bowel ischemia, no incidence reported), or pancreatitis. Patients with familial hyperlipoproteinemia may be at greater risk of pancreatitis while on estrogen therapy, which may greatly increase their serum triglycerides. Estrogens may induce peliosis hepatis, a very rare consequence of taking estrogens and combined oral contraceptives that is characterized by the presence of blood-filled spaces.[51257] Persistent or severe abdominal symptoms should be evaluated by a medical professional. Conjugated estrogens should be discontinued in any patient developing jaundice, cholestasis, or severe abdominal pain, and the patient should be evaluated.[40617]

      Deep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, myocardial infarction, and stroke have been reported with estrogens and/or progestin therapy. The use of estrogens in postmenopausal women, with or without a progestin, carries a risk for thromboembolism, and cardiovascular events such as myocardial infarction (MI) or stroke. Detailed information regarding what is known about thromboembolic and cardiovascular risk in postmenopausal women is available in the boxed warnings and precautions section of the product labeling for the products, as these risks must be considered prior to use of HRT in women, and with consideration to age and other risk factors for these events. Risks vary with the use of estrogen-alone vs. use of estrogen with progestin therapy. Should any of these events occur or be suspected, discontinue the estrogen or estrogen-progestin therapy immediately.[40617] [43846] [43845]

      Conjugated estrogens can cause sodium and fluid retention and peripheral vasodilation, resulting in edema or mild weight gain. They should be prescribed cautiously to patients in whom edema formation would be detrimental. Estrogens also can slightly increase blood pressure, occasionally causing hypertension. Data indicate in most patients the change is not clinically significant. In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. During clinical trials with various conjugated estrogens, such reactions occurred in < 5% or patients.[40617] [43845] In the PEPI trial, postmenopausal women 45—65 years of age randomized to any hormone replacement therapy regimen containing conjugated estrogens experienced increases in both systolic and diastolic blood pressure of 3—5% after the first year of treatment, but the increases were not statistically different from placebo.[24010]

      Headache has been reported in greater than 5% of patients receiving conjugated estrogens by any route, and has been reported in patients receiving chronic HRT.[40617] A severe headache may be a warning sign of a serious adverse event such as a stroke or retinal problems (e.g., thrombosis) in the eye. Discontinue the estrogen pending examination if there is sudden partial or complete loss of vision or sudden onset of migraine. If examination reveals a serious event, estrogens should be permanently discontinued. In some women, headache patterns are hormonally influenced. A number of changes can occur when a woman initiates HRT and include 1) migraines can appear for the first time, 2) a change in frequency, severity and duration of migraine headaches may be seen, or 3) an improvement or decrease in the occurrence of migraine headaches. When initiating therapy an individual's headache pattern should be observed and if migraines worsen consider discontinuing therapy.[40617]

      Nervous system and mood disturbances occur in some women taking conjugated estrogens for hormonal replacement therapy. These changes can include mental depression (5—7%), dizziness (1—7%), fatigue or asthenia (1.4—8%), nervousness or anxiety (2—5%) or insomnia (2.9—7%). Paresthesias (0—6%) have also been reported. Less common central nervous system events (<5%) include chorea, emotional lability, irritability, exacerbation of epilepsy, and dementia. Possible growth potentiation of a benign meningioma may occur.

      Conjugated estrogens and other estrogens used for hormone replacement can cause a variety of dermatological reactions; most occur in <5% of patients.[40617] Melasma and chloasma, in the form of tan or brown patches, may develop on the forehead, cheeks, temples and upper lip. These patches may persist after the drug is discontinued. Other infrequent reactions include urticaria, erythema nodosum, alopecia, hirsutism, or rash (unspecified). Erythematous eruptions, with or without pruritus, may also occur. In some cases estrogens may induce or aggravate an existing acne vulgaris or cause an acneiform rash. An injection site reaction with pain and redness may be associated with parenteral use.[43846]

      Retinal thrombosis has been reported in patients receiving estrogens such as conjugated estrogens. Discontinue medication pending examination if there is sudden visual impairment either partial or complete or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema, visual loss, or retinal vascular lesions, permanently discontinue estrogens. Exogenous estrogen use can cause a conical cornea to develop from steepening or increased curvature of the cornea, caused by thinning of the stroma. Patients with contact lenses may develop intolerance to their lenses.[40617]

      Conjugated estrogens and medroxyprogesterone combinations can cause impaired carbohydrate metabolism and impaired glucose tolerance, leading to hyperglycemia in some women taking HRT. In the PEPI trial, fasting glucose levels were lower, and mean 2-hour glucose levels were 8% higher, in combined HRT treated women versus placebo in all treatment arms. The effects appeared to be consistent across demographic, clinical, and lifestyle variables.[24010] Limited clinical studies of estrogen regimens have not noted significant alterations in glucose metabolism in healthy post-menopausal women. However, altered glucose tolerance secondary to decreased insulin sensitivity may be important for patients with hyperglycemia or diabetes mellitus. They should be observed for changes in glucose tolerance when initiating or discontinuing conjugated estrogens therapy.[40617]

      Conjugated estrogens are known to cause teratogenesis during pregnancy and are in FDA category X. Increased risk of a wide variety of fetal abnormalities, including modified development of sexual organs, cardiovascular anomalies and limb defects, have been reported following the use of estrogens in pregnant women.[40617] The use of diethylstilbestrol, DES is well known for creating disturbances in the reproductive systems of both male and female offspring; similar disturbances are reported to occur in female offspring of rats exposed to other estrogens during gestation. In any patient in whom pregnancy is suspected, pregnancy should be ruled out before continuing the use of conjugated estrogens.

