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    Estrogen with Progestogen Combinations, Excluding Hormonal Contraceptives
    Estrogens, Excluding Hormonal Contraceptives

    BOXED WARNING

    Dementia, geriatric

    Hormone replacement therapy (HRT), both estrogen/progestin combination therapy (e.g., estradiol; norethindrone) 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

    Oral and transdermal combination of the principal human estrogen (estradiol) and a progestin (norethindrone); norethindrone is added to estrogen therapy to reduce risk for endometrial hyperplasia
    Primarily used in women with an intact uterus to treat moderate to severe vasomotor and genitourinary symptoms associated with menopause; the oral product is additionally indicated for the prevention of osteoporosis in postmenopausal women
    Transdermal system is also used for hormone replacement in women with an intact uterus who have had an oophorectomy, or who have hypogonadism or primary ovarian failure

    COMMON BRAND NAMES

    Activella, Amabelz, CombiPatch, Lopreeza, Mimvey, Mimvey Lo

    HOW SUPPLIED

    Activella/Amabelz/Estradiol, Norethindrone/Estradiol, Norethindrone Acetate/Lopreeza/Mimvey/Mimvey Lo Oral Tab: 0.5-0.1mg, 1-0.5mg
    CombiPatch Transdermal Film ER: 24h, 0.05-0.14mg, 0.05-0.25mg

    DOSAGE & INDICATIONS

    For treatment of moderate to severe vasomotor symptoms (hot flashes) of menopause and/or related genitourinary symptoms including atrophic vaginitis, vulvar atrophy (kraurosis vulvae) in women with an intact uterus.
    Continuous combined regimen - for women who do not want to resume menses.
    Oral dosage (oral combination tablets; e.g., Activella)
    Adult menopausal and postmenopausal females

    1 tablet (0.5 mg estradiol and 0.1 mg of norethindrone acetate) OR 1 tablet (1 mg estradiol and 0.5 mg norethindrone acetate) PO once daily for vasomotor symptoms; initiate at the lowest dose. For vulvar/vaginal atrophy, use 1 tablet (1 mg estradiol/0.5 mg norethindrone acetate) PO once daily. When prescribed for isolated genitourinary symptoms, topical vaginal products should be considered. Re-evaluate at 3 to 6 month intervals to determine if the dose and/or if continued hormone therapy is appropriate. The North American Menopause Society (NAMS) Guidelines support the initiation of hormone therapy around the time of menopause if no contraindications to use exist and use is acceptable to the individual patient, as hormone therapy is the most effective treatment for vasomotor and genitourinary symptoms and has been shown to prevent bone loss and fracture.

    Transdermal dosage (bi-weekly transdermal patch; e.g., CombiPatch)
    Adult menopausal and postmenopausal females

    Apply 1 transdermal patch system (delivering 0.05 mg estradiol/0.14 mg norethindrone acetate per day) topically to the lower abdomen; remove and replace the patch twice weekly (every 3 to 4 days). If a greater progestin dose is desired, use the 0.05 mg estradiol with 0.25 mg norethindrone acetate per day transdermal patch. Irregular bleeding may occur, especially within the first 6 months, but generally decreases with time. When prescribed for isolated genitourinary symptoms, topical vaginal products should be considered. Re-evaluate at 3 to 6 month intervals to determine if the dose and/or if continued hormone therapy is appropriate. The North American Menopause Society (NAMS) Guidelines support the initiation of hormone therapy around the time of menopause if no contraindications to use exist and use is acceptable to the individual patient, as hormone therapy is the most effective treatment for vasomotor and genitourinary symptoms and has been shown to prevent bone loss and fracture.

    Sequential regimen - for women who wish to have regular withdrawal bleeding.
    Transdermal dosage (bi-weekly transdermal patch; e.g., CombiPatch)
    Adult menopausal and postmenopausal females

    A 0.05 mg/day estradiol-only transdermal system is worn for the first 14 days according to product directions. For the remaining 14 days of the 28-day cycle, apply 1 transdermal patch system (delivering 0.05 mg estradiol/0.14 mg norethindrone acetate per day) topically to the lower abdomen; remove and replace the patch twice weekly (every 3 to 4 days). If a greater progestin dose is desired, use the 0.05 mg estradiol with 0.25 mg norethindrone acetate per day transdermal patch. Women should be advised that monthly withdrawal bleeding often occurs. When prescribed for isolated genitourinary symptoms, topical vaginal products should be considered. Re-evaluate at 3 to 6 month intervals to determine if the dose and/or if continued hormone therapy is appropriate. The North American Menopause Society (NAMS) Guidelines support the initiation of hormone therapy around the time of menopause if no contraindications to use exist and use is acceptable to the individual patient, as hormone therapy is the most effective treatment for vasomotor and genitourinary symptoms and has been shown to prevent bone loss and fracture.

    For osteoporosis prophylaxis in postmenopausal women with an intact uterus.
    Oral dosage (oral tablets; e.g., Activella)
    Adult menopausal or postmenopausal females

    1 tablet (0.5 mg estradiol and 0.1 mg of norethindrone acetate) OR (1 mg estradiol and 0.5 mg norethindrone acetate) PO once daily for women at significant risk of osteoporosis. Initiate with the lowest dose. Reevaluate the need and appropriateness of hormone therapy at 3 to 6 month intervals; carefully consider non-estrogen medications. 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 estradiol; norethindrone 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 female hypogonadism, oophorectomy, or primary ovarian failure in women with an intact uterus.
    Continuous combined regimen - for women who do not want to resume menses.
    Transdermal dosage (bi-weekly transdermal patch; e.g., CombiPatch)
    Adult females

    Apply 1 transdermal patch system (delivering 0.05 mg estradiol/0.14 mg norethindrone acetate per day) topically to the lower abdomen; remove and replace the patch twice weekly (every 3 to 4 days). If a greater progestin dose is desired, use the 0.05 mg estradiol with 0.25 mg norethindrone acetate per day transdermal patch. Irregular bleeding may occur, especially within the first 6 months, but generally decreases with time. Re-evaluate at 3 to 6 month intervals to determine if the dose and/or if continued hormone therapy is appropriate.

    Sequential regimen - for women who wish to have regular withdrawal bleeding.
    Transdermal dosage (bi-weekly transdermal patch; e.g., CombiPatch)
    Adult females

    A 0.05 mg/day estradiol-only transdermal system is worn for the first 14 days according to product directions. For the remaining 14 days of the 28-day cycle, apply 1 transdermal patch system (delivering 0.05 mg estradiol/0.14 mg norethindrone acetate per day) topically to the lower abdomen; remove and replace the patch twice weekly (every 3 to 4 days). If a greater progestin dose is desired, use the 0.05 mg estradiol with 0.25 mg norethindrone acetate per day transdermal patch. Women should be advised that monthly withdrawal bleeding often occurs. Re-evaluate at 3 to 6 month intervals to determine if the dose and/or if continued hormone therapy is appropriate.

