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Dec.02.2021

Ethinyl Estradiol; Norethindrone Acetate

Indications/Dosage

Labeled

  • atrophic vaginitis
  • contraception
  • hot flashes
  • menopause
  • osteoporosis prophylaxis

NOTE: OC Products containing 50 mcg estrogen should be used only when medically indicated. Examples of potential medical indications for products containing 50 mcg of estrogen include a history of known contraceptive failure on the 50 mcg products, or increased hepatic metabolism of OCs, such as occurs with some anticonvulsant medications.

Off-Label

  • acne vulgaris
  • amenorrhea
  • dysfunctional uterine bleeding
  • endometriosis
  • hirsutism
  • polycystic ovary syndrome
† Off-label indication

For routine contraception

Oral dosage (monophasic products; e.g., Loestrin, Larin, Microgestin, Junel)

Adult and Adolescent females

1 tablet (containing either 1 mg norethindrone acetate in combination with 20 mcg of ethinyl estradiol or alternatively, 1.5 mg norethindrone acetate in combination with 30 mcg of ethinyl estradiol) PO once daily for 21 days, followed by a period of 7 days without drug. Repeat dosage cycles begin on the eighth day after taking the last hormonally active tablet. Administration of most combination OCs begins on the first Sunday after or on which bleeding has started. However, some clinicians and manufacturers suggest that administration begin on day 1 of the menstrual cycle to decrease the risk of early ovulation. If administration begins on day 1, spotting and breakthrough bleeding may be more common during the initial dosage cycle.[57612]

Oral dosage (monophasic contraceptive products; e.g., Loestrin, Larin, Microgestin, Junel)

Adult and Adolescent females

Follow dose as for routine contraception. Improvement may not be noticeable for 2 to 4 months. Prolonged treatment may be needed to control condition.[58791]

Oral dosage (monophasic contraceptive products; e.g., Loestrin, Larin, Microgestin, Junel)

Adult and Adolescent females

Follow dose as for routine contraception. Treatment for 6 to 12 months may be required; OCs have limited utility when the underlying cause of the condition is not related to a hypoestrogenic or hyperandrogenic state.[58791] [58792] [58793]

For the treatment of endometriosis† to induce endometrial involution to a 'resting' phase and reduce the size and growth of endometrial tissue in females with no contraindications to hormonal contraceptives, have achieved menarche, and who desire contraception

Oral dosage (monophasic contraceptive products; e.g., Loestrin, Larin, Microgestin, Junel)

Adult and Adolescent females

Follow dose as for routine contraception; alternatively, the active tablets can be given continuously. Combined hormonal contraceptives can reduce endometriosis-associated dyspareunia, dysmenorrhea, and non-menstrual pelvic pain. Treatment for 6 to 9 months may be needed to induce endometrial atrophy and reduce symptoms.[57749]

Oral dosage (tablets with 0.5 mg norethindrone acetate/2.5 mcg ethinyl estradiol OR 1 mg of norethindrone acetate/5 mcg ethinyl estradiol; e.g., FEMHRT Low Dose, FEMHRT, Fyavolv, Jinteli)

Adult menopausal and postmenopausal females

1 tablet (containing norethindrone acetate 0.5 mg with ethinyl estradiol 2.5 mcg OR containing norethindrone acetate 1 mg with ethinyl estradiol 5 mcg) PO once daily. Use lowest effective dose. Reevaluate the appropriateness of hormonal replacement therapy (HRT) at 3 to 6-month intervals.[43360] When treating isolated genitourinary symptoms, consider vaginal topical therapy.[50638] The North American Menopause Society (NAMS) Guidelines support the initiation of HRT around the time of menopause if no contraindications and use is acceptable to the individual patient, as HRT 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 and guidelines generally recommend against use in these women. Decisions regarding whether to continue systemic HRT in women older than 60 years of age should be made on an individual basis for quality of life, persistent vasomotor symptoms, or prevention of bone loss and fracture, with consideration given to alternative treatments for prevention of bone loss and other health issues.[50638] [52408]

For postmenopausal osteoporosis prophylaxis in women with an intact uterus

Oral dosage (tablets with 0.5 mg norethindrone acetate/2.5 mcg ethinyl estradiol OR 1 mg of norethindrone acetate/5 mcg ethinyl estradiol; e.g., FEMHRT Low Dose, FEMHRT, Fyavolv, Jinteli)

Adult postmenopausal females

1 tablet (containing norethindrone acetate 0.5 mg with ethinyl estradiol 2.5 mcg OR containing norethindrone acetate 1 mg with ethinyl estradiol 5 mcg) PO once daily. Use the lowest effective dose. Reassess the appropriateness of hormonal therapy at 3 to 6-month intervals; consider the appropriateness of non-estrogen medications.[43360] 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 first-line prevention due to the known risks of HRT (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, based on individual assessment of risk vs. benefit. Beyond the age of 60 years, other agents are preferred due to the known risks of HRT. 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 consistent with treatment goals and risks. Estrogen therapy should not be used in patients with known osteoporosis; the risks outweigh the moderate benefit seen in postmenopausal women with established osteoporosis.[52408] [62806] [66837] [67122] [67125]

Therapeutic Drug Monitoring

Maximum Dosage Limits

  • Adults

    1 tablet (5 mcg estradiol with 1 mg norethindrone max dose)/day PO for menopausal symptoms or osteoporosis prevention. For oral contraception, 1 tablet/day PO as per product prescribed.

  • Geriatric

    1 tablet (5 mcg estradiol with 1 mg norethindrone max dose)/day PO for menopausal symptoms or osteoporosis prevention.

  • Adolescents

    For oral contraception, 1 tablet/day PO as per product prescribed.

  • Children

    Not indicated in prepubescent females.

Patients with Hepatic Impairment Dosing

Contraindicated for use in patients with known liver impairment or disease.[57612][43360]

Patients with Renal Impairment Dosing

These products have not been studied in subjects with renal impairment.[57612][43360]

† Off-label indication
Revision Date: 12/02/2021, 12:15:25 PM

References

43360 - FEMHRT (norethindrone acetate/ethinyl estradiol) tablet package insert. Irvine CA: Allergan USA, 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.57612 - Loestrin 1/20 and 1.5/30 21-day (norethindrone acetate and ethinyl estradiol) package insert. Lake Wales PA: TEVA Pharmaceuticals; 2023 Jan.57749 - Dunselman GA, Vermeulen N, Becker C, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod 2014;29:400-12.58791 - American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins-Gynecology. ACOG Practice Bulletin No. 110: Noncontraceptive uses of Hormonal Contraceptives. Obstet Gynecol 2010;115:206-218. Reaffirmed 2020.58792 - Legro RS, Arslanian SA, Ehrmann DA, et al. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2013;98:4565-92.58793 - Practice bulletin no. 136: management of abnormal uterine bleeding associated with ovulatory dysfunction. Obstet Gynecol 2013 Jul;122:176-85.62806 - 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

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Aurovela 1/20 21-Day Tablet (65862-0939) (Aurobindo Pharma USA Inc.) null

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Gildess 1/20 21-Day Tablet (00603-7607) (Par Pharmaceuticals, an Endo Company) (off market)Gildess 1/20 21-Day Tablet package photo

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Junel 1/20 21-Day Tablet (00555-9025) (Teva Pharmaceuticals USA) nullJunel 1/20 21-Day Tablet package photo

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

LARIN 1/20 21-Day Tablet (16714-0408) (NorthStar Rx LLC) nullLARIN 1/20 21-Day Tablet package photo

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Loestrin 1/20 21-Day Tablet (00071-0915) (Allergan USA, Inc.) (off market)

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Loestrin 1/20 21-Day Tablet (51285-0079) (Teva Pharmaceuticals USA) (off market)Loestrin 1/20 21-Day Tablet package photo

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Loestrin 1/20 21-Day Tablet (51285-0079) (Teva Women's Health, Inc.) (off market)

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Loestrin 1/20 21-Day Tablet (51285-0131) (Teva Women's Health, Inc.) null

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Microgestin 1/20 21-Day Tablet (52544-0276) (Mayne Pharma) (off market)

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Microgestin 1/20 21-Day Tablet (51862-0868) (Mayne Pharma) null

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Microgestin 1/20 21-Day Tablet (51862-0007) (Mayne Pharma) (off market)

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Microgestin 1/20 21-Day Tablet (52544-0950) (Teva/Actavis US) (off market)Microgestin 1/20 21-Day Tablet package photo

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Microgestin 1/20 21-Day Tablet (52544-0276) (Teva/Actavis US) (off market)Microgestin 1/20 21-Day Tablet package photo

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Norethindrone Acetate/Ethinyl Estradiol 1mg/0.02mg Tablet (68462-0132) (Glenmark Pharmaceuticals) nullNorethindrone Acetate/Ethinyl Estradiol 1mg/0.02mg Tablet package photo

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Norethindrone Acetate/Ethinyl Estradiol 1mg/0.02mg Tablet (00378-7280) (Mylan Pharmaceuticals Inc.) nullNorethindrone Acetate/Ethinyl Estradiol 1mg/0.02mg Tablet package photo

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Aurovela 1.5/30 21-Day Tablet (65862-0935) (Aurobindo Pharma USA Inc.) null

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Gildess 1.5/30 21-Day Tablet (00603-7606) (Par Pharmaceuticals, an Endo Company) (off market)Gildess 1.5/30 21-Day Tablet package photo

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Hailey 1.5/30 21-Day Tablet (68462-0504) (Glenmark Pharmaceuticals) null

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Junel 1.5/30 21-Day Tablet (00555-9027) (Teva Pharmaceuticals USA) nullJunel 1.5/30 21-Day Tablet package photo

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

LARIN 1.5/30 21-Day Tablet (16714-0407) (NorthStar Rx LLC) nullLARIN 1.5/30 21-Day Tablet package photo

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Loestrin 1.5/30 21-Day Tablet (00071-0916) (Allergan USA, Inc.) (off market)

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Loestrin 1.5/30 21-Day Tablet (51285-0082) (Teva Pharmaceuticals USA) (off market)Loestrin 1.5/30 21-Day Tablet package photo

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Loestrin 1.5/30 21-Day Tablet (51285-0082) (Teva Women's Health, Inc.) (off market)

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Loestrin 1.5/30 21-Day Tablet (51285-0127) (Teva Women's Health, Inc.) null

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Microgestin 1.5/30 21-Day Tablet (51862-0279) (Mayne Pharma) (off market)Microgestin 1.5/30 21-Day Tablet package photo

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Microgestin 1.5/30 21-Day Tablet (51862-0872) (Mayne Pharma) nullMicrogestin 1.5/30 21-Day Tablet package photo

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Microgestin 1.5/30 21-Day Tablet (52544-0951) (Teva/Actavis US) (off market)Microgestin 1.5/30 21-Day Tablet package photo

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Microgestin 1.5/30 21-Day Tablet (52544-0290) (Teva/Actavis US) (off market)Microgestin 1.5/30 21-Day Tablet package photo

Norethindrone Acetate, Ethinyl Estradiol Oral tablet

Norethindrone Acetate/Ethinyl Estradiol 1.5mg/0.03mg Tablet (00378-7274) (Mylan Pharmaceuticals Inc.) null

Norethindrone Acetate, Ethinyl Estradiol Oral tablet [Estrogen Replacement/Osteoporosis]

Femhrt Low Dose 0.5/2.5 Tablet (00430-0145) (Allergan USA, Inc.) (off market)Femhrt Low Dose 0.5/2.5 Tablet package photo

Norethindrone Acetate, Ethinyl Estradiol Oral tablet [Estrogen Replacement/Osteoporosis]

Fyavolv 0.5/0.0025 Tablet (68180-0827) (Lupin Pharmaceuticals, Inc.) null

Norethindrone Acetate, Ethinyl Estradiol Oral tablet [Estrogen Replacement/Osteoporosis]

Fyavolv 0.5-0.0025mg Tablet (68180-0827) (Lupin Pharmaceuticals, Inc.) null

Norethindrone Acetate, Ethinyl Estradiol Oral tablet [Estrogen Replacement/Osteoporosis]

Jevantique Lo 0.5/2.5 Tablet (52544-0236) (Teva/Actavis US) (off market)

Norethindrone Acetate, Ethinyl Estradiol Oral tablet [Estrogen Replacement/Osteoporosis]

Norethindrone Acetate/Ethinyl Estradiol 0.5mg/2.5mcg Tablet (68462-0656) (Glenmark Pharmaceuticals) nullNorethindrone Acetate/Ethinyl Estradiol 0.5mg/2.5mcg Tablet package photo

Norethindrone Acetate, Ethinyl Estradiol Oral tablet [Estrogen Replacement/Osteoporosis]

Norethindrone Acetate/Ethinyl Estradiol 0.5mg-2.5mcg Tablet (75834-0129) (Nivagen Pharmaceuticals) nullNorethindrone Acetate/Ethinyl Estradiol 0.5mg-2.5mcg Tablet package photo

Norethindrone Acetate, Ethinyl Estradiol Oral tablet [Estrogen Replacement/Osteoporosis]

Femhrt 1/5 Tablet (00430-0544) (Allergan USA, Inc.) (off market)Femhrt 1/5 Tablet package photo

Norethindrone Acetate, Ethinyl Estradiol Oral tablet [Estrogen Replacement/Osteoporosis]

Femhrt 1/5 Tablet (00071-0144) (Pfizer Inc.) (off market)Femhrt 1/5 Tablet package photo

Norethindrone Acetate, Ethinyl Estradiol Oral tablet [Estrogen Replacement/Osteoporosis]

Fyavolv 1/0.005 Tablet (68180-0828) (Lupin Pharmaceuticals, Inc.) nullFyavolv 1/0.005 Tablet package photo

Norethindrone Acetate, Ethinyl Estradiol Oral tablet [Estrogen Replacement/Osteoporosis]

Fyavolv 1-0.005mg Tablet (68180-0828) (Lupin Pharmaceuticals, Inc.) null

Norethindrone Acetate, Ethinyl Estradiol Oral tablet [Estrogen Replacement/Osteoporosis]

Jevantique Tablet (52544-0237) (Teva/Actavis US) (off market)

Norethindrone Acetate, Ethinyl Estradiol Oral tablet [Estrogen Replacement/Osteoporosis]

Jinteli 1/5 Tablet (00093-3122) (Teva Pharmaceuticals USA) nullJinteli 1/5 Tablet package photo

Norethindrone Acetate, Ethinyl Estradiol Oral tablet [Estrogen Replacement/Osteoporosis]

Norethindrone Acetate/Ethinyl Estradiol 1mg/5mcg Tablets (68462-0657) (Glenmark Pharmaceuticals) null

Norethindrone Acetate, Ethinyl Estradiol Oral tablet [Estrogen Replacement/Osteoporosis]

Norethindrone Acetate/Ethinyl Estradiol 1mg-5mcg Tablet (75834-0130) (Nivagen Pharmaceuticals) nullNorethindrone Acetate/Ethinyl Estradiol 1mg-5mcg Tablet package photo

Description/Classification

Description

Ethinyl estradiol and norethindrone acetate are an estrogen and progestin, respectively, that are found in combination products for oral contraception or for hormone replacement therapy (HRT) for women's health. Ethinyl estradiol is a potent, synthetic estrogen. Norethindrone acetate is a first generation oral progestin with moderate androgenic and slight estrogenic activity relative to newer progestins. Norethindrone acetate is known as norethisterone acetate outside of the United States. Many ethinyl estradiol; norethindrone acetate products are used as routine oral contraceptives. Combined hormonal contraceptives can be used in female patients from menarche to over the age of 40 years and up until the time of menopause with the proper selection of products. The choice of a routine hormonal contraceptive for any given patient is based on the individual's contraceptive needs, underlying medical conditions or risk factors for adverse effects, and individual preferences for use. All combined oral contraceptives (COCs) have risks related to venous and arterial thromboembolism, particularly in women who smoke; all combined hormonal contraceptive labels contain a boxed warning about tobacco smoking. The Centers for Disease Control's U.S. Medical Eligibility Criteria describe considerations for risk vs. benefits, including medical conditions or attributes that contraindicate use; these criteria can help prescribing practitioners in product selection for individual patients.[48201] Certain combination products with ethinyl estradiol; norethindrone acetate are exclusively used for hormonal replacement therapy (HRT) for osteoporosis prophylaxis and/or to treat vasomotor and genitourinary symptoms associated with menopause in women with an intact uterus; a progestin, when added to estrogen replacement therapy, reduces, but does not completely eliminate, the risk for endometrial hyperplasia. However, the addition of a progestin to an estrogen regimen may present additional risks for individual women. Patients should be prescribed HRT products with the indication of use and individual risk:benefit in mind, and for the shortest duration consistent with the treatment goals of the individual. Boxed warnings for HRT relate to cardiovascular, dementia and cancer risks in the menopausal/post-menopausal population.[50638][50517] Ethinyl estradiol/norethindrone acetate oral contraceptive products were first approved by the FDA prior to 1982. Products for menopausal symptoms and post-menopausal osteoporosis prophylaxis were first FDA-approved in October 1999.

Classifications

  • Genito-urinary System and Sex Hormones
    • Sex Hormones and Modulators of the Genital System
      • Estrogen with Progestogen Combinations, Excluding Hormonal Contraceptives
      • Hormonal Contraceptives
        • Monophasic or Fixed Dose Contraceptives
          • Monophasic Contraceptives
Revision Date: 11/14/2017, 01:07:25 PM

References

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;65:1-103.50517 - Watts NB, Bilezikian JP, Camacho PM, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract 2010;16 (Suppl 3):1-37.50638 - 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.
  • Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Eye/face and respiratory protection may be needed during preparation and administration.[63664][67506][67507]

Route-Specific Administration

Oral Administration

Hormonal replacement tablet formulations for menopause (e.g., Femhrt Low Dose 0.5/2.5, Fyavolv, Femhrt 1/5, Jevantique Lo, Jinteli 1/5):

  • Take daily at approximately the same time each day.
  • May take with or without food.
  • Some products are provided in blister cards. Begin with the first dose in each card and follow the order of the pack, to aide patient compliance. When finished with a blister card, begin a new blister card pack the next day. Tablets are taken continuously[43360]

 

Oral contraceptive (OC) formulations (e.g., Loestrin, Microgestin, Junel, Larin):

  • To minimize nausea, administer with or after the evening meal or at bedtime. Take at the same time each day to ensure maximum contraceptive efficacy.
  • Absorption may be incomplete in cases of severe vomiting or diarrhea. If these symptoms occur, additional contraceptive measures should be taken. If vomiting occurs within 3 to 4 hours after administration, this can be regarded as a missed dose.
  • For biphasic and triphasic products, explanation of tablet sequencing and different tablet colors may be needed.
  • Some contraceptive packs contain inert tablets. The inert tablets are included so that the daily dosage cycle can be continuous. This reduces the chance of missed doses. The extra tablets are taken at the end of the cycle.