      Cases of anaphylactoid reactions with or without angioedema, requiring emergency medical treatment, have been reported during post marketing use of conjugated estrogen oral tablets. Reported symptoms include hives, pruritis, swollen lips-tongue-face, bronchospasm, abdominal pain, or vomiting. Angioedema involving the tongue, larynx, face, hands, and feet requiring medical intervention has occurred post marketing. Patients who develop these symptoms following treatment should discontinue use not be re-challenged with oral conjugated estrogen. Other potential events related to hypersensitivity can include erythema multiforme, urticaria and other rashes.[43846] [40617]

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

      There is an association of unopposed estrogen therapy and endometrial hyperplasia in women with an intact uterus.  Unopposed estrogen therapy can promote endometrial hyperplasia in approximately 10% of patients with an intact uterus, and thus increase the risk of endometrial cancer. Adding a progestin to estrogen therapy has been shown to reduce, but not eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. With concurrent progestin use (cyclically or continuously), the incidence of endometrial hyperplasia due to conjugated estrogens is estimated to be 1% or less. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal vaginal bleeding. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15-to 24-fold for 5 to 10 years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose.[43845] [40617] [59299] [60224] [23505] [27272]

      Numerous epidemiologic studies have examined the effects of estrogen and estrogen-progestin hormone replacement therapy (HRT) on the development of new primary malignancy (e.g., breast cancer, endometrial cancer, ovarian cancer) in postmenopausal women. Detailed clinical study information regarding what is known about cancer risk in postmenopausal women is available in the boxed warnings and precautions section of the product labeling for the products, as these risks must be considered prior to use of HRT in women, and with consideration to age and other risk factors for these events. The risk for endometrial cancer is increased in women who take unopposed estrogen. Adding a progestin to estrogen therapy has been shown to reduce, but not eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Proper surveillance is important. At diagnosis endometrial cancers in estrogen recipients are generally of an earlier stage and a lower grade and show less myometrial invasion than tumors in women who have not used estrogen. The Women's Health Initiative (WHI) estrogen plus progestin study reported increased risks of invasive breast cancer in patients taking combined estrogen-progestin HRT vs. placebo. The potential risk of breast cancer may increase with longer duration of use. Women who used hormonal therapy for menopausal symptoms also had an increased risk for ovarian cancer, but data are still uncertain if risk is associated with a specific duration of use.[23505] [27272] [32125] [27273] [40617] [43846] [43845] [59299] [60224] [50638]

      Hormone replacement therapy (HRT), both estrogen/progestin combination therapy and estrogen alone therapy, fails to prevent mild impaired cognition (memory loss) and is positively associated with the risk of developing dementia in women 65 years and older; do not use HRT to prevent or treat dementia or preserve cognition (memory).[40617] When data from the 2 populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI 1.19 to 2.60, p = 0.005). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women.[27451] [32126] [50638] In the Women’s Health Initiative Memory Study (WHIMS) estrogen plus progestin ancillary study, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo. After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia.  The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95% CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 vs. 22 cases per 10,000 women-years.[27451] In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo. After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95% CI, 0.83 to 2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years.[32126]

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

      Musculoskeletal adverse events associated with conjugated estrogens include back pain (13-14%), arthralgia (3.5—14%), leg muscle cramps (3—7%), and myalgia (5—9%). Rates of these reactions are often similar to those seen in patients taking placebo.[40617] In some cases, muscle cramps may be indicative of an exacerbation of hypocalcemia (pre-existing condition). Arthralgia may be aggravated by estrogen-induced fluid retention.

      Miscellaneous adverse events associated with conjugated estrogens include porphyria. Respiratory reactions may include increased cough, exacerbations of asthma (bronchospasm), pharyngitis, rhinitis, or sinusitis, or mild upper respiratory infection; rates of respiratory reactions are similar to those observed with placebo.[40617]

      Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, discontinue the estrogen and take appropriate measures to reduce the serum calcium concentration.[40617]

      Revision Date: 11/05/2018, 03:36:38 PM

      References

      23505 - Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016-37.24010 - The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA 1995;273:199-208.25473 - The Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-13.27272 - Rossouw JE, Anderson GL, Prentice RL, et al. The Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333.27273 - Lacey JV, Mink PJ, Lubin JH, et al. Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 2002;288:334-341.27451 - Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The Women's Health Initiative Memory Study: A randomized controlled trial (WHIMS). JAMA 2003;289:2651-62.27457 - Steiner JE, Subak L, Grady D, et al. Hormone therapy for prevention of urinary incontinence: the HERS Study. Obstet Gynecol 2003;101(Suppl):S10.32125 - Stefanick ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 2006;295:1647-57.32126 - Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's health initiative memory study. JAMA 2004;291:2947-58.40617 - Premarin tablets (conjugated estrogens, equine) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2017 Nov.43845 - Premarin Vaginal Cream (conjugated estrogens, equine vaginal cream) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2017 Nov.43846 - Premarin I.V. (conjugated estrogens, equine injection) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2017 Nov.50638 - The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022 July. [Epub aheadof print]51257 - Radzikowska E, Maciejewski R, Janicki K, et al. The relationship between estrogen and the development of liver vascular disorders. Ann Univ Mariae Curie Sklodowska Med. 2001;56:189-93.59299 - Cenestin tablets (synthetic conjugated estrogens) package insert. North Wales, PA: Teva Women's Health; 2017 Nov.60224 - Enjuvia tablets (synthetic conjugated estrogens, B) tablets package insert. North Wales, PA: Teva Women's Health, Inc.; 2017 Nov.

      Contraindications/Precautions

      Absolute contraindications are italicized.

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

      Do not use conjugated estrogens products in patients with a known hypersensitivity to the hormones or any of the specific product ingredients; conjugated estrogens are contraindicated in patients with known anaphylactic reactions or history of angioedema to the drug. Cases of both anaphylactic reactions and angioedema have been reported in patients taking estrogens, including conjugated estrogens. Events have developed in minutes and have required emergency medical treatment. Exogenous estrogens may also induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema, which can be hormonally sensitive. Conjugated estrogens vaginal cream contains benzyl alcohol and should be used with caution in those with benzyl alcohol hypersensitivity; allergic-type reactions, including bronchospasm or other bronchial events, may occur in certain susceptible individuals.[40617] [43845] [43846] [59299] [60224]

      Estrogens are generally contraindicated in patients with a history of, or known or suspected breast cancer. The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms, requiring further evaluation. All women taking estrogen with or without a progestin should receive an annual clinical breast examination, perform monthly self-examinations, and have regular mammograms as recommended by their health care professional based on patient age, risk factors, and prior mammogram results.[40617] [43845] [59299] [60224] Since the 1970's, numerous epidemiological studies have examined the association of estrogens or combined hormone replacement therapy (HRT) and breast cancer (new primary malignancy).[23505] The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the Womens Health Initiative (WHI) substudy of conjugated estrogens (CE, 0.625 mg/day)-alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily estrogen monotherapy was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80].[27531] [32125] The most important randomized clinical trial providing information about breast cancer in patients taking combined estrogen-progestin HRT regimens is the WHI substudy of CE (0.625 mg/day) plus MPA (2.5 mg/day).[27530] [27272] After a mean follow-up of 5.6 years, the WHI estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA vs. placebo. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same WHI substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the combined HRT group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the 2 groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the 2 groups.[27530] Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with combined HRT as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.[40617] [43845] [59299] [60224] While estrogen therapy may be used rarely for the palliative treatment of advanced breast cancer in men and women, estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.[40617] [43845] [59299] [60224]