    MAXIMUM DOSAGE

    Adults

    Estradiol 1 mg/day PO and norethindrone acetate 0.5 mg/day PO; transdermally 0.05 mg/day estradiol with 0.25 mg/day norethindrone acetate.

    Elderly

    Estradiol 1 mg/day PO and norethindrone acetate 0.5 mg/day PO; transdermally 0.05 mg/day estradiol with 0.25 mg/day norethindrone acetate.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    The effect of hepatic impairment on the pharmacokinetics of estradiol; norethindrone has not been studied; dosing recommendations are not available from the manufacturer. Estradiol and norethindrone are contraindicated in the presence of jaundice or in markedly impaired hepatic disease of any type.

    Renal Impairment

    The effect of renal impairment on the pharmacokinetics of estradiol; norethindrone has not been studied; dosing recommendations are not available from the manufacturer.

    ADMINISTRATION

    Oral Administration

    Administer daily at approximately the same time each day.
    May be administered with or without food.

    Topical Administration
    Transdermal Patch Formulations

    Transdermal patch system (e.g., Combipatch):
    To apply, after opening the pouch, remove one side of the protective liner and immediately apply the transdermal system to an area of skin on the lower abdomen. Place on a smooth, clean, dry, and intact area of the skin. Do not apply to oily, damaged, or irritated skin. Avoid the waistline since tight clothing may impair adherence or change drug delivery. Do not apply to or near the breasts.
    Press the system firmly in place with the hand for at least 10 seconds. Make sure there is good contact to the skin, especially at the edges of the system.
    Once in place, the transdermal system should not be exposed to the sun for prolonged periods of time.
    Patients may bathe while wearing the system. Care should be taken that the system does not become dislodged during bathing and other activities.
    If a system should fall off, the same system may be reapplied to another area of the abdomen. If necessary, a new system may be applied, in which case, the original treatment schedule should continue.
    Only 1 system should be applied at any 1 time during the 3- to 4- day dosing interval. Remove the old system before applying a new one.
    The sites of application must be rotated, with an interval of at least 1 week allowed between applications to the same site.

    STORAGE

    Activella:
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in a dry place
    Amabelz :
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in a dry place
    CombiPatch:
    - Do not store outside of the sealed pouch
    - May be stored at room temperature not exceeding 77 degrees F for up to 6 months
    - Prior to dispensing, store in refrigerator (36 to 46 degrees F)
    - Protect from extreme heat
    Lopreeza:
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in a dry place
    Mimvey :
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in a dry place
    Mimvey Lo:
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in a dry place

    CONTRAINDICATIONS / PRECAUTIONS

    Breast cancer

    Estrogens are generally contraindicated in patients with known, suspected, or history of breast cancer. Estrogen and estrogen/progestin therapy, such as estradiol; norethindrone, in postmenopausal women has been associated with an increased risk of breast cancer. In the past, high-dose estrogen therapy was used in selected men and postmenopausal women with inoperable, progressive cancer of the breast, but this therapy is rarely used today. Since 1970, numerous epidemiological studies have examined the association of exogenous estrogen and breast cancer. Epidemiologic studies have reported an increased risk of breast cancer in association with increasing duration of postmenopausal treatment with estrogens, with or without progestin. This association was reanalyzed in original data from 51 studies that involved treatment with various doses and types of estrogens, with and without progestin. In the reanalysis, an increased risk of having breast cancer diagnosed became apparent after about 5 years of continued treatment, and subsided after treatment had been discontinued for about 5 years. Some later studies have suggested that treatment with estrogen and progestin increases the risk of breast cancer more than treatment with estrogen alone. In the estrogen-progestin sub-study of the WHI trial , there were more diagnoses of breast cancer in the HRT group compared to the placebo group, with a hazard ratio of 1.24. The breast cancers diagnosed in the HRT group had similar histology and grade to those found in the placebo group, but the women receiving HRT were more likely to be diagnosed with a more invasive cancer (hazard ratio 1.24) that was larger in size (1.7 cm HRT vs. 1.5 cm placebo), node positive (25.9% HRT vs. 15.8% placebo), and diagnosed at a more advanced stage (regional/metastatic 25.4% HRT vs. 16% placebo) compared to those who received placebo. The increased risk of breast cancer became apparent after 4 years on combined HRT. Women reporting prior postmenopausal use of estrogen and/or estrogen with progestin had a higher relative risk for breast cancer associated with combined HRT than those who had never used these hormones. In the estrogen-only 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 to the associated increase risk of breast cancer, at least 1 abnormal mammogram was discovered in a total of 31.5% of women in the combined HRT group compared to 21.2% of placebo patients, with an absolute increase in abnormal mammograms of about 4% per year in women receiving combined HRT; similarly, in women receiving estrogen only, 36.2% of women had mammograms with abnormalities during the trial, compared to only 28.1% of women receiving placebo (p < 0.001). Accordingly, after a thorough review of the available data, the World Health Organization International Agency for Research on Cancer (WHO IARC) has classified combined menopausal HRT as carcinogenic to humans; the agency indicates that the risk of breast cancer which is confined mostly to current or recent users increases with duration of use and is higher than the risk in women taking estrogen-only regimens. All women taking estrogen with or without a progestin should receive an annual clinical breast examination, perform monthly self-examinations, and have regular mammograms as recommended by their health care professional.

    Hypercalcemia, hypocalcemia

    Estrogens, including combination HRT such as estradiol; norethindrone, are not recommended in patients with hypercalcemia associated with tumors or metabolic bone disease because estrogens influence the metabolism of calcium and phosphorus. In particular, severe hypercalcemia may occur in patients with breast cancer with bone metastases. If hypercalcemia occurs, 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 endometrial cancer in women with an intact uterus. These studies were summarized in a review published in 1992 of hormonal replacement therapy in postmenopausal women. The majority of these studies have shown an increased risk of endometrial cancer in women who have received exogenous estrogens without concomitant progestin. 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. Accordingly, the WHO IARC has classified combined menopausal HRT as carcinogenic to humans when progestins are taken for < 10 days/month; the agency also indicates that when progestins are taken daily, the risk of endometrial cancer is similar to that in women who have never used hormonal therapy. Based on limited clinical trials with the use of estradiol-norethindrone transdermally, the incidence of hyperplasia of the endometrium is estimated to be 0.8—1.1% or less. Because of the risk of endometrial carcinoma, women taking exogenous estrogen who are experiencing persistent abnormal vaginal bleeding should receive adequate diagnostic tests to rule out malignancy. Estradiol; norethindrone combinations are contraindicated in patients with preexisting endometrial hyperplasia.