 

OC administration instructions for patients:

  • Instruct patient on risks and warnings associated with hormonal contraceptives.
  • Missing pills can cause spotting or light bleeding.
  • The length of time required for using a second method of contraception after drug initiation is slightly different for each manufacturer. In general, a second, non-hormonal form of contraception should be used until active ethinyl estradiol; norethindrone acetate tablets have been taken for at least 7 consecutive days.
  • Each manufacturer has slightly different recommendations for missed pills. Patients should be instructed to review the patient information leaflet that accompanies the prescription each time it is filled.

 

General recommendations for missed OC doses:

  • If 1 dose is missed, the patient should take it as soon as she remembers and then take the next pill at the regular time as usual. It may be necessary to take 2 tablets in one day. Some manufacturers recommend that a second method of non-hormonal contraception be used for at least 7 days after restarting the pills.
  • If 2 doses in a row are missed, 2 tablets should be taken on both the day the missed doses are remembered and the following day. The regular schedule should then be continued. A second method of non-hormonal contraception should be used for at least 7 days after restarting the pills.
  • If 3 or more doses in a row are missed, the patient should not take the missed pills. Recommendations for restarting the pills can be found in the patient information leaflet that accompanies the prescription each time it is filled. A second method of contraception should be used for at least 7 days after the pills are restarted.

Clinical Pharmaceutics Information

From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database
    Revision Date: 04/27/2022, 04:56:20 PM

    References

    43360 - FEMHRT (norethindrone acetate/ethinyl estradiol) tablet package insert. Irvine CA: Allergan USA, 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
    • alopecia
    • amenorrhea
    • anorexia
    • anxiety
    • arthralgia
    • asthenia
    • back pain
    • breakthrough bleeding
    • breast discharge
    • breast enlargement
    • diplopia
    • dysmenorrhea
    • emotional lability
    • fatigue
    • gingivitis
    • headache
    • hirsutism
    • irritability
    • leukorrhea
    • libido decrease
    • libido increase
    • maculopapular rash
    • mastalgia
    • melasma
    • menorrhagia
    • menstrual irregularity
    • muscle cramps
    • musculoskeletal pain
    • myalgia
    • nausea
    • pelvic pain
    • photosensitivity
    • pruritus
    • rash
    • rhinitis
    • sinusitis
    • urticaria
    • vaginal discharge
    • vaginal irritation
    • vomiting
    • weight gain
    • weight loss

    Moderate

    • candidiasis
    • cataracts
    • cervical dysplasia
    • cholelithiasis
    • cholestasis
    • colitis
    • cystitis
    • depression
    • edema
    • elevated hepatic enzymes
    • endometrial hyperplasia
    • fluid retention
    • galactorrhea
    • hepatitis
    • hyperlipidemia
    • hypertension
    • hypertriglyceridemia
    • impaired cognition
    • jaundice
    • lactation suppression
    • migraine
    • peliosis hepatis
    • urinary incontinence
    • vaginitis

    Severe

    • anaphylactoid reactions
    • angioedema
    • bowel ischemia
    • breast cancer
    • cholecystitis
    • dementia
    • endometrial cancer
    • erythema multiforme
    • erythema nodosum
    • hepatoma
    • intracranial bleeding
    • lupus-like symptoms
    • myocardial infarction
    • new primary malignancy
    • optic neuritis
    • ovarian cancer
    • pancreatitis
    • papilledema
    • porphyria
    • pulmonary embolism
    • retinal thrombosis
    • stroke
    • thromboembolism
    • thrombosis
    • visual impairment

    Breakthrough bleeding and spotting are sometimes encountered, especially during the first 3 months of oral contraceptive use such as ethinyl estradiol; norethindrone acetate. When breakthrough bleeding occurs cyclically after the first 3 months, the time the menstrual irregularity occurs in the cycle can indicate which component (i.e., estrogen or progestin) requires readjustment. In the event of breakthrough vaginal bleeding, consider nonhormonal causes and take adequate diagnostic measures to rule out malignancy or pregnancy. If pathology has been excluded, time or a change to another formulation may solve the problem. Change in menstrual flow (menstrual irregularity, 5%) and amenorrhea have also been reported and are believed to be drug-related. Amenorrhea and oligomenorrhea have been reported in patients taking ethinyl estradiol; norethindrone acetate; in patients using it for contraception, amenorrhea occurred in 32% to 49% of patients with the incidence increasing with duration of use. For patients taking it for HRT, amenorrhea occurred in up to 90% of patients after 1 year of treatment. With continuous administration of the combined HRT regimen, amenorrhea usually occurs within 2—3 months of treatment. Amenorrhea is desirable in many women and not considered to be an adverse effect. In the event of amenorrhea, rule out pregnancy. Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was pre-existent. Other adverse effects may include dysmenorrhea (4%), menorrhagia (5%), metrorrhagia (5%), and pelvic pain (2—6%).[43360]

    Breast tenderness or mastalgia (2—9%), breast enlargement, and breast discharge or secretion have been reported in patients receiving oral contraceptives such as ethinyl estradiol; norethindrone acetate and are believed to be drug-related. Galactorrhea and lactation suppression may also occur.[43360]

    Vaginitis (2—6%) and vaginal candidiasis (2—6%) have been reported in patients receiving ethinyl estradiol; norethindrone acetate, regardless of indication. Symptoms of these include vaginal discharge (leukorrhea) and/or vaginal irritation. Urinary tract infection (2—6.2%) has also been reported. Other adverse events reported when used for hormone replacement therapy (HRT) include changes in cervical erosion, or enlargement of uterine leiomyomatas (fibroids).[43360]

    Oral contraceptives may cause edema (fluid retention) and, thus, weight gain. An increased risk of hypertension has been associated with the use of combined oral contraceptives (COCs) such as ethinyl estradiol; norethindrone acetate. An increase in blood pressure is more likely in older oral contraceptive users and with continued use. The incidence of hypertension increases with increasing concentrations of progestogens. Close monitoring of blood pressures is recommended for patients at risk for hypertension; discontinue ethinyl estradiol; norethindrone acetate if significant elevation of blood pressure occurs. Blood pressures usually return to normal after discontinuation of therapy, and no difference in the occurrence of hypertension exists among ever- and never-users.[48201] An increase in fluid retention and increased blood pressure may also occur with estrogen-progestin hormone replacement therapy. Discontinue HRT if significant increases in blood pressure occur.[43360]

    HORMONE REPLACEMENT THERAPY (HRT): An increased risk of  venous thromboembolism (VTE), including pulmonary embolism (PE), deep venous thrombosis (DVT), 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 HRT immediately.[43360] 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 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 (such as myocardial infarction) 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] [43360] ORAL CONTRACEPTIVES: Combined oral contraceptives (COCs, such as ethinyl estradiol; norethindrone acetate) are associated with an increased risk of thromboembolic and thrombotic disease. The risk for the development of VTE, such as deep venous thrombosis and/or pulmonary embolism is approximately 3 to 6 times greater in OC users than in nonusers. In several studies, the risk was reported to be substantially higher in smokers compared with nonsmokers, and especially if the woman smoker was over 35 years of age. The relative risk of venous thromboembolism (VTE) in women who have predisposing conditions is twice that of women without such medical conditions. The risk of VTE due to COC use gradually disappears after the combined hormonal contraceptive is discontinued. VTE risk is highest in the first year of use and when a combination oral contraceptive is started or re-started after a break in use of 4 weeks or more. Estrogens decrease levels of antithrombin-III and increase the production of blood clotting factors VII, VIII, IX and X; risks increase with ethinyl estradiol doses more than 50 mcg/day. Serious thromboembolic events, such as myocardial infarction or cerebrovascular accidents, are reported rarely in users of COCs who do not smoke.[48201]

    HORMONE REPLACEMENT THERAPY (HRT): In the WHI estrogen plus progestin substudy, a statistically significant increased risk of thromboembolic stroke was reported in women 50 to 79 years of age receiving daily estrogen plus progestin HRT compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women- years). The increase in risk was demonstrated after the first year and persisted. Should a stroke occur or be suspected, estrogen plus progestin HRT should be discontinued immediately.[43360] ORAL CONTRACEPTIVES: An increase in both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes) has been shown in users of combined oral contraceptives (COCs) such as ethinyl estradiol; norethindrone acetate. In general, the risk is greatest among older, hypertensive women over the age of 35 years who also smoke. Hypertension was found to be a risk factor for both users and non-users for both types of strokes while smoking interacted to increase the risk for hemorrhagic strokes. In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension. The relative risk of hemorrhagic stroke (intracranial bleeding) is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users, and 25.7 for users with severe hypertension. The attributable risk also is greater in women in their mid-thirties or older and among smokers.[50744] Although the risk of stroke in users of COCs appears to be related to estrogen amount (i.e., increased risk has been demonstrated with products containing 50 mcg or more but not for products containing l35 mcg or less of ethinyl estradiol), further studies are needed to clarify the relationship of type of progestin to risk of stroke in users of OCs.[48201]

    Clinical case reports of retinal thrombosis associated with estrogen hormone replacement therapy (HRT) and oral contraceptive use exist. Optic neuritis, which may lead to partial or complete loss of vision has been reported in users of oral contraceptives, however the association has been neither confirmed nor refuted. Likewise, cataracts have been reported during oral contraceptive use without evidence of causality.[44124] 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. Any change in vision or visual acuity should be examined by an ophthalmologist. In the event of unexplained visual impairment, onset of proptosis or diplopia, papilledema, or retinal vascular lesions, discontinue ethinyl estradiol; norethindrone acetate. Immediately take appropriate diagnostic and therapeutic measures.[43360] 

    Depression (2—5.8%) has been reported in patients receiving oral contraceptives such as ethinyl estradiol; norethindrone acetate and is believed to be drug-related. During clinical studies, anxiety (2%), depression (2—5.8%), mood swings/emotional lability (2—6%), and nervousness (1.6—5.4%) were reported in patients receiving ethinyl estradiol; norethindrone acetate, regardless of indication.[43360] Fatigue, asthenia, and irritability have also been reported. In addition, libido increase or libido decrease may occur; specifically, in women receiving ethinyl estradiol; norethindrone acetate for HRT, positive changes in libido may occur as a result of improvements in vulvar and vaginal atrophy. Carefully observe women with a history of depression. Discontinue ethinyl estradiol; norethindrone acetate if depression recurs to a serious degree. Also, stop ethinyl estradiol; norethindrone acetate in patients who become significantly depressed to try to determine whether the depression is drug related.

    During oral contraceptive studies, headache (2—7%) was reported in patients receiving ethinyl estradiol; norethindrone acetate; in hormone replacement studies, the incidence of headache was higher (15.2—18.2%).[43360] Migraine has been reported in patients receiving oral contraceptives such as ethinyl estradiol; norethindrone acetate and is believed to be drug-related. A number of changes can occur when a woman initiates oral contraceptive therapy 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 ethinyl estradiol; norethindrone acetate therapy, observe an individual's migraine pattern.The onset or exacerbation of migraine or development of headache with a new pattern that is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause.

    Ethinyl estradiol; norethindrone acetate can cause a variety of dermatological reactions such as maculopapular rash, rash (unspecified), and pruritus. Anaphylactoid reactions including urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms have also been reported in patients receiving oral contraceptives.[43360] Melasma, 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. Photosensitivity can be experienced with oral contraceptive use and protective clothing and sunscreens should be employed when exposed to sunlight or UV light.[57603] An association of oral contraceptives with acne vulgaris, hirsutism, alopecia, erythema multiforme, or erythema nodosum has been neither confirmed nor refuted. Although oral contraceptives can be used to treat acne vulgaris, in some cases they may induce or aggravate an existing acne vulgaris (2—6%). Oral contraceptives have not been shown to increase the incidence of skin cancer of any type, including melanoma.

    Some women taking estrogens or oral contraceptives notice tenderness, swelling, or minor bleeding of their gums, which may lead to gingivitis. Proper attention to oral care and regular dental visits during ethinyl estradiol; norethindrone acetate therapy are recommended.

    Exogenous estrogen use has been associated with gastrointestinal adverse reactions. Events occurring during oral contraceptive or hormone replacement therapy (HRT) trials, or during post marketing surveillance of either, include: nausea, vomiting, abdominal pain (HRT trials: 5.3% to 6.8%), abdominal cramps, bloating, cholestatic jaundice, and gallbladder disease including cholecystitis, cholelithiasis, and cholestasis.[43360] [57612] Cholestatic jaundice of pregnancy or jaundice with prior oral contraceptive use are contraindications for ethinyl estradiol; norethindrone acetate use. Discontinue ethinyl estradiol; norethindrone acetate if jaundice develops, as steroid hormones may be poorly metabolized in patients with impaired liver function.[57612] The increased risk of gallbladder disease associated with oral contraceptive use may be minimal, especially with the use of oral contraceptive formulations that contain lower hormonal doses of estrogens and progestogens. Other GI events including colitis, elevated hepatic enzymes, hepatitis, hyperlipidemia, and anorexia with weight loss may also occur with oral contraceptive use. Rare but serious gastrointestinal events which may occur with oral contraceptive use include peliosis hepatis, Budd-Chiari syndrome, or hepatic vein obstruction. Peliosis hepatis, a very rare consequence of taking estrogens and combined oral contraceptives, is characterized by the presence of blood-filled spaces.[51257] In rare cases, oral contraceptives can cause benign but dangerous liver tumors. Indirect calculations have estimated the attributable risk of hepatoma to be in the range of 3.3 cases per 100,000 for users, a risk that increases after 4 or more years of use. These benign liver tumors can rupture and cause fatal internal bleeding.[57612] In patients with familial defects of lipoprotein metabolism receiving estrogen-containing preparations, significant elevations of plasma triglycerides (hypertriglyceridemia) leading to pancreatitis have been reported. In hormone therapy studies, digestive system adverse events were reported in (9.6% to 13.1%) of patients. Post marketing reports have included cases of enlargement of hepatic hemangiomas and pancreatitis.[43360] Numerous cases of bowel ischemia have been reported during combined estrogen and progesterone use; mesenteric vein thrombus due to hypercoagulability is the proposed mechanism.[57614]

    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).[43360] 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 estrogen plus progestin or placebo. After an average follow-up of 4 years, 40 women in the estrogen plus progestin group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for estrogen plus progestin vs. placebo was 2.05 (95% CI, 1.21 to 3.48). The absolute risk of probable dementia for estrogen plus progestin vs. 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 estrogen-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 estrogen-alone vs. placebo was 1.49 (95% CI, 0.83 to 2.66). The absolute risk of probable dementia for estrogen-alone versus placebo was 37 vs. 25 cases per 10,000 women-years.[32126]

    In women with a history of cardiovascular disease, the use of estrogen and progestin combination therapy (e.g., ethinyl estradiol; norethindrone acetate) 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]

    Myalgia (7.8% to 8.6%), arthralgia (2.9% to 5.8%), back pain (4.7% to 5.3%), and musculoskeletal pain have been noted with combined oral contraceptives (COCs) such as ethinyl estradiol; norethindrone acetate. Systemic lupus erythematosus (lupus-like symptoms) has been reported in COC users.[57612] Arthralgias, leg muscle cramps, and myalgia have been reported with ethinyl estradiol; norethindrone acetate for hormonal replacement therapy (HRT) in postmarketing use.[43360]

    Cystitis has been noted with combined oral contraceptives such as ethinyl estradiol; norethindrone acetate.[57612]

    Rhinitis (12.7% to 15.1%) and sinusitis (2% to 9.4%) have been noted with ethinyl estradiol; norethindrone acetate combination oral contraceptives and hormone replacement therapy; however, incidence rates are similar to those reported with placebo.[57612] [43360]

    Aggravation of porphyria has been noted with estrogens; including hormone replacement and oral contraceptives products such as ethinyl estradiol; norethindrone acetate.[43360] [57612]