      Conjugated estrogens are contraindicated in the presence of estrogen-responsive tumors, including ovarian cancer. The Women's Health Initiative (WHI) estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer in women taking combined hormone replacement therapy (HRT). After an average follow-up of 5.6 years, the relative risk for ovarian cancer for estrogen (conjugated estrogens, CE) plus a progestin (medroxyprogesterone, MPA) versus placebo was 1.58 (95% CI, 0.77 to 3.24). The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years.[17829] A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used HRT for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risk associated with current use of hormonal therapy was 1.41 (95% CI, 1.32 to 1.5); there was no difference in the risk estimates by duration of the exposure (less than 5 years [median of 3 years] vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI, 1.27 to 1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.[43845] [40617] [59299] [60224]

      Estrogen therapy is contraindicated in patients with known estrogen-dependent malignancies. There is an association of unopposed estrogen therapy and endometrial cancer in women with an intact uterus. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal vaginal bleeding. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15-to 24-fold for 5 to 10 years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. With concurrent progestin use (cyclically or continuously), the incidence of endometrial hyperplasia due to conjugated estrogens is estimated to be 1% or less.[43845] [40617] [59299] [60224] [23505] [27272]

      Estrogens are contraindicated in the presence of vaginal cancer, cervical cancer, uterine cancer, or other estrogen-responsive tumors. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important; all women receiving estrogen treatment should have an annual pelvic examination and other diagnostic or screening tests, such as cervical cytology, as clinically indicated or as generally recommended based on age, risk factors, and other individual needs. Because estrogens influence the growth of endometrial tissues, use conjugated estrogens cautiously in women with endometriosis or uterine leiomyomata (uterine fibroids). A few cases of malignant transformation of residual endometrial growths have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of a progestin should be considered to reduce the risk of endometrial tissue growth.[43845] [40617] [59299] [60224]

      Estrogens are contraindicated in patients with an active or past history of stroke, thrombophlebitis, thromboembolism, thromboembolic disease, or myocardial infarction (MI). An increased risk of cerebrovascular disease (stroke) and deep venous thrombosis (DVT) has been reported with unopposed estrogen therapy. An increased risk of thromboembolism, including pulmonary embolism (PE), DVT, stroke and myocardial infarction (MI) has been reported with estrogen plus progestin hormone replacement therapy (HRT). Should any of these events occur or be suspected, discontinue conjugated estrogens immediately.[40617] [43845] [59299] [60224] Estrogens are also contraindicated for patients with known protein C deficiency, protein S deficiency, or antithrombin deficiency or other known thrombophilic disorders associated with increased risk of venous thrombosis. Other risk factors for arterial vascular disease (e.g., hypertension, diabetes, tobacco smoking, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) [e.g., personal history or family history of VTE, obesity, or systemic lupus (SLE)] should be monitored and managed appropriately.[40617] [43845] [59299] [60224] A positive relationship between estrogen use and an increased risk for thromboembolism has been demonstrated. In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) was increased for women receiving daily unopposed estrogen compared to placebo (30 vs. 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 vs. 15 per 10,000 women years). The increase in VTE risk was demonstrated during the first 2 years. In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving estrogen plus progestin HRT compared to women receiving placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted.[17825] [27272] Estrogens with or without progestins should not be used for the prevention of cardiac disease or cardiovascular disease (e.g., coronary artery disease). In the Women's Health Initiative (WHI) estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as non-fatal MI, silent MI, or CHD death ) was reported in women receiving conjugated estrogen-alone compared to placebo. Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE-alone vs. placebo) in women with less than 10 years since menopause (8 vs. 16 per 10,000 women-years). In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily estrogen plus progestin compared to women receiving placebo (41 vs. 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5.[27272] [17808] Studies have also shown no cardiovascular benefit to the use of estrogens or estrogen-progestin therapy for secondary prevention in women with documented cardiac disease or CHD.[25473] [27270] Estrogens also increase the risk for stroke. In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen-alone compared to women in the same age group receiving placebo (45 vs. 33 per 10,000 women-years). The increase in risk was demonstrated in the first year and persisted. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving estrogen-alone versus those receiving placebo (18 vs. 21 per 10,000 women-years). In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen plus progestin HRT compared to women in the same age group receiving placebo (33 vs. 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. Women over the age of 65 years were at increased risk for non-fatal stroke.[38488] [27272] Patients with hypertension should be monitored closely for increases in blood pressure if estrogens are administered. In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogen therapy. In a large, randomized, placebo controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. Estrogens may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as a cardiac disease, warrant careful observation when estrogens are prescribed.[40617] [43845] [59299] [60224] In men treated with estrogens for palliation of prostate or breast cancer, estrogens have increased the risk of nonfatal MI, PE, and thrombophlebitis.

      If feasible, estrogen therapy should be discontinued at least 4 to 6 weeks before any surgery associated with an increased risk of thromboembolism, or during any periods of prolonged immobilization. The decision on when to resume estrogens after such procedures or conditions would be based on the perceived additional thromboembolic risk from estrogen use and the need for estrogen therapy; resume only after the patient is fully ambulatory. In addition, women taking conjugated estrogens should be advised to move about periodically during travel involving prolonged immobilization.[40617] [43845] [59299] [60224]

      Conjugated estrogens are contraindicated 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 as an oral contraceptive inadvertently during early pregnancy. However, increased risk of a wide variety of fetal abnormalities, including modified development of sexual organs, cardiovascular anomalies and limb defects, have been reported following the chronic use of estrogens in pregnant women. There is no FDA-approved indication for the use of conjugated estrogens in pregnancy.[40617] [43845] [59299] [60224]

