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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, myocardial infarction, protein C deficiency, protein S deficiency, renal disease, stroke, thromboembolic disease, thrombophlebitis, tobacco smoking, valvular heart disease

    Combined hormonal contraceptive agents and estrogen-containing hormonal therapies, 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, thromboembolic disease, or valvular heart disease with complications. Hormonal combined oral contraceptives (COCs) and estrogen-containing hormone replacement therapies have been associated with thromboembolic disease 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). Because tobacco smoking increases the risk of DVT, myocardial infarction, stroke and other thromboembolic disease, patients receiving COCs or estrogen-containing hormone replacement therapies are strongly advised not to smoke. Risk is especially high for female smokers 35 years of age or older or those who smoke 15 or more cigarettes per day. 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 for those who take COCs. 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 combined oral contraceptives (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, hyperlipidemia, 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 oral contraceptives gradually disappears. Route of administration may influence risk as well. 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 ethinyl estradiol; norethindrone acetate if blood pressure rises significantly. Combined hormonal contraceptives and hormonal replacement therapies may also cause fluid retention, and patients predisposed to complications from edema, such as those with cardiac or renal disease, should be closely monitored. Estrogen-progestin replacement therapy in postmenopausal women should be used with caution in patients with cardiac disease as the risk of serious adverse events may be increased. Estrogens with or without progestins should not be used for the prevention of cardiac disease in postmenopausal women. Results from the estrogen substudy of the WHI trial indicate that estrogens alone, when used for hormone replacement therapy, do not affect (either increase or decrease) heart disease, although an increase in the number of strokes and VTE have been observed in women receiving estrogen compared to placebo. In the estrogen-progestin substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as non-fatal MI and CHD death) and stroke, and a 2-fold greater rate of VTE, including DVT and PE, were observed with estrogen-progestin HRT compared to placebo. The increase in risk was observed in year one and persisted. In postmenopausal women with documented heart disease, the HERS trial demonstrated no cardiovascular benefit to using estrogen-progestin HRT as secondary prevention. During an average follow-up of 4.1 years, treatment did not reduce the overall rate of CHD events in postmenopausal women with established coronary artery disease. There were more CHD events in the HRT-treated group than in the placebo group in year 1, but not during the subsequent years. Over two thousand women from the original HERS trial agreed to participate in an open label extension of HERS, known as HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the estrogen-progestin HRT group and the placebo group in HERS, HERS II, and overall. In men treated with estrogen for palliation of advanced prostate and breast carcinoma, estrogens have increased the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.

    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. The WHIMS study, an ancillary study of the WHI trial to assess the effects of HRT on cognitive function in geriatric women (65 years of age or older), found that patients receiving either active treatment or placebo had similar rates of developing mild cognitive impairment. Also, patients receiving combination or estrogen only HRT were more likely than patients receiving placebo to be diagnosed with dementia (pooled hazard ratio 1.76, 95% CI 1.19—2.60, P=0.005). In the population of patients taking combination HRT, ninety percent of the cases of dementia occurred in women older than 70 years with Alzheimer's disease being the most common classification; differences between the 2 treatment groups (combination HRT vs. placebo) were apparent after one year of treatment. When analyzed separately, the risk of dementia was increased in patients taking estrogen only therapy (hazard ratio 1.49, 95% CI 0.83—2.66) and in patients taking combination HRT (hazard ratio 2.05, 95% CI 1.21—3.48); however, this finding did not reach statistical significance in patients receiving estrogen only. An explanation for this may be because statistical power of the study was diminished as it was stopped early and fewer patients were enrolled than originally planned due to the early discontinuation of the WHI trial. Regardless, a protective effect of HRT was not found. Administration of HRT should be avoided in women 65 years of age and older, and HRT should not be used to prevent or treat dementia or preserve cognition (memory). The applicability of this finding to the typical user of HRT (i.e., younger, symptomatic women taking hormone replacement therapy to relieve menopausal symptoms) is unclear. According to the Beers Criteria, oral and topical patch forms of estrogens (with or without progestins) are considered potentially inappropriate medications (PIMs) for use in geriatric patients and should be avoided due to evidence of carcinogenic potential (i.e., breast and endometrium) and lack of cardiovascular or cognitive protective effects in older women. 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 menopausal and post-menopausal 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 therapy around the time of menopause if no contraindications to use exist and use is acceptable to the individual patient, as hormone therapy is the most effective treatment for vasomotor and genitourinary symptoms and has been shown to prevent bone loss and fracture.