    The issue of hormonal influences on the development of cancers has been widely researched for many decades. The risks of various cancers for combined oral contraceptive (COC) use in premenopausal women differ from the risks associated with hormone replacement therapy (HRT) in postmenopausal women. HORMONE REPLACEMENT THERAPY POSTMENOPAUSE: 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. 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. Due to breast cancer and other cancer risks, combined HRT should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.[43360] [27272] [32125] [27273] [50638] There is an association of unopposed estrogen therapy and endometrial cancer in women with an intact uterus. Adding a progestin to estrogen therapy has been shown to reduce, but not eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. 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. Among combined estrogen/progestin HRT users, roughly 10% will have some endometrial thickening. Postmarketing reports of endometrial hyperplasia have been reported in women receiving combined estrogen/progestin HRT; however, the incidence of endometrial hyperplasia is estimated to be 1% or less in these patients.[43360] [50638] [23505] [27272] Women who used HRT for menopausal symptoms also had an increased risk for ovarian cancer, but data are still uncertain if risk is associated with a specific duration of use. The contraindications and precautions sections for the ethinyl estradiol-norethindrone acetate HRT product labels more fully discuss the data and what is known about HRT use with respect to risks for various cancers.[43360] [27272] [32125] [27273] [50638] ORAL CONTRACEPTIVES: Most studies have been performed with combined oral contraceptives (COCs), and the risks related to combined hormonal contraceptives, regardless of route of administration, are thought to be similar. In general, the data suggest an increased risk of cervical cancer among combined oral contraceptive (COC) users, with a decreased risk for endometrial and ovarian cancers. Epidemiology studies have not found a consistent association between use of COCs and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (less than 6 months since last use) and current users with longer duration of COC use.[57612] [62904] Several large, well-designed observational studies have provided data regarding the risk of breast cancer with combined oral contraceptive (COC) use.[27233] [24750] [27234] Breast cancers diagnosed in current or previous COC users tend to be less advanced clinically than in never-users. The risk of breast cancer is only slightly increased in current and recent COC users (i.e., within 10 years); however, 10 years after COC cessation, the risk of breast cancer appears to be similar to that in those patients that have never used COCs.[62647] From one large study published in 2017, the risk of breast cancer was higher among women who currently or recently used contemporary hormonal contraceptives than among women who had never used hormonal contraceptives, and this risk increased with longer durations of use; however, absolute increases in risk were small. The absolute risk of breast cancer associated with any hormonal contraceptive use was 13 per 100,000 women-years, which corresponds to 1 extra case of breast cancer for every 7,690 COC users in 1 year.[62904] Moreover, the same study data suggest that any increased risk of breast cancer usually disappears rapidly after an interruption in the use of COCs.[62904] There continues to be controversy regarding the risk of COC use in women with a family history of breast cancer (e.g., BRCA mutations). However, evidence does not suggest that the increased risk for breast cancer among women with either a family history of breast cancer or breast cancer susceptibility genes is modified by the use of COCs.[48201] Patients should be instructed to perform monthly self-breast examination and report any breast changes, lumps, or discharge to their health care professional. If breast cancer is suspected in a woman who is taking hormonal contraceptives, the contraceptive should be discontinued.[57612] Some studies suggest that COC use has been associated with an increase in the risk of cervical cancer or intraepithelial neoplasia; however, such findings may be due to differences in sexual behavior, presence of the human papillomavirus (HPV) and other factors. HPV is thought to be the cause of more than 90% of all cervical cancers, although, hormonal factors may influence risk. The relative risk of invasive cervical cancer of 1.37 after 4 years of use; relative risk increased to 1.6 after 8 years of use. Because a potential for cervical dysplasia may exist, regularly evaluate patients taking COCs via cervical cytology screening as recommended per standards of care.[62647] A meta-analysis of 10 studies indicated significant trends for a reduced risk for endometrial and ovarian cancer with increased duration of COC use. Risk of endometrial or ovarian cancers may be reduced by up to 60% with 4 or more years of use.[25198] Data suggest COCs do not protect against hereditary forms of ovarian cancer (e.g., women who carry BRCA1 or BRCA2 gene alterations).[25199] Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (more than 8 years) COC users. However, these cancers are rare in the United States, and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than 1 per million users.[62647] [57612]

    Revision Date: 05/04/2022, 01:13:08 PM

    References

    17808 - Hsia J, Langer RD, Manson JE, et al. Conjugated equine estrogens and coronary heart disease. The Women's Health Initiative. Arch Intern Med. 2006;166:357-365.17825 - Cushman M, Kuller LH, Prentice R, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA. 2004;292:1573-1580.23505 - Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016-37.24750 - Collaborative Group of Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 1996;347:1713-27.25198 - Schlesselman J. Net effect of oral contraceptive use on the risk of cancer in women in the United States. Obstet Gynecol 1995;85:793-801.25199 - Modan B, Hartge P, Hirsh-Yechezkel G, et al. Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation. N Engl J Med 2001;345:235-40.25473 - 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;280:605-13.27233 - The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. Oral Contraceptive use and the risk of breast cancer. N Engl J Med 1986;315:405-411.27234 - Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. [Women's Contraceptive and Reproductive Experiences (Women's CARE) Study]. N Engl J Med 2002;346:2025-2032.27270 - 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;288:321-333.27273 - 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;291:2947-58.43360 - FEMHRT (norethindrone acetate/ethinyl estradiol) tablet package insert. Irvine CA: Allergan USA, Inc; 2017 Nov.44124 - Loestrin FE 1/20 and 1.5/30 (norethindrone acetate and ethinyl estradiol) package insert. Lake Wales PA: TEVA Pharmaceuticals; 2023 Jan.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;65:1-103.50638 - The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022 July. [Epub aheadof print]50744 - Desogen (desogestrel and ethinyl estradiol) package insert. Whitehouse Station, NJ: Merck Sharp and Dohme Corp; 2017 Aug.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;56:189-93.57603 - Morison WL. Solar urticaria due to progesterone compounds in oral contraceptives. Photodermatol Photoimmunol Photomed. 2003;19:155-657612 - Loestrin 1/20 and 1.5/30 21-day (norethindrone acetate and ethinyl estradiol) package insert. Lake Wales PA: TEVA Pharmaceuticals; 2023 Jan.57614 - Cappell MS. Colonic toxicity of administered drugs and chemicals. Am J Gastroenterol 2004;99:1175-90.62647 - International Agency for Research on Cancer (IARC) Working Group on the Evaluation of Carcinogenic Risk to Humans. COMBINED ESTROGEN–PROGESTOGEN CONTRACEPTIVES. In: Pharmaceuticals. Lyon, France: a publication of the International Agency for Research on Cancer (IARC);2012;100A:283-311. Available at: www.ncbi.nlm.nih.gov/books/NBK30433462904 - Morch LS, Skovlund CW, Hannaford PC, et al. Contemporary Hormonal Contraception and the Risk of Breast Cancer. N Engl J Med. 2017;377:2228-2239.

    Contraindications/Precautions

    Absolute contraindications are italicized.

    • atrial fibrillation
    • breast cancer
    • cerebrovascular disease
    • cervical cancer
    • coronary artery disease
    • coronary thrombosis
    • diabetes mellitus
    • endometrial cancer
    • hepatic disease
    • hepatocellular cancer
    • history of angioedema
    • migraine
    • myocardial infarction
    • new primary malignancy
    • ovarian cancer
    • pregnancy
    • protein C deficiency
    • protein S deficiency
    • retinal thrombosis
    • stroke
    • thromboembolic disease
    • thromboembolism
    • thrombophlebitis
    • tobacco smoking
    • uterine cancer
    • vaginal bleeding
    • vaginal cancer
    • valvular heart disease
    • acquired immunodeficiency syndrome (AIDS)
    • breast-feeding
    • cardiac disease
    • children
    • chloasma
    • contact lenses
    • corticosteroid therapy
    • dementia
    • depression
    • edema
    • endocarditis
    • endometrial hyperplasia
    • gallbladder disease
    • geriatric
    • headache
    • hepatitis
    • hereditary angioedema
    • human immunodeficiency virus (HIV) infection
    • hypercalcemia
    • hypercholesterolemia
    • hyperlipidemia
    • hypertension
    • hypertriglyceridemia
    • hypocalcemia
    • hypoparathyroidism
    • hypothyroidism
    • jaundice
    • obesity
    • obstetric delivery
    • porphyria
    • renal disease
    • sexually transmitted disease
    • surgery
    • systemic lupus erythematosus (SLE)
    • uterine leiomyomata
    • visual disturbance
    Use of norethindrone acetate; ethinyl estradiol, as with other contraceptive and hormone replacement steroids, may result in clinical changes that influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. Specific laboratory test interference has not been reported.[43360][57612]

    Norethindrone acetate; ethinyl estradiol combined hormonal oral contraceptive (COC) products do not protect against human immunodeficiency virus (HIV) infection or other sexually transmitted disease. Patients with known HIV infection or acquired immunodeficiency syndrome (AIDS) should be aware that COC use will not prevent the transmission of HIV or other diseases to their partner(s).[57612]

    Combined hormonal oral contraceptives (COCs) and estrogen-containing hormonal replacement therapy (HRT) products are contraindicated in patients with a current or past history of stroke, cerebrovascular disease, coronary artery disease, coronary thrombosis, myocardial infarction, thrombophlebitis, thromboembolism or thromboembolic disease, or valvular heart disease with complications. Hormonal COCs and estrogen-containing HRT have been associated with thromboembolism such as deep venous thrombosis (DVT) and pulmonary embolism (PE). COCs and estrogen-containing HRT are also generally contraindicated in women who have thrombogenic valvular or thrombogenic rhythm diseases of the heart (e.g., subacute bacterial endocarditis with valvular disease, or atrial fibrillation), or known inherited or acquired hypercoagulopathies (e.g., protein S deficiency, protein C deficiency, Factor V Leiden, prothrombin G20210A mutation, antithrombin deficiency, antiphospholipid antibodies).[43360] [57612] [48201] COMBINED ORAL HORMONAL CONTRACEPTIVES: COCs have been associated with thromboembolism such as deep venous thrombosis (DVT). Should a thromboembolic event occur or be suspected, the COC should be discontinued immediately.[57612] Because tobacco smoking increases the risk of thromboembolism, DVT, myocardial infarction, stroke and other thromboembolic disease, patients receiving COCs are strongly advised not to smoke. Risk is especially high for female smokers more than 35 years of age or those who smoke 15 or more cigarettes per day. Therefore, COCs are generally considered contraindicated in women over the age of 35 years who are tobacco smokers. A positive relationship between estrogen dosage and thromboembolic disease has been demonstrated, and oral products containing 50-mcg ethinyl estradiol should not be used unless medically indicated. In addition, certain progestins may increase thromboembolic risk. The overall risk of venous thromboembolism in women using COCs has been estimated to be 3 to 9 per 10,000 woman-years. Preliminary data from a large, prospective cohort safety study suggests that the risk is greatest during the first 6 months after initially starting COC therapy or restarting (following a break from therapy 4 weeks or more) with the same or different combination product. The risk of arterial thromboses, such as stroke and myocardial infarction, is especially increased in women with other risk factors for these events. Pre-existing high blood pressure, kidney disease, hypercholesterolemia, diabetes with vascular disease, and patients who are morbidly obese may also increase risk. After a COC is discontinued, the risk of thromboembolic disease due to COCs gradually disappears. Because of their association with elevations in blood pressure, COCs should be used cautiously in patients with mild to moderate hypertension or kidney disease; use is contraindicated in patients with uncontrolled or severe hypertension or hypertension with vascular disease. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin. Blood pressure should be monitored closely in individuals with high blood pressure; discontinue the COC if blood pressure rises significantly. COCs may also cause fluid retention, and patients predisposed to complications from edema, such as those with cardiac disease or renal disease, should be closely monitored.[57612] [48201] HORMONE REPLACEMENT THERAPY (HRT): An increased risk of thromboembolism, such as pulmonary embolism (PE), DVT, as well as cardiovascular events, such as stroke and myocardial infarction (MI) has been reported with estrogen plus progestin hormone replacement therapy (HRT) in postmenopausal women. Should any of these events occur or be suspected, discontinue HRT immediately.[43360] Estrogens with or without progestins should not be used for the prevention of cardiac disease or cardiovascular disease (e.g., coronary artery disease). Patients with certain risk factors for arterial vascular disease (e.g., hypertension, diabetes, tobacco smoking, hypercholesterolemia, and morbidly obese) and/or venous thromboembolism (VTE) [e.g., personal history or family history of VTE, obese or systemic lupus (SLE)] should be monitored and managed appropriately during HRT use.[43360] 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]  In the Women's Health Initiative (WHI) estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as non-fatal MI, silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo. Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE-alone vs. placebo) in women with less than 10 years since menopause (8 vs. 16 per 10,000 women-years). In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily estrogen plus progestin compared to women receiving placebo (41 vs. 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5.[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 older than 65 years of age were at increased risk for non-fatal stroke.[38488] [27272] Patients with hypertension should be monitored closely for increases in blood pressure if HRT is administered. In a few case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogen HRT therapy. In a large, randomized, placebo controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. Estrogen-based HRT 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.[43360]

    Surgery can increase the risk for thromboembolism from combined hormonal contraceptives(COCs) and estrogen-based hormone replacement therapy (HRT). If feasible, discontinue norethindrone acetate; ethinyl estradiol products at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism, and during and following any prolonged immobilization. The decision on when to resume COCs or HRT after such procedures or conditions would be based on the perceived additional thromboembolic risk; resume only after the patient is fully ambulatory. In addition, advise treated patients to move about periodically during travel involving prolonged immobilization.[57612] [43360]

    Because of the increased potential for embolic risk, combined oral contraceptives (COCs) containing ethinyl estradiol; norethindrone acetate are contraindicated in women who currently have diabetes mellitus and are over 35 years of age, diabetes mellitus with hypertension or with vascular disease or end-organ damage, or diabetes mellitus of greater than 20 years duration.[43360] Patients with diabetes mellitus should be observed for changes in glucose tolerance when initiating or discontinuing estrogen therapy with COC or as hormone replacement therapy (HRT), since estrogen therapy may exacerbate diabetes. Altered glucose tolerance secondary to decreased insulin sensitivity has been reported.[43360] [57612]

    Women who are being treated for dyslipidemia should be followed closely if they elect to use combined hormonal oral contraceptives (COCs) or hormone replacement therapy (HRT). Some progestogens may elevate LDL levels and may render the control of hyperlipidemia more difficult. Females with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs. Consider discontinuation of treatment if pancreatitis occurs.[43360] [57612]

    Ethinyl estradiol; norethindrone acetate combined hormonal oral contraceptive (COC) products are contraindicated in patients with migraine or other headache that is accompanied by focal neurological symptoms, such as aura, or women over age 35 with any migraine headaches. COCs 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 medically evaluated, and in some patients, such changes may indicate cerebrovascular events.[57612] Similarly to COC products, estrogen-based hormone replacement therapy (HRT) may cause an exacerbation of migraine, and should be used with caution in women with these conditions.[43360]

    Do not use norethindrone acetate; ethinyl estradiol products in patients with a known hypersensitivity to any of the specific product ingredients; ethinyl estradiol is contraindicated in patients with known anaphylactic reactions or history of angioedema to the drug. Cases of both anaphylactic reactions and angioedema have been reported in patients taking estrogens. 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.[57612] [43360]

    Given the increased prevalence of hypercoagulable states in patients with systemic lupus erythematosus (SLE) (in particular antiphospholipid antibodies and lupus anticoagulant) and the risk factors for thromboembolism, consider risks vs. benefit of COC or estrogen-based HRT use in these patients. Avoid COC or estrogen-based HRT use in SLE patients with a history of venous or arterial thrombosis or the presence of a hypercoagulable state. If COCs are initiated in SLE patients without hypercoagulable states, choose a low-dose estrogen contraceptive (e.g., ethinyl estradiol 35 mcg per day or less); consider use of a progestin-only contraceptive. Combined hormonal oral contraceptive (COC) or estrogen-based hormone replacement therapy (HRT) use has also been reported to induce, unmask, or exacerbate SLE; more data are needed.[31435] [48201] [43360]

    Discontinue norethindrone acetate; ethinyl estradiol products if pregnancy is detected; there is no reason to continue combined oral hormonal contraceptives (COCs) during pregnancy. Estrogen-based hormone replacement therapy (HRT) should not be used during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to COCs before conception or during early pregnancy. For any patient who has missed two consecutive periods, pregnancy should be ruled out. If the patient has not adhered to the prescribed COC schedule, consider the possibility of pregnancy at the first missed period. Discontinue COC use if pregnancy is confirmed.[43360] [57612]

    Estrogen-based hormone replacement therapy (HRT) should not be used during lactation.[43360] Manufacturers recommend avoidance of combined hormonal oral contraceptives (COCs) if possible until a mother has completely weaned her child.[57612] Small amounts of oral contraceptive steroids (estrogens and progestins) have been identified in the milk of nursing mothers and a few reports of effects on the infant exist, including jaundice and breast enlargement. Experts often recommend avoidance of estrogen-containing hormonal contraceptives, in the first 21 days postpartum due to maternal post-partum risks for thromboembolism following obstetric delivery, and the potential for COCs to interfere with the establishment of lactation. It is generally accepted that estrogen-containing combined hormonal contraceptives may be used after this period in healthy women without other risk factors; general monitoring of the infant for effects such as appetite changes, breast changes and proper weight gain and growth should occur.[48201] Estrogens, including ethinyl estradiol (EE), have been reported to interfere with milk production and duration of lactation in some women, particularly at doses of 30 mcg per day or more.[48204] One study found that lower dose oral combined contraceptives (e.g., 10 mcg per day EE) may not affect lactation.[48200] However, a systematic review concluded that the available evidence, even from randomized controlled trials, is limited and of poor quality; proper trials are needed.[48202] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. Alternate contraceptive agents for consideration for use during breast-feeding include non-hormonal contraceptive methods and also progestin-only contraceptives (e.g., medroxyprogesterone injection).[48201]

    LIVER/GI SYSTEM ISSUES with COMBINED HORMONAL ORAL CONTRACEPTIVES: Combined oral contraceptives (COCs) are contraindicated in patients with hepatic disease. Because of the association with cholestasis and hepatic neoplasms, estrogens are contraindicated in the presence of hepatocellular cancer, hepatic adenoma, other liver tumors (benign or malignant), or markedly impaired liver function (e.g., uncompensated cirrhosis). Do not use COCs in patients with a history of cholestatic jaundice/pruritus of pregnancy or jaundice from prior hormonal contraceptives; these conditions can recur with subsequent COC use. Discontinue use of the COC if jaundice develops during combined oral contraceptive use. Steroid hormones may be poorly metabolized in patients with liver impairment. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded. Patients with hepatitis C who are being treated with ombitasvir/paritaprevir/ritonavir, with or without dasabuvir are also contraindicated to receive COCs. During clinical trials with the hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications. Discontinue COCs before starting hepatitis C therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir; a COC can be restarted approximately 2 weeks following completion of treatment with the hepatitis C combination drug regimen. Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long term (more than 8 years) COC users. However, the attributable risk of liver cancers in COC users is less than 1 case per million users. Use COCs with caution in patients with pre-existing gallbladder disease; however, recent studies have shown that the relative risk of developing gallbladder disease among COC users appears minimal due to the use of products that contain lower doses of hormones.[57612] [48201] LIVER/GI SYSTEM ISSUES with ESTROGEN-BASED HRT POSTMENOPAUSE: Ethinyl estradiol; norethindrone acetate HRT products are contraindicated in the presence of hepatocellular cancer, hepatic adenoma, or in severe hepatic disease of any type. Estrogens and progestins 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] [43360]

    Mood disorders, like depression, may be aggravated in women taking combined oral hormonal contraceptives (COCs). Data regarding the association of COCs with onset of depression or exacerbation of existing depression are limited. If significant depression occurs, norethindrone acetate; ethinyl estradiol products should be discontinued.[57612] Mood disorders, like depression, may be aggravated in women taking estrogen-based hormone replacement therapy (HRT); if significant depression occurs, the HRT should be discontinued.[43360]