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

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

    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, such as norethindrone, in HRT regimens may also lower the risk.

    Pregnancy

    Estradiol and norethindrone are contraindicated during pregnancy and are 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. In any patient in whom pregnancy is suspected, pregnancy should be ruled out before continuing estrogen-progestin use. There is no known indication for the use of these drugs during pregnancy.

    Breast-feeding

    Estrogens and progestins do distribute to breast milk in small quantities, and occasionally have been reported to interfere with milk production during lactation. Less than 10% of an estradiol dose, and a similar amount of norethindrone, passes into breast milk. They should be used with caution in lactating women. The American Academy of Pediatrics has generally considered estrogens and certain progestins to be compatible with breast-feeding due to a probable lack of significant effect on the nursing infant.

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

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

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

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

    Diabetes mellitus

    Estradiol-norethindrone combinations should be used with caution in patients with diabetes mellitus. In clinical trials, estradiol-norethindrone combinations did not affect oral glucose tolerance tests and did not alter insulin sensitivity in healthy post-menopausal women. Although the effects appear to be minimal during therapy with progestins, altered glucose tolerance secondary to decreased insulin sensitivity has been reported in some women taking hormonal replacement therapy. Patients with hyperglycemia or diabetes mellitus should be observed for changes in glucose tolerance when initiating or discontinuing estrogen therapy.

    Cardiac disease, cerebrovascular disease, coronary artery disease, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, myocardial infarction, protein C deficiency, protein S deficiency, stroke, thromboembolic disease, thrombophlebitis, tobacco smoking

    Estrogen therapies have been associated with an increased risk of cerebrovascular disease (i.e., stroke), venous thrombosis (venous thromboembolism or VTE) and pulmonary embolism, and the addition of a progestin to estrogen therapy adds an increased risk of cardiovascular events such as myocardial infarction. Estrogens are contraindicated in patients with an active or past history of stroke, myocardial infarction, thrombophlebitis, or thromboembolic disease. ;Estradiol, like other estrogens, is contraindicated for patients with known protein C deficiency, protein S deficiency, or antithrombin deficiency or other known thrombophilic disorders associated with increased risk of venous thrombosis. Should any of these occur or be suspected, discontinue conjugated estrogens immediately. A positive relationship between estrogen dosage and blood clotting has been demonstrated. Estrogens decrease levels of antithrombin-III and increase the production of blood clotting factors VII, VIII, IX and X. Because tobacco smoking increases the risk of DVT, myocardial infarction, and other thromboembolic disease, estrogen-containing treatment should be used cautiously in smokers. Risk is especially high for female cigarette smokers 35 years of age or older. Patients should be advised not to smoke. Risk factors for heart disease (e.g., hypertension, diabetes mellitus, tobacco use, hyperlipidemia, hypercholesterolemia and/or hypertriglyceridemia, obesity) should be managed appropriately. Because estrogens may cause fluid retention, patients with conditions that may be affected by this factor, such as a cardiac disease, should be carefully monitored when estrogens are prescribed. Furthermore, estrogens with or without progestins should not be used for the prevention of cardiac disease. In the estrogen sub-study of the WHI trial, estrogen alone does not affect (either increase or decrease) heart disease, although an increase in the number of strokes and VTE were been observed in women receiving estrogen HRT compared to placebo. In the estrogen-progestin sub-study of WHI, an increased risk of coronary heart disease (CHD) events (defined as non-fatal MI and CHD death) and stroke, and a 2-fold greater rate of VTE, including DVT and PE, were observed with estrogen-progestin HRT compared to placebo. The increase in risk was observed in year one and persisted. In postmenopausal women with documented cardiac disease, 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 prostate and breast cancer, estrogens have increased the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.

    Systemic lupus erythematosus (SLE)

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

    Surgery

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

    Depression

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

    Hypothyroidism, thyroid disease

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

    Contact lenses, visual disturbance

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

    Children

    Estrogens are not indicated in 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.

    Dementia, geriatric

    Hormone replacement therapy (HRT), both estrogen/progestin combination therapy (e.g., estradiol; norethindrone) 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 estradiol; norethindrone. Events have developed in minutes and have required emergency medical treatment. Therefore, as with other estrogens, estradiol; norethindrone is contraindicated in patients with a history of anaphylaxis or angioedema to estradiol. In addition, exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema (HAE).

    ADVERSE REACTIONS

    Severe

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

    Moderate

    vaginitis / Delayed / 6.0-13.0
    fluid retention / Delayed / 1.0-10.0
    depression / Delayed / 3.0-9.0
    peripheral edema / Delayed / 6.0-6.0
    endometrial hyperplasia / Delayed / 0-1.0
    candidiasis / Delayed / Incidence not known
    cervicitis / Delayed / Incidence not known
    cervical dysplasia / Delayed / Incidence not known
    vaginal bleeding / Delayed / Incidence not known
    galactorrhea / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    peliosis hepatis / Delayed / Incidence not known
    cholelithiasis / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    hypertension / Early / Incidence not known
    migraine / Early / Incidence not known
    erythema / Early / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    secondary malignancy / Delayed / Incidence not known
    impaired cognition / Early / Incidence not known
    urinary incontinence / Early / Incidence not known
    hypocalcemia / Delayed / Incidence not known
    hypercalcemia / Delayed / Incidence not known
    hypothyroidism / Delayed / Incidence not known

