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    Estrogen with Progestogen Combinations, Excluding Hormonal Contraceptives
    Monophasic Contraceptives

    BOXED WARNING

    Atrial fibrillation, cardiac disease, cerebrovascular disease, coronary artery disease, coronary thrombosis, endocarditis, hypercholesterolemia, hypertension, myocardial infarction, protein C deficiency, protein S deficiency, stroke, thromboembolic disease, thromboembolism, thrombophlebitis, tobacco smoking, valvular heart disease

    Combined hormonal contraceptive agents and estrogen-containing hormonal replacement therapy (HRT), such as ethinyl estradiol; norethindrone acetate 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 combined oral contraceptives (COCs) and estrogen-containing HRT have been associated with thromboembolism such as deep venous thrombosis (DVT). COCs and hormone replacement therapies containing estrogen are also generally contraindicated in women with high risks for thromboembolism, including those 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). ORAL CONTRACEPTIVES: Hormonal combined oral 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. 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, morbid obesity, or patients with diabetes with vascular disease 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 or renal disease, should be closely monitored. 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. 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 obesity) and/or venous thromboembolism (VTE) [e.g., personal history or family history of VTE, obesity, or systemic lupus (SLE)] should be monitored and managed appropriately during HRT use. 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.  In the Women's Health Initiative (WHI) estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as non-fatal MI, silent MI, or CHD death ) was reported in women receiving estrogen-alone compared to placebo. Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE-alone vs. placebo) in women with less than 10 years since menopause (8 vs. 16 per 10,000 women-years). In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily estrogen plus progestin compared to women receiving placebo (41 vs. 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5. Studies have also shown no cardiovascular benefit to the use of estrogens or estrogen-progestin therapy for secondary prevention in women with documented cardiac disease or CHD. Estrogens also increase the risk for stroke. In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen-alone compared to women in the same age group receiving placebo (45 vs. 33 per 10,000 women-years). The increase in risk was demonstrated in the first year and persisted. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving estrogen-alone versus those receiving placebo (18 vs. 21 per 10,000 women-years). In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen plus progestin HRT compared to women in the same age group receiving placebo (33 vs. 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. Women over the age of 65 years were at increased risk for non-fatal stroke. Patients with hypertension should be monitored closely for increases in blood pressure if HRT is administered. In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogen therapy. In a large, randomized, placebo controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. 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.

    Breast cancer, hypercalcemia, new primary malignancy

    Ethinyl estradiol; norethindrone acetate products, including combined 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. 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. Since the 1970's, numerous epidemiological studies have examined the association of estrogens or combined HRT and breast cancer. 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. 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. Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with combined HRT as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.. While estrogen therapy may be used rarely for the palliative treatment of advanced breast cancer in men and women, estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level. HORMONAL CONTRACEPTION: There is substantial evidence that use of COCs does not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings. Several large, well designed observational studies have provided data regarding the risk of breast cancer with combined oral contraceptive (COC) use. 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. Moreover, the same study data suggest that any increased risk of breast cancer usually disappears rapidly after an interruption in the use of COCs. 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. 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.

    Dementia, geriatric

    Hormone replacement therapy (HRT) with ethinyl estradiol; norethindrone acetate 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. Administration of HRT should generally be avoided in women 65 years of age and older, and HRT should not be used to prevent or treat dementia or preserve cognition (memory). Overall risk vs. benefit should be considered along with the goals of use of HRT for the individual patient when considering whether to continue HRT in a geriatric woman over 65 years of age. According to the Beers Criteria, oral and topical patch 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. The Beers expert panel considers use of intra-vaginal preparations acceptable for the management of dyspareunia, lower urinary tract infections, and other vaginal/vulvar symptoms.

    DEA CLASS

    Rx

    DESCRIPTION

    Combined oral contraceptive (COC) or hormone replacement therapy (HRT) depending on product; ethinyl estradiol is an estrogen; norethindrone acetate is a progestin of moderate androgenic and slight estrogenic activity
    COC products used for routine contraception in adolescent and premenopausal females; all COCs contain a boxed warning regarding the increased risk for thromboembolism in women who smoke
    HRT-oriented products used to treat symptoms of menopause or for osteoporosis prophylaxis in menopausal women; NOT effective as contraceptives; boxed warnings for HRT relate to cardiovascular, dementia, and cancer risks

    COMMON BRAND NAMES

    femhrt 1/5, Fravolv, Fyavolv, Gildess, 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

    HOW SUPPLIED

    Ethinyl Estradiol, Norethindrone/femhrt 1/5/Fravolv/Fyavolv/Gildess/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/Norethindrone Acetate, Ethinyl Estradiol Oral Tab: 0.5-2.5mcg, 1-0.02mg, 1-5mcg, 1.5-0.03mg

    DOSAGE & INDICATIONS

    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.