    For osteoporosis prophylaxis in postmenopausal 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 menopausal and post-menopausal 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. Response to therapy can be predicted by pretreatment serum estradiol concentrations and can be assessed during treatment by measurement of biochemical markers of bone formation/resorption and/or bone mineral density. For the primary prevention of chronic conditions in postmenopausal women except for those less than 50 years who have had surgical menopause, the US Preventive Services Task Force (USPSTF) recommends AGAINST the use of combined estrogen and progestin in women with an intact uterus. Estrogen with or without progestin is of moderate benefit in reducing the incidence of fractures. However, in most postmenopausal women, the USPSTF concludes with high certainty that the chronic disease prevention benefits of combined estrogen and progestin do NOT outweigh the harms such as the risk for stroke, deep venous thrombosis, pulmonary embolism, gallbladder disease, dementia, invasive breast cancer, and urinary incontinence. However, the recommendation is for an average-risk population; consider each woman's net balance of benefits and harms. If ethinyl estradiol; norethindrone acetate is prescribed, use the lowest effective dose for the shortest duration that is consistent with an individual's treatment goals and risks.

    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

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

    Combined hormonal contraceptive agents and estrogen-containing hormonal therapies, 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, thromboembolic disease, or valvular heart disease with complications. Hormonal combined oral contraceptives (COCs) and estrogen-containing hormone replacement therapies have been associated with thromboembolic disease 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). Because tobacco smoking increases the risk of DVT, myocardial infarction, stroke and other thromboembolic disease, patients receiving COCs or estrogen-containing hormone replacement therapies are strongly advised not to smoke. Risk is especially high for female smokers 35 years of age or older or those who smoke 15 or more cigarettes per day. 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 for those who take COCs. 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 combined oral contraceptives (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, hyperlipidemia, 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 oral contraceptives gradually disappears. Route of administration may influence risk as well. 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 ethinyl estradiol; norethindrone acetate if blood pressure rises significantly. Combined hormonal contraceptives and hormonal replacement therapies may also cause fluid retention, and patients predisposed to complications from edema, such as those with cardiac or renal disease, should be closely monitored. Estrogen-progestin replacement therapy in postmenopausal women should be used with caution in patients with cardiac disease as the risk of serious adverse events may be increased. Estrogens with or without progestins should not be used for the prevention of cardiac disease in postmenopausal women. Results from the estrogen substudy of the WHI trial indicate that estrogens alone, when used for hormone replacement therapy, do not affect (either increase or decrease) heart disease, although an increase in the number of strokes and VTE have been observed in women receiving estrogen compared to placebo. In the estrogen-progestin substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as non-fatal MI and CHD death) and stroke, and a 2-fold greater rate of VTE, including DVT and PE, were observed with estrogen-progestin HRT compared to placebo. The increase in risk was observed in year one and persisted. In postmenopausal women with documented heart disease, the HERS trial demonstrated no cardiovascular benefit to using estrogen-progestin HRT as secondary prevention. During an average follow-up of 4.1 years, treatment did not reduce the overall rate of CHD events in postmenopausal women with established coronary artery disease. There were more CHD events in the HRT-treated group than in the placebo group in year 1, but not during the subsequent years. Over two thousand women from the original HERS trial agreed to participate in an open label extension of HERS, known as HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the estrogen-progestin HRT group and the placebo group in HERS, HERS II, and overall. In men treated with estrogen for palliation of advanced prostate and breast carcinoma, estrogens have increased the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.

    Pregnancy

    Estrogen-progestin combination therapy, including ethinyl estradiol; norethindrone acetate, is contraindicated during pregnancy and is labeled FDA pregnancy risk category X. Increased risk of a wide variety of fetal abnormalities, including modified development of sexual organs, cardiovascular anomalies, and limb defects, have been reported following the use of estrogens or synthetic progestins alone in pregnant women. With the exception of effects on sexual development, the majority of recent studies do not indicate a teratogenic effect of oral contraceptives when taken inadvertently during early pregnancy. In any patient in whom pregnancy is suspected, pregnancy should be ruled out before continuing oral contraceptive use. In addition, oral contraceptive use may change 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.