    Mild

    amenorrhea / Delayed / 54.0-65.0
    mastalgia / Delayed / 25.0-48.0
    dysmenorrhea / Delayed / 20.0-31.0
    breakthrough bleeding / Delayed / 3.0-26.0
    headache / Early / 17.0-25.0
    skin irritation / Early / 2.0-23.0
    back pain / Delayed / 9.0-15.0
    diarrhea / Early / 4.0-14.0
    abdominal pain / Early / 6.0-14.0
    asthenia / Delayed / 8.0-13.0
    nausea / Early / 8.0-12.0
    weight gain / Delayed / 9.0-9.0
    insomnia / Early / 3.0-8.0
    breast enlargement / Delayed / 2.0-7.0
    dizziness / Early / 6.0-7.0
    emotional lability / Early / 1.0-6.0
    anxiety / Delayed / 3.0-6.0
    rash (unspecified) / Early / 5.0-6.0
    arthralgia / Delayed / 6.0-6.0
    menorrhagia / Delayed / 2.0-5.0
    acne vulgaris / Delayed / 4.0-5.0
    libido decrease / Delayed / Incidence not known
    libido increase / Delayed / Incidence not known
    breast discharge / Delayed / Incidence not known
    vomiting / Early / Incidence not known
    fatigue / Early / Incidence not known
    irritability / Delayed / Incidence not known
    melasma / Delayed / Incidence not known
    hirsutism / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    alopecia / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    diplopia / Early / Incidence not known
    muscle cramps / Delayed / 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; 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.
    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.
    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.
    Acetaminophen; Propoxyphene: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as propoxyphene may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    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.
    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.
    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.
    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. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
    Amoxicillin; Clarithromycin; Omeprazole: (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. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
    Amoxicillin; 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 estradiol may be reduced when coadministered with aprepitant, fosaprepitant and for 28 days after the last dose. The exact mechanism for this interaction has not been described. Ethinyl estradiol is a CYP3A4 substrate and aprepitant, fosaprepitant is a CYP3A4 inducer; however, aprepitant, fosaprepitant is also a dose-dependent weak-to-moderate CYP3A4 inhibitor. When administered as an oral 3-day regimen (125mg/80mg/80mg) in combination with ondansetron and dexamethasone, aprepitant decreased trough concentrations of ethinyl estradiol and norethindrone by up to 64% for 3 weeks post-treatment. When ethinyl estradiol and norgestimate were administered on days 1 to 21 and aprepitant (40mg) give as a single dose on day 8, the AUC of ethinyl estradiol decreased by 4% on day 8 and by 29% on day 12; the AUC of norelgestromin increased by 18% on day 8, and decreased by 10% on day 12. Trough concentrations of both ethinyl estradiol and norelgestromin were generally lower after coadministration of aprepitant (40mg) on day 8 compared to administration without aprepitant. Specific studies have not been done with other hormonal contraceptives (e.g., progestins, non-oral combination contraceptives), an alternative or additional non-hormonal method of birth control during treatment and for 28 days after treatment is prudent to avoid potential for contraceptive failure. Additionally, although not specifically studied, because estrogens are CYP3A4 substrates, the efficacy of estrogens or progestins when used for hormone replacement may also be reduced. The clinical significance of this is not known since aprepitant, fosaprepitant is only used intermittently. (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 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.
    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.
    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.
    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. (Moderate) Atazanavir has been shown to decrease the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should be instructed to report any estrogen- related adverse events.
    Atazanavir; Cobicistat: (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) 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) Atazanavir has been shown to decrease the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should be instructed to report any estrogen- related adverse events.
    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.
    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.
    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.
    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.
    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.
    Calcium: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Canagliflozin: (Minor) Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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.
    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.
    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 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.
    Cefuroxime: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Cephalexin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ceritinib: (Moderate) Use caution when combining ceritinib, a time-dependent inhibitor of CYP3A4, with substrates that are primarily metabolized by CYP3A4, such as oral contraceptives, as ethinyl estradiol, mestranol, or progestin exposure may be increased. Females of reproductive potential should avoid becoming pregnant and are instructed to utilize effective contraceptive methods during ceritinib therapy and for at least 2 weeks following completion of therapy. Monitor for hormonal side effects if co-use is necessary to fulfill contraceptive requirements.
    Charcoal: (Major) Note that charcoal exerts a nonspecific effect, and many medications can be adsorbed by activated charcoal; repeat doses may decrease the enterohepatic recycling of some drugs. Activated charcoal dietary supplements may have the potential to reduce the effectiveness of oral contraceptives. Data clearly demonstrating this interaction are not available. Ovulatory potential was studied during the use of two monophasic oral contraceptive pill preparations, after repeated mid-cycle administration of activated charcoal to treat diarrhea in women. None of eleven women ovulated. Repeated charcoal treatment, when administered 3 hours after but at least 12 hours before pill intake, did not alter oral contraceptive efficacy.
    Chenodiol: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
    Chloramphenicol: (Moderate) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as chloramphenicol may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, anti-infectives that disrupt the normal GI flora, including chloramphenicol, may potentially decrease the effectiveness of estrogen-containing oral contraceptives. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include chloramphenicol.
    Chlorpropamide: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Ciclesonide: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Cimetidine: (Minor) Cimetidine has been reported to reduce the hepatic clearance of endogenous estradiol. The clinical significance of cimetidine's action on exogenous estrogens, like oral contraceptives, is uncertain. Patients who ingest cimetidine might experience an increase in certain estrogen-related side effects.
    Ciprofloxacin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Cisatracurium: (Minor) Estrogens have been associated in rare cases with pseudocholinesterase deficiency. Since non-depolarizing neuromuscular blockers are metabolized by cholinesterase, prolonged neuromuscular blockade may occur in individuals on concurrent therapy with estrogens.
    Clarithromycin: (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. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
    Clindamycin: (Moderate) 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.
    Clobazam: (Major) The addition of non-hormonal forms of contraception are recommended during concurrent use of clobazam and hormonal contraceptives. Concurrent administration of clobazam, a weak CYP3A4 inducer, with estrogens, oral contraceptives (OCs), non-oral combination contraceptives, or progestins may increase the elimination of these hormones. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Patients taking these hormones for indications other than contraception may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy. (Moderate) Concurrent administration of clobazam, a weak CYP3A4 inducer, with estrogens, may increase the elimination of these hormones. Patients may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
    Cobicistat: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Moderate) Consider the benefits and risk of administering elvitegravir with ethinyl estradiol; norgestimate and other combination oral contraceptives. Concurrent use may result in elevated norgestimate and reduced ethinyl estradiol serum concentrations. Risk associated with these altered concentrations may include increased insulin resistance, dyslipidemia, acne, and venous thrombosis. Consider alternative non-hormonal methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Moderate) Consider the benefits and risk of administering elvitegravir with ethinyl estradiol; norgestimate and other combination oral contraceptives. Concurrent use may result in elevated norgestimate and reduced ethinyl estradiol serum concentrations. Risk associated with these altered concentrations may include increased insulin resistance, dyslipidemia, acne, and venous thrombosis. Consider alternative non-hormonal methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS.