    For treatment of moderate to severe vasomotor symptoms (hot flashes) of menopause and/or related genitourinary symptoms including atrophic vaginitis, vulvar atrophy (kraurosis vulvae) in women with an intact uterus.
    Oral dosage (tablets with 2.5 estradiol/0.5 mg norethindrone acetate OR 5 mcg estradiol/1 mg of norethindrone acetate; e.g., FEMHRT Low Dose, FEMHRT, Fyavolv, Jinteli, Jentique Lo)
    Adult females

    1 tablet (containing ethinyl estradiol 2.5 mcg and norethindrone acetate 0.5 mg OR containing ethinyl estradiol 5 mcg and norethindrone acetate 1 mg) PO once daily. Use lowest effective dose. Reevaluate the appropriateness of hormonal therapy at 3 to 6 month intervals. When treating isolated genitourinary symptoms, consider vaginal topical therapy. The North American Menopause Society (NAMS) Guidelines support the initiation of hormone replacement therapy (HRT) around the time of menopause if no contraindications to use exist and use is acceptable to the individual patient, as hormone therapy is the most effective treatment for vasomotor and genitourinary symptoms and has been shown to prevent bone loss and fracture. Early initiation of HRT and continuation of use at until the median age of menopause (52 years) is recommended in women with premature natural or surgically induced menopause. HRT for vasomotor symptoms and/or increased risk for bone loss around the time of menopause may be considered in those women aged younger than 60 years or who are fewer than 10 years from menopause onset. For women who initiate HRT more than 10 or 20 years from menopause onset or are aged 60 years or older, the benefit-risk ratio is less favorable due to known risks for HRT (e.g., stroke, myocardial infarction, venous thromboembolism, dementia, urinary incontinence), and guidelines generally recommend against use in these women. Decisions regarding whether to continue systemic HRT in women aged older than 60 years should be made on an individual basis for quality of life, persistent vasomotor symptoms, or prevention of bone loss and fracture, with consideration given to alternative treatments for prevention of bone loss and other health issues.

    For osteoporosis prophylaxis due to menopause (natural or surgical) in women with an intact uterus.
    Oral dosage (tablets with 2.5 mcg estradiol/0.5 mg norethindrone acetate OR 5 mcg estradiol/1 mg of norethindrone acetate; e.g., FEMHRT Low Dose, FEMHRT, Fyavolv, Jinteli, Jentique Lo)
    Adult females

    1 tablet (containing ethinyl estradiol 2.5 mcg and norethindrone acetate 0.5 mg OR containing ethinyl estradiol 5 mcg and norethindrone acetate 1 mg) PO once daily for women at significant risk for osteoporosis. Use lowest effective dose. Reevaluate the appropriateness of hormonal therapy at 3 to 6 month intervals; consider the appropriateness of non-estrogen medications. In postmenopausal women with low bone mineral density, there is good evidence that standard-dose estrogen therapy reduces reduces the risk for osteoporotic fractures, including hip, spine, and all non-spine fractures; however, estrogens are not generally recommended as a first-line prevention tactic due to the known risks of estrogen treatment (e.g., thromboembolism, cerebrovascular events) relative to other treatments. Women who need osteoporosis prophylaxis who are younger than 60 years or who are within 10 years of menopause onset may be given consideration for estrogen therapy, based on individual assessment of risk vs. benefit. Beyond the age of 60 years, other agents are preferred due to the known risks associated with hormonal therapy. Consider each woman's net balance of individual benefits and harms. If estrogen with or without a progestin is prescribed, use the lowest effective dose for the shortest duration that is consistent with an individual's treatment goals and risks. Estrogen therapy should not be used in patients with known osteoporosis; the risks outweigh the moderate benefit seen in postmenopausal women with established osteoporosis.

    For the treatment of moderate acne vulgaris† related to sebum overproduction in females who have no known contraindications to oral contraceptives, desire contraception, have achieved menarche, and are unresponsive to topical anti-acne medications.
    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.

    For the treatment or adjuvant treatment of amenorrhea†, abnormal uterine bleeding† (dysfunctional uterine bleeding†), hirsutism†, hypermenorrhea†, or polycystic ovary syndrome† related to hypoestrogenic or hyperandrogenic conditions in females who have no known contraindications to oral contraceptives, desire contraception, have achieved menarche, and have been evaluated for causes of the condition.
    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.