    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). Do not use estrogens in patients with a history of cholestatic jaundice/pruritus of pregnancy or jaundice from prior hormonal contraceptives; these conditions can recur with subsequent COC or hormone replacement use. Discontinue use of ethinyl estradiol; norethindrone acetate if jaundice develops during combined oral contraceptive use. Steroid hormones may be poorly metabolized in patients with liver impairment. Acute or chronic disturbances of liver function may necessitate the discontinuation of 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 pre-existing gallbladder disease and acute or intermittent porphyria. Based on evidence from the HERS trial, the risk of gallbladder disease may be more prevalent in those postmenopausal women with established coronary heart disease who receive oral estrogen-progestin combinations.

    Breast-feeding, obstetric delivery

    Both progestins and estrogens, like ethinyl estradiol (EE), appear to be excreted into breast milk. Manufacturers recommend avoidance of combined hormonal oral contraceptives (OCs) 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. Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and a few reports of effects on the infant exist, including jaundice and breast enlargement. Other experts often recommend avoidance of estrogen-containing hormonal contraceptives, 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 OCs to interfere with the establishment of lactation. It is generally accepted that estrogen-containing combined contraceptives may be used after this period in healthy women without other risk factors; general monitoring of the infant for effects such as appetite changes, breast changes and proper weight gain and growth should occur. Estrogens, including ethinyl estradiol, have been reported to interfere with milk production and duration of lactation in some women, particularly at doses of 30 mcg/day EE or more. One study found that lower dose oral combined contraceptives (e.g., 10 mcg/day EE) may not affect lactation. However, a systematic review concluded that the available evidence, even from randomized controlled trials, is limited and of poor quality; the authors concluded that properly designed and conducted trials are needed to make determinations on the appropriateness of hormonal contraception during lactation and the effects on the health and growth of the infant. However, in general, deleterious effects have not been noted in most infants. 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).

    Diabetes mellitus

    Although the effects appear to be minimal in most non-diabetic patients receiving hormone therapy with estrogen-progestin combinations, altered glucose tolerance secondary to decreased insulin sensitivity has been reported. Patients with hyperglycemia or diabetes mellitus should be observed for changes in glucose tolerance when initiating or discontinuing ethinyl estradiol; norethindrone therapy. Because of the increased potential for embolic risk, combined OCs should be used cautiously in patients with diabetes with vascular involvement.

    Hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia

    Estrogens generally have a favorable effect on blood lipids, and reduce LDL and increase HDL cholesterol concentrations. Progestins, however, may attenuate some of these effects by raising LDL and may make control of pre-existing hyperlipidemia more difficult. Serum triglycerides increase with estrogen administration. A small proportion of women may have persistent hypertriglyceridemia while using ethinyl estradiol; norethindrone. Patients with familial hyperlipoproteinemia may develop elevations in triglycerides while taking exogenous estrogens which may predispose them to pancreatitis; caution is warranted in these individuals.

    Systemic lupus erythematosus (SLE)

    Approximately 85% of patients diagnosed with systemic lupus erythematosus (SLE) are females, giving support to the notion that hormonal influences, especially estrogen, contribute to the pathophysiology of SLE. Accordingly, 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—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.

    Surgery

    Patients undergoing elective surgery of a type associated with an increased risk of thromboembolism should usually stop ethinyl estradiol; norethindrone acetate at least 4 weeks prior and 2 weeks after surgery, dependent upon the continued potential for thromboembolic risk. Combination estrogen-progestin therapy should also be stopped during and after any prolonged immobilization.

    Hypertension

    Ethinyl estradiol; norethindrone acetate is contraindicated in patients with uncontrolled hypertension. Because of their association with elevations in blood pressure, hormonal contraceptive agents should be used cautiously in patients with controlled hypertension or kidney disease. Blood pressure should be monitored closely in these individuals. Any significant increase in blood pressure while on estrogen-progestin therapy may require discontinuation of the medication. Estrogen-progestin therapy may also cause fluid retention, and patients predisposed to complications from edema should be closely monitored.

    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.

    Headache, migraine

    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. The cause of headache requires evaluation by a health care provider.