    Colistimethate, Colistin, Polymyxin E: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Conivaptan: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Corticosteroids: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Corticotropin, ACTH: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Cortisone: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Cosyntropin: (Minor) Use cosyntropin cautiously in patients taking estrogens as these patients may exhibit abnormally high basal plasma cortisol concentrations and a decreased response to the test.
    Cyclosporine: (Moderate) Estrogens and/or progestins in oral contraceptives or non-oral combination contraceptives may inhibit the metabolism of cyclosporine. Delayed cyclosporine clearance and elevated cyclosporine concentrations can lead to seizures, nephrotoxicity and/or hepatotoxicity. Additionally, estrogens are metabolized by CYP3A4; cyclosporine may increase plasma concentrations of estrogens and cause estrogen-related side effects. If estrogens or progestins are initiated or discontinued, the patient's cyclosporine concentrations should be monitored closely. Additionally, patients should be monitored for estrogenic side effects if these drugs are used concomitantly.
    Dabrafenib: (Major) Avoid concomitant use of dabrafenib and hormonal contraceptives; decreased hormonal contraceptive concentrations and loss of efficacy may occur. Use of an alternative non-hormonal contraceptive method of birth control is recommended during treatment for 2 weeks after the last dose of dabrafenib. Dabrafenib is a moderate CYP3A4 inducer and many hormonal contraceptive are CYP3A4 substrates.
    Dalbavancin: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Danazol: (Minor) As danazol inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives, including oral contraceptives.
    Dantrolene: (Moderate) Concomitant use of dantrolene and estrogens may increase the risk of developing hepatotoxicity. While a definite drug interaction with dantrolene and estrogen therapy has not yet been established, caution should be observed if the two drugs are to be given concomitantly. Hepatotoxicity has occurred more often, for example, in women over 35 years of age receiving concomitant estrogen therapy.
    Dapagliflozin: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (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.
    Dapagliflozin; Metformin: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (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.
    Dapagliflozin; Saxagliptin: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (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) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Daptomycin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Darunavir: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norethindrone have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norethindrone. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Darunavir is expected to increase the metabolism of estradiol. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
    Darunavir; Cobicistat: (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. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norethindrone have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norethindrone. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Darunavir is expected to increase the metabolism of estradiol. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. For example, ritonavir (also found in combinations like lopinavir; ritonavir, and used as a booster in many HIV treatment regimens) may decrease the metabolism of norethindrone, raising norethindrone concentrations. Women receiving norethindrone for hormone replacement or contraception should report potential hormonal adverse effects (e.g., bleeding pattern changes, acne, emotional lability) or any changes in efficacy (e.g., noted changes in bleeding patterns) to their prescribers. Because norethindrone-containing contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive norethindrone contraception concurrently with ritonavir should use an additional barrier method of contraception such as condoms. (Moderate) Ritonavir has been shown to increase the metabolism of ethinyl estradiol. Ritonavir is a substrate and inhibitor of CYP3A4. It is not known if the effects of protease inhibitors are similar on estradiol; however, estradiol is metabolized by CYP3A4, similar to ethinyl estradiol.
    Dasatinib: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as dasatinib may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Deferasirox: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Deflazacort: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Delafloxacin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Delavirdine: (Minor) As delavirdine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives, including oral contraceptives.
    Demeclocycline: (Moderate) It 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.
    Desiccated Thyroid: (Minor) The administration of estrogens can increase circulating concentrations of thyroxine-binding globulin. Increased amounts of thyroxine-binding globulin may result in a reduced clinical response to thyroid hormones. Some hypothyroid patients on estrogen may require larger doses of thyroid hormones.
    Dexamethasone: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Dicloxacillin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Diltiazem: (Minor) As diltiazem inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Doripenem: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Doxacurium: (Minor) Estrogens have been associated in rare cases with pseudocholinesterase deficiency. Since non-depolarizing neuromuscular blockers are metabolized by cholinesterase, prolonged neuromuscular blockade may occur in individuals on concurrent therapy with estrogens.
    Doxycycline: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Dulaglutide: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as combined hormonal oral contraceptives (OCs). Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, estrogens can impair glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving greater than 50 mcg of ethinyl estradiol or equivalent estrogen per day. However, any patient with diabetes may need to monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Duloxetine: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as duloxetine may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Efavirenz: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations. (Moderate) Estrogens are CYP3A4 substrates and efavirenz is a CYP3A4 inducer; concomitant use of efavirenz-containing products (including efavirenz; emtricitabine; tenofovir) may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., menopausal symptoms, breakthrough bleeding, reduced efficacy) if these drugs are used together.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations. (Moderate) Estrogens are CYP3A4 substrates and efavirenz is a CYP3A4 inducer; concomitant use of efavirenz-containing products (including efavirenz; emtricitabine; tenofovir) may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., menopausal symptoms, breakthrough bleeding, reduced efficacy) if these drugs are used together.
    Elvitegravir: (Moderate) Consider the benefits and risk of administering elvitegravir with ethinyl estradiol; norgestimate and other combination oral contraceptives. Concurrent use may result in elevated norgestimate and reduced ethinyl estradiol serum concentrations. Risk associated with these altered concentrations may include increased insulin resistance, dyslipidemia, acne, and venous thrombosis. Consider alternative non-hormonal methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS.
    Empagliflozin: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (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.
    Empagliflozin; Linagliptin: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Empagliflozin; Metformin: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (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.
    Enasidenib: (Major) Use enasidenib and hormonal contraceptives together with caution; concomitant use may alter hormone contraceptive levels resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for at least 1 month after treatment with enasidenib. Enasidenib is a CYP3A4 inducer and inhibitor in vitro and many oral hormonal contraceptives are metabolized by CYP3A4. Coadministration may result in increased or decreased hormonal contraceptive levels; however, the clinical significance of this potential drug interaction is unknown
    Ertapenem: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Erythromycin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Minor) As erythromycin inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Erythromycin; Sulfisoxazole: (Moderate) 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. (Minor) As erythromycin inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Eslicarbazepine: (Major) Coadministration of eslicarbazepine with oral contraceptives may result in contraceptive failure. Coadministration of eslicarbazepine and ethinyl estradiol and levonorgestrel has resulted in decreased plasma concentrations of these hormones. Instruct females of child-bearing potential to use additional or non-hormonal contraception during therapy with eslicarbazepine and after treatment has been discontinued for at least one menstrual cycle.