    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.

    †Indicates off-label use

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Contraindicated for use in patients with known liver impairment or disease.

    Renal Impairment

    These products have not been studied in subjects with renal impairment.

    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
     
    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.

    STORAGE

    femhrt 1/5:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Fravolv:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Fyavolv:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Gildess:
    - Store below 86 degrees F
    Jevantique:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Jinteli 1/5:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Junel 1.5/30:
    - Store below 86 degrees F
    Junel 1/20:
    - Store below 86 degrees F
    LARIN:
    - Store below 86 degrees F
    Loestrin 1.5/30:
    - Store below 86 degrees F
    Loestrin 1/20:
    - Store below 86 degrees F
    Microgestin 1.5/30:
    - Store below 86 degrees F
    Microgestin 1/20:
    - Store below 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Hereditary angioedema, history of angioedema

    Do not use ethinyl estradiol; norethindrone acetate 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.

    Atrial fibrillation, cardiac disease, cerebrovascular disease, coronary artery disease, coronary thrombosis, endocarditis, hypercholesterolemia, hypertension, myocardial infarction, protein C deficiency, protein S deficiency, stroke, thromboembolic disease, thromboembolism, thrombophlebitis, tobacco smoking, valvular heart disease

    Combined hormonal contraceptive agents and estrogen-containing hormonal replacement therapy (HRT), such as ethinyl estradiol; norethindrone acetate 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 combined oral contraceptives (COCs) and estrogen-containing HRT have been associated with thromboembolism such as deep venous thrombosis (DVT). COCs and hormone replacement therapies containing estrogen are also generally contraindicated in women with high risks for thromboembolism, including those 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). ORAL CONTRACEPTIVES: Hormonal combined oral 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. 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, morbid obesity, or patients with diabetes with vascular disease 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 or renal disease, should be closely monitored. 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. 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 obesity) and/or venous thromboembolism (VTE) [e.g., personal history or family history of VTE, obesity, or systemic lupus (SLE)] should be monitored and managed appropriately during HRT use. 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.  In the Women's Health Initiative (WHI) estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as non-fatal MI, silent MI, or CHD death ) was reported in women receiving estrogen-alone compared to placebo. Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE-alone vs. placebo) in women with less than 10 years since menopause (8 vs. 16 per 10,000 women-years). In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily estrogen plus progestin compared to women receiving placebo (41 vs. 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5. Studies have also shown no cardiovascular benefit to the use of estrogens or estrogen-progestin therapy for secondary prevention in women with documented cardiac disease or CHD. Estrogens also increase the risk for stroke. In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen-alone compared to women in the same age group receiving placebo (45 vs. 33 per 10,000 women-years). The increase in risk was demonstrated in the first year and persisted. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving estrogen-alone versus those receiving placebo (18 vs. 21 per 10,000 women-years). In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen plus progestin HRT compared to women in the same age group receiving placebo (33 vs. 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. Women over the age of 65 years were at increased risk for non-fatal stroke. Patients with hypertension should be monitored closely for increases in blood pressure if HRT is administered. In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogen therapy. In a large, randomized, placebo controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. 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.

    Surgery

    If feasible, ethinyl estradiol; norethindrone acetate combined oral contraceptive (COC) or hormonal replacement therapy (HRT) should be discontinued at least 4 to 6 weeks before any surgery associated with an increased risk of thromboembolism, or during any periods of prolonged immobilization. The decision on when to resume estrogens after such procedures or conditions would be based on the perceived additional thromboembolic risk from estrogen use and the need for estrogen therapy; resume only after the patient is fully ambulatory. In addition, women taking COCs or HRT should be advised to move about periodically during travel involving prolonged immobilization.

    Pregnancy

    Ethinyl estradiol; norethindrone acetate products are contraindicated during pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from combined oral contraceptives (COCs) inadvertently during early pregnancy. Estradiol and other estrogens freely cross the placenta to the fetus. Increased risk of a wide variety of fetal abnormalities, including modified development of sexual organs, cardiovascular anomalies and limb defects, have been reported following the continued use of estrogens in pregnant women. In any patient in whom pregnancy is suspected, pregnancy should be ruled out before continuing estrogen use. In addition, oral contraceptive use may alter folate metabolism, and women who discontinue oral contraceptives to pursue pregnancy should preferably wait 3 months for folate concentrations to normalize if possible. Folate supplementation should be given once pregnant to reduce the incidence of neural tube defects.

