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  • CLASSES

    Monophasic Contraceptives
    Triphasic Contraceptives

    BOXED WARNING

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

    Combined hormonal contraceptive agents are contraindicated in patients with a current or past history of stroke, cerebrovascular disease, coronary artery disease, coronary thrombosis, myocardial infarction, thrombophlebitis, thromboembolism or thromboembolic disease, or valvular heart disease with complications. Hormonal combined oral contraceptives (COCs) have been associated with thromboembolism such as deep venous thrombosis (DVT) and pulmonary embolism (PE). COCs are also generally contraindicated in women who have thrombogenic valvular or thrombogenic rhythm diseases of the heart (e.g., subacute bacterial endocarditis with valvular disease, or atrial fibrillation), or a known inherited or acquired hypercoagulopathies (e.g., protein S deficiency, protein C deficiency, Factor V Leiden, prothrombin G20210A mutation, antithrombin deficiency, antiphospholipid antibodies). Because tobacco smoking increases the risk of thromboembolism, DVT, myocardial infarction, stroke and other thromboembolic disease, patients receiving COCs are strongly advised not to smoke. Risk is especially high for female smokers over 35 years of age or those who smoke 15 or more cigarettes per day. Therefore, COCs are generally considered contraindicated in women over the age of 35 years who are tobacco smokers. A positive relationship between estrogen dosage and thromboembolic disease has been demonstrated, and oral products containing 50-mcg ethinyl estradiol should not be used unless medically indicated. In addition, certain progestins may increase thromboembolic risk. The overall risk of venous thromboembolism in women using COCs has been estimated to be 3 to 9 per 10,000 woman-years. Preliminary data from a large, prospective cohort safety study suggests that the risk is greatest during the first 6 months after initially starting COC therapy or restarting (following a break from therapy 4 weeks or more) with the same or different combination product. The risk of arterial thromboses, such as stroke and myocardial infarction, is especially increased in women with other risk factors for these events. Pre-existing high blood pressure, kidney disease, hypercholesterolemia, hyperlipidemia, diabetes with vascular disease, and morbidly obese patients may also increase risk. After a COC is discontinued, the risk of thromboembolic disease due to oral contraceptives gradually disappears. Because of their association with elevations in blood pressure, COCs should be used cautiously in patients with mild to moderate hypertension or kidney disease; use is contraindicated in patients with uncontrolled or severe hypertension or hypertension with vascular disease. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin. Blood pressure should be monitored closely in individuals with high blood pressure; discontinue norethindrone acetate; ethinyl estradiol; ferrous fumarate if blood pressure rises significantly. COCs may also cause fluid retention, and patients predisposed to complications from edema, such as those with renal disease or cardiac disease, should be closely monitored.

    DEA CLASS

    Rx

    DESCRIPTION

    Combined oral contraceptive (COC) containing a synthetic estrogen and norethindrone acetate, a progestin with moderate androgenic and slight estrogenic activity
    Ferrous fumarate tablets provide a small amount of iron supplement during menses but no significant therapeutic value
    Used for routine contraception in adolescent and adult premenopausal females; some products are additionally approved for acne treatment in these populations
    All COCs contain a boxed warning regarding the increased risk for thromboembolism in women who smoke

    COMMON BRAND NAMES

    Aurovela 24 Fe 1/20, Aurovela Fe, Blisovi 24 Fe, Blisovi Fe, Charlotte 24 Fe, Estrostep Fe, Finzala, Gemmily, Gildess 24 Fe, Gildess Fe 1.5/30, Gildess Fe 1/20, Hailey 24 Fe, Hailey Fe 1.5/30, Junel Fe 1.5/30, Junel Fe 1/20, Junel Fe 24, Larin Fe, Lo Loestrin Fe, Loestrin 24 Fe, Loestrin FE 1.5/30, Loestrin FE 1/20, Lomedia 24 Fe, Melodetta, Merzee, Mibelas 24 Fe, Microgestin 24 Fe, Microgestin Fe 1.5/30, Microgestin Fe 1/20, Minastrin, Tarina 24 Fe, Tarina Fe 1/20, Taysofy, Taytulla, Tilia Fe, Tri-Legest Fe

    HOW SUPPLIED

    Aurovela 24 Fe 1/20/Aurovela Fe/Blisovi 24 Fe/Blisovi Fe/Estrostep Fe/Ethinyl Estradiol, Norethindrone;Ferrous Fumarate/Ferrous Fumarate;Norethindrone Acetate, Ethinyl Estradiol/Gildess 24 Fe/Gildess Fe 1.5/30/Gildess Fe 1/20/Hailey 24 Fe/Hailey Fe 1.5/30/Junel Fe 1.5/30/Junel Fe 1/20/Junel Fe 24/Larin Fe/Lo Loestrin Fe/Loestrin 24 Fe/Loestrin FE 1.5/30/Loestrin FE 1/20/Lomedia 24 Fe/Microgestin 24 Fe/Microgestin Fe 1.5/30/Microgestin Fe 1/20/Tarina 24 Fe/Tarina Fe 1/20/Tilia Fe/Tri-Legest Fe Oral Tab: 10-75-1-10mcg, 75-1-0.02mg, 75-1-0.02-0.03-0.035mg, 75-1.5-0.03mg
    Charlotte 24 Fe/Ethinyl Estradiol, Norethindrone;Ferrous Fumarate/Ferrous Fumarate;Norethindrone Acetate, Ethinyl Estradiol/Melodetta/Mibelas 24 Fe/Minastrin Oral Tab Chew: 75-1-20mcg
    Ethinyl Estradiol, Norethindrone;Ferrous Fumarate/Ferrous Fumarate;Norethindrone Acetate, Ethinyl Estradiol/Gemmily/Merzee/Taysofy/Taytulla Oral Cap: 75-1-20mcg

    DOSAGE & INDICATIONS

    For routine contraception.
    Oral dosage (monophasic products; e.g., Gildess Fe, Loestrin Fe, Junel Fe, Larin Fe, Microgestin Fe)
    Adult and Adolescent females

    1 active hormone tablet (containing either 1 mg norethindrone acetate; 0.02 mg ethinyl estradiol or alternatively, 1.5 mg norethindrone acetate; 0.03 mg ethinyl estradiol) PO once daily for 21 days, followed by 1 iron tablet (75 mg ferrous fumarate) PO once daily for 7 days. Pills should be taken in the order directed on the blister pack. The cycle should be repeated every 28 days. Administration of most combination OCs begins on the first Sunday after or on which bleeding has started. However, some clinicians and manufacturers suggest that administration begin on day 1 of the menstrual cycle to decrease the risk of early ovulation. If administration begins on day 1, spotting and breakthrough bleeding may be more common during the initial dosage cycle.

    Oral dosage (monophasic products; e.g., Loestrin 24 Fe, Lomedia 24 Fe)
    Adult and Adolescent females

    1 active hormone tablet (1 mg norethindrone acetate; 0.02 mg ethinyl estradiol) PO once daily for 24 days, followed by 1 iron tablet (75 mg ferrous fumarate) PO once daily for 4 days. Pills should be taken in the order directed on the blister pack. The cycle should be repeated every 28 days. Administration can begin on the first Sunday after or on which bleeding has started or the first day of bleeding. When switching from a 21-day combination hormonal contraceptive regimen, the patient should wait 7 days after her last tablet, patch, or ring before starting Loestrin 24 Fe. When switching from a 28-day combination OC regimen, the patient should begin Loestrin 24 Fe on the day after the last tablet. If a patient is