    Ethotoin: (Moderate) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins in patients receiving phenytoin (the active metabolite of fosphenytoin) concurrently. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; if oral contraceptive failure occurs, the additive effects could potentially heighten the risk of neural tube defects in pregnancy. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on phenytoin or fosphenytoin, with dose adjustments made based on clinical efficacy.
    Exemestane: (Severe) Estrogens, including hormonal contraceptives, could interfere competitively with the pharmacologic action of the aromatase inhibitors. The goal of aromatase inhibitor therapy is to decrease circulating estrogen concentrations and inhibit the growth of hormonally-responsive cancers. Estrogen therapy is not recommended during aromatase inhibitor treatment, due to opposing pharmacologic actions. Aromatase inhibitors (e.g., aminoglutethimide, anastrozole, exemestane, letrozole, testolactone, vorozole) exhibit their antiestrogenic effects by reducing the peripheral conversion of adrenally synthesized androgens (e.g., androstenedione) to estrogens through inhibition of the aromatase enzyme.
    Exenatide: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as combined hormonal oral contraceptives (OCs). Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, estrogens can impair glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving greater than 50 mcg of ethinyl estradiol or equivalent estrogen per day. However, any patient with diabetes may need to monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Felbamate: (Major) Based on very limited data, it appears felbamate can accelerate the clearance of the estrogen component of some oral contraceptives. Patients who experience breakthrough bleeding while receiving these drugs together should notify their prescribers. An alternate or additional form of contraception should be used during concomitant treatment. Additionally, patients taking non-oral combination contraceptives or estrogens or progestins for hormone replacement therapy may also experience reduced clinical efficacy; dosage adjustments may be necessary. (Major) Estrogens and progestins are both susceptible to drug interactions with hepatic enzyme inducing drugs. Estrogens are metabolized by CYP3A4. Anticonvulsants that stimulate the activity of this enzyme include: barbiturates (including primidone), carbamazepine, felbamate, oxcarbazepine, phenytoin or fosphenytoin (and possibly ethotoin), and topiramate. The anticonvulsants mentioned may cause oral contraceptive failure, especially when low-dose estrogen regimens (e.g., ethinyl estradiol is < 50 mcg/day) are used. Epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism and the higher risk for oral contraceptive failure. During oral contraceptive failure, the additive effects could potentially heighten the risk of neural tube defects in pregnancy. Women on OCs and enzyme-inducing anticonvulsant medications concurrently should report breakthrough bleeding to their prescribers. Oral contraceptive formulations containing higher dosages of ethinyl estradiol (i.e., 50 mcg ethinyl estradiol) may be needed to increase contraceptive efficacy. It may be prudent for some women who receive OCs concurrently with enzyme-inducing anticonvulsants to use an additional contraceptive method to protect against unwanted pregnancy. Higher dosages of oral contraceptives (e.g., ethinyl estradiol >= 50 mcg/day) or a second contraceptive method are typically suggested if women use an enzyme-inducing anti-epileptic drug or a barbiturate. Proper intake of folic acid should also be ensured.
    Fidaxomicin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Flibanserin: (Moderate) The concomitant use of flibanserin and multiple weak CYP3A4 inhibitors, including oral contraceptives, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the risks of combination therapy with multiple weak CYP3A4 inhibitors and flibanserin should be discussed with the patient. In one study of 24 healthy women, the effect of 100 mg flibanserin once daily for 2 weeks on the pharmacokinetics of a single dose of ethinyl estradiol 30 mcg/levonorgestrel 150 mcg was evaluated. Flibanserin increased the AUC and Cmax of ethinyl estradiol by 1.09-fold and 1.1-fold, respectively. Flibanserin decreased the levonorgestrel AUC by 1.06-fold. During pre-marketing evaluation of flibanserin, patients who reported using oral contraceptives had a greater incidence of CNS effects than flibenserin-treated patients who did not report oral contraceptive use, including dizziness (13.4% vs. 9.9%), somnolence (12.3% vs. 10.6%), and fatigue (11.4% vs. 7.5%).
    Fluconazole: (Minor) As fluconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Fludrocortisone: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Flunisolide: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Fluoxetine: (Minor) As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Fluoxetine; Olanzapine: (Minor) As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Fluticasone: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Fluticasone; Salmeterol: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Fluticasone; Vilanterol: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Formoterol; Mometasone: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Fosamprenavir: (Major) Clinically significant hepatic transaminase elevations may occur with concomitant use of fosamprenavir, boosted with ritonavir, and oral contraceptives; fosamprenavir should not be coadministered with oral contraceptives. Additionally, hormonal contraceptives, estrogens, and progestins may decrease the serum concentrations of fosamprenavir's active metabolite, amprenavir, which could lead to loss of virologic response and possible viral resistance. Oral contraceptives and non-oral combination contraceptives should not be administered with fosamprenavir. Alternative methods of non-hormonal contraception are recommended. 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. Coadministration of medroxyprogesterone, a CYP3A substrate with fosamprenavir, a strong CYP3A inhibitor should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via the CYP3A4 in vitro. It is not known if fosamprenavir alters the metabolism of other 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. In women receiving oral contraceptives containing drospirenone, consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors, such as atazanavir, long-term and concomitantly. Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. (Major) Fosamprenavir should not be administered with oral contraceptives due to the risk of clinically significant hepatic transaminase elevations; a similar response could be expected with HRT. Additionally, hormonal contraceptives, estrogens, and progestins may decrease the serum concentrations of fosamprenavir's active metabolite, amprenavir, which could lead to loss of virologic response and possible viral resistance. If these drugs are used together, carefully monitor the patient for adverse hepatic effects, decreased virologic response, and viral resistance.
    Fosphenytoin: (Moderate) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins in patients receiving phenytoin (the active metabolite of fosphenytoin) concurrently. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; if oral contraceptive failure occurs, the additive effects could potentially heighten the risk of neural tube defects in pregnancy. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on phenytoin or fosphenytoin, with dose adjustments made based on clinical efficacy.
    Gemifloxacin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used with antibiotics. Oral contraceptives (estrogen/progesterone) reduced the AUC and Cmax of gemifloxacin by 19% and 12%, respectively. These reductions are considered to be clinically insignificant. Gemifloxacin did not affect the pharmacokinetics of an ethinyl estradiol/levonorgestrel oral contraceptive product in healthy females. It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Gentamicin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Glimepiride: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Glimepiride; 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) 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.
    Glimepiride; Rosiglitazone: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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. (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.
    Glipizide: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Glipizide; Metformin: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) 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.
    Glyburide: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Glyburide; Metformin: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) 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.
    Glycylcyclines: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Gonadotropin-Releasing Hormone Analogs: (Major) Concomitant use of estrogens with GnRH analogs is relatively contraindicated, as estrogens could counteract the therapeutic effect of GnRH analogs for various hormone-sensitive conditions. In the rare cases that these drugs are used together, close clinical monitoring for the desired clinical and hormonal response is necessary.