    Contact lenses, glaucoma, visual disturbance

    Estrogens can increase the curvature of the cornea and may lead to intolerance of contact lenses. Consistent with potential thrombotic effects of oral contraceptives, there have been clinical case reports of retinal thrombosis or retinal vascular occlusion. Any change in vision or visual acuity should be examined by an ophthalmologist, and periodic eye examination is recommended in most patients during oral contraceptive use. Patients developing any unexplained visual disturbance require evaluation; if retinal vascular occlusion occurs, hormonal oral contraception should be discontinued. Long-term oral contraceptive use may play a potential role in the development of glaucoma. According to research presented at a meeting of the American Acadamy of Opthomology, the use of oral contraceptives for > 3 years, irrespective of formulation, was associated with a reported doubling of the incidence of glaucoma. Research data from the National Health and Nutrition Examination Survey (NHANES) included questionnaire responses administered by the Centers for Disease Control. Survey respondents (3406 women, >= 40 years of age) reported on oral contraceptive use between 2005 and 2008; participants completed the survey's vision and reproductive health questionnaire and underwent eye exams. Women reporting oral contraceptive use for > 3 years were 2.05 times as likely to also report a diagnosis of glaucoma. Although causality was not determined, 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.

    Breast cancer

    Estrogens, whether used as an oral contraceptive or for hormone replacement therapy, are generally contraindicated in patients with pre-existing breast cancer, except in those patients appropriate for palliative therapy. Since 1970, numerous epidemiological studies have examined the association of exogenous estrogen and breast cancer. Epidemiologic studies have reported an increased risk of breast cancer in association with increasing duration of postmenopausal treatment with estrogens, with or without progestin. This association was reanalyzed in original data from 51 studies that involved treatment with various doses and types of estrogens, with and without progestin. In the reanalysis, an increased risk of having breast cancer diagnosed became apparent after about 5 years of continued treatment, and subsided after treatment had been discontinued for about 5 years. Some later studies have suggested that treatment with estrogen and progestin increases the risk of breast cancer more than treatment with estrogen alone. In the estrogen-progestin substudy of the WHI trial , there were more diagnoses of breast cancer in the HRT group compared to the placebo group, with a hazard ratio of 1.24. The breast cancers diagnosed in the HRT group had similar histology and grade to those found in the placebo group, but the women receiving HRT were more likely to be diagnosed with a more invasive cancer (hazard ratio 1.24) that was larger in size (1.7 cm HRT vs. 1.5 cm placebo), node positive (25.9% HRT vs. 15.8% placebo), and diagnosed at a more advanced stage (regional/metastatic 25.4% HRT vs. 16% placebo). The increased risk of breast cancer became apparent after 4 years on combined HRT. Women reporting prior postmenopausal use of estrogen and/or estrogen with progestin had a higher relative risk for breast cancer associated with combined HRT than those who had never used these hormones. In the estrogen-only substudy of WHI, NO increased risk of breast cancer in estrogen-treated women compared to placebo was found, even in women who used estrogen replacement therapy for 25 years or longer. Furthermore, the hazards ratio for invasive breast cancer in women taking estrogen only versus placebo after a mean follow-up of 7.1 years was 0.8 (95% CI 0.62—1.04, P=0.09) in favor of estrogen therapy. In addition, several large, well designed observational studies have provided conflicting data regarding the risk of breast cancer with oral contraceptive use. A landmark case control study, the Cancer and Steroid Hormone (CASH) study, was published in 1986 and reported a lack of association between OC use and breast cancer. However, in 1996, the results of a meta-analysis of 54 studies specifically looking at the effects of OCs in more than 150,000 women were published. A statistically significant (but slight) risk for breast carcinoma existed for women taking OCs; the risk steadily diminished to baseline over 10 years following discontinuation. The breast cancers diagnosed in this study tended to be localized and less advanced. The value of the data from this meta-analysis was limited because of variances in study designs and patient follow up; however, the controversy over steroid hormone exposure and the risk of breast cancer continued. In 2002, the results of the Women's CARE trial were reported. No associations between past or present use of OCs and breast cancer were observed; the study included 4575 women with breast cancer and 4682 controls between the ages of 35—64 years old; > 75% of the study participants had used OCs. After a thorough review of the available data, the World Health Organization International Agency for Research on Cancer (WHO IARC) has classified both combined menopausal HRT and combination estrogen-progestin oral contraceptives as carcinogenic to humans; the agency indicates that the risk of breast cancer in women taking combined menopausal HRT, which is confined mostly to current or recent users, increases with duration of use and is higher than the risk in women taking estrogen-only regimens. For oral contraceptives, the risk of breast cancer is slightly increased in current and recent users (i.e., within 10 years); however, 10 years after cessation, the risk of breast cancer appears to be similar to that in those patient that have never used OCs. All women taking ethinyl estradiol; norethindrone acetate, either as hormone replacement therapy or as an oral contraceptive should receive an annual clinical breast examination and perform monthly self-examinations. In addition, regular mammograms should be performed as indicated by health care professionals.