      Caution should be used if a breast-feeding mother is receiving conjugated estrogens; in general, these products should not be used during lactation. 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 breast milk of women receiving estrogen-alone therapy. Estrogens are not approved by the FDA for the treatment of postpartum breast engorgement.[40617] [43845] [59299] [60224]

      Estrogens are contraindicated in the presence of hepatocellular cancer, hepatic adenoma, or in severe hepatic disease of any type. Estrogens may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, estrogens should be discontinued. Estrogens should also be used cautiously in patients with acute intermittent, or variegate hepatic porphyria, which can be exacerbated. Estrogens have been reported during trials to increase the risk of gallbladder disease (e.g., cholestasis, cholelithiasis and cholecystitis) by roughly 2- to 4-fold in postmenopausal women; use with caution in patients with a history of gallbladder disease.[25473] [40617] [43845] [59299] [60224]

      Patients with systemic lupus erythematosus (SLE) may have increased risk for thromboembolism and should be managed appropriately when estrogen therapy is considered.[40617] [43845] [59299] [60224] Approximately 85% of patients diagnosed with systemic lupus erythematosus (SLE) are females, giving support to the notion that hormonal influences, especially estrogen, contribute to the pathophysiology of SLE. Accordingly, hormone replacement therapy (HRT) has been reported to induce, unmask, and exacerbate lupus; case reports, anecdotal data, and the prospective Nurses Health Study indicate that a temporal relationship between HRT and lupus exist. However, several retrospective studies dispute a relationship between estrogens and lupus, and the SELENA trial, a large prospective, randomized clinical trial evaluating the safety of estrogen therapy (both as oral contraceptives and HRT in postmenopausal women) in patients with SLE has been completed and is being analyzed. Determining the risk of estrogen therapy in SLE patients is important as postmenopausal women with lupus can benefit from HRT; not only does it offer relief from postmenopausal symptoms (vasomotor symptoms, genital symptoms, and emotional lability), but it has the additional benefit of protecting patients from bone fracture and postmenopausal or drug-induced (i.e., chronic corticosteroid or cyclophosphamide therapy) osteoporosis. Women with hypercoagulable states are at increased risk of venous thromboembolism when taking HRT; given the increased prevalence of hypercoagulable states in patients with SLE (in particular antiphospholipid antibodies), the use of HRT in this population may be even more risky as the incidence of strokes, heart attacks, and blood clots is increased in general in women taking HRT. Unfortunately, definitive recommendations regarding the use of HRT in patients with SLE are not available. The results of the SELENA trial should provide evidence regarding the use of HRT in this population.[31435] [31436]

      In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of estrogen treatment if pancreatitis occurs.[40617] [43845] [59299] [60224]

      Retinal vascular thrombosis has been reported in women receiving estrogens. Any visual disturbance should be examined by an ophthalmologist. Discontinue the estrogen pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine with visual changes. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.[40617] [43845] [59299] [60224] Estrogen therapy may cause an exacerbation of migraine or a change in headache patterns and should be used with caution in women with migraine. Patients who complain of migraine with focal neurologic visual changes should be evaluated, and in some patients, such changes may indicate cerebrovascular events. Estrogens can increase the curvature of the cornea and may lead to intolerance of contact lenses.

      Patients with risk factors for arterial vascular disease (e.g., diabetes mellitus), which may increase the risk for thromboembolism, should be monitored and managed appropriately during estrogen therapy. Patients with diabetes mellitus should be observed for changes in glucose tolerance when initiating or discontinuing estrogen therapy, since estrogen therapy may exacerbate diabetes. Altered glucose tolerance secondary to decreased insulin sensitivity has been reported.[40617] [43845] [59299] [60224]

      Use estrogens 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.[40617] [43845] [59299] [60224]

      Because estrogens may cause fluid retention, conditions that might be affected by fluid retention, such as heart disease or renal disease, require careful observation. Estrogen therapy may also cause an exacerbation of asthma, seizure disorder, and hepatic hemangiomas in some patients and should be used with caution in women with these conditions.[40617] [43845] [59299] [60224]

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

      Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.[40617] [43845] [59299] [60224]

      Hormone replacement therapy (HRT), both estrogen/progestin combination therapy and estrogen alone therapy, has been found to fail to prevent mild cognitive impairment (memory loss) and to increase the risk of dementia in women 65 years and older.[40617] [43845] [59299] [60224] Administration of HRT should generally be avoided in women 65 years of age and older, and HRT should not be used to prevent or treat dementia or preserve cognition (memory). Overall risk vs. benefit should be considered along with the goals of use of HRT for the individual patient when considering whether to continue HRT in a geriatric woman over 65 years of age.[27451] [32126] [50638] 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. According to the Beers Criteria, oral, topical patch, or other systemic forms of estrogens (with or without progestins), are considered potentially inappropriate medications (PIMs) for use in geriatric patients and should be avoided due to evidence of carcinogenic potential (i.e., breast and endometrium) and lack of cardiovascular or cognitive protective effects in older women. Additionally, the Beers expert panel recommends avoiding oral or transdermal estrogen in elderly women with any type of urinary incontinence due to lack of efficacy. The Beers expert panel considers use of vaginal estrogens acceptable for the management of dyspareunia, recurrent lower urinary tract infections, and other vaginal/vulvar symptoms.[63923]

      The safety and efficacy of estrogens have not been established in neonates, infants or children. Estrogens are not indicated in children because estrogens promote epiphysial closure. In young children, overdose of estrogens have not been reported to cause serious ill effects. However, nausea is common. Vaginal withdrawal bleeding may occur in female children exposed to estrogens in large doses. Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay; however, if estrogen is administered to adolescent patients whose bone growth is not complete, these patients should be monitored periodically for bone maturation and effects on epiphyseal centers.[40617] [43845] [59299] [60224] Premarin vaginal cream contains benzyl alcohol; inadvertent exposure to benzyl alcohol is associated with 'gasping syndrome' in neonates.[43845]