    Grapefruit juice: (Minor) Grapefruit juice has been reported to decrease the metabolism of some estrogens. Grapefruit juice contains a compound that inhibits CYP3A4 in enterocytes. Estrogen levels may increase by up to 30 percent with chronic use. The clinical significance of the interaction is unknown. It is possible that estrogen induced side effects could be increased in some individuals. Patients should be advised to not significantly alter their grapefruit juice ingestion.When chronically ingesting any CYP3A4 inhibitor ( > 30 days) with estrogens, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
    Griseofulvin: (Major) The concurrent use of griseofulvin and oral contraceptives can reduce contraceptive efficacy and result in an unintended pregnancy and/or breakthrough bleeding. This risk is particularly serious because griseofulvin is contraindicated during pregnancy due to the risk of teratogenic and abortifacient effects. An alternate or additional form of contraception should be used during concomitant treatment and continued for 1 month after griseofulvin discontinuation. If these drugs are used together, counsel the patient about the risk of pregnancy and teratogenic effects, and instruct the patient to notify the prescriber if they experience breakthrough bleeding while receiving these drugs together. Additionally, patients taking non-oral combination contraceptives or progestins for hormone replacement therapy may also experience reduced clinical efficacy. (Moderate) Concomitant use of griseofulvin and oral contraceptives has been reported to reduce the efficacy of the oral contraceptive and cause breakthrough bleeding. Patients who experience breakthrough bleeding while receiving these drugs together should notify their prescribers. An alternate or additional form of contraception should be used during concomitant treatment and should be continued for 1 month after griseofulvin discontinuation. Additionally, patients taking non-oral combination contraceptives, estrogens, or progestins for hormone replacement therapy may also experience reduced clinical efficacy; dosage adjustments may be necessary.
    Guarana: (Minor) Use guarana cautiously in female patients who use oral contraceptives as serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol or combined hormonal oral contraceptives. This interaction occurs from the inhibition of methylxanthine oxidation in the liver. Patients should be informed of increased side effects associated with the caffeine component of guarana, such as nausea or tremors.
    Hemin: (Moderate) Hemin works by inhibiting aminolevulinic acid synthetase. Estrogens increase the activity of this enzyme should not be used with hemin.
    Hyaluronidase, Recombinant; Immune Globulin: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Hyaluronidase: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Hydantoins: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; if oral contraceptive failure occurs, the additive effects could potentially heighten the risk of neural tube defects in pregnancy. (Moderate) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins in patients receiving phenytoin (the active metabolite of fosphenytoin) concurrently. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; if oral contraceptive failure occurs, the additive effects could potentially heighten the risk of neural tube defects in pregnancy. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on phenytoin or fosphenytoin, with dose adjustments made based on clinical efficacy.
    Hydralazine: (Minor) The administration of estrogens can increase fluid retention, which increases blood pressure, thereby antagonizing the antihypertensive effects of hydralazine.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Minor) The administration of estrogens can increase fluid retention, which increases blood pressure, thereby antagonizing the antihypertensive effects of hydralazine.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Minor) The administration of estrogens can increase fluid retention, which increases blood pressure, thereby antagonizing the antihypertensive effects of hydralazine.
    Hydrocortisone: (Moderate) Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known. Estrogens are CYP3A4 substrates and dexamethasone is a CYP3A4 inducer; concomitant use may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., breakthrough bleeding), oral contraceptives, or non-oral combination contraceptives if these drugs are used together.
    Icosapent ethyl: (Moderate) Estrogens may exacerbate hypertriglyceridemia and should be discontinued or changed to alternate therapy, if possible, prior to initiation of icosapent ethyl.
    Idelalisib: (Moderate) Idelalisib is a strong CYP3A inhibitor, and ethinyl estradiol (EE) is a CYP3A substrate. Use caution in dose selection, as the hormonal side effects of ethinyl estradiol may be increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib. Females of reproductive potential should avoid becoming pregnant during idelalisib therapy, using effective contraception during treatment and for at least 1 month after the last dose. Thus, use idelalisib with caution in combination with any combination oral contraceptives, most of which contain EE or mestranol (which is converted to EE). In addiiton, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly.
    Imatinib: (Minor) As imatinib inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Imipenem; Cilastatin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Incretin Mimetics: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as combined hormonal oral contraceptives (OCs). Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, estrogens can impair glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving greater than 50 mcg of ethinyl estradiol or equivalent estrogen per day. However, any patient with diabetes may need to monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. (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 progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) 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, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Indinavir: (Moderate) Indinavir has been shown to decrease the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should be instructed to report any estrogen- related adverse events. (Moderate) Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. The AUC for norethindrone increased by 26+/-14%, respectively, when a combined oral contraceptive was coadministered with indinavir. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as indinavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives with indinavir should use an additional barrier method of contraception such as condoms.
    Insulin Degludec; Liraglutide: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as combined hormonal oral contraceptives (OCs). Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, estrogens can impair glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving greater than 50 mcg of ethinyl estradiol or equivalent estrogen per day. However, any patient with diabetes may need to monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Insulin Glargine; Lixisenatide: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as combined hormonal oral contraceptives (OCs). Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, estrogens can impair glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving greater than 50 mcg of ethinyl estradiol or equivalent estrogen per day. However, any patient with diabetes may need to monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Insulins: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives, including progestins. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving rifampin concurrently. other rifamycins (e.g., rifabutin and rifapentine), may also induce hepatic enzymes. Since the dosage of norethindrone for contraception cannot be modified, an alternate or additional form of contraception should be considered in patients requiring therapy with rifamycins. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Patients taking norethindrone for other indications may need to be monitored for reductions in clinical effect of the progestin.
    Isoniazid, INH; Rifampin: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives, including progestins. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving rifampin concurrently. other rifamycins (e.g., rifabutin and rifapentine), may also induce hepatic enzymes. Since the dosage of norethindrone for contraception cannot be modified, an alternate or additional form of contraception should be considered in patients requiring therapy with rifamycins. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Patients taking norethindrone for other indications may need to be monitored for reductions in clinical effect of the progestin.