    Norethindrone acetate; ethinyl estradiol products, including combined hormonal oral contraceptives (COCs) and hormone replacement therapy (HRT), are contraindicated in patients with a history of, or known or suspected breast cancer, as breast cancer is a hormonally-sensitive tumor. COMBINED HORMONAL CONTRACEPTION: Epidemiology studies have not found a consistent association between use of COCs and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (less than 6 months since last use) and current users with longer duration of COC use. Several large, well-designed observational studies have provided data regarding the risk of breast cancer with combined oral contraceptive (COC) use.[27233] [24750] [62647] From one large study published in 2017, the risk of breast cancer was higher among women who currently or recently used contemporary hormonal contraceptives than among women who had never used hormonal contraceptives, and this risk increased with longer durations of use; however, absolute increases in risk were small. The absolute risk of breast cancer associated with any hormonal contraceptive use was 13 per 100,000 women-years, which corresponds to 1 extra case of breast cancer for every 7,690 COC users in 1 year.[62904] Moreover, the same study data suggest that any increased risk of breast cancer usually disappears rapidly after an interruption in the use of COCs.[62904] There continues to be controversy regarding the risk of COC use in women with a family history of breast cancer (e.g., BRCA mutations). However, evidence does not suggest that the increased risk for breast cancer among women with either a family history of breast cancer or breast cancer susceptibility genes is modified by the use of COCs.[48201] All women taking COCs should receive clinical breast examinations and perform monthly self-examinations as recommended by their health care professional based on patient age, known risk factors, and current standards of care. If breast cancer is suspected in a woman who is taking hormonal contraceptives, the contraceptive should be discontinued.[48201] ESTROGEN-BASED HORMONE REPLACEMENT THERAPY (HRT): Studies suggest that the use of estrogen-progestin HRT in postmenopausal women increases the risk for invasive breast cancer (new primary malignancy). The use of estrogen-alone and estrogen plus progestin HRT has been reported to result in an increase in abnormal mammograms, requiring further evaluation. All women taking estrogen with or without a progestin as HRT 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.[43360] Since the 1970s, numerous epidemiological studies have examined the association of estrogens or combined HRT and breast cancer.[23505] The most important randomized clinical trial providing information about breast cancer in patients taking combined estrogen-progestin HRT regimens is the WHI substudy of estogen-progestin therapy.[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 estogen-progestin vs. placebo. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for estrogen/progestin compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years for estrogen/progestin compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years for estrogen/progestin compared with placebo. In the same WHI substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the combined HRT group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the 2 groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the 2 groups.[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. While estrogen therapy may be used rarely for the palliative treatment of advanced breast cancer in men and women, estrogen HRT use may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of HRT should be stopped and appropriate measures taken to reduce the serum calcium level.[43360]

    Estrogen-based hormone regimens are contraindicated in the presence of cervical cancer or other estrogen-responsive tumors.[57612] [43360] COMBINED HORMONAL ORAL CONTRACEPTIVES (COCs): Most cervical cancers are related to the presence of the human papillomavirus (HPV), but hormonal factors influence risk. In women taking COCs, studies have found an increased risk of cervical cancer compared with never-users. The risk appears to increase with duration of use and appears to decline when COCs are discontinued. Clinical surveillance of all women using COCs is important; all women receiving COC treatment should have a 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.[48201] [57612] ESTROGEN-BASED HORMONE REPLACEMENT THERAPY: An increased risk for cervical dysplasia or cancer has NOT been noted with the use of estrogen-progestin hormone replacement therapy (HRT) postmenopause.[50638] Because estrogens influence the growth of endometrial tissues, use estradiol or other 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, consider the addition of a progestin to estrogen therapy, such as the use of estradiol; norethindrone products, to reduce the risk of endometrial tissue growth. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin HRT is important; all women receiving estrogen treatment should have a 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.[43360]

    Norethindrone acetate; ethinyl estradiol combined oral contraceptive (COC) and hormonal replacement therapy (HRT) products are contraindicated in women with estrogen-dependent neoplasms, including ovarian cancer. ORAL CONTRACEPTIVES: Many studies have documented a protective effect of COCs against ovarian cancer, with the protective effects increasing with duration of use; the protective effects appear to persist for 15 years or more after stopping COC use.[25198] [48201] [57612] [62647] HORMONE REPLACEMENT THERAPY (HRT): The use of HRT increases ovarian cancer risk in peri- and postmenopausal women. What is known about the risk of ovarian cancer due to HRT is derived from data available for estrogen-alone and estrogen plus progestin products. The Women's Health Initiative (WHI) estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for estrogen plus progestin versus placebo was 1.58 (95% CI 0.77 to 3.24). The absolute risk for estrogen plus progestin versus placebo was 4 versus 3 cases per 10,000 women-years.[17829] A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risk associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.5); there was no difference in the risk estimates by duration of the exposure (less than 5 years [median of 3 years] vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI 1.27 to 1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.[43360]

    Combined oral contraceptives (COCs) and hormone replacement therapy (HRT) are contraindicated in the presence of vaginal cancer, cervical cancer, uterine cancer, or other estrogen-responsive tumors. Clinical surveillance of all women using COCs or HRT is important; all women receiving COC or HRT treatment should have a 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.[43360] [48201][57612] Because estrogens influence the growth of endometrial tissues, use estradiol or other estrogens for HRT 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 HRT therapy. For women known to have residual endometriosis post-hysterectomy, consider the addition of a progestin to estrogen HRT, such as the use of norethindrone acetate; ethinyl estradiol products, to reduce the risk of endometrial tissue growth.[43360]

    Norethindrone acetate; ethinyl estradiol products are contraindicated in patients with known estrogen-dependent malignancies, such as endometrial cancer.[43360] [57612] HORMONE REPLACEMENT THERAPY (HRT): There is an association of unopposed estrogen therapy and endometrial cancer in women with an intact uterus. Adding a progestin to estrogen therapy has been shown to reduce, but not eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. 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, such as choosing a combination HRT product, the incidence of endometrial hyperplasia due to estrogen therapy is estimated to be 1% or less.[43360] [23505] [27272] HORMONAL CONTRACEPTIVES: Hormonal contraceptives are contraindicated in women with undiagnosed vaginal bleeding; evaluate such patients before use and determine if a contraindication exists.[48201] [57612] Unlike HRT, the use of combined oral contraceptives (COCs) appears to have a protective effect on the endometrium. In women using COCs, a meta-analysis of 10 studies indicates a significant trend in decreasing endometrial carcinoma risk with increasing duration of COC use. The beneficial effects of COCs in this regard may persist for 15 years or more after COC use ceases.[25198] [48201] [62647]

    The estrogen component of combined oral hormonal contraceptives or HRT may raise the serum concentrations of thyroid-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. Doses of thyroid hormone replacement for hypothyroidism may need to be increased, as indicated by clinical and laboratory monitoring for the individual. Cortisol replacement therapy (e.g., corticosteroid therapy) may also need adjusted for some patients.[43360] [57612]

    Chloasma may occur with combined oral hormonal contraceptive (COC) use, especially in women with a history of chloasma gravidarum (melasma). Advise females who tend to develop chloasma to avoid exposure to the sun or ultraviolet (UV) exposure while taking norethindrone acetate; ethinyl estradiol for birth control.[57612]

    Preexisting morbid obesity is one factor that may increase cardiovascular or thromboembolic risks associated with combination hormonal contraceptive use. Consider the presence of obesity and other underlying risk factors that may increase the risk of cardiovascular disease or thromboembolism, particularly for women over 35 years of age.[57612] Obesity may also increase thromboembolic risks due to HRT in postmenopausal women.[43360] Limited literature suggests that the effectiveness of some hormonal contraceptive formulations might decrease with increasing body mass index (BMI). However, the evidence is conflicting; there are also data to suggest that the efficacy of most combined hormonal contraceptive products (with a few known exceptions) does not seem to be compromised in women who are overweight.[48201] [66895]

    Estrogen replacement therapy, such as the use of norethindrone acetate; ethinyl estradiol as HRT for menopause or osteoporosis, should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.[43360]

    The safety and efficacy of norethindrone acetate; ethinyl estradiol hormone replacement therapy (HRT) have not been established in pediatric patients.[43360] The safety and efficacy of hormonal contraceptive products have only been established in females of reproductive age. Safety and efficacy of hormonal birth control is expected to be the same for postpubertal children under the age of 16 and for users 16 years of age and older. Use of hormonal contraceptive products in female children before menarche is not indicated.[57612]

    Hormone replacement therapy (HRT) with norethindrone acetate; ethinyl estradiol should not be used for the prevention of dementia. 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.[43360] 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, 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]

    Revision Date: 05/04/2022, 12:57:28 PM

    References

    17808 - Hsia J, Langer RD, Manson JE, et al. Conjugated equine estrogens and coronary heart disease. The Women's Health Initiative. Arch Intern Med. 2006;166:357-365.17825 - Cushman M, Kuller LH, Prentice R, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA. 2004;292:1573-1580.17829 - Anderson GL, Judd HL, Kaunitz AM, et al. Women's Health Initiative Investigators. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial. JAMA 2003;290:1739-1748.23505 - Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016-37.24750 - Collaborative Group of Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 1996;347:1713-27.25198 - Schlesselman J. Net effect of oral contraceptive use on the risk of cancer in women in the United States. Obstet Gynecol 1995;85:793-801.25473 - 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;280:605-13.27233 - The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. Oral Contraceptive use and the risk of breast cancer. N Engl J Med 1986;315:405-411.27270 - 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;289:3243-53.31435 - Askanase AD. Estrogen therapy in systemic lupus erythematosus. Treat Endocrinol 2004;3:19-26.32126 - 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;297:1465-1477.43360 - FEMHRT (norethindrone acetate/ethinyl estradiol) tablet package insert. Irvine CA: Allergan USA, Inc; 2017 Nov.48200 - Toddywalla VS , Joshi L, Virkar K. Effect of contraceptive steroids on human lactation. Am J Obstet Gynecol. 1977;127:245-249.48201 - 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;65:1-103.48202 - Truitt ST, Fraser AB, Grimes DA, et al. Hormonal contraception during lactation. . Systematic review of randomized controlled trials. Contraception. 2003;68:233-238.48204 - Tankeyoon M, Dusitsin N, Chalapati S, et al. Effects of hormonal contraceptives on milk volume and infant growth. WHO Special Programme of Research, Development and Research Training in Human Reproduction, Task Force on Oral Contraceptives. Contraception. 1984;30:505–522.50638 - The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022 July. [Epub aheadof print]57612 - Loestrin 1/20 and 1.5/30 21-day (norethindrone acetate and ethinyl estradiol) package insert. Lake Wales PA: TEVA Pharmaceuticals; 2023 Jan.62647 - International Agency for Research on Cancer (IARC) Working Group on the Evaluation of Carcinogenic Risk to Humans. COMBINED ESTROGEN–PROGESTOGEN CONTRACEPTIVES. In: Pharmaceuticals. Lyon, France: a publication of the International Agency for Research on Cancer (IARC);2012;100A:283-311. Available at: www.ncbi.nlm.nih.gov/books/NBK30433462904 - Morch LS, Skovlund CW, Hannaford PC, et al. Contemporary Hormonal Contraception and the Risk of Breast Cancer. N Engl J Med. 2017;377:2228-2239.63923 - 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;00:1-21.66895 - Simmons KB, Edelman AB. Hormonal contraception and obesity. Fertil Steril. 2016;106:1282-1288. Epub 2016 Aug 23.

    Mechanism of Action

    The net effects of the combination of ethinyl estradiol; norethindrone acetate combinations are dependent on the age and hormonal status of the female patient (i.e., pre- or post-menopausal) and the dosage of the combination administered.

    • Oral contraceptive activity: The primary action of the combination of an estrogen with a progestin is to suppress the hypothalamic-pituitary system, decreasing the secretion of gonadotropin-releasing hormone (GnRH). Progestins blunt luteinizing hormone (LH) release, and estrogens suppress follicle-stimulating hormone (FSH) from the anterior pituitary. Both estrogen and progestin ultimately inhibit maturation and release of the dominant ovule. In addition, viscosity of the cervical mucus increases with hormonal contraceptive use, which increases the difficulty of sperm entry into the uterus. Alteration in endometrial tissues also occurs, which reduces the likelihood of implantation of the fertilized ovum. The contraceptive effect is reversible.[44124] When traditional regimens of oral contraception are discontinued, ovulation usually returns within three menstrual cycles but can take up to 6 months in some women. Pituitary function and ovarian functions recover more quickly than endometrial activity, which can take up to 3 months to regain normal histology. Both estrogens and progestins are responsible for a number of other metabolic changes. The summary of these changes is dependent on the net actions of the estrogen and progestin combinations. Such total effects may only be clinically significant for some predisposed individuals. At the cellular level, estrogens and progestins diffuse into their target cells and interact with a protein receptor. Metabolic responses to estrogens and progestins require an interaction between DNA and the hormone-receptor complex. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins. Estrogens generally have a favorable effect on blood lipids, and lack of estrogen is now recognized as a risk factor for myocardial infarction. Estrogens reduce LDL and increase HDL cholesterol concentrations. Serum triglycerides increase with estrogen administration. Folate metabolism and excretion is increased by estrogens and may lead to slight serum folate deficiency. Estrogens also enhance sodium and fluid retention. Progestins are classified according to their progestational, estrogenic and androgenic properties. Progestins can alter hepatic carbohydrate metabolism, increase insulin resistance, and have either little to slightly favorable effects on serum lipoproteins. Less androgenic progestins have only slight effects on carbohydrate metabolism. More androgenic progestins can aggravate acne. Serious adverse events, like thrombosis, have long been associated with the estrogen component of oral contraceptives but may be the result of both estrogen and progestin components. The mechanism for thrombosis may be associated with increased clotting factor production and/or decreases in anti-thrombin III. Minor side effects can be addressed by choosing formulations that take advantage of relative estrogen, progestin, and androgenic potencies.[60767]
    • Hormone replacement activity: In post-menopausal women, ethinyl estradiol is administered in dosages to 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. Estrogens appear to prevent osteoporosis associated with menopause as opposed to reversing disease that has already developed. Estrogens generally have a favorable effect on blood lipids, particularly on LDL-cholesterol, and cardiovascular health after 5 years of use. Estrogens also enhance sodium and fluid retention. Progestins, when added to postmenopausal estrogen therapies, attenuate some of the positive effects of estrogens on HDL-cholesterol, but usually the LDL-cholesterol benefits are retained. Norethindrone acetate converts a proliferative endometrium into a secretory one in women with adequate estrogen replacement, reducing endometrial growth and the risk of endometrial carcinoma versus women with an intact uterus who take estrogens unopposed. The mode of action against endometrial cancer has not been determined, but may be related to decreasing nuclear estradiol receptors and suppression of epithelial DNA synthesis in endometrial tissues. Amenorrhea occurs in most menopausal women within several months of combined oral estrogen-norethindrone acetate use.[43360]
    Revision Date: 11/17/2017, 04:48:22 PM

    References

    43360 - FEMHRT (norethindrone acetate/ethinyl estradiol) tablet package insert. Irvine CA: Allergan USA, Inc; 2017 Nov.44124 - Loestrin FE 1/20 and 1.5/30 (norethindrone acetate and ethinyl estradiol) package insert. Lake Wales PA: TEVA Pharmaceuticals; 2023 Jan.60767 - Brunton LB, Lazo JS, Parker KL, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th ed. New York: McGraw-Hill; 2006.

    Pharmacokinetics

    Ethinyl estradiol; norethindrone acetate is administered orally.

    • Ethinyl estradiol: Ethinyl estradiol is widely distributed. Ethinyl estradiol is highly but non-specifically protein-bound to albumin. Ethinyl estradiol induces an increase in the serum concentrations of both sex hormone-binding globulin (SHBG) and corticosteroid binding globulin (CBG). Ethinyl estradiol is primarily metabolized in the liver via CYP3A4 to 2-hydroxy-ethinylestradiol. Both ethinyl estradiol and its hydroxylated and methylated metabolites undergo glucuronide and sulfate conjugation. Estrogen conjugates can be hydrolyzed back to the active drug in the GI tract and then undergo entero-hepatic recycling. Excretion of estrogen-progestin steroids as inactive metabolites occurs via the urine and feces. Elimination half-life is approximately 26 hours for ethinyl estradiol at steady state. It is the prolonged biologic effects of the hormone that allows for once-daily administration.
    • Norethindrone acetate: Norethindrone acetate is a prodrug that requires conversion to norethindrone via hydrolysis to become the active drug, norethindrone.[54845] Norethindrone is widely distributed. Norethindrone is strongly protein-bound, primarily to albumin and sex hormone-binding globulin (SHBG). Approximately 10% of norethindrone is metabolized by oxidative reduction, and the remainder via conjugation to the sulfate and glucuronate salts. No appreciable entero-hepatic recycling occurs. Interestingly, norethindrone is aromatized to a slight degree in tissues of the liver and ovary to ethinyl estradiol. This may be of clinical significance. Excretion of estrogen-progestin steroids as inactive metabolites occurs via the urine and feces. Elimination half-life is approximately 5 to 14 hours for norethindrone at steady state. It is the prolonged biologic effects of the hormone that allows for once-daily administration.

     

    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A4, CYP2B6, CYP2C19, CYP2C9, P-glycoprotein (P-gp)

    • Ethinyl Estradiol: In vitro and in vivo studies indicate that estrogens are partially metabolized by CYP3A4. Interactions with drugs that are inhibitors or inducers of CYP3A4 are possible.[47343][57085] Ethinyl estradiol is a substrate of the drug transporter P-gp.[60859] While ethinyl estradiol is an in vitro inhibitor of CYP2B6, 2C19, and 3A4 and an in vitro substrate of 2C9, clinically significant drug interactions are not expected through these pathways.