    Hypercalcemia, hypocalcemia

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

    Endometrial cancer, endometrial hyperplasia, vaginal bleeding

    Since 1970, at least 35 epidemiological studies have examined the association of exogenous estrogen and an increased incidence of cancer of the endometrium in women with an intact uterus. The majority of these studies have shown an increased risk of endometrial cancer in women who have received exogenous estrogens without concomitant progestin. The pooled estimate of the relative risk compared to women who never used estrogen is 2.31. Histologic and clinical data, as well as limited epidemiologic data suggest that the addition of a progestin to estrogen therapy offsets the risk of endometrial cancer caused by exogenous estrogen, however, the data for estrogen with concomitant progestin are not as extensive as for estrogen alone. The best available epidemiological evidence is from one case-control study that showed no increased risk for endometrial cancer when progestins were used with estrogen for at least 10 days/month. Similarly, in women using OCs, a meta-analysis of 10 studies indicates a significant trend in decreasing endometrial carcinoma risk with increasing duration of combined OC use. The beneficial effects of OCs in this regard may persist for 15 years after OC use ceases. However, in those women with known endometrial cancer or endometrial hyperplasia, estrogen therapy is contraindicated. Furthermore, because of the risk of endometrial carcinoma, women taking exogenous estrogens who are experiencing abnormal vaginal bleeding should receive adequate diagnostic tests to rule out malignancy. Ethinyl estradiol; norethindrone acetate therapy is contraindicated in patients with preexisting endometrial hyperplasia.

    Cervical cancer

    Estrogens are contraindicated in patients with pre-existing cervical cancer. An association between oral contraceptive use and cervical cancer has been demonstrated. Generally, the risk of invasive cervical cancer in women who use oral contraceptives is greatest in women who take OCs for more than 5 years. Accordingly, the WHO IARC has classified combination estrogen-progestin oral contraceptives as a carcinogen in the development of cervical cancer. Evaluation of patients via cervical cytology screening should be performed prior to ethinyl estradiol; norethindrone acetate use.

    Ovarian cancer

    Ethinyl estradiol; norethindrone acetate is contraindicated in women with estrogen-dependent carcinomas, such as ovarian cancer. While many studies have documented that estrogen-containing contraceptives exert a protective effect against ovarian cancer, a modestly-increased risk has been associated with estrogen replacement therapy in peri- and postmenopausal women. In a cohort of 240,073 peri- and postmenopausal women, a total of 436 ovarian cancer deaths were observed. The overall risk ratio for estrogen therapy was calculated to be 1.15, however the authors qualified these data by stating that recommended doses of estrogen for hormone replacement therapy (HRT) have decreased since 1978 and newer recommendations to include medroxyprogesterone or other progestins in HRT regimens may also lower the risk.

    Endometriosis, uterine cancer, uterine leiomyomata, vaginal cancer

    Oral contraceptives and hormone replacement therapy are contraindicated in patients with known or suspected estrogen-dependent carcinoma (e.g., vaginal cancer, uterine cancer, ovarian cancer). In addition, oral contraceptive agents are contraindicated in women with undiagnosed vaginal bleeding. Use ethinyl estradiol; norethindrone acetate with caution in patients with uterine leiomyomata (fibroids) or endometriosis because hormonal therapy can cause fibroids to increase in size.

    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.

    Children, infants, neonates

    The safety and efficacy of ethinyl estradiol; norethindrone acetate contraceptives have not been established in neonates, infants, or pre-menarchal female children. The safety and efficacy of ethinyl estradiol; norethindrone acetate (e.g., FEMHRT) as hormone replacement therapy has not been established in pediatric patients and is not indicated for this use in this population. When used as an oral contraceptive, ethinyl estradiol; norethindrone acetate may be used in post-menarchal female children and adolescents. The safety and efficacy of oral contraceptive products have only been established in females of reproductive age. Safety and efficacy of ethinyl estradiol; norethindrone acetate is expected to be the same for postpubertal children under the age of 16 and for users 16 years of age and older. Estrogens are not indicated in young children because estrogens promote epiphysial closure. Per the manufacturers, serious ill effects have not been reported following the acute ingestion of large oral doses of estrogen-progestin containing products by young children.