      Revision Date: 02/14/2019, 11:48:38 AM

      References

      17808 - Hsia J, Langer RD, Manson JE, et al. Conjugated equine estrogens and coronary heart disease. The Women's Health Initiative. Arch Intern Med. 2006;166:357-365.17825 - Cushman M, Kuller LH, Prentice R, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA. 2004;292:1573-1580.17829 - Anderson GL, Judd HL, Kaunitz AM, et al. Women's Health Initiative Investigators. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial. JAMA 2003;290:1739-1748.23505 - Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016-37.25473 - The Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-13.27270 - Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:49-57.27272 - Rossouw JE, Anderson GL, Prentice RL, et al. The Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333.27451 - Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The Women's Health Initiative Memory Study: A randomized controlled trial (WHIMS). JAMA 2003;289:2651-62.27530 - Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women: The Women's Health Initiative Randomized Trial. JAMA 2003;289:3243-53.27531 - Li CI, Malone KE, Porter PL, et al. Relationship between long durations and different regimens of hormone therapy and risk of breast cancer. JAMA 2003;289:3254-63.31435 - Askanase AD. Estrogen therapy in systemic lupus erythematosus. Treat Endocrinol 2004;3:19-26.31436 - Petri M. Exogenous estrogen in systemic lupus erythematosus: oral contraceptives and hormone replacement therapy. Lupus 2001;10:222-632125 - Stefanick ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 2006;295:1647-57.32126 - Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's health initiative memory study. JAMA 2004;291:2947-58.38488 - Rossoun JE, Prentice RL, Manson JE. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465-1477.40617 - Premarin tablets (conjugated estrogens, equine) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2017 Nov.43845 - Premarin Vaginal Cream (conjugated estrogens, equine vaginal cream) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2017 Nov.43846 - Premarin I.V. (conjugated estrogens, equine injection) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2017 Nov.50638 - The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022 July. [Epub aheadof print]59299 - Cenestin tablets (synthetic conjugated estrogens) package insert. North Wales, PA: Teva Women's Health; 2017 Nov.60224 - Enjuvia tablets (synthetic conjugated estrogens, B) tablets package insert. North Wales, PA: Teva Women's Health, Inc.; 2017 Nov.63923 - The American Geriatrics Society 2019 Beers Criteria Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 2019;00:1-21.

      Mechanism of Action

      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. After menopause estrone is the primary circulating estrogen; it is derived from the peripheral conversion of androstenedione by an aromatase enzyme found in adipose tissues. Estrone is converted to small amounts of estradiol in peripheral tissues. Estrogens increase the rate of synthesis of DNA, RNA, and some proteins. 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, however, the decrease in progesterone secretion is the more significant factor causing menstruation.

       

      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, they generally do not reverse bone density loss that has already developed. 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 [25473][27270][27271], the Women's Health Initiative study [27272], 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.

      Revision Date: 07/06/2017, 01:43:04 PM

      References

      25473 - The Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-13.27270 - Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:49-57.27271 - Hulley S, Furberg C, Barrett-Connor E, et al. Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:58-66.27272 - Rossouw JE, Anderson GL, Prentice RL, et al. The Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333.

      Pharmacokinetics

      Conjugated estrogens are administered orally, intramuscularly, intravenously, intravaginally, or by local vulvar application. Conjugated estrogens bind primarily to albumin; unconjugated estrogens bind both to albumin and sex-hormone-binding globulin. Similar to that of endogenous estrogens, conjugated estrogens are widely distributed throughout the body and are found in higher concentration in the sex hormone target organs.

       

      Metabolism occurs in the same manner as endogenous estrogens. There is a dynamic equilibrium of metabolic interconversions; most transformations take place in the liver. Conjugated estrogens are metabolized primarily in the liver to glucuronide and sulfate conjugates of estradiol, estrone, and estriol. These products are eliminated in the urine. A portion of the conjugates are excreted into the intestine through the biliary system; hydrolysis in the gut allows for enterohepatic recirculation of the estrogens. In postmenopausal women, a significant portion of the sulfate conjugates exist as estrone sulfate, which serves as a reservoir for the formation of the more active estrogens, estradiol and estriol. The apparent terminal half life of conjugated estrone is 4—18.5 hours and the half-life of conjugated equilin is 4—17 hours.

       

      Affected cytochrome P450 isoenzymes: none

      Route-Specific Pharmacokinetics

      Oral Route

      Conjugated estrogens are rapidly absorbed from the GI tract after oral administration; the tablets are designed to release the estrogens slowly over a period of several hours.

      Other Route(s)

      Vaginal Route

      Conjugated estrogens are absorbed systemically when given by the vaginal route. The degree of systemic absorption via the vaginal route is dependent on the frequency of use, dose prescribed, and degree of vaginal mucosal atrophy present.

      Special Populations

      Hepatic Impairment

      The pharmacokinetics of conjugated estrogens have not been studied in patients with hepatic impairment. In general, estrogen use is not recommended in patients with severe hepatic disease or jaundice.

      Renal Impairment

      The pharmacokinetics of conjugated estrogens have not been studied in patients with renal impairment.

      Revision Date: 08/01/2013, 01:06:47 PM

      Pregnancy/Breast-feeding

      pregnancy

      Conjugated estrogens are contraindicated 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 as an oral contraceptive inadvertently during early pregnancy. However, increased risk of a wide variety of fetal abnormalities, including modified development of sexual organs, cardiovascular anomalies and limb defects, have been reported following the chronic use of estrogens in pregnant women. There is no FDA-approved indication for the use of conjugated estrogens in pregnancy.[40617] [43845] [59299] [60224]

      breast-feeding

      Caution should be used if a breast-feeding mother is receiving conjugated estrogens; in general, these products should not be used during lactation. 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 breast milk of women receiving estrogen-alone therapy. Estrogens are not approved by the FDA for the treatment of postpartum breast engorgement.[40617] [43845] [59299] [60224]

      Revision Date: 11/20/2017, 08:05:37 AM

      References

      40617 - Premarin tablets (conjugated estrogens, equine) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2017 Nov.43845 - Premarin Vaginal Cream (conjugated estrogens, equine vaginal cream) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2017 Nov.59299 - Cenestin tablets (synthetic conjugated estrogens) package insert. North Wales, PA: Teva Women's Health; 2017 Nov.60224 - Enjuvia tablets (synthetic conjugated estrogens, B) tablets package insert. North Wales, PA: Teva Women's Health, Inc.; 2017 Nov.