    Breast-feeding, obstetric delivery

    Caution should be used if a breast-feeding mother is receiving ethinyl estradiol; norethindrone acetate products. In general, these products should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens and progestins have been identified in the milk of women receiving combined hormonal replacement therapy (HRT) or combined hormonal oral contraceptives (OCs). Avoidance of COCs during lactation is recommended if possible until a mother has completely weaned her child. Similarly, hormone replacement therapy with EE; norethindrone acetate should be approached with caution during lactation. Experts often recommend avoidance of estrogen-containing COCs, in the first 21 days postpartum (or longer, if other risks for thromboembolism exist) due to maternal post-partum clot risks following obstetric delivery , and the potential for COCs to interfere with the establishment of lactation. It is generally accepted that estrogen-containing COCs 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. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA. Alternate contraceptive agents for consideration include non-hormonal contraceptive methods and also progestin-only contraceptives, such as medroxyprogesterone injection (e.g., Depo-Provera).

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

    Combined oral contraceptives (COCs) and hormone replacement regimens containing ethinyl estradiol; norethindrone acetate 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). 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, COC or hormone replacement use should be discontinued. Estrogens and progestins may be poorly metabolized in women with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of hormonal therapy or COC use until markers of liver function return to normal and hormonal 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 combined oral contraceptives prior to starting hepatitis C therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir; COCs 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. In general, COCs and hormonal replacement regimens containing estrogens should 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.

    Contact lenses, glaucoma, headache, migraine, visual disturbance

    Ethinyl estradiol; norethindrone acetate is contraindicated in patients with headache, such as migraine, that is accompanied by focal neurological symptoms, such as aura. Oral contraceptives and hormonal replacement therapy may cause the onset or exacerbate a migraine or cause the development of headache with a new pattern which is recurrent, persistent, or severe. Patients who complain of migraine with focal neurologic visual changes should be evaluated, and in some patients, such changes may indicate cerebrovascular events. The cause of headache requires evaluation by a health care provider. Retinal vascular thrombosis has been reported in women receiving estrogens. Any visual disturbance should be examined by an ophthalmologist. Discontinue estradiol; norethindrone acetate pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine with visual changes. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued. Estrogens can increase the curvature of the cornea and may lead to intolerance of contact lenses. Long-term oral contraceptive use may play a potential role in the development of glaucoma; experts caution patients and providers to be aware of this association and recommend glaucoma screening for patients with additional risk factors. Black patients, patients with a family history of glaucoma, and patients with a history of ocular hypertension or existing visual field defects represent groups with additional risk factors.

    Asthma, renal disease, seizure disorder

    Because estradiol; norethindrone acetate may cause fluid retention, conditions that might be affected by fluid retention, such as heart disease or renal disease, require careful observation. Estrogen therapy may also cause an exacerbation of asthma, seizure disorder, and hepatic hemangiomas in some patients and should be used with caution in women with these conditions.

    Breast cancer, hypercalcemia, new primary malignancy

    Ethinyl estradiol; norethindrone acetate products, including combined 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. 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. Since the 1970's, numerous epidemiological studies have examined the association of estrogens or combined HRT and breast cancer. 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. 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. Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with combined HRT as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.. While estrogen therapy may be used rarely for the palliative treatment of advanced breast cancer in men and women, estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level. HORMONAL CONTRACEPTION: There is substantial evidence that use of COCs does not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings. Several large, well designed observational studies have provided data regarding the risk of breast cancer with combined oral contraceptive (COC) use. 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. Moreover, the same study data suggest that any increased risk of breast cancer usually disappears rapidly after an interruption in the use of COCs. 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. 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.

    Ovarian cancer

    Ethinyl estradiol; norethindrone acetate combined oral contraceptive (COC) and hormonal replacement therapy 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 decades after stopping use. 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. 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.

    Cervical cancer

    Estrogens are contraindicated in the presence of cervical cancer or other estrogen-responsive tumors. Most cervical cancers are related to the presence of the human papillomavirus (HPV), but hormonal factors influence risk. In women taking combined oral contraceptives (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. An increased risk for cervical dysplasia or cancer has NOT been noted with the use of estrogen-progestin hormone replacement therapy (HRT) postmenopause. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin hormone replacement therapy (HRT) or COC is important; all women receiving estrogen HRT or COC treatment should have an annual pelvic examination and other diagnostic or screening tests, such as cervical cytology, as clinically indicated or as generally recommended based on age, risk factors, and other individual needs.

    Endometrial cancer, endometrial hyperplasia, vaginal bleeding

    Ethinyl estradiol; norethindrone acetate products are contraindicated in patients with known estrogen-dependent malignancies, such as endometrial cancer. HORMONRE 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 an ethinyl estradiol; norethindrone acetate combination HRT products, the incidence of endometrial hyperplasia due to estrogen therapy is estimated to be 1% or less. HORMONAL CONTRACEPTIVES: 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 after OC use ceases.