    Route-Specific Pharmacokinetics

    Oral Route

    • ethinyl estradiol: Ethinyl estradiol is absorbed with maximum plasma concentrations generally occurring 1—2 hours post dose. The maximum concentration of ethinyl estradiol is decreased by 47% when administered with food; however, the extent of absorption is not affected. Following oral administration in the third cycle of use as an oral contraceptive, 83% of ethinyl estradiol survives absorption and first pass through the liver. Estrogens are metabolized in the GI mucosa during absorption and in the liver. The major 1st-pass metabolite of ethinyl estradiol is its sulfate conjugate.
    • norethindrone acetate: Norethindrone acetate is absorbed with maximum plasma concentrations generally occurring 1—2 hours post dose. The maximum concentration of norethindrone is decreased by 53% when administered with food; however, the extent of absorption is not affected. Following oral administration in the third cycle of use as an oral contraceptive, 47—73% of norethindrone acetate survives absorption and first pass through the liver. Norethindrone acetate is completely and rapidly deacetylated to its active form, norethindrone, after oral administration.[43360]

    Special Populations

    Hepatic Impairment

    Ethinyl estradiol; norethindrone acetate combinations have not been studied in patients with hepatic impairment. However, steroid hormones may be poorly metabolized in patients with impaired liver function. These products are contraindicated in patients with known liver disease or dysfunction.[57612][43360]

    Renal Impairment

    The pharmacokinetics of these products have not been studied in subjects with renal impairment.[57612][43360] In premenopausal women with chronic renal failure undergoing peritoneal dialysis who received multiple doses of an oral contraceptive containing ethinyl estradiol and norethindrone, plasma ethinyl estradiol concentrations were higher and norethindrone concentrations were unchanged compared to concentrations in premenopausal women with normal renal function.[57612]

    Revision Date: 07/13/2017, 03:25:37 PM

    References

    43360 - FEMHRT (norethindrone acetate/ethinyl estradiol) tablet package insert. Irvine CA: Allergan USA, Inc; 2017 Nov.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;37:1667-75.54845 - Stanczyk FZ, Roy S. Metabolism of levonorgestrel, norethindrone, andstructurally related contraceptive steroids. Contraception. 1990;42:67-96. Review.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;46:133-57.57612 - Loestrin 1/20 and 1.5/30 21-day (norethindrone acetate and ethinyl estradiol) package insert. Lake Wales PA: TEVA Pharmaceuticals; 2023 Jan.60859 - Kim WY, Benet LZ. P-glycoprotein (P-gp/MDR1)-Mediated Efflux of Sex-Steroid Hormones and Modulation of P-gp Expression In Vitro. Pharmaceutical Research 2004;21:1284.

    Pregnancy/Breast-feeding

    pregnancy

    Discontinue norethindrone acetate; ethinyl estradiol products if pregnancy is detected; there is no reason to continue combined oral hormonal contraceptives (COCs) during pregnancy. Estrogen-based hormone replacement therapy (HRT) should not be used during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to COCs before conception or during early pregnancy. For any patient who has missed two consecutive periods, pregnancy should be ruled out. If the patient has not adhered to the prescribed COC schedule, consider the possibility of pregnancy at the first missed period. Discontinue COC use if pregnancy is confirmed.[43360] [57612]

    breast-feeding, obstetric delivery

    Estrogen-based hormone replacement therapy (HRT) should not be used during lactation.[43360] Manufacturers recommend avoidance of combined hormonal oral contraceptives (COCs) if possible until a mother has completely weaned her child.[57612] Small amounts of oral contraceptive steroids (estrogens and progestins) have been identified in the milk of nursing mothers and a few reports of effects on the infant exist, including jaundice and breast enlargement. Experts often recommend avoidance of estrogen-containing hormonal contraceptives, in the first 21 days postpartum due to maternal post-partum risks for thromboembolism following obstetric delivery, and the potential for COCs to interfere with the establishment of lactation. It is generally accepted that estrogen-containing combined hormonal contraceptives may be used after this period in healthy women without other risk factors; general monitoring of the infant for effects such as appetite changes, breast changes and proper weight gain and growth should occur.[48201] Estrogens, including ethinyl estradiol (EE), have been reported to interfere with milk production and duration of lactation in some women, particularly at doses of 30 mcg per day or more.[48204] One study found that lower dose oral combined contraceptives (e.g., 10 mcg per day EE) may not affect lactation.[48200] However, a systematic review concluded that the available evidence, even from randomized controlled trials, is limited and of poor quality; proper trials are needed.[48202] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. Alternate contraceptive agents for consideration for use during breast-feeding include non-hormonal contraceptive methods and also progestin-only contraceptives (e.g., medroxyprogesterone injection).[48201]

    Revision Date: 09/20/2021, 06:04:17 PM

    References

    43360 - FEMHRT (norethindrone acetate/ethinyl estradiol) tablet package insert. Irvine CA: Allergan USA, Inc; 2017 Nov.48200 - Toddywalla VS , Joshi L, Virkar K. Effect of contraceptive steroids on human lactation. Am J Obstet Gynecol. 1977;127:245-249.48201 - 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;65:1-103.48202 - Truitt ST, Fraser AB, Grimes DA, et al. Hormonal contraception during lactation. . Systematic review of randomized controlled trials. Contraception. 2003;68:233-238.48204 - Tankeyoon M, Dusitsin N, Chalapati S, et al. Effects of hormonal contraceptives on milk volume and infant growth. WHO Special Programme of Research, Development and Research Training in Human Reproduction, Task Force on Oral Contraceptives. Contraception. 1984;30:505–522.57612 - Loestrin 1/20 and 1.5/30 21-day (norethindrone acetate and ethinyl estradiol) package insert. Lake Wales PA: TEVA Pharmaceuticals; 2023 Jan.

    Interactions

    Level 1 (Severe)

    • Anastrozole
    • Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir
    • Letrozole
    • Ombitasvir; Paritaprevir; Ritonavir
    • Ribociclib; Letrozole
    • Testolactone
    • Tranexamic Acid

    Level 2 (Major)

    • Acitretin
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    • Apalutamide
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    • Armodafinil
    • Artemether; Lumefantrine
    • Aspirin, ASA; Butalbital; Caffeine
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    • Atazanavir
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    • Calaspargase pegol
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    • Elagolix
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    • Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide
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    Level 3 (Moderate)

    • Acetaminophen
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    • Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine
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    • Acetaminophen; Dextromethorphan; Phenylephrine
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    • Triamcinolone
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    • Tucatinib
    • Valproic Acid, Divalproex Sodium
    • Vancomycin
    • Vincristine
    • Vincristine Liposomal
    • Vonoprazan; Amoxicillin
    • Vonoprazan; Amoxicillin; Clarithromycin
    • Vorapaxar
    • Voriconazole

    Level 4 (Minor)