      Interactions

      Level 1 (Severe)

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

      Level 2 (Major)

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

      Level 3 (Moderate)

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

      Level 4 (Minor)

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

      References

      805 - The sixth report of the Joint National Committee on detection, evaluation, and treatment of high blood pressure. National Institute of Health publication No 99-4080. 1997;1-64.2455 - Kroboth PD, Slalek FS, Pittenger AL et al. DHEA and DHEA-S: a review. J Clin Pharmacol 1999;39:327-348.2786 - Kivisto KT, Villikka K, Nyman L, et al. Tamoxifen and toremifene concentrations in plasma are greatly decreased by rifampin. Clin Pharmacol Ther 1998;64:648-54.3486 - Chan CH. Dantrolene sodium and hepatic injury. Neurology 1990;40:1427-1432.4718 - Hansten PD, Horn JR. Cytochrome P450 Enzymes and Drug Interactions, Table of Cytochrome P450 Substrates, Inhibitors, Inducers and P-glycoprotein, with Footnotes. In: The Top 100 Drug Interactions - A guide to Patient Management. 2008 Edition. Freeland, WA: H&H Publications; 2008:142-157.4744 - Premarin (conjugated estrogens, equine) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2003 Jul.4846 - Teslac (testolactone) package insert. Princeton, NJ: Mead-Johnson Oncology Products, Bristol-Myers Squibb, Co.; 1998 Dec.4948 - Accolate (zafirlukast) package insert. Wilmington, DE: AstraZeneca; 2015 Dec.4970 - McAuley JW, Anderson GD. Treatment of epilepsy in women of reproductive age: pharmacokinetic considerations. Clin Pharmacokinet 2002;41:559-79. Review.4971 - No author listed. Oral contraceptives and drug interactions. Patient guide. Female patient 1992;17:107-8.5066 - Parlodel (bromocriptine) tablets and capsules package insert. Parsippany, NJ: Validus Pharmaceuticals LLC; 2021 Jul.5172 - Sustiva (efavirenz) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2019 Oct.5221 - Synercid (dalfopristin; quinupristin) package insert. New York, NY: Pfizer Laboratories; 2017 Mar.5306 - Mattison RH, Cramer JA, Darney PD, et al. Oral contraceptive use by women with epilepsy. JAMA 1986;256:238-40.5307 - Lewis DP, VanDyke DC, Stumbo PJ, et al. Drug and environmental factors associated with adverse pregnancy outcomes Part 1: Antiepileptic drugs, contraceptives, smoking and folate. Ann Pharmacother 1998;32:802-17.5837 - Femara (letrozole) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2018 April.5847 - Aromasin (exemestane) tablets package insert. New York, NY: Pfizer Inc; 2018 May.6098 - Arimidex (anastrozole) package insert. Baudette, MN: ANI Pharmaceuticals, Inc; 2018 Dec.6300 - Crawford P. Interactions between antiepileptic drugs and hormonal contraception. CNS Drugs. 2002;16:263-72.6395 - US Food and Drug Administration (FDA). Guidance for Industry. Noncontraceptive Estrogen Drug Products for the Treatment of Vasomotor Symptoms and Vulvar and Vaginal Atrophy Symptoms - Recommended Prescribing Information for Health Care Providers and Patient Labeling. Document No. 6932. Division of Dockets Management (HFA-305), Food and Drug Administration, Rockville, MD; Issued November 2005. Retrieved Sept 2016. Available at: http://www.fda.gov/cder/guidance/guidance.htm.6702 - Panhematin® (hemin for injection) package insert. Deerfield, IL: Ovation Pharmaceuticals, Inc.; 2006 Aug.6807 - Humatrope (somatropin) package insert. Indianapolis, IN: Eli Lilly and Company; 2019 Oct.7006 - Felbatol® (felbamate) package insert. Somerset, NJ: MedPointe Pharmaceuticals; 2002 Dec.7241 - Saano V, Glue P, Banfield CR, et al. Effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive. Clin Pharmacol Ther. 1995;58:523-31.7622 - U.S. Food and Drug Administration (FDA). Labeling for Combined Hormonal Contraceptives; Draft Guidance for Industry. Federal Register Volume 83, Issue 1 (January 2, 2018); p.131-133 Docket No. FDA-2017-D-1846 [FR Document #2017-28252] Division of Dockets Management, Food and Drug Administration, Rockville, MD; Retrieved Sept. 2021. Guidance download available at: https://www.fda.gov/media/110050/download8953 - Kendall A, Dowsett M, Folkerd E, et al. Caution: vaginal estradiol appears to be contraindicated in postmenopausal women on adjuvant aromatase inhibitors. Ann Oncol 2006;17:584-7.17825 - Cushman M, Kuller LH, Prentice R, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA. 2004;292:1573-1580.22005 - Perucca E. Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol 2006;61(3):246-255.28001 - Hansten PD, Horn JR. Cytochrome P450 Enzymes and Drug Interactions, Table of Cytochrome P450 Substrates, Inhibitors, Inducers and P-glycoprotein, with Footnotes. In: The Top 100 Drug Interactions - A guide to Patient Management. 2008 Edition. Freeland, WA: H&H Publications; 2008:142-157.28025 - Premarin (conjugated estrogens, equine) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2003 Jul.28078 - Urso 250 / Urso Forte (ursodiol) package insert. Birmingham AL: Axcan Scandipharm Inc.; 2023 Jan.28082 - Actigall (ursodiol) package insert. Morristown,NJ: Watson Pharmaceuticals Inc. Oct 201428123 - Teslac (testolactone) package insert. Princeton, NJ: Mead-Johnson Oncology Products, Bristol-Myers Squibb, Co.; 1998 Dec.28142 - Reyataz (atazanavir) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2020 Sept.28200 - Sedapap (acetaminophen; butalbital) package insert. Atlanta, GA: Mikart, Inc.; 2001 Jul.28211 - Henderson L, Yue QY, Bergquist C, et al. St John's wort (Hypericum perforatum): drug interactions and clinical outcomes. Br J Clin Pharmacol 2002;54:349-56.28315 - Norvir (ritonavir capsules) package insert. North Chicago, IL: AbbVie Inc; 2020 Oct.28378 - Topamax (topiramate) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2022 Oct.28451 - Lamictal (lamotrigine) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2021 Mar.28482 - Archer JSM, Archer DF. Oral contraceptive efficacy and antibiotic interaction: A myth debunked. J Am Acad Dermatol 2002;46:917-23.28483 - Priftin (rifapentine) package insert. Bridgewater, NJ: Sanofi-Aventis Pharmaceuticals Inc.; 2020 Jun.28496 - Tracleer (bosentan) package insert. South San Francisco, CA: Actelion Pharmaceuticals US, Inc.; 2019 May.28502 - Fiorinal (butalbital; aspirin; caffeine) capsules package insert. Madison, NJ: Allergan USA, Inc.; 2021 Apr.28509 - Dickinson BD, Altman RD, Nielsen NH, Sterling ML, for the Council on Scientific Affairs, American Medical Association (AMA). Drug interactions between oral contraceptives and antibiotics. Obstet Gynecol 2001;98:853-60. Review.28535 - Cerebyx (fosphenytoin sodium) package insert. New York, NY: Pfizer Labs; 2022 Apr.28549 - Coumadin (warfarin tablets) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2017 Aug.28550 - Glucophage and Glucophage XR (metformin HCl tablets and extended-release tablets) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2018 May.28577 - Lewis DP, VanDyke DC, Stumbo PJ, et al. Drug and environmental factors associated with adverse pregnancy outcomes Part 1: Antiepileptic drugs, contraceptives, smoking and folate. Ann Pharmacother 1998;32:802-17.28731 - Crixivan (indinavir) package insert. Whitehouse Station, NJ: Merck & Co., Inc.; 2016 Sept.28771 - Dilantin Kapseals (extended phenyotin sodium capsules, USP) package insert. Morris Plains, NJ: Parke Davis; 1999 Aug.28839 - Viracept (nelfinavir mesylate) package insert. Research Triangle Park, NC: ViiV Healthcare Company; 2021 Mar.28946 - Vitrase (hyaluronidase ovine) injection package insert. Bridgewater, NJ: Bausch & Lomb Pharmaceuticals Inc.; 2018 May.28995 - Invirase (saquinavir) package insert. South San Francisco, CA: Genentech Inc.; 2020 Sept.29012 - Lexiva (fosamprenavir calcium) package insert. Research Triangle Park, NC: ViiV Healthcare; 2019 Mar29014 - Trileptal (oxcarbazepine) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2019 Jan.29101 - Femara (letrozole) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2018 April.29110 - Aromasin (exemestane) tablets package insert. New York, NY: Pfizer Inc; 2018 May.29140 - McLintock LA, Dykes A, Tait RC, et al. Interaction between hormone replacement therapy preparations and oral anticoagulant therapy. BJOG 2003;110:777-9.29210 - Mycobutin (rifabutin) package insert. New York, NY: Pharmacia and Upjohn, Co.; 2021 Sep.29360 - Arimidex (anastrozole) package insert. Baudette, MN: ANI Pharmaceuticals, Inc; 2018 Dec.29603 - Evista (raloxifene) package insert. Indianapolis, IN: Eli Lilly and Company; 2018 Jun.29653 - US Food and Drug Administration (FDA). Guidance for Industry. Noncontraceptive Estrogen Drug Products for the Treatment of Vasomotor Symptoms and Vulvar and Vaginal Atrophy Symptoms - Recommended Prescribing Information for Health Care Providers and Patient Labeling. Document No. 6932. Division of Dockets Management (HFA-305), Food and Drug Administration, Rockville, MD; Issued November 2005. Retrieved Sept 2016. Available at: http://www.fda.gov/cder/guidance/guidance.htm.29678 - Maurer G. Metabolism of cyclosporine. Transplant Proc 1985;17(Suppl 1):19-26.29679 - Deray G, le Hoang P, Cacoub P, et al. Oral contraceptive interaction with cyclosporin. Lancet 1987;1:158-9.29779 - Deltasone (prednisone) tablet package insert. Petaluma, CA: Oculus Innovative Sciences, Inc.; 2017 Nov.29821 - Fioricet with codeine (acetaminophen; butalbital; caffeine; codeine) capsules package insert. Parsippany, NJ: Actavis Pharma, Inc.; 2021 Mar.29964 - Gris-Peg (griseofulvin ultramicrosize) package insert. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2016 Apr..30314 - Rifadin capsules and injection (rifampin) package insert. Bridgewater, NJ: Sanofi-Aventis, LLC; 2021 Dec.30487 - Curry CE, Butler DM. Constipation. In: Handbook of Nonprescription Drugs. 12th ed. Washington, DC: American Pharmaceutical Association 2000;285:273-300.30585 - Pandit MK, Burke J, Gustafson AB, et al. Drug-induced disorders of glucose tolerance. Ann Intern Med 1993;118:529-39.30675 - Equetro (carbamazepine extended-release capsules) package insert. Parsippany, NJ: Validus Pharmaceuticals LLC; 2022 Oct.30676 - Emend (aprepitant oral products) package insert. Whitehouse Station, NJ: Merck & Co.,Inc.; 2019 Nov.30858 - U.S. Food and Drug Administration (FDA). Labeling for Combined Hormonal Contraceptives; Draft Guidance for Industry. Federal Register Volume 83, Issue 1 (January 2, 2018); p.131-133 Docket No. FDA-2017-D-1846 [FR Document #2017-28252] Division of Dockets Management, Food and Drug Administration, Rockville, MD; Retrieved Sept. 2021. Guidance download available at: https://www.fda.gov/media/110050/download31241 - Requip (ropinirole hydrochloride) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2021 Jul.31320 - Aptivus (tipranavir) package insert. Ridgefield, CT: Boehringer Ingelheim; 2020 Jun.32432 - Prezista (darunavir) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2022 Oct.32946 - Elestrin (estradiol topical gel) package insert. Somerset, NJ: Meda Pharmaceuticals Inc; 2020 Oct.33528 - Metopirone (metyrapone) capsule package insert. Farmingdale, NJ: Direct Success, Inc; 2020 Feb.33675 - Nieman LK. Medical therapy of Cushing's disease. Pituitary 2002;5:77-82.33718 - Intelence (etravirine) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2019 July.37102 - Chenodal 250 mg (chenodiol tablets) package insert. Fort Collins, CO: Manchester Pharmaceuticals, Inc.; 2009 Oct.37613 - Lysteda (tranexamic acid) package insert. Parsippany, NJ: Ferring