    Endometriosis, uterine cancer, uterine leiomyomata, vaginal cancer

    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 an annual pelvic examination and other diagnostic or screening tests, such as cervical cytology, as clinically indicated or as generally recommended based on age, risk factors, and other individual needs. Because estrogens influence the growth of endometrial tissues, use estradiol 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 HRT, such as the use of estradiol; norethindrone products, to reduce the risk of endometrial tissue growth.

    Systemic lupus erythematosus (SLE)

    Patients with systemic lupus erythematosus (SLE) may have increased risk for thromboembolism and should be managed appropriately when estrogen therapy is considered. Approximately 85% of patients diagnosed with systemic lupus erythematosus (SLE) are females, giving support to the notion that hormonal influences, especially estrogen, contribute to the pathophysiology of SLE. Accordingly, estrogen-progestin therapy when used either as an OC or for hormone replacement therapy has been reported to induce, unmask, and exacerbate lupus; case reports and other anecdotal data indicate that a temporal relationship between exogenous estrogen-progestin therapy and lupus flares exist. However, several retrospective studies dispute a relationship between estrogens causing or exacerbating lupus, and a large prospective, randomized clinical trial (SELENA) evaluating the safety of estrogen therapy (both as OCs and hormone replacement therapy in postmenopausal women) has been completed and is being analyzed. Determining the risk of estrogen therapy in SLE patients is important as women with lupus benefit from estrogens; not only do they offer reliable birth control or symptom relief from postmenopausal symptoms, but they also possibly protect patients requiring chronic corticosteroid therapy from bone fractures and osteoporosis. Women with hypercoagulable states are at increased risk of venous thromboembolism when taking estrogens; given the increased prevalence of hypercoagulable states in patients with SLE (in particular antiphospholipid antibodies and lupus anticoagulant), presence of a hypercoagulable state should be determined prior to initiation of estrogens in this population. Estrogens should be avoided in SLE patients with a history of venous or arterial thrombosis or the presence of a hypercoagulable state. If OCs are initiated in SLE patients without hypercoagulable states, low-dose estrogen contraceptives (i.e., 30 to 35 mcg of ethinyl estradiol or equivalent) should be used and consideration to a progestin-only contraceptive should be given. In addition, it may be prudent to avoid estrogen therapy in patients with unstable or severe SLE or a history of SLE exacerbation with estrogen therapy until more data regarding the use of estrogens in this population are available. The results of the SELENA trial should provide evidence regarding the use of estrogen therapy in this population.

    Diabetes mellitus

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

    Obesity

    Pre-existing morbid obesity can be one factor that may increase cardiovascular or thromboembolic risks associated with combination oral contraceptive (COC) or hormone replacement therapy (HRT) use; this risk factor should be managed appropriately during COC or HRT treatment. Preliminary studies have suggested that obesity may be a risk factor for COC failure, particularly with the predominantly lower-dose (i.e., less than 50 mcg/day) estrogen formulations available; more studies are needed.

    Hypertriglyceridemia, pancreatitis

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

    Hypothyroidism, thyroid disease

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

    Depression

    Mood disorders, like depression, may be aggravated in women taking ethinyl estradiol; norethindrone acetate. Women with a history of depression may need special monitoring. Low-dose oral contraceptive products may have minimal effect on depressive symptoms. If significant depression occurs, therapy should be discontinued.

    Hypocalcemia, hypoparathyroidism

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

    Chloasma

    Chloasma may occasionally occur during combined oral contraceptive (COC) treatment, especially in women with a history of chloasma gravidarum. Women with a tendency for chloasma should avoid sunlight (UV) exposure while taking ethinyl estradiol; norethindrone acetate for birth control.

    Acquired immunodeficiency syndrome (AIDS), human immunodeficiency virus (HIV) infection, sexually transmitted disease

    Ethinyl estradiol; norethindrone acetate combined oral contraceptives (COCs) do not protect against human immunodeficiency virus (HIV) infection or other sexually transmitted disease. Conversely, 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 blood-borne diseases to their partner(s).

    Dementia, geriatric

    Hormone replacement therapy (HRT) with ethinyl estradiol; norethindrone acetate 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. Administration of HRT should generally be avoided in women 65 years of age and older, and HRT should not be used to prevent or treat dementia or preserve cognition (memory). Overall risk vs. benefit should be considered along with the goals of use of HRT for the individual patient when considering whether to continue HRT in a geriatric woman over 65 years of age. According to the Beers Criteria, oral and topical patch 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. The Beers expert panel considers use of intra-vaginal preparations acceptable for the management of dyspareunia, lower urinary tract infections, and other vaginal/vulvar symptoms.