    • Acarbose
    • Acetohexamide
    • Aliskiren; Amlodipine
    • Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ
    • Alogliptin
    • Alogliptin; Metformin
    • Alogliptin; Pioglitazone
    • Alpha-glucosidase Inhibitors
    • Alprazolam
    • Amlodipine
    • Amlodipine; Atorvastatin
    • Amlodipine; Benazepril
    • Amlodipine; Celecoxib
    • Amlodipine; Olmesartan
    • Amlodipine; Valsartan
    • Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ
    • Ascorbic Acid, Vitamin C
    • Aspirin, ASA; Caffeine
    • Aspirin, ASA; Caffeine; Orphenadrine
    • Atorvastatin
    • Atorvastatin; Ezetimibe
    • Bromocriptine
    • Cabozantinib
    • Caffeine
    • Caffeine; Sodium Benzoate
    • Calcium
    • Calcium-channel blockers
    • Canagliflozin
    • Canagliflozin; Metformin
    • Chenodiol
    • Chlordiazepoxide
    • Chlordiazepoxide; Amitriptyline
    • Chlordiazepoxide; Clidinium
    • Chlorpropamide
    • Clevidipine
    • Clonazepam
    • Clorazepate
    • Cosyntropin
    • Dapagliflozin
    • Dapagliflozin; Metformin
    • Dapagliflozin; Saxagliptin
    • Daratumumab; Hyaluronidase
    • Delavirdine
    • Diazepam
    • Diltiazem
    • Dipeptidyl Peptidase-4 Inhibitors
    • Doxazosin
    • Empagliflozin
    • Empagliflozin; Linagliptin
    • Empagliflozin; Linagliptin; Metformin
    • Empagliflozin; Metformin
    • Enalapril; Felodipine
    • Ergotamine; Caffeine
    • Ertugliflozin
    • Ertugliflozin; Metformin
    • Ertugliflozin; Sitagliptin
    • Estazolam
    • Felodipine
    • Fluconazole
    • Flurazepam
    • Frovatriptan
    • Glimepiride
    • Glimepiride; Rosiglitazone
    • Glipizide
    • Glipizide; Metformin
    • Glyburide
    • Glyburide; Metformin
    • grapefruit juice
    • Green Tea
    • Hyaluronidase
    • Hyaluronidase, Recombinant; Immune Globulin
    • Hydralazine
    • Hydralazine; Hydrochlorothiazide, HCTZ
    • Hydralazine; Isosorbide Dinitrate, ISDN
    • Insulins
    • Isradipine
    • Levamlodipine
    • Levothyroxine
    • Levothyroxine; Liothyronine (Porcine)
    • Levothyroxine; Liothyronine (Synthetic)
    • Linagliptin
    • Linagliptin; Metformin
    • Liothyronine
    • Lorazepam
    • Mecamylamine
    • Meglitinides
    • Metformin
    • Metformin; Repaglinide
    • Metformin; Rosiglitazone
    • Metformin; Saxagliptin
    • Metformin; Sitagliptin
    • Miconazole
    • Miconazole; Petrolatum; Zinc Oxide
    • Midazolam
    • Miglitol
    • Mineral Oil
    • Minoxidil
    • Naratriptan
    • Nicardipine
    • Nifedipine
    • Nimodipine
    • Nisoldipine
    • Nitroprusside
    • Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ
    • Oxazepam
    • Perindopril; Amlodipine
    • Pertuzumab; Trastuzumab; Hyaluronidase
    • Phenothiazines
    • Phenoxybenzamine
    • Pioglitazone
    • Pioglitazone; Glimepiride
    • Pioglitazone; Metformin
    • Pramlintide
    • Prazosin
    • Quazepam
    • Rasagiline
    • Reserpine
    • Rituximab; Hyaluronidase
    • Rosiglitazone
    • Rosuvastatin
    • Rosuvastatin; Ezetimibe
    • Saxagliptin
    • SGLT2 Inhibitors
    • Simvastatin; Sitagliptin
    • Sitagliptin
    • Sulfonylureas
    • Telmisartan; Amlodipine
    • Temazepam
    • Terazosin
    • Thiazolidinediones
    • Thyroid hormones
    • Tolazamide
    • Tolbutamide
    • Trandolapril; Verapamil
    • Trastuzumab; Hyaluronidase
    • Tricyclic antidepressants
    • Ursodeoxycholic Acid, Ursodiol
    • Verapamil
    • Zolmitriptan
    • Zonisamide
    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] Acetaminophen: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors. [31082] Acetaminophen; Aspirin: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] Acetaminophen; Caffeine: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors. [31082] Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors. [31082] Acetaminophen; Caffeine; Pyrilamine: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors. [31082] Acetaminophen; Chlorpheniramine: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] Acetaminophen; Codeine: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] Acetaminophen; Dextromethorphan: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] Acetaminophen; Diphenhydramine: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] Acetaminophen; Hydrocodone: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] Acetaminophen; Oxycodone: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] Acetaminophen; Pentazocine: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] Acetaminophen; Pseudoephedrine: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] Acetohexamide: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [6266] Acitretin: (Major) Acitretin reduces the efficacy of oral progestin only contraceptives. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy. [5225] Adagrasib: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor. [63694] [68325] Aliskiren; Amlodipine: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] Alogliptin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. [7347] Alogliptin; Metformin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. [7347] (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 like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. [28550] [30585] [62853] Alogliptin; Pioglitazone: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. [7347] (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [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] (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [4995] Alprazolam: (Minor) Oral contraceptives can increase the effects of alprazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to alprazolam. [4760] [7486] Amikacin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Aminoglycosides: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Amlodipine: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] Amlodipine; Atorvastatin: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly. [5460] (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] Amlodipine; Benazepril: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] Amlodipine; Celecoxib: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] Amlodipine; Olmesartan: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] Amlodipine; Valsartan: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] 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] (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment. [22005] [28502] [29653] [29821] [30802] [30858] [30890] [33322] [42126] [46375] [48201] [48254] [49996] [57048] [57271] [57649] [59800] [62899] Amoxicillin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Amoxicillin; Clarithromycin; Omeprazole: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin. [28238] [28482] [28509] [31698] [34329] Amoxicillin; Clavulanic Acid: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Ampicillin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Ampicillin; Sulbactam: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] 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) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. 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. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). [62874] [63694] (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 estrogens (including ethinyl estradiol) and/or progestins 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] (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 progestins 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. Progestins are CYP3A4 substrates 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. The clinical significance of this is not known since aprepitant, fosaprepitant is only used intermittently. [30676] [40617] [47343] [57085] Armodafinil: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation. [33467] (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estrogens and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation. [33467] Artemether; Lumefantrine: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including non-oral combination contraceptives, oral contraceptives, and progestin contraceptives (i.e. norethindrone). This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended. [35401] [4744] (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including oral contraceptives. This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended. [35401] [4744] (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal treatments, including progestin-only contraceptives (e.g., norethindrone). This may be due to a CYP3A4 interaction. Additional use of a non-hormonal method of birth control is recommended when norethindrone is used for birth control. Women receiving norethindrone hormone replacement or contraceptives with artemether; lumefantrine should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. [35401] [4744] Ascorbic Acid, Vitamin C: (Minor) Ascorbic acid, vitamin C acts as a competitive inhibitor of the sulfation of ethinyl estradiol in the gastrointestinal tract wall and may increase the bioavailability by 50%. Patients who ingest ascorbic acid supplements may experience an increase in estrogen related side effects. [6395] 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] (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment. [22005] [28502] [29653] [29821] [30802] [30858] [30890] [33322] [42126] [46375] [48201] [48254] [49996] [57048] [57271] [57649] [59800] [62899] (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors. [31082] 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] (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment. [22005] [28502] [29653] [29821] [30802] [30858] [30890] [33322] [42126] [46375] [48201] [48254] [49996] [57048] [57271] [57649] [59800] [62899] (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors. [31082] Aspirin, ASA; Caffeine: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors. [31082] Aspirin, ASA; Caffeine; Orphenadrine: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors. [31082] Atazanavir: (Major) Atazanavir may decrease the metabolism of oral contraceptives and non-oral combination contraceptives; the mean exposure and minimum serum concentrations of ethinyl estradiol and norethindrone are increased when administered with atazanavir 400 mg daily. However, if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased; data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. [28142] (Major) If ethinyl estradiol is administered with atazanavir boosted with ritonavir, it is recommended that the dose of ethinyl estradiol be at least 35 mcg. However, the dose of ethinyl estradiol should be no more than 30 mcg when administered with atazanavir that is NOT boosted by ritonavir. The mean exposure and minimum serum concentrations of ethinyl estradiol are increased when administered with atazanavir; but if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased. Data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. [28142] Atazanavir; Cobicistat: (Major) Atazanavir may decrease the metabolism of oral contraceptives and non-oral combination contraceptives; the mean exposure and minimum serum concentrations of ethinyl estradiol and norethindrone are increased when administered with atazanavir 400 mg daily. However, if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased; data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. [28142] (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. [51664] [58000] (Major) If ethinyl estradiol is administered with atazanavir boosted with ritonavir, it is recommended that the dose of ethinyl estradiol be at least 35 mcg. However, the dose of ethinyl estradiol should be no more than 30 mcg when administered with atazanavir that is NOT boosted by ritonavir. The mean exposure and minimum serum concentrations of ethinyl estradiol are increased when administered with atazanavir; but if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased. Data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. [28142] (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns. [51664] [58000] Atorvastatin: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly. [5460] Atorvastatin; Ezetimibe: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly. [5460] Azelastine; Fluticasone: (Moderate) Monitor for corticosteroid-related adverse events if corticosteroids are used with estrogens. Concurrent use may increase the exposure of corticosteroids. Estrogens may decrease the hepatic clearance of corticosteroids thereby increasing their effect. [29779] [54049] Azithromycin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Aztreonam: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Bacitracin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] 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] (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment. [22005] [28502] [29653] [29821] [30802] [30858] [30890] [33322] [42126] [46375] [48201] [48254] [49996] [57048] [57271] [57649] [59800] [62899] 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] (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. 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. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. [33322] [57648] [66875] Benzhydrocodone; Acetaminophen: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] 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) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy. [4791] [4792] (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] Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Blinatumomab: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as ethinyl estradiol. The dose of the concomitant drug may need to be adjusted. [58559] Bosentan: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary. [28496] (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] (Minor) Bromocriptine is used to restore ovulation and ovarian function in amenorrheic women. 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] (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment. [22005] [28502] [29653] [29821] [30802] [30858] [30890] [33322] [42126] [46375] [48201] [48254] [49996] [57048] [57271] [57649] [59800] [62899] 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] (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment. [22005] [28502] [29653] [29821] [30802] [30858] [30890] [33322] [42126] [46375] [48201] [48254] [49996] [57048] [57271] [57649] [59800] [62899] (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] 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] (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment. [22005] [28502] [29653] [29821] [30802] [30858] [30890] [33322] [42126] [46375] [48201] [48254] [49996] [57048] [57271] [57649] [59800] [62899] (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors. [31082] 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] (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment. [22005] [28502] [29653] [29821] [30802] [30858] [30890] [33322] [42126] [46375] [48201] [48254] [49996] [57048] [57271] [57649] [59800] [62899] (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors. [31082] Cabozantinib: (Minor) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with cabozantinib is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown. [52506] [60738] [60859] Caffeine: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine in an effort to minimize caffeine-related side effects such as nausea or tremors. [7854] (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors. [31082] Caffeine; Sodium Benzoate: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors. [31082] Calaspargase pegol: (Major) The concomitant use of calaspargase pegol and oral contraceptives may reduce the efficacy of oral contraceptives. Women of reproductive potential should use a non-hormonal method of birth control during therapy and for at least 3 months after the last calaspargase pegol dose due to the risk of fetal harm. [63842] Calcium: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis. [6395] Calcium-channel blockers: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] 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] (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [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 like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. [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] (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [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] (Major) Advise patients taking progestin 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 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. Progestins are CYP3A substrates and carbamazepine is a strong CYP3A inducer. Concurrent administration may increase progestin elimination. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). [28024] [30675] [33322] [41237] [42126] [48201] [57036] [57588] [57648] [63694] Carbapenems: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Cefaclor: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Cefadroxil: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Cefazolin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Cefdinir: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Cefditoren: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Cefepime: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Cefiderocol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Cefixime: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Cefotaxime: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Cefotetan: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Cefoxitin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Cefpodoxime: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Cefprozil: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Ceftaroline: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Ceftazidime: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Ceftazidime; Avibactam: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Ceftibuten: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Ceftizoxime: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Ceftolozane; Tazobactam: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Ceftriaxone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Cefuroxime: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] 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] (Major) Women taking both progestins 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. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination. [33322] [57648] [64768] Cephalexin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Ceritinib: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate. [40617] [47343] [57094] Charcoal: (Major) Note that charcoal exerts a nonspecific effect, and many medications can be adsorbed by activated charcoal; repeat doses may decrease the enterohepatic recycling of some drugs. Activated charcoal dietary supplements may have the potential to reduce the effectiveness of oral contraceptives. Data clearly demonstrating this interaction are not available. Ovulatory potential was studied during the use of two monophasic oral contraceptive pill preparations, after repeated mid-cycle administration of activated charcoal to treat diarrhea in women. None of eleven women ovulated. Repeated charcoal treatment, when administered 3 hours after but at least 12 hours before pill intake, did not alter oral contraceptive efficacy. [6833] [6834] 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: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include chloramphenicol. [28482] [28509] [29624] [31698] Chlordiazepoxide: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines. [7486] Chlordiazepoxide; Amitriptyline: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines. [7486] Chlordiazepoxide; Clidinium: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines. [7486] Chlorpropamide: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [6266] 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] Ciprofloxacin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Clarithromycin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin. [28238] [28482] [28509] [31698] [34329] Clevidipine: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] Clindamycin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Clobazam: (Major) Clobazam induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with clobazam. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking clobazam. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Clobazam may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on clobazam, with adjustments made based on clinical efficacy. [46370] Clonazepam: (Minor) Oral contraceptives can increase the effects of clonazepam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to clonazepam. [4718] [7486] Clorazepate: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines. [7486] Cobicistat: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. [51664] [58000] (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns. [51664] [58000] Cobimetinib: (Major) If concurrent use of cobimetinib and ethinyl estradiol is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and ethinyl estradiol is a weak in vitro inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors. [40617] [47343] [57085] [60281] Colesevelam: (Moderate) Administer oral contraceptives containing ethinyl estradiol at least 4 hours prior to a colesevelam dose to avoid an interaction and reduce the potential for loss of contraceptive efficacy. Colesevelam has been shown to significantly decrease the AUC of ethinyl estradiol (EE) in oral contraceptives by about 24% when the drugs are administered at the same time. When the 2 drug products were given 4 hours apart, the drug interaction risk was lessened. Patients should separate times of administration and clinicians should be alert for evidence of an interaction. Consider alternative therapy if indicated. [30812] Colistimethate, Colistin, Polymyxin E: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Colistin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] 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] Dabrafenib: (Major) Avoid concomitant use of dabrafenib and hormonal contraceptives; decreased hormonal contraceptive concentrations and loss of efficacy may occur. Use of an alternative non-hormonal contraceptive method of birth control is recommended during treatment for 2 weeks after the last dose of dabrafenib. Dabrafenib is a moderate CYP3A4 inducer and many hormonal contraceptive are CYP3A4 substrates. [54802] Dalbavancin: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] 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) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. [7347] (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) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. [7347] (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 like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. [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) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. [7347] (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] (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. [7347] Daptomycin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] 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: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. [32432] [58763] (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norethindrone have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norethindrone. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. [32432] [58763] Darunavir; Cobicistat: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. [51664] [58000] (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. [32432] [58763] (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norethindrone have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norethindrone. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. [32432] [58763] (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns. [51664] [58000] Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. [51664] [58000] (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. [32432] [58763] (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norethindrone have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norethindrone. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. [32432] [58763] (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns. [51664] [58000] Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting the hepatitis C regimen, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with the hepatitis C regimen. [58664] (Contraindicated) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting dasabuvir; ombitasvir; paritaprevir; ritonavir, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with dasabuvir; ombitasvir; paritaprevir; ritonavir. [58664] (Major) Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. [46638] [5044] (Moderate) Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. For example, ritonavir (also found in combinations like lopinavir; ritonavir, and used as a booster in many HIV treatment regimens) may decrease the metabolism of norethindrone, raising norethindrone concentrations. Women receiving norethindrone for hormone replacement or contraception should report potential hormonal adverse effects (e.g., bleeding pattern changes, acne, emotional lability) or any changes in efficacy (e.g., noted changes in bleeding patterns) to their prescribers. Because norethindrone-containing contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive norethindrone contraception concurrently with ritonavir should use an additional barrier method of contraception such as condoms. [58679] [7731] Deferasirox: (Moderate) Counsel patients to use non-hormonal methods of contraception during treatment with deferasirox. Deferasirox may induce the CYP3A4 metabolism of hormonal contraceptives; thereby decreasing their effectiveness. [30858] [31807] 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] Delafloxacin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Delavirdine: (Minor) The concentration of ethinyl estradiol may increase during concurrent administration of delavirdine. However, the clinical significance of this interaction is unknown. [5206] Demeclocycline: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] 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] Diazepam: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines. [7486] Dicloxacillin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Diltiazem: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] 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] Doripenem: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Doxazosin: (Minor) Estrogen-containing oral contraceptives may induce fluid retention and may increase blood pressure in some patients taking antihypertensive agents. Such patients should be monitored to confirm that the desired antihypertensive effect is being obtained. [24233] [27999] Doxercalciferol: (Moderate) CYP450 enzyme inhibitors, like ethinyl estradiol, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if CYP450 inhibitors are coadministered with doxercalciferol. [30802] [51248] Doxorubicin Liposomal: (Moderate) Ethinyl Estradiol is a mild CYP3A4 inhibitor and doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ethinyl estradiol and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity. [47343] [56361] [57085] Doxorubicin: (Moderate) Ethinyl Estradiol is a mild CYP3A4 inhibitor and doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ethinyl estradiol and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity. [47343] [56361] [57085] Doxycycline: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Dronabinol: (Moderate) Use caution if coadministration of dronabinol with ethinyl estradiol is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; ethinyl estradiol is a weak inhibitor of CYP3A4 in vitro. Concomitant use may result in elevated plasma concentrations of dronabinol. [30431] [40617] [47343] [57085] [60951] Dronedarone: (Moderate) Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ethinyl estradiol (EE) is an inhibitor of CYP3A4 and is a substrate of CYP3A and P-gp. Concomitant use of dronedarone with ethinyl estradiol may increase dronedarone concentrations. Data from clinical studies indicate dronedarone did not increase ethinyl estradiol or levonorgestrel concentrations in healthy subjects receiving dronedarone concomitantly with oral contraceptives. Use caution with any combined oral contraceptives or combined hormonal replacements containing EE, as most of these products contain EE, or they contain mestranol, which is converted to EE. [36101] Efavirenz: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations. [28442] [46638] Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations. [28442] [46638] Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations. [28442] [46638] Elagolix: (Major) During use of elagolix, females of childbearing potential should use non-hormonal methods of contraception for the duration of treatment and for 28 days following the discontinuation of therapy. Estrogen-containing injectable, implantable, transdermal, vaginal or oral contraceptives are expected to reduce the efficacy of elagolix. The effect of progestin-only contraceptives on elagolix is not known. However, elagolix is a weak to moderate inducer of CYP3A4, and many estrogens and progestins are metabolized via this enzyme. Thus, elagolix may decrease plasma concentrations of hormonal contraceptives. Coadministration of elagolix 200 mg twice daily and a combined oral contraceptive (COC) containing 0.1 mg levonorgestrel decreases the plasma concentrations of levonorgestrel by 27%, potentially affecting contraceptive efficacy. Coadministration of elagolix with COCs containing norethindrone acetate did not show reduction in plasma concentrations of norethindrone. Elagolix may also increase contraceptive concentrations. Coadministration of a COC (containing 20 mcg ethinyl estradiol/0.1 mg levonorgestrel) following administration of elagolix 200 mg twice daily for 14 days increases the plasma ethinyl estradiol concentration by 2.2-fold compared to this COC alone; this may lead to increased risk of ethinyl estradiol-related adverse events including thromboembolic disorders and vascular events. [63387] Elagolix; Estradiol; Norethindrone acetate: (Major) During use of elagolix, females of childbearing potential should use non-hormonal methods of contraception for the duration of treatment and for 28 days following the discontinuation of therapy. Estrogen-containing injectable, implantable, transdermal, vaginal or oral contraceptives are expected to reduce the efficacy of elagolix. The effect of progestin-only contraceptives on elagolix is not known. However, elagolix is a weak to moderate inducer of CYP3A4, and many estrogens and progestins are metabolized via this enzyme. Thus, elagolix may decrease plasma concentrations of hormonal contraceptives. Coadministration of elagolix 200 mg twice daily and a combined oral contraceptive (COC) containing 0.1 mg levonorgestrel decreases the plasma concentrations of levonorgestrel by 27%, potentially affecting contraceptive efficacy. Coadministration of elagolix with COCs containing norethindrone acetate did not show reduction in plasma concentrations of norethindrone. Elagolix may also increase contraceptive concentrations. Coadministration of a COC (containing 20 mcg ethinyl estradiol/0.1 mg levonorgestrel) following administration of elagolix 200 mg twice daily for 14 days increases the plasma ethinyl estradiol concentration by 2.2-fold compared to this COC alone; this may lead to increased risk of ethinyl estradiol-related adverse events including thromboembolic disorders and vascular events. [63387] Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. [51664] [58000] (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns. [51664] [58000] (Moderate) Consider the benefits and risk of administering elvitegravir with ethinyl estradiol; norgestimate and other combination oral contraceptives. Concurrent use may result in elevated norgestimate and reduced ethinyl estradiol serum concentrations. Risk associated with these altered concentrations may include increased insulin resistance, dyslipidemia, acne, and venous thrombosis. Consider alternative non-hormonal methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. [46638] [58001] Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. [51664] [58000] (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns. [51664] [58000] (Moderate) Consider the benefits and risk of administering elvitegravir with ethinyl estradiol; norgestimate and other combination oral contraceptives. Concurrent use may result in elevated norgestimate and reduced ethinyl estradiol serum concentrations. Risk associated with these altered concentrations may include increased insulin resistance, dyslipidemia, acne, and venous thrombosis. Consider alternative non-hormonal methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. [46638] [58001] Empagliflozin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. [60134] (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) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. [60134] (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. [7347] (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) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. [60134] (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. [7347] (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 like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. [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) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. [60134] (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 like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. [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] Enalapril; Felodipine: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] Encorafenib: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy. [63317] Enzalutamide: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). [51727] [63694] (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] Eravacycline: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Ergotamine; Caffeine: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors. [31082] Ertapenem: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] 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] (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [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 like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. [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] (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [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] (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. [7347] (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [30585] [62853] Erythromycin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Eslicarbazepine: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle. [56436] Estazolam: (Minor) Ethinyl estradiol may inhibit the clearance of estazolam. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to such benzodiazepines. [7486] 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] (Major) Women taking both progestins and etravirine should report breakthrough bleeding to their prescribers. 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 one month after discontinuation of etravirine. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and etravirine is a strong CYP3A4 inducer. [33322] [33718] [57648] [63694] 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] Exenatide: (Moderate) Separate the administration times of exenatide and estrogen and progestin containing oral contraceptives. Advise patients to take estrogen and progestin containing oral contraceptives at least 1 hour before exenatide. Exenatide slows gastric emptying and simultaneous coadministration may reduce the rate and extent of estrogen and progestin oral absorption which may reduce efficacy. Additionally, estrogens can impair glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day. [30585] [44456] [48491] [62853] Felbamate: (Major) Based on very limited data, it appears felbamate can accelerate the clearance of the estrogen component of some oral contraceptives. Patients who experience breakthrough bleeding while receiving these drugs together should notify their prescribers. An alternate or additional form of contraception should be used during concomitant treatment. Additionally, patients taking non-oral combination contraceptives or estrogens or progestins for hormone replacement therapy may also experience reduced clinical efficacy; dosage adjustments may be necessary. [7006] [7241] (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] Felodipine: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] Fidaxomicin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Flibanserin: (Moderate) The concomitant use of flibanserin and multiple weak CYP3A4 inhibitors, including oral contraceptives, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the risks of combination therapy with multiple weak CYP3A4 inhibitors and flibanserin should be discussed with the patient. In one study of 24 healthy women, the effect of 100 mg flibanserin once daily for 2 weeks on the pharmacokinetics of a single dose of ethinyl estradiol 30 mcg/levonorgestrel 150 mcg was evaluated. Flibanserin increased the AUC and Cmax of ethinyl estradiol by 1.09-fold and 1.1-fold, respectively. Flibanserin decreased the levonorgestrel AUC by 1.06-fold. During pre-marketing evaluation of flibanserin, patients who reported using oral contraceptives had a greater incidence of CNS effects than flibenserin-treated patients who did not report oral contraceptive use, including dizziness (13.4% vs. 9.9%), somnolence (12.3% vs. 10.6%), and fatigue (11.4% vs. 7.5%). [60099] Fluconazole: (Minor) CYP3A4 inhibitors such as fluconazole may increase plasma hormone concentrations of ethinyl estradiol. Fluconazole tablets, administered concomitantly with oral contraceptives containing ethinyl estradiol have resulted in an overall mean increase in ethinyl estradiol compared to placebo. However, in some patients there are decreases up to 47% of ethinyl estradiol concentrations. The available data indicate that the decreases in some individual ethinyl estradiol AUC values with fluconazole treatment are likely due to random variation. While there is evidence that fluconazole can inhibit the metabolism of ethinyl estradiol, there is no evidence that fluconazole is a net inducer of ethinyl estradiol metabolism. The clinical significance of these effects is unknown. [28674] [40226] 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] Flurazepam: (Minor) Ethinyl estradiol may inhibit the clearance of flurazepam. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to benzodiazepines. [7486] 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] (Major) Avoid concurrent use of contraceptives and hormone replacement therapies (HRT) containing progestins with fosamprenavir. Alternative methods of non-hormonal contraception are recommended. Concomitant use may decrease the efficacy of both the progestin 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 progestins 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] Fostemsavir: (Major) When administering ethinyl estradiol concurrently with fostemsavir, do not exceed a maximum daily ethinyl estradiol dose of 30 mcg. Caution is advised, particularly in patients with additional risk factors for thromboembolic events. In a drug interactions study, the systemic concentration of ethinyl estradiol was increased when given with fostemsavir. [65666] Frovatriptan: (Minor) Retrospective analysis of pharmacokinetic data from females across trials indicated that the mean Cmax and AUC of frovatriptan are 30% higher in those subjects taking oral contraceptives (e.g., those containing ethinyl estradiol) compared to those not taking oral contraceptives. The clinical significance of the interaction has not been established. Hormone replacement therapy regimens (HRT) are not thought to interact, based on data with other 'triptans' with similar pharmacokinetic interactions with oral contraceptives. [29266] Gemifloxacin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used with antibiotics. Oral contraceptives (estrogen/progesterone) reduced the AUC and Cmax of gemifloxacin by 19% and 12%, respectively. These reductions are considered to be clinically insignificant. Gemifloxacin did not affect the pharmacokinetics of an ethinyl estradiol/levonorgestrel oral contraceptive product in healthy females. It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28424] [28482] [28509] Gentamicin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Glecaprevir; Pibrentasvir: (Major) Coadministration of glecaprevir with ethinyl estradiol is not recommended due to an increased risk of ALT elevations associated with ethinyl estradiol. In drug interaction studies, coadministration of ethinyl estradiol-containing oral contraceptives with glecaprevir; pibrentasvir resulted in a 28% to 40% increase in the AUC of ethinyl estradiol. [25473] [48151] [51257] [62201] (Major) Coadministration of pibrentasvir with ethinyl estradiol is not recommended due to an increased risk of ALT elevations associated with ethinyl estradiol. In drug interaction studies, coadministration of ethinyl estradiol-containing oral contraceptives with glecaprevir; pibrentasvir resulted in a 28% to 40% increase in the AUC of ethinyl estradiol. [25473] [48151] [51257] [62201] Glimepiride: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [6266] Glimepiride; Rosiglitazone: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [30585] [62853] (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [6266] Glipizide: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [6266] 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] (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. [28550] [30585] [62853] (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [6266] Glyburide: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [6266] 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] (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. [28550] [30585] [62853] (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [6266] Glycylcyclines: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] 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] Green Tea: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine like green tea, to minimize caffeine-related side effects such as nausea or tremors. [4664] Griseofulvin: (Major) The concurrent use of griseofulvin and oral contraceptives can reduce contraceptive efficacy and result in an unintended pregnancy and/or breakthrough bleeding. This risk is particularly serious because griseofulvin is contraindicated during pregnancy due to the risk of teratogenic and abortifacient effects. An alternate or additional form of contraception should be used during concomitant treatment and continued for 1 month after griseofulvin discontinuation. If these drugs are used together, counsel the patient about the risk of pregnancy and teratogenic effects, and instruct the patient to notify the prescriber if they experience breakthrough bleeding while receiving these drugs together. Additionally, patients taking non-oral combination contraceptives or progestins for hormone replacement therapy may also experience reduced clinical efficacy. [28509] [45723] [58441] [59800] (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] Hydantoins: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. 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 hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). [28535] [28771] [42126] [48201] [57036] [57588] [57648] [63694] 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] Idelalisib: (Moderate) Idelalisib is a strong CYP3A inhibitor, and ethinyl estradiol (EE) is a CYP3A substrate. Use caution in dose selection, as the hormonal side effects of ethinyl estradiol may be increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib. Females of reproductive potential should avoid becoming pregnant during idelalisib therapy, using effective contraception during treatment and for at least 1 month after the last dose. Thus, use idelalisib with caution in combination with any combination oral contraceptives, most of which contain EE or mestranol (which is converted to EE). In addiiton, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. [31698] [47343] [4744] [57675] Imipenem; Cilastatin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Imipenem; Cilastatin; Relebactam: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Indinavir: (Major) Indinavir decreases the metabolism of oral contraceptives and non-oral combination contraceptives; the AUC for ethinyl estradiol and norethindrone increased by 24+/-17% and 26+/-14%, respectively, when coadministered with indinavir. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as indinavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives with PIs should use an additional barrier method of contraception such as condoms. [28731] [46638] (Moderate) Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. The AUC for norethindrone increased by 26+/-14%, respectively, when a combined oral contraceptive was coadministered with indinavir. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as indinavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives with indinavir should use an additional barrier method of contraception such as condoms. [28731] [46638] [58679] [7731] Insulin Glargine; Lixisenatide: (Moderate) Separate the administration times of lixisenatide and estrogen and progestin containing oral contraceptives. Advise patients to take estrogen and progestin containing oral contraceptives at least 1 hour before or 11 hours after lixisenatide. Lixisenatide slows gastric emptying and simultaneous coadministration may reduce the rate and extent of estrogen and progestin oral absorption which may reduce efficacy. Additionally, estrogens can impair glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day. [30585] [48491] [61024] [62853] 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] (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. [60172] Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with ethinyl estradiol may result in increased serum concentrations of both drugs. Ethinyl estradiol is a substrate and inhibitor of the hepatic isoenzyme CYP3A4 and substrate of the drug transporter P-glycoprotein (P-gp); isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of CYP3A4 and an inhibitor of P-gp. Caution and close monitoring are advised if these drugs are used together. [40617] [47343] [57085] [59042] 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] (Major) Women taking both progestins and rifampin should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed rifampin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of rifampin. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and rifampin is a strong CYP3A4 inducer. [30314] [33322] [57648] 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] (Major) Women taking both progestins and rifampin should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed rifampin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of rifampin. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and rifampin is a strong CYP3A4 inducer. [30314] [33322] [57648] Isradipine: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] Itraconazole: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as itraconazole 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. [41929] Ivosidenib: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives. [63368] Kanamycin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Ketoconazole: (Moderate) Monitor for an increase in the incidence and severity of estrogen-related adverse effects during concomitant use of ethinyl estradiol and ketoconazole. Concomitant use may increase ethinyl estradiol exposure. Ethinyl estradiol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. [41929] [43307] [58441] 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] (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis. [28451] [44123] [48201] Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin. [28238] [28482] [28509] [31698] [34329] Lefamulin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Leflunomide: (Moderate) Carefully consider the type and dose of oral contraceptives in patients taking leflunomide.Leflunomide may increase the effects of oral contraceptives. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Following repeated teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. [49634] 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] Lesinurad: (Major) Lesinurad induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with lesinurad. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking lesinurad. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Lesinurad may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lesinurad, with adjustments made based on clinical efficacy. [60473] Lesinurad; Allopurinol: (Major) Lesinurad induces CYP3A4, which may reduce the concentrations of estrogen and progestin hormones. Hormonal contraceptives may not be reliable when coadministered with lesinurad. Females taking hormonal-based birth control should use additional non-hormonal methods and not rely solely on hormonal contraceptive methods when taking lesinurad. Hormonal contraceptives include combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins and includes oral, injectable, transdermal, vaginal inserts, and implantable forms of hormonal birth control. Lesinurad may also reduce the effectiveness of other estrogens or progestins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lesinurad, with adjustments made based on clinical efficacy. [60473] 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] Levamlodipine: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] Levofloxacin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Levoketoconazole: (Moderate) Monitor for an increase in the incidence and severity of estrogen-related adverse effects during concomitant use of ethinyl estradiol and ketoconazole. Concomitant use may increase ethinyl estradiol exposure. Ethinyl estradiol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. [41929] [43307] [58441] 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: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. [7347] Linagliptin; Metformin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. [7347] (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 like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. [28550] [30585] [62853] Lincomycin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Lincosamides: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Linezolid: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] 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] Lixisenatide: (Moderate) Separate the administration times of lixisenatide and estrogen and progestin containing oral contraceptives. Advise patients to take estrogen and progestin containing oral contraceptives at least 1 hour before or 11 hours after lixisenatide. Lixisenatide slows gastric emptying and simultaneous coadministration may reduce the rate and extent of estrogen and progestin oral absorption which may reduce efficacy. Additionally, estrogens can impair glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day. [30585] [48491] [61024] [62853] Lomitapide: (Major) Concomitant use of lomitapide and oral contraceptives may significantly increase the serum concentration of lomitapide. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Oral Contraceptives are weak CYP3A4 inhibitors; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors. In addition, females of reproductive potential must use effective contraception during lomitapide therapy. Because vomiting and diarrhea have been frequently reported during lomitapide therapy and hormone absorption from oral contraceptives may be incomplete in the presence of vomiting or diarrhea, warn patients that the use of additional contraceptive methods is warranted if vomiting or diarrhea occur. [52698] 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: (Major) Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. [46638] [5044] (Moderate) Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. For example, ritonavir (also found in combinations like lopinavir; ritonavir, and used as a booster in many HIV treatment regimens) may decrease the metabolism of norethindrone, raising norethindrone concentrations. Women receiving norethindrone for hormone replacement or contraception should report potential hormonal adverse effects (e.g., bleeding pattern changes, acne, emotional lability) or any changes in efficacy (e.g., noted changes in bleeding patterns) to their prescribers. Because norethindrone-containing contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive norethindrone contraception concurrently with ritonavir should use an additional barrier method of contraception such as condoms. [58679] [7731] Lorazepam: (Minor) Ethinyl estradiol may enhance the metabolism of lorazepam. It appears glucuronide conjugation of lorazepam is increased in the presence of combined hormonal oral contraceptives; the clinical significance of this interaction is not determined. [7486] 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] (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. 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. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer. [33322] [57648] [63732] Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia). [59891] Mafenide: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] 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] Mecamylamine: (Minor) Ethinyl estradiol may induce fluid retention and may increase blood pressure in some patients taking antihypertensive agents, like mecamylamine. Such patients should be monitored to confirm that the desired antihypertensive effect is being obtained. [24233] [40219] 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] (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [7053] Meropenem: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Meropenem; Vaborbactam: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] 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 like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. [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] (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. [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] (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. [28550] [30585] [62853] (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [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] (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. [28550] [30585] [62853] (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. [7347] 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] (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. [28550] [30585] [62853] (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. [7347] 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] (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment. [22005] [28502] [29653] [29821] [30802] [30858] [30890] [33322] [42126] [46375] [48201] [48254] [49996] [57048] [57271] [57649] [59800] [62899] 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] Metronidazole: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] 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] Miconazole: (Minor) Miconazole vaginal products may be administered with most hormonal contraceptives containing ethinyl estradiol, as most of the time any increase in ethinyl estradiol AUC is minimal and unlikely to cause significant side effects, though some patients may notice breast tenderness or nausea. In patients using contraceptive vaginal rings, water-based miconazole products are preferred. Oil-based miconazole vaginal products appear to increase ethinyl estradiol exposure from the contraceptive vaginal rings. Water-based miconazole vaginal products or an alternative oral therapy may be used concurrently with vaginal rings containing ethinyl estradiol. In drug interaction studies with ethinyl estradiol-containing vaginal rings, single-dose vaginal administration of a 1,200 mg miconazole suppository increased the systemic exposure of ethinyl estradiol by 16% to 67%, depending on the contraceptive vaginal ring in use. When 200 mg miconazole vaginal suppositories were administered, the ethinyl estradiol systemic exposures were also increased, with a maximal reported increase of 42% on day 3 of miconazole vaginal suppository use. Multiple doses of a 200 mg miconazole nitrate vaginal cream with the etonogestrel; ethinyl estradiol ring increased the mean serum concentration of ethinyl estradiol by up to 40%. Water-based vaginal miconazole cream did not affect the pharmacokinetics of the segesterone acetate; ethinyl estradiol vaginal ring. [43310] [63429] Miconazole; Petrolatum; Zinc Oxide: (Minor) Miconazole vaginal products may be administered with most hormonal contraceptives containing ethinyl estradiol, as most of the time any increase in ethinyl estradiol AUC is minimal and unlikely to cause significant side effects, though some patients may notice breast tenderness or nausea. In patients using contraceptive vaginal rings, water-based miconazole products are preferred. Oil-based miconazole vaginal products appear to increase ethinyl estradiol exposure from the contraceptive vaginal rings. Water-based miconazole vaginal products or an alternative oral therapy may be used concurrently with vaginal rings containing ethinyl estradiol. In drug interaction studies with ethinyl estradiol-containing vaginal rings, single-dose vaginal administration of a 1,200 mg miconazole suppository increased the systemic exposure of ethinyl estradiol by 16% to 67%, depending on the contraceptive vaginal ring in use. When 200 mg miconazole vaginal suppositories were administered, the ethinyl estradiol systemic exposures were also increased, with a maximal reported increase of 42% on day 3 of miconazole vaginal suppository use. Multiple doses of a 200 mg miconazole nitrate vaginal cream with the etonogestrel; ethinyl estradiol ring increased the mean serum concentration of ethinyl estradiol by up to 40%. Water-based vaginal miconazole cream did not affect the pharmacokinetics of the segesterone acetate; ethinyl estradiol vaginal ring. [43310] [63429] Midazolam: (Minor) Oral contraceptives can increase the effects of midazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to midazolam. [7486] Mifepristone: (Major) Mifepristone is a progesterone-receptor antagonist and will interfere with the effectiveness of hormonal contraceptives. Therefore, non-hormonal contraceptive methods should be used in Cushing's patients taking mifepristone. [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] Miltefosine: (Moderate) Miltefosine-induced vomiting and/or diarrhea may affect absorption of oral contraceptives and compromise their efficacy. If vomiting or diarrhea occur during miltefosine therapy, advise females to use an additional non-oral method of effective contraception. [56867] 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] Minocycline: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] 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) Avoid coadministration of mitotane with norethindrone if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of mitotane. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on mitotane, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and mitotane should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Norethindrone is a substrate of CYP3A4 and mitotane is a strong CYP3A4 inducer. Concurrent administration of mitotane with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). [41934] [48152] (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] Mivacurium: (Moderate) Plasma cholinesterase activity may be diminished by chronic administration of oral contraceptives; consider the possibility of prolonged neuromuscular block after administration of mivacurium in patients with reduced plasma cholinesterase activity. The use of a peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of neuromuscular blocker, and to determine whether adjustments need to be made to the dose with subsequent administration. [42613] [65534] 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] (Major) Women taking both progestins and mobocertinib should report breakthrough bleeding to their prescribers. 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 one month after discontinuation of mobocertinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A substrates and mobocertinib is a weak CYP3A inducer. [33322] [57648] [63694] [66990] Modafinil: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of ethinyl estradiol in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. [41243] (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary. [4718] [4744] [5259] 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] Morphine: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine. [43307] [58441] Morphine; Naltrexone: (Moderate) Combination oral contraceptives have been shown to decrease plasma concentrations of morphine, due to induction of conjugation. Monitor for decreased efficacy of morphine. [43307] [58441] Moxifloxacin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28423] [28482] [28509] Mycophenolate: (Moderate) Mycophenolate mofetil may not have any influence on the ovulation suppressing action of ethinyl estradiol. However, it is recommended that hormonal contraceptives be given to women receiving mycophenolate and additional birth control methods be considered. [4702] [4873] Nafcillin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Naratriptan: (Minor) Concurrent use of oral contraceptives (e.g, those containing ethinyl estradiol) reduced naratriptan clearance by 32% and volume of distribution by 22% during clinical trials. The decrease in clearance resulted in slightly higher plasma levels of naratriptan. A clinical significance to this interaction has not been established. Estrogen-based hormone replacement therapy had no effect on the pharmacokinetics of naratriptan in postmenopausal females. [6005] Nelfinavir: (Major) Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. Nelfinavir increases the metabolism of hormonal contraception; coadministration with a combined oral contraceptive containing norethindrone results in an 18% decrease in norethindrone plasma concentrations. Women receiving hormonal contraceptives or hormone replacement with norethindrone while receiving nelfinavir should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive norethindrone-containing contraceptives concurrently with nelfinavir to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. [28839] [58679] [7731] (Major) Nelfinavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration with ethinyl estradiol; norethindrone results in a 47% decrease in ethinyl estradiol plasma concentrations and an 18% decrease in norethindrone plasma concentrations. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as nelfinavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. [28839] Neomycin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Nevirapine: (Moderate) Nevirapine may decrease plasma concentrations of oral contraceptives and non-oral combination contraceptives (i.e., ethinyl estradiol and norethindrone). However despite lower exposures, literature suggests that use of nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. Thus, the manufacturer states that no dose adjustments are needed when these drugs are used for contraception in combination with nevirapine. When these oral contraceptives are used for hormone replacement and given with nevirapine, the therapeutic effect of the hormonal therapy should be monitored. [42456] (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] Nicardipine: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] Nifedipine: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] Nimodipine: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] Nirmatrelvir; Ritonavir: (Major) Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. [46638] [5044] (Major) The FDA recommends consideration of an additional, non-hormonal method of contraception during the 5 days of treatment with ritonavir-boosted nirmatrelvir and until one menstrual cycle after stopping ritonavir-boosted nirmatrelvir. However, the NIH COVID-19 guidelines suggest the potential decrease in ethinyl estradiol exposure is not expected to be clinically significant during the 5 days of therapy. [65314] [67203] (Moderate) Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. For example, ritonavir (also found in combinations like lopinavir; ritonavir, and used as a booster in many HIV treatment regimens) may decrease the metabolism of norethindrone, raising norethindrone concentrations. Women receiving norethindrone for hormone replacement or contraception should report potential hormonal adverse effects (e.g., bleeding pattern changes, acne, emotional lability) or any changes in efficacy (e.g., noted changes in bleeding patterns) to their prescribers. Because norethindrone-containing contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive norethindrone contraception concurrently with ritonavir should use an additional barrier method of contraception such as condoms. [58679] [7731] Nisoldipine: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] Nitrofurantoin: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Nitroprusside: (Minor) The administration of estrogens may increase blood pressure, and thereby antagonizing the antihypertensive effects of nitroprusside. [805] Ofloxacin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] 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] Omadacycline: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting the hepatitis C regimen, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with the hepatitis C regimen. [58664] (Major) Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. [46638] [5044] (Moderate) Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. For example, ritonavir (also found in combinations like lopinavir; ritonavir, and used as a booster in many HIV treatment regimens) may decrease the metabolism of norethindrone, raising norethindrone concentrations. Women receiving norethindrone for hormone replacement or contraception should report potential hormonal adverse effects (e.g., bleeding pattern changes, acne, emotional lability) or any changes in efficacy (e.g., noted changes in bleeding patterns) to their prescribers. Because norethindrone-containing contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive norethindrone contraception concurrently with ritonavir should use an additional barrier method of contraception such as condoms. [58679] [7731] 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] (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Oritavancin: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] 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] Oxacillin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Oxazepam: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines. [7486] Oxcarbazepine: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as oxcarbazepine. Concurrent administration of oxcarbazepine progestins may increase the hormone's elimination. A high percentage of breakthrough bleeding has been reported in the literature from the combined use of oxcarbazepine and oral contraceptives; the results of one study demonstrated that the mean AUC of ethinyl estradiol/levonorgestrel was decreased by 52% when coadministered with oxcarbazepine. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs, or higher-dose hormonal regimens may be indicated where acceptable or applicable as pregnancy has been reported in patients taking the hepatic enzyme inducing drug phenytoin concurrently with hormonal contraceptives. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; if oral contraceptive failure occurs, the additive effects could potentially heighten the risk of neural tube defects in pregnancy. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on oxcarbazepine, with dose adjustments made based on clinical efficacy. [22005] [5307] [55436] [57046] [57048] [5749] [57648] [6300] (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] Paromomycin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Pazopanib: (Moderate) Pazopanib is a substrate for CYP3A4. Ethinyl estradiol is an inhibitor of CYP3A4. Concurrent administration may result in increased pazopanib concentrations. Dose reduction of pazopanib may be necessary when coadministration of pazopanib and ethinyl estradiol is required. [37098] Pegaspargase: (Major) Avoid the concomitant use of pegaspargase and oral hormonal contraceptives due to the potential for decreased contraceptive efficacy and risk of fetal harm from pegaspargase. Women of reproductive potential should use an effective non-hormonal method of birth control during therapy and for at least 3 months after the last pegaspargase dose. [61310] Penicillin G Benzathine: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillins and their derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use (i.e., amoxicillin, chloramphenicol, neomycin, nitrofurantoin, sulfonamides, etc.) may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Penicillin G Benzathine; Penicillin G Procaine: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillins and their derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use (i.e., amoxicillin, chloramphenicol, neomycin, nitrofurantoin, sulfonamides, etc.) may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Penicillin G Procaine: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillins and their derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use (i.e., amoxicillin, chloramphenicol, neomycin, nitrofurantoin, sulfonamides, etc.) may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Penicillin G: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillins and their derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use (i.e., amoxicillin, chloramphenicol, neomycin, nitrofurantoin, sulfonamides, etc.) may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Penicillin V: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillins and their derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use (i.e., amoxicillin, chloramphenicol, neomycin, nitrofurantoin, sulfonamides, etc.) may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] 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] (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment. [22005] [28502] [29653] [29821] [30802] [30858] [30890] [33322] [42126] [46375] [48201] [48254] [49996] [57048] [57271] [57649] [59800] [62899] Perindopril; Amlodipine: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] 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] Pexidartinib: (Major) Avoid the concomitant use of pexidartinib and hormone-containing contraceptives; the effectiveness of hormonal contraceptives may be decreased resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for 1 month after treatment with pexidartinib. Advise these patients to use an effective, non-hormonal method of contraception. Pexidartinib is a moderate CYP3A inducer and many oral contraceptives are metabolized by CYP3A. [64535] Phenobarbital: (Major) Women taking both estrogens and barbiturates should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed barbiturates. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of barbiturates. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on barbiturates, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and barbiturate are strong CYP3A4 inducers. Concurrent administration may increase estrogen elimination. [22005] [28200] [28502] [29653] [29821] [30858] [40617] [48201] [49996] [51268] [56579] [57271] (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment. [22005] [28502] [29653] [29821] [30802] [30858] [30890] [33322] [42126] [46375] [48201] [48254] [49996] [57048] [57271] [57649] [59800] [62899] Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Women taking both estrogens and barbiturates should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed barbiturates. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of barbiturates. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on barbiturates, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and barbiturate are strong CYP3A4 inducers. Concurrent administration may increase estrogen elimination. [22005] [28200] [28502] [29653] [29821] [30858] [40617] [48201] [49996] [51268] [56579] [57271] (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment. [22005] [28502] [29653] [29821] [30802] [30858] [30890] [33322] [42126] [46375] [48201] [48254] [49996] [57048] [57271] [57649] [59800] [62899] Phenothiazines: (Minor) Oral contraceptives may also cause additive photosensitization with phenothiazines. [5765] Phenoxybenzamine: (Minor) Estrogen-containing oral contraceptive may induce fluid retention and may increase blood pressure in some patients taking antihypertensive agents. Such patients should be monitored to confirm that the desired antihypertensive effect is being obtained. [4716] [805] 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] (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers. [22005] [28378] [33941] [48201] [57046] [57048] [57588] [57648] 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: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [30585] [62853] Pioglitazone; Glimepiride: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [30585] [62853] (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [6266] 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] (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. [28550] [30585] [62853] (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [30585] [62853] Piperacillin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Piperacillin; Tazobactam: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Pitolisant: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy. [64562] Plazomicin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Polymyxin B: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Posaconazole: (Moderate) Posaconazole and ethinyl estradiol should be coadministered with caution due to an increased potential for adverse events. Both posaconazole and ethinyl estradiol are inhibitors of CYP3A4, an isoenzyme partially responsible for the metabolism of ethinyl estradiol. Further, both ethinyl estradiol and posaconazole are substrates of the drug efflux protein, P-glycoprotein, which when administered together may increase the absorption or decrease the clearance of the other drug. This complex interaction may cause alterations in the plasma concentrations of both posaconazole and ethinyl estradiol, ultimately resulting in an increased risk of adverse events. [32723] [4744] 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] (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [7053] Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Either additive or antagonistic effects could potentially occur if prasterone is combined with estrogen therapy. [2455] (Moderate) Either additive or antagonistic effects could potentially occur if prasterone is combined with progestins. [2455] Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Either additive or antagonistic effects could potentially occur if prasterone is combined with estrogen therapy. [2455] (Moderate) Either additive or antagonistic effects could potentially occur if prasterone is combined with progestins. [2455] Prazosin: (Minor) Estrogen-containing oral contraceptive may induce fluid retention and may increase blood pressure in some patients taking antihypertensive agents. Such patients should be monitored to confirm that the desired antihypertensive effect is being obtained. [4716] [805] 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] Pretomanid: (Major) Avoid coadministration of pretomanid with oral contraceptives, especially in patients with impaired hepatic function, due to increased risk for hepatotoxicity. Monitor for evidence of hepatotoxicity if coadministration is necessary. If new or worsening hepatic dysfunction occurs, discontinue hepatotoxic medications. [63549] [64561] 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] (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment. [22005] [28502] [29653] [29821] [30802] [30858] [30890] [33322] [42126] [46375] [48201] [48254] [49996] [57048] [57271] [57649] [59800] [62899] Quazepam: (Minor) Ethinyl estradiol may inhibit the clearance of quazepam. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to benzodiazepines. [7486] 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] Ramelteon: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as ethinyl estradiol, may lead to increases in the serum concentrations of ramelteon. [4718] Ranolazine: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition. [4718] Rasagiline: (Minor) Monitor for dopaminergic adverse effects during concurrent use of rasagiline and ethinyl estradiol. Increased rasagiline concentrations are possible, but not likely. A dose reduction of rasagiline may be necessary in the rare patient. Rasagiline is primarily metabolized by CYP1A2. Oral contraceptives containing ethinyl estradiol are noted to be CYP1A2 inhibitors, but published clinical evidence of drug-drug interactions due to this effect are lacking. [32223] [56579] Reserpine: (Minor) Estrogen-containing oral contraceptive may induce fluid retention and may increase blood pressure in some patients taking antihypertensive agents. Such patients should be monitored to confirm that the desired antihypertensive effect is being obtained. [4716] [805] Ribociclib: (Moderate) Use caution if coadministration of ribociclib with ethinyl estradiol is necessary, as the systemic exposure of ethinyl estradiol may be increased resulting in an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness). Ribociclib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate. [29653] [30858] [40617] [47343] [57085] [61816] 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] (Moderate) Use caution if coadministration of ribociclib with ethinyl estradiol is necessary, as the systemic exposure of ethinyl estradiol may be increased resulting in an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness). Ribociclib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate. [29653] [30858] [40617] [47343] [57085] [61816] 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] (Major) Women taking both progestins and rifampin should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed rifampin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of rifampin. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and rifampin is a strong CYP3A4 inducer. [30314] [33322] [57648] 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] (Major) Women taking both progestins and rifapentine should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed rifapentine. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of rifapentine. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and rifapentine is a strong CYP3A4 inducer. [33322] [57648] [65685] Riluzole: (Moderate) Monitor patients for increased riluzole-related adverse events, such as gastrointestinal symptoms and elevated hepatic enzymes, when hormonal contraceptives are prescribed concurrently. Serum concentrations of riluzole, a CYP1A2 substrate, may increase when oral contraceptives, moderate CYP1A2 inhibitors, are used concurrently. In vitro findings suggest an increase in riluzole exposure is likely when a CYP1A2 inhibitor is given. [29747] [57048] Ritonavir: (Major) Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. [46638] [5044] (Moderate) Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. For example, ritonavir (also found in combinations like lopinavir; ritonavir, and used as a booster in many HIV treatment regimens) may decrease the metabolism of norethindrone, raising norethindrone concentrations. Women receiving norethindrone for hormone replacement or contraception should report potential hormonal adverse effects (e.g., bleeding pattern changes, acne, emotional lability) or any changes in efficacy (e.g., noted changes in bleeding patterns) to their prescribers. Because norethindrone-containing contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive norethindrone contraception concurrently with ritonavir should use an additional barrier method of contraception such as condoms. [58679] [7731] 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] Roflumilast: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel. [43551] Romidepsin: (Major) The concomitant use of romidepsin and ethinyl estradiol may reduce the efficacy of ethinyl estradiol. Because romidepsin can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use an alternative effective contraception method (e.g., condoms or intrauterine devices) during treatment with romidepsin and for at least 1 month after the final dose. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies. [37292] 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] Rosiglitazone: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [30585] [62853] Rosuvastatin: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention. [27988] Rosuvastatin; Ezetimibe: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention. [27988] Rufinamide: (Major) Coadministration of hormonal contraceptives with rufinamide may reduce hormone concentrations and therefore reduce the clinical efficacy of hormonal contraceptives. If coadministration is necessary, recommend patients use additional non-hormonal forms of contraception. Hormonal contraceptives are metabolized by CYP3A4 and rufinamide is a weak CYP3A4 inducer. [34590] Ruxolitinib: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as ethinyl estradiol, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure. [46782] Saquinavir: (Major) The concurrent use of saquinavir boosted with ritonavir and oral contraceptives should be avoided if possible due to the potential for decreased contraceptive effectiveness. Saquinavir may increase the metabolism of oral contraceptives and non-oral combination contraceptives. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as saquinavir/ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Women who receive hormonal contraceptives concurrently with PIs should use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. Furthermore, the oral contraceptive, ethinyl estradiol, may inhibit CYP3A4 mediated metabolism of saquinavir, potentially resulting in elevated saquinavir plasma concentrations and the development of saquinavir-related adverse effects. [28995] [46638] Sarilumab: (Moderate) Utilize caution with concomitant use of sarilumab and CYP3A4 substrate drugs, such as combined hormonal oral contraceptives, where a decrease in effectiveness is undesirable. Inhibition of IL-6 signaling by sarilumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping sarilumab. In vitro, sarilumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. [61976] Saxagliptin: (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. [7347] 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] (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment. [22005] [28502] [29653] [29821] [30802] [30858] [30890] [33322] [42126] [46375] [48201] [48254] [49996] [57048] [57271] [57649] [59800] [62899] Selegiline: (Moderate) Consider a selegiline dose reduction to minimize the risk for selegiline-related adverse reactions during concomitant ethinyl estradiol use. Concomitant use may increase selegiline exposure. [68188] 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] Siltuximab: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy. [57062] Simvastatin; Sitagliptin: (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. [7347] Sincalide: (Moderate) Sincalide-induced gallbladder ejection fraction may be affected by concurrent oral contraceptives. False study results are possible in patients with drug-induced hyper- or hypo-responsiveness; thorough patient history is important in the interpretation of procedure results. [9348] [9349] Sitagliptin: (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. [7347] Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with ethinyl estradiol. Taking these drugs together may increase the plasma concentrations velpatasvir and ethinyl estradiol, potentially resulting in adverse events. Velpatasvir is a CYP2B6 and CYP3A4 substrate; ethinyl estradiol is an in vitro inhibitor of CYP2B6 and CYP3A4. In addition, ethinyl estradiol is a substrate for the drug transporter P-glycoprotein (P-gp); velpatasvir is a P-gp inhibitor. [40617] [47343] [57085] [60911] Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with ethinyl estradiol. Taking these drugs together may increase the plasma concentrations velpatasvir and ethinyl estradiol, potentially resulting in adverse events. Velpatasvir is a CYP2B6 and CYP3A4 substrate; ethinyl estradiol is an in vitro inhibitor of CYP2B6 and CYP3A4. In addition, ethinyl estradiol is a substrate for the drug transporter P-glycoprotein (P-gp); velpatasvir is a P-gp inhibitor. [40617] [47343] [57085] [60911] 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) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). [42126] [48201] [57202] [57588] [57648] [63694] (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: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. Additionally, dalfopristin; quinupristin is a major inhibitor of cytochrome P450 3A4 and may decrease the elimination of drugs metabolized by this enzyme including ethinyl estradiol and norethindrone. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. [28482] [28509] [31698] Streptomycin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Succinylcholine: (Moderate) Plasma cholinesterase activity may be diminished by chronic administration of oral contraceptives; consider the possibility of prolonged neuromuscular block after administration of succinylcholine in patients with reduced plasma cholinesterase activity. The use of a peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of neuromuscular blocker, and to determine whether adjustments need to be made to the dose with subsequent administration. [42039] [65534] Sugammadex: (Major) If an oral contraceptive is taken the same day sugammadex is administered, the patient must use an additional, non-hormonal contraceptive method or back-up method of contraception for the next 7 days. Sugammadex may bind to progestogen, resulting in a decrease in progestogen exposure. The administration of a bolus dose of sugammadex results in actions that are essentially equivalent to missing one or more doses of contraceptives containing estrogen or progestogen, including combination oral contraceptives, non-oral combination contraceptives, or progestins. [60450] Sulfadiazine: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Sulfasalazine: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Sulfonamides: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] 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] (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [6266] Tacrolimus: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects. [4718] 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] (Major) Women taking both progestins and tazemetostat should report breakthrough bleeding to their prescribers. 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 1 month after discontinuation of tazemetostat. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and tazemetostat is a weak CYP3A4 inducer. [33322] [57648] [64952] Tedizolid: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances.Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Telavancin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Telmisartan; Amlodipine: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] Temazepam: (Minor) Ethinyl estradiol may enhance the metabolism of temazepam. Because temazepam clearance is increased by combined oral contraceptives, mean plasma concentration may be decreased. The clinical significance of this interaction is not determined. [30723] Temsirolimus: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with temsirolimus is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may to lead to increased concentrations of ethinyl estradiol. [50586] [60859] Terazosin: (Minor) Estrogen-containing oral contraceptive may induce fluid retention and may increase blood pressure in some patients taking antihypertensive agents. Such patients should be monitored to confirm that the desired antihypertensive effect is being obtained. [4716] [805] Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering ethinyl estradiol. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C19 and CYP3A4; ethinyl estradiol is an inhibitor of these enzymes. Monitor patients for adverse reactions if these drugs are coadministered. [37590] [43880] [43881] [56538] Teriflunomide: (Moderate) Teriflunomide may increase the effects of oral contraceptives. Following consecutive teriflunomide doses, mean ethinyl estradiol Cmax and AUC increased 1.58- and 1.54-fold, respectively, during coadministration. Levonorgestrel Cmax increased 1.33-fold and AUC 1.41-fold during coadministration. Use caution when selecting the type and dose of oral contraceptives in patients taking teriflunomide. [51794] 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] Tetracycline: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Thalidomide: (Moderate) Thalidomide and hormone contraceptives should be used cautiously due an increased risk of thromboembolism. The pharmacokinetic parameters of norethindrone/estradiol were not affected when a single dose of norethindrone 1 mg/estradiol 75 micrograms was administered in 10 healthy women who were receiving thalidomide 200 mg/day (at steady state levels). [49713] Theophylline, Aminophylline: (Moderate) Theophylline or aminophylline concentrations may be increased during administration with ethinyl estradiol. This interaction occurs from the inhibition of methylxanthine oxidation in the liver. A aminophylline or theophylline dose adjustment may be needed in some patients. Estrogen-containing hormonal contraceptives decrease theophylline clearance in a dose-dependent fashion and may cause up to a 30% increase in thephylline concentrations. [31082] [44232] [44294] 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] (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [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] Tigecycline: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Tinidazole: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Tipranavir: (Major) It is not known if tipranavir alters the metabolism of norethindrone-only contraception; tipranavir has been reported to reduce efficacy of other hormonal contraceptives. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. Women receiving norethindrone hormone replacement or contraceptives with tipranavir should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception are recommended in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with tipranavir should use an additional barrier method of contraception such as condoms. [46638] [58679] [8102] (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. [46638] [8102] Tirzepatide: (Major) Advise patients receiving tirzepatide and oral contraceptives to switch to a non-oral contraceptive method or to add a barrier method of contraception for 4 weeks after initiation and for 4 weeks after each dose escalation of tirzepatide. Tirzepatide delays gastric emptying and may reduce the rate and extent of estrogen and progestin absorption which may reduce efficacy. Gastric emptying delays are greatest after the first dose of tirzepatide and diminish over time. Hormonal contraceptives that are not administered orally should not be affected. Additionally, estrogens can impair glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day. [30585] [48491] [62853] [67631] Tizanidine: (Major) Avoid concomitant use of tizanidine and oral contraceptives as increased tizanidine exposure may occur. If use together is necessary, initiate tizanidine with a single 2 mg dose and increase by 2 to 4 mg/day based on clinical response. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occurs. A retrospective analysis of population pharmacokinetic data found that the clearance of tizanidine was 50% lower in females taking oral contraceptives compared to those not on oral contraceptives. [52430] 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] Tobramycin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Tocilizumab: (Moderate) Utilize caution with concomitant use of tocilizumab and CYP3A4 substrate drugs, such as combined hormonal oral contraceptives, where a decrease in effectiveness is undesirable. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. [38283] Tolazamide: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [6266] Tolbutamide: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. [6266] 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] (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers. [22005] [28378] [33941] [48201] [57046] [57048] [57588] [57648] 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] Tramadol; Acetaminophen: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. [41929] Trandolapril; Verapamil: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] 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] Trimethoprim: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Tucatinib: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with tucatinib is necessary. Ethinyl estradiol is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. [40617] [57085] [65295] Ulipristal: (Major) Avoid concurrent use of ulipristal and progestin-containing hormonal contraceptives or other progestins. Hormonal contraceptives may be started or resumed no sooner than 5 days after ulipristal treatment. Also, a reliable barrier method of contraception should be used during the same menstrual cycle in which ulipristal was administered (until the next menstrual period). Progestin-containing contraceptives may impair the ability of ulipristal to delay ovulation. Ulipristal may reduce the effectiveness of progestin-containing hormonal contraceptives by competitively binding at the progesterone receptor. [41569] [50623] 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] Vancomycin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Verapamil: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients. [805] Vincristine Liposomal: (Moderate) In vitro, ethinyl estradiol is a mild CYP3A4 inhibitor, and vincristine is a CYP3A substrate. Theoretically, coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together. [29472] [47343] [57085] Vincristine: (Moderate) In vitro, ethinyl estradiol is a mild CYP3A4 inhibitor, and vincristine is a CYP3A substrate. Theoretically, coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together. [29472] [47343] [57085] Vonoprazan; Amoxicillin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. [28482] [28509] (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin. [28238] [28482] [28509] [31698] [34329] Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and ethinyl estradiol. Vorapaxar is a CYP3A4 substrate. Ethinyl estradiol inhibits CYP3A4 in vitro. Increased serum concentrations of vorapaxar are possible when vorapaxar is coadministered with ethinyl estradiol. Increased exposure to vorapaxar may increase the risk of bleeding complications. [47343] [4744] [57151] Voriconazole: (Moderate) Ethinyl estradiol and norethindrone increases the Cmax and AUC of voriconazole and voriconazole increases the Cmax and AUC of both ethinyl estradiol and norethindrone. [4882] (Moderate) Voriconazole may increase plasma concentrations of ethinyl estradiol by inhibiting CYP3A4 , resulting in estrogen-related side effects such as nausea and breast tenderness. Ethinyl estradiol, when combined with norethindrone, may also increase the Cmax and AUC of voriconazole. [27982] [29036] [41929] [42851] 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] Zolmitriptan: (Minor) Retrospective data indicate that mean plasma concentrations of zolmitriptan were generally higher in females taking oral contraceptives (e.g., those containing ethinyl estradiol) compared to those not taking oral contraceptives. Mean Cmax and AUC of zolmitriptan were found to be higher by 30% and 50%, respectively, and Tmax was delayed by one-half hour in females taking oral contraceptives. The effect of zolmitriptan on the pharmacokinetics of oral contraceptives has not been studied. The clinical significance of these interactions has not been established. Hormone replacement therapy regimens (HRT) are not thought to interact, based on data with other 'triptans' with similar pharmacokinetic interactions with oral contraceptives. [28445] Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ethinyl estradiol is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates. [28843]
    Revision Date: 02/02/2023, 02:26:00 AM

    References

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    Monitoring Parameters

    • pap smear
    • pelvic exam

    US Drug Names

    • Aurovela
    • femhrt 1/5
    • Fravolv
    • Fyavolv
    • Gildess
    • Hailey 1.5/30
    • Jevantique
    • Jinteli 1/5
    • Junel 1.5/30
    • Junel 1/20
    • LARIN
    • Loestrin 1.5/30
    • Loestrin 1/20
    • Microgestin 1.5/30
    • Microgestin 1/20
    ;