    Acquired immunodeficiency syndrome (AIDS), human immunodeficiency virus (HIV) infection

    Ethinyl estradiol; norethindrone acetate does not protect against human immunodeficiency virus (HIV) infection or other sexually transmitted diseases. Conversely, patients with known HIV infection or acquired immunodeficiency syndrome (AIDS) should be aware that the use of this hormonal combination will not prevent the transmission of HIV or other diseases to their partner(s).

    Obesity

    Preliminary studies have suggested that obesity may be a risk factor for OC (e.g., ethinyl estradiol; norethindrone acetate) failure, particularly with the predominantly lower-dose (i.e., < 50 mcg/day) estrogen formulations available; more studies are needed. Also, pre-existing morbid obesity can be one factor that may increase cardiovascular or thromboembolic risks associated with combination hormonal contraceptive or estrogen use in selected individuals.

    Chloasma

    Chloasma may occasionally occur, 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 or for menopausal symptoms.

    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. The WHIMS study, an ancillary study of the WHI trial to assess the effects of HRT on cognitive function in geriatric women (65 years of age or older), found that patients receiving either active treatment or placebo had similar rates of developing mild cognitive impairment. Also, patients receiving combination or estrogen only HRT were more likely than patients receiving placebo to be diagnosed with dementia (pooled hazard ratio 1.76, 95% CI 1.19—2.60, P=0.005). In the population of patients taking combination HRT, ninety percent of the cases of dementia occurred in women older than 70 years with Alzheimer's disease being the most common classification; differences between the 2 treatment groups (combination HRT vs. placebo) were apparent after one year of treatment. When analyzed separately, the risk of dementia was increased in patients taking estrogen only therapy (hazard ratio 1.49, 95% CI 0.83—2.66) and in patients taking combination HRT (hazard ratio 2.05, 95% CI 1.21—3.48); however, this finding did not reach statistical significance in patients receiving estrogen only. An explanation for this may be because statistical power of the study was diminished as it was stopped early and fewer patients were enrolled than originally planned due to the early discontinuation of the WHI trial. Regardless, a protective effect of HRT was not found. Administration of HRT should be avoided in women 65 years of age and older, and HRT should not be used to prevent or treat dementia or preserve cognition (memory). The applicability of this finding to the typical user of HRT (i.e., younger, symptomatic women taking hormone replacement therapy to relieve menopausal symptoms) is unclear. According to the Beers Criteria, oral and topical patch forms of estrogens (with or without progestins) are considered potentially inappropriate medications (PIMs) for use in geriatric patients and should be avoided due to evidence of carcinogenic potential (i.e., breast and endometrium) and lack of cardiovascular or cognitive protective effects in older women. 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.

    Angioedema, hereditary angioedema

    Cases of both anaphylactic reactions and angioedema have been reported in patients taking exogenous estrogens. Events have developed in minutes and have required emergency medical treatment. Ethinyl estradiol is generally contraindicated in patients who have a history of anaphylaxis or angioedema to the drug. In addition, exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema, which may be hormonally sensitive.

    ADVERSE REACTIONS

    Severe

    thrombosis / Delayed / 0-1.0
    pulmonary embolism / Delayed / 0-1.0
    thromboembolism / Delayed / 0-1.0
    myocardial infarction / Delayed / 0-1.0
    intracranial bleeding / Delayed / 0-1.0
    stroke / Early / 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
    pancreatitis / Delayed / 0-1.0
    hepatoma / Delayed / 0-1.0
    porphyria / Delayed / 0-1.0
    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
    lupus-like symptoms / 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
    hepatitis / Delayed / 0-1.0
    peliosis hepatis / Delayed / 0-1.0
    jaundice / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 0-1.0
    lactation suppression / Early / Incidence not known
    fluid retention / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    hypertension / Early / Incidence not known
    migraine / Early / Incidence not known
    cholestasis / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    cholelithiasis / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    hyperlipidemia / Delayed / Incidence not known
    cervical dysplasia / Delayed / Incidence not known
    secondary malignancy / Delayed / Incidence not known
    endometrial hyperplasia / Delayed / Incidence not known
    impaired cognition / Early / Incidence not known
    urinary incontinence / Early / Incidence not known
    cystitis / Delayed / Incidence not known