    Children, infants

    The safety and efficacy of ethinyl estradiol; norethindrone acetate (e.g., FemHRT) as hormone replacement therapy (HRT) has not been established in pediatric patients. The safety and efficacy of combined oral contraceptive (COC) products have only been established in females of reproductive age (e.g., postmenarchal females), and are not indicated in premenarchal children or infants. Estrogens are not indicated in young children because estrogens promote epiphysial closure. Serious ill effects have not been reported following the acute ingestion of large oral doses of estrogen-progestin containing products by young children.

    ADVERSE REACTIONS

    Severe

    thromboembolism / Delayed / 0-1.0
    intracranial bleeding / Delayed / 0-1.0
    optic neuritis / Delayed / 0-1.0
    papilledema / Delayed / 0-1.0
    retinal thrombosis / Delayed / 0-1.0
    visual impairment / Early / 0-1.0
    hepatoma / Delayed / 0-1.0
    pancreatitis / Delayed / 0-1.0
    porphyria / Delayed / 0-1.0
    myocardial infarction / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    stroke / Early / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    erythema nodosum / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    bowel ischemia / Delayed / Incidence not known
    cholecystitis / Delayed / Incidence not known
    dementia / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    endometrial cancer / Delayed / Incidence not known
    ovarian cancer / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    breast cancer / Delayed / Incidence not known

    Moderate

    candidiasis / Delayed / 2.0-6.0
    vaginitis / Delayed / 2.0-6.0
    depression / Delayed / 2.0-5.8
    galactorrhea / Delayed / 0-1.0
    cataracts / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 0-1.0
    jaundice / Delayed / 0-1.0
    peliosis hepatis / Delayed / 0-1.0
    hepatitis / Delayed / 0-1.0
    endometrial hyperplasia / Delayed / 0-1.0
    lactation suppression / Early / Incidence not known
    fluid retention / Delayed / Incidence not known
    hypertension / Early / Incidence not known
    edema / Delayed / Incidence not known
    migraine / Early / Incidence not known
    cholelithiasis / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    hyperlipidemia / Delayed / Incidence not known
    impaired cognition / Early / Incidence not known
    urinary incontinence / Early / Incidence not known
    cystitis / Delayed / Incidence not known
    cervical dysplasia / Delayed / Incidence not known