Pharmaceuticals Inc.; 2020 Dec.40617 - Premarin tablets (conjugated estrogens, equine) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2017 Nov.41237 - Tegretol (carbamazepine) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2018 Mar.41243 - Provigil (modafinil) package insert. Frazer, PA: Cephalon; 2015 Jan.41365 - Hylenex Recombinant (hyaluronidase human recombinant) injection package insert. San Diego, CA: Halozyme Therapeutics, Inc.; 2016 Jan.41366 - Amphadase (hyaluronidase bovine) injection package insert. Rancho Cucamonga, CA: Amphastar Pharmaceuticals, Inc.; 2014 May.41934 - Lysodren (mitotane) package insert. Princeton, NJ: Bristol-Myers Squibb Oncology; 2021 June.42456 - Viramune (nevirapine) tablets and oral suspension package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2022 Jun.43709 - Cosyntropin injection package insert. Rockford, IL: Mylan Institutional LLC; 2021 July.43942 - Levothroid (levothyroxine sodium tablet) package insert. Shenandoah, IA: Lloyd Pharmaceutical; 2011 June.44735 - Depacon (valproate sodium injection) package insert. North Chicago, IL: Abbvie Inc.; 2020 May.46370 - Onfi (clobazam) package insert. Deerfield, IL: Lundbeck Inc.; 2023 Jan.47343 - Chang SY, Chen C, Yang Z, et al. Further assessment of 17alpha-ethinyl estradiol as an inhibitor of different human cytochrome P450 forms in vitro. Drug Metab Dispos 2009;37:1667-75.48201 - US Department of Health and Human Services/Centers for Disease Control and Prevention. U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR Recomm Rep. 2016;65:1-103.48697 - Korlym (mifepristone) tablet package insert. Menlo Park, CA: Corcept Therapeutics; 2019 Nov.49472 - Revlimid (lenalidomide) capsules package insert. Summit, NJ: Celgene Corporation; 2014 Sept.49509 - Dantrium capsules (dantrolene sodium) package insert. Chestnut Ridge, NY: Par Pharmaceuticals; 2017 May.49996 - Shenfield GM. Oral contraceptives. Are drug interactions of clinical significance? Drug Saf. 1993;9(1):21-37.50666 - Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.51268 - Estrace (estradiol tablet) package insert. Irvine, CA; Allergan USA, Inc; 2016 Dec.51295 - Renoux C, Dell'Aniello S, Suissa S. Hormone replacement therapy and the risk of venous thromboembolism: a population-based study. J Thromb Haemost 2010;8:979-86.51323 - Vascepa (icosapent ethyl) package insert. Bridgewater, NJ: Amarin Pharma Inc.; 2019 Dec.51727 - Xtandi (enzalutamide) capsule and tablet package insert. Northbrook, IL:Astellas Pharma US, Inc.; 2022 Sept.53344 - Osphena (ospemifene) tablets package insert. Florham Park, N.J: Shionogi, Inc.; 2019 Jan.53562 - Synthroid (levothyroxine) tablets. North Chicago, IL: AbbVie Inc.; 2022 Aug.54049 - Solu-cortef (hydrocortisone sodium succinate) injection package insert. New York, NY: Pharmacia & Upjohn Co.; 2021 May.54612 - Arimidex (anastrozole) package insert. Wilmington DE: AstraZeneca Pharmaceuticals LP; 2013 May.55436 - Patsalos PN, Berry DJ, Bourgeois BF. Antiepileptic drugs--best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia 2008;49:1239-1276.56074 - Duavee (conjugated estrogens and bazedoxifene) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2022 Dec.56579 - Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Updated Mar 10, 2020. Retrieved from the World Wide Web at www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm56753 - Metreleptin (Myalept) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2022 Feb.57085 - Zhang H, Cui D, Wang B, et al. Pharmacokinetic drug interactions involving 17alpha-ethinylestradiol: a new look at an old drug. Clin Pharmacokinet 2007;46:133-57.57202 - Zhou S, Chan E, Pan S, et al. Pharmacokinetic interactions of drugs with St John's wort. J Psychopharmacol 2004;18:262-76.57271 - Phenobarbital tablets package insert. Eatontown, NJ: West-ward Pharmaceuticals Corp.; 2012 Mar.59747 - Targretin (bexarotene) capsules package insert. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2013 May.62853 - Amin M, Suksomboon N. Pharmacotherapy of type 2 diabetes mellitus: an update on drug-drug interactions. Drug Saf. 2014;37:903-919.62874 - Erleada (apalutamide) tablets package insert. Horsham, PA: Janssen Products, LP; 2022 Nov.63732 - Lorbrena (lorlatinib) tablets package insert. New York, NY: Pfizer Labs; 2021 March.64768 - Xcorpi (cenobamate) tablets package insert. Paramus, NJ: SK Life Science, Inc.; 2022 Jun.64952 - Tazverik (tazemetostat) tablet package insert. Cambridge, MA: Epizyme, Inc.; 2020 June.66564 - American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins-Gynecology. ACOG Practice Bulletin No. 206: Use of Hormonal Contraception in Women With Coexisting Medical Conditions. Obstet Gynecol. 2019;133:e128-e150. Erratum in: Obstet Gynecol. 2019;133:1288. Reaffirmed 2020.66700 - Lumakras (sotorasib) tablet package insert. Thousand Oaks, CA: Amgen, Inc.; 2022 Nov.66875 - Welireg (belzutifan) tablets package insert. Whitehouse Station, NJ: Merck Sharp and Dohme Corp.; 2021 Aug.66990 - Exkivity (mobocertinib) capsules package insert. Lexington, MA: Takeda Pharmaceuticals America, Inc.; 2021 Sept.67403 - Pyrukynd (mitapivat) tablets package insert.Cambridge, MA: Agios Pharmaceuticals, Inc.; 2022 Feb.67543 - Camzyos (mavacamten) package insert. Brisbane, CA: MyoKardia, Inc.; 2022 May.67846 - Wilson PW, Garrison RJ, Castelli WP. Postmenopausal estrogen use, cigarette smoking, and cardiovascular morbidity in women over 50. The Framingham Study. N Engl J Med. 1985 Oct 24;313(17):1038-43.68183 - Cejtin HE. Care of the human immunodeficiency virus-infected menopausal woman. Am J Obstet Gyn 2012;207:87-93.

      Monitoring Parameters

      • pap smear
      • pelvic exam

      US Drug Names

      • Cenestin
      • Enjuvia
      • Premarin
      ;