    Mild

    amenorrhea / Delayed / 0-90.0
    breakthrough bleeding / Delayed / 83.9-83.9
    rhinitis / Early / 12.7-15.1
    breast enlargement / Delayed / 1.0-10.0
    leukorrhea / Delayed / 1.0-10.0
    vaginal discharge / Delayed / 1.0-10.0
    vaginal irritation / Early / 1.0-10.0
    appetite stimulation / 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
    sinusitis / Delayed / 2.0-9.4
    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 (unspecified) / Early / Incidence not known
    gingivitis / Delayed / Incidence not known
    anorexia / Delayed / Incidence not known
    weight loss / Delayed / Incidence not known
    musculoskeletal pain / Early / Incidence not known

    DRUG INTERACTIONS

    Acarbose: (Minor) Estrogens can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with any of these agents is instituted or discontinued.
    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. Additionally, estrogens can impair glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving greater than 50 mcg of ethinyl estradiol or equivalent estrogen per day. However, any patient with diabetes may need to monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Aliskiren; Amlodipine: (Minor) 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 can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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.
    Alogliptin; Pioglitazone: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Alpha-glucosidase Inhibitors: (Minor) Estrogens can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with any of these agents is instituted or discontinued. (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.
    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: (Severe) Bosentan is a significant inducer of CYP3A hepatic enzymes. 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. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. In addition, bosentan is teratogenic and is contraindicated during pregnancy. An interaction study has demonstrated that coadministration of bosentan and an oral contraceptive product (ethinyl estradiol; norethindrone) produced average decreases in norethindrone and ethinyl estradiol serum concentrations of 14% and 31%, respectively; however, decreases in drug exposure were are as high as 56% and 66%, respectively, in individual subjects. Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. Effective contraception through additional forms of contraception must be practiced. The manufacturer recommends that follow-up pregnancy tests be obtained monthly for women of childbearing potential taking bosentan. Additionally, estrogens and progestins used for hormone replacement therapy 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. (Severe) Bosentan is a significant inducer of CYP3A hepatic enzymes. Hormonal contraceptives, including oral contraceptives, injectable, transdermal, and implantable contraceptives may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. In addition, bosentan is teratogenic and is contraindicated during pregnancy. An interaction study has demonstrated that coadministration of bosentan and an oral contraceptive product (ethinyl estradiol; norethindrone) produced average decreases in norethindrone and ethinyl estradiol serum concentrations of 14% and 31%, respectively; however, decreases in drug exposure were are as high as 56% and 66%, respectively, in individual subjects.
    Brigatinib: (Major) Coadministration of brigatinib may reduce the efficacy of hormonal contraceptives. Because brigatinib can cause fetal harm if administered to a pregnant woman, females of reproductive potential should use effective non-hormonal contraception during treatment with brigatinib and for at least 4 months after the final dose. Brigatinib induces CYP3A4 and 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.
    Cabazitaxel: (Major) Cabazitaxel is a CYP3A4 substrate, and concomitant use of cabazitaxel with strong CYP3A4 inhibitors such as ethinyl estradiol is expected to increase cabazitaxel concentrations. Concomitant administration of cabazitaxel and strong CYP3A4 inhibitors should be avoided. Consider alternative therapies with low enzyme induction potential.
    Cabozantinib: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ethinyl estradiol may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a substrate of P-gp; the clinical relevance of this finding is unknown. Cabozantinib is also a CYP3A4 substrate while ethinyl estradiol is a weak CYP3A4 inhibitor in vitro; however, this is not expected to have a clinically relevant effect.
    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) Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) 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.
    Canagliflozin; Metformin: (Minor) Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) 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.
    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 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.
    Cefdinir: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Cefditoren: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Cefepime: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Cefixime: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Cefotaxime: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Cefotetan: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Cefoxitin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Cefpodoxime: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Cefprozil: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ceftaroline: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ceftazidime: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ceftazidime; Avibactam: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ceftibuten: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ceftizoxime: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ceftriaxone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During lo