    Mild

    amenorrhea / Delayed / 0-90.0
    breakthrough bleeding / Delayed / 83.9-83.9
    breast enlargement / Delayed / 1.0-10.0
    leukorrhea / Delayed / 1.0-10.0
    vaginal irritation / Early / 1.0-10.0
    vaginal discharge / Delayed / 1.0-10.0
    weight gain / Delayed / 1.0-10.0
    irritability / Delayed / 1.0-10.0
    fatigue / Early / 1.0-10.0
    libido increase / Delayed / 1.0-10.0
    asthenia / Delayed / 1.0-10.0
    libido decrease / Delayed / 1.0-10.0
    vomiting / Early / 1.0-10.0
    abdominal pain / Early / 1.0-10.0
    mastalgia / Delayed / 2.0-9.0
    myalgia / Early / 7.8-8.6
    pelvic pain / Delayed / 2.0-6.0
    emotional lability / Early / 2.0-6.0
    acne vulgaris / Delayed / 2.0-6.0
    arthralgia / Delayed / 2.9-5.8
    back pain / Delayed / 4.7-5.3
    menstrual irregularity / Delayed / 5.0-5.0
    menorrhagia / Delayed / 5.0-5.0
    dysmenorrhea / Delayed / 4.0-4.0
    anxiety / Delayed / 2.0-2.0
    breast discharge / Delayed / 0-1.0
    diplopia / Early / 0-1.0
    headache / Early / 10.0
    nausea / Early / 10.0
    melasma / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    photosensitivity / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    hirsutism / Delayed / Incidence not known
    rash / Early / Incidence not known
    gingivitis / Delayed / Incidence not known
    anorexia / Delayed / Incidence not known
    weight loss / Delayed / Incidence not known
    muscle cramps / Delayed / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    rhinitis / Early / Incidence not known
    sinusitis / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acarbose: (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis.
    Acetaminophen: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects. (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.
    Acetaminophen; Butalbital: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. 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. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. 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; these women should ensure adequate folate supplementation. (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Butalbital; Caffeine: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. 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. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. 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; these women should ensure adequate folate supplementation. (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects. (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.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. 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. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. 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; these women should ensure adequate folate supplementation. (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects. (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.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects. (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.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects. (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.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects. (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.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Codeine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Dextromethorphan: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Diphenhydramine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Hydrocodone: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Oxycodone: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Pentazocine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Propoxyphene: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as propoxyphene may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Acetaminophen; Pseudoephedrine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Tramadol: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    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.
    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.
    Albiglutide: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as combined hormonal oral contraceptives (OCs). Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. atients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis.
    Aliskiren; Amlodipine: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Alogliptin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Alogliptin; Metformin: (Minor) Estrogens, 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. (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. (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.
    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.
    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. (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.
    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.
    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.
    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.
    Amiodarone: (Minor) Amiodarone inhibits CYP3A4, and may increase serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) if coadministered.
    Amitriptyline; Chlordiazepoxide: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
    Amlodipine: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    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. (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Amlodipine; Benazepril: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Amlodipine; Olmesartan: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Amlodipine; Telmisartan: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Amlodipine; Valsartan: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Amobarbital: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. 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. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. 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; these women should ensure adequate folate supplementation.
    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.
    Amoxicillin; Clarithromycin; Lansoprazole: (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. (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.
    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. (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.
    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.
    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.
    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.
    Amprenavir: (Severe) Amprenavir may interact with most estrogens and progestins. Oral contraceptives in particular should not be coadministered with amprenavir. Oral contraceptives have been shown to decrease the serum concentrations of amprenavir, which could lead to loss of virologic response and possible viral resistance to amprenavir. Alternative methods of non-hormonal contraception are recommended if amprenavir is prescribed. (Major) Progestins may decrease the serum concentrations of amprenavir, which could lead to loss of virologic response and possible viral resistance. Oral contraceptives and non-oral combination contraceptives should not be administered with amprenavir. Alternative methods of non-hormonal contraception are recommended if amprenavir is prescribed. Additionally, data on the effects that other protease inhibitors have on the serum concentrations of estrogens and progestins are complex; some protease inhibitors increase and others decrease the metabolism of hormonal contraceptives. It is not known if amprenavir alters the metabolism of hormonal contraceptives or other estrogen or progestin products. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with protease inhibitors should use an additional barrier method of contraception such as condoms.
    Anastrozole: (Severe) Estrogen therapy is not recommended during aromatase inhibitor treatment, due to opposing pharmacologic actions. Estrogens, including those found in hormonal contraceptives, could interfere competitively with the pharmacologic action of the aromatase inhibitors such as Anastrozole. The goal of aromatase inhibitor therapy is to decrease circulating estrogen concentrations and inhibit the growth of hormonally-responsive cancers. Aromatase inhibitors exhibit their antiestrogenic effects by reducing the peripheral conversion of adrenally synthesized androgens (e.g., androstenedione) to estrogens through inhibition of the aromatase enzyme.
    Apalutamide: (Major) Estrogens are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins may increase the hormone's elimination. Women taking both hormones 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. Ethinyl estradiol is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    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. (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.
    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. (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.
    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. (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. (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.
    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.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. 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. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. 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; these women should ensure adequate folate supplementation. (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.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. 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. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. 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; these women should ensure adequate folate supplementation. (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.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (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.