    Isotretinoin: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Itraconazole: (Minor) As itraconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Kanamycin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ketoconazole: (Minor) As ketoconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Lamotrigine: (Major) Adult and adolescent women receiving combination oral contraceptives with lamotrigine may require close clinical monitoring and lamotrigine dosage adjustments as there is potential for decreased efficacy of both lamotrigine and the oral contraceptive. Estrogen-containing hormonal contraceptives may increase lamotrigine clearance during coadministration; in addition, side effects from lamotrigine such as dizziness, ataxia, and diplopia may occur during the placebo/off week, when lamotrigine clearance decreases. It is unknown if an interaction exists with non-oral combination contraceptives or hormone replacement therapy; however, it is possible that similar interactions could occur. Progestin-only products are not thought to change lamotrigine plasma levels. The specific dosage adjustment recommendations vary according to the type of hormonal contraception used and the presence or absence of other enzyme-inducing drug therapy. In one study, an oral contraceptive containing ethinyl estradiol; levonorgestrel 30 mcg/150 mcg administered for approximately 4.6 cycles (21 days of ethinyl estradiol (EE); levonorgestrel followed by 7 days of placebo) increased the clearance of lamotrigine 2-fold with mean decreases in AUC and Cmax of 52% and 39%, respectively. Trough lamotrigine concentrations increased an average of 2-fold by the end of the placebo week. Administration of lamotrigine 300 mg/day did not affect the kinetics of the EE component in a small group of female subjects. However, the AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively. The clinical outcome of these changes has not been studied. It is possible that EE; levonorgestrel efficacy could be reduced. Although not specifically recommended by the manufacturer, consideration should be given to prescribing progestin-only contraceptives or extended cycle combined hormonal contraceptives (e.g., Seasonale, Seasonique) to minimize lamotrigine serum concentration fluctuations). No adjustments to the initial lamotrigine dosing titration schedule are needed in women starting estrogen-containing contraceptives other than those recommended for initiation of lamotrigine in patients receiving other selected AEDs. The maintenance dose of lamotrigine following the initial titration or in those already stable on the drug will likely need to be increased 2-fold more than the usual recommended target dose to maintain consistent plasma levels in those not receiving enzyme-inducing medications (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin or other drugs, like rifampin, that increase lamotrigine glucuronidation, like ritonavir). Dose increases should begin when the oral contraceptive is started, and continue based upon response, not to exceed 50 to 100 mg/day per week unless lamotrigine plasma levels or response warrant otherwise. Gradual transient increases in lamotrigine plasma levels may occur during the placebo week, and may be larger if dose changes are made just prior to this phase in the hormone cycle, possibly resulting in lamotrigine toxicity. Therefore dose changes limited to the pill-free week are not recommended; if adverse effects continue to occur during the pill-free week, the overall maintenance dose may need adjustment. No dose adjustments should be needed in those stable on lamotrigine while starting or stopping estrogen-containing contraceptives and receiving enzyme-inducing medications. The lamotrigine maintenance dose will likely need to be decreased as much as 50% to maintain a consistent lamotrigine plasma level in those stopping estrogen-containing contraceptives and not receiving enzyme-inducing medications. Dosage decreases should not exceed 25% of the total daily dose per week over 2 weeks, unless lamotrigine plasma levels or response warrant otherwise. Until further data becomes available, close monitoring of lamotrigine for efficacy and toxicity is warranted in all situations.
    Lenalidomide: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
    Lesinurad: (Major) Hormonal contraceptives, including combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins. This includes injectable, transdermal, and implantable forms. Hormonal contraceptives may not be reliable when coadministered with lesinurad. Females should use additional, non-hormonal methods of contraception and not rely solely on hormonal contraceptive methods when taking lesinurad.
    Lesinurad; Allopurinol: (Major) Hormonal contraceptives, including combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins. This includes injectable, transdermal, and implantable forms. Hormonal contraceptives may not be reliable when coadministered with lesinurad. Females should use additional, non-hormonal methods of contraception and not rely solely on hormonal contraceptive methods when taking lesinurad.
    Letrozole: (Severe) Estrogens, including hormonal contraceptives, could interfere competitively with the pharmacologic action of the aromatase inhibitors. The goal of aromatase inhibitor therapy is to decrease circulating estrogen concentrations and inhibit the growth of hormonally-responsive cancers. Estrogen therapy is not recommended during aromatase inhibitor treatment, due to opposing pharmacologic actions. Aromatase inhibitors (e.g., aminoglutethimide, anastrozole, exemestane, letrozole, testolactone, vorozole) exhibit their antiestrogenic effects by reducing the peripheral conversion of adrenally synthesized androgens (e.g., androstenedione) to estrogens through inhibition of the aromatase enzyme.
    Levofloxacin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Levothyroxine: (Minor) The administration of estrogens can increase circulating concentrations of thyroxine-binding globulin. Increased amounts of thyroxine-binding globulin may result in a reduced clinical response to thyroid hormones. Some hypothyroid patients on estrogen may require larger doses of thyroid hormones.
    Linagliptin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Linagliptin; Metformin: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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.
    Lincomycin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Lincosamides: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Linezolid: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Liothyronine: (Minor) The administration of estrogens can increase circulating concentrations of thyroxine-binding globulin. Increased amounts of thyroxine-binding globulin may result in a reduced clinical response to thyroid hormones. Some hypothyroid patients on estrogen may require larger doses of thyroid hormones.
    Liotrix: (Minor) The administration of estrogens can increase circulating concentrations of thyroxine-binding globulin. Increased amounts of thyroxine-binding globulin may result in a reduced clinical response to thyroid hormones. Some hypothyroid patients on estrogen may require larger doses of thyroid hormones.
    Liraglutide: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as combined hormonal oral contraceptives (OCs). Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, estrogens can impair glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving greater than 50 mcg of ethinyl estradiol or equivalent estrogen per day. However, any patient with diabetes may need to monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Lixisenatide: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as combined hormonal oral contraceptives (OCs). Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, estrogens can impair glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving greater than 50 mcg of ethinyl estradiol or equivalent estrogen per day. However, any patient with diabetes may need to monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Lomitapide: (Major) Concomitant use of lomitapide and oral contraceptives may significantly increase the serum concentration of lomitapide. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Oral Contraceptives are weak CYP3A4 inhibitors; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors. In addition, females of reproductive potential must use effective contraception during lomitapide therapy. Because vomiting and diarrhea have been frequently reported during lomitapide therapy and hormone absorption from oral contraceptives may be incomplete in the presence of vomiting or diarrhea, warn patients that the use of additional contraceptive methods is warranted if vomiting or diarrhea occur.
    Lopinavir; Ritonavir: (Moderate) Lopinavir; ritonavir increases the metabolism of estrogens. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency. Patients should be instructed to report any breakthrough bleeding or adverse events to their prescribers. (Moderate) Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. For example, ritonavir (also found in combinations like lopinavir; ritonavir, and used as a booster in many HIV treatment regimens) may decrease the metabolism of norethindrone, raising norethindrone concentrations. Women receiving norethindrone for hormone replacement or contraception should report potential hormonal adverse effects (e.g., bleeding pattern changes, acne, emotional lability) or any changes in efficacy (e.g., noted changes in bleeding patterns) to their prescribers. Because norethindrone-containing contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive norethindrone contraception concurrently with ritonavir should use an additional barrier method of contraception such as condoms. (Moderate) Ritonavir has been shown to increase the metabolism of ethinyl estradiol. Ritonavir is a substrate and inhibitor of CYP3A4. It is not known if the effects of protease inhibitors are similar on estradiol; however, estradiol is metabolized by CYP3A4, similar to ethinyl estradiol.
    Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Meglitinides: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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.
    Melatonin: (Moderate) Caution should be exercised when using melatonin in patients taking estrogens (i.e., combined oral contraceptives, non-oral combination contraceptives or estrogen for hormone replacement therapy), which increase melatonin levels by inhibiting melatonin metabolism via CYP1A1 and CYP1A2.
    Mephobarbital: (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 i