    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. (Major) Atazanavir may decrease the metabolism of oral contraceptives and non-oral combination contraceptives; the mean exposure and minimum serum concentrations of ethinyl estradiol 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 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.
    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. (Major) Atazanavir may decrease the metabolism of oral contraceptives and non-oral combination contraceptives; the mean exposure and minimum serum concentrations of ethinyl estradiol 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 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. (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. (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.
    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.
    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.
    Atracurium: (Minor) Estrogens have been associated in rare cases with pseudocholinesterase deficiency. Since non-depolarizing neuromuscular blockers are metabolized by cholinesterase, prolonged neuromuscular blockade may occur in individuals on concurrent therapy with estrogens.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. 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. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. 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; these women should ensure adequate folate supplementation.
    Azelastine; Fluticasone: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    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.
    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.
    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.
    Barbiturates: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. 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. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. 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; these women should ensure adequate folate supplementation. (Major) Barbiturates can accelerate the hepatic clearance of estrogens and progestins. As a result, the effectiveness of oral contraceptives or other hormonal contraceptives can be lost. Pregnancy has been reported during therapy with both estrogen or progestin containing contraceptives in patients receiving barbiturates (e.g., phenobarbital). It may be prudent to use an additional contraceptive method to protect against unwanted pregnancy. For patients taking estrogens for other indications, like hormone replacement, a higher dose of estrogen may be required during barbiturate therapy.
    Beclomethasone: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. 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. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. 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; these women should ensure adequate folate supplementation.
    Bendamustine: (Moderate) Use bendamustine and ethinyl estradiol together with caution; concomitant use may result in increased bendamustine plasma concentrations and increased bendamustine toxicity. Use of alternative agents should be considered. Bendamustine is metabolized by CYP1A2 to form the active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4); however, cytotoxic activity is primarily due to the parent bendamustine compound. CYP1A2 inhibitors, such as ethinyl estradiol, may increase plasma concentrations of bendamustine and decrease plasma concentrations of its active metabolites.
    Betamethasone: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    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. (Moderate) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including estrogens. It is recommended that two reliable forms of contraception be used simultaneously, unless abstinence is the chosen method, during oral bexarotene therapy. Because of the potential interaction with hormonal contraceptives, it is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy. Patients receiving estrogens or progestins should report any breakthrough bleeding to their prescribers.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) It 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.
    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.
    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.
    Boceprevir: (Major) Boceprevir reduces the Cmax of norethindrone by 17%, which may be sufficient to decrease the effectiveness of combined oral contraceptives containing less than 1 mg of norethindrone (ethinyl estradiol; norethindrone, ethinyl estradiol; norethindrone acetate, mestranol; norethindrone); concurrent use of these products are contraindicated. Instead, the manufacturer recommends use of contraceptives that contain ethinyl estradiol and at least 1 mg of norethindrone. Boceprevir recipients and their partners are also required to use a second, non-hormonal, form of birth control while on therapy and for at least 6 months after treatment. (Major) Close clinical monitoring for signs of estrogen deficiency is advised when administering ethinyl estradiol in combination with boceprevir. When used concurrently, ethinyl estradiol plasma concentrations may be decreased, potentially resulting in impaired efficacy. If ethinyl estradiol dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment.
    Bosentan: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
    Brigatinib: (Major) Coadministration of brigatinib may reduce the efficacy of hormonal contraceptives. Because brigatinib can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use effective non-hormonal contraception during treatment with brigatinib and for at least 4 months after the final dose. Brigatinib induces CYP3A4 and ethinyl estradiol is a CYP3A4 substrate.
    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. (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.
    Budesonide: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Budesonide; Formoterol: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Butabarbital: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. 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. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. 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; these women should ensure adequate folate supplementation.
    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.
    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. (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.
    Caffeine; Ergotamine: (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.
    Calcium: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Calcium-channel blockers: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Canagliflozin: (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis.
    Canagliflozin; Metformin: (Minor) Patients receiving antidiabetic agents 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. (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.
    Capecitabine: (Minor) Use caution if coadministration of capecitabine with ethinyl estradiol is necessary, and monitor for an increase in ethinyl estradiol-related adverse reactions. Ethinyl estradiol is a CYP2C9 substrate in vitro; capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. In a drug interaction study, the mean AUC of another CYP2C9 substrate, S-warfarin (single dose), significantly increased after coadministration with capecitabine; the maximum observed INR value also increased by 91%.
    Carbamazepine: (Major) Concomitant use of carbamazepine with hormonal products may render the hormonal product less effective. The plasma concentrations of the hormones may be decreased because carbamazepine induces the activity of hepatic metabolic enzymes. 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 progestins for other indications may need to be monitored for reductions in clinical effect of the progestin. (Major) Concurrent administration of estrogens with carbamazepine may reduce plasma estrogen concentrations and therefore reduce the clinical efficacy of estrogen products. If an estrogen-containing product is being used for contraception, consider an alternate or additional form of contraception; unintended pregnancy has occurred in women who relied on hormonal contraceptives and received carbamazepine. The alternative contraceptive agent may need to be continued for 1 month after discontinuation of carbamazepine. Women taking estrogen for hormone replacement may require a dosage adjustment. Women taking estrogen products for any indication and carbamazepine should report breakthrough bleeding to their prescriber. Estrogens are metabolized by CYP3A4, and carbamazepine is a potent CYP3A4 inducer. Additionally, patients taking both anticonvulsants and estrogen may be at higher risk of folate deficiency secondary to additive effects on folate metabolism. If contraceptive failure occurs, the additive effects could potentially heighten the risk of neural tube defects in the fetus.
    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.
    Carbenicillin: (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.
    Carvedilol: (Moderate) Increased concentrations of ethinyl estradiol may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a P-gp substrate.
    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.
    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.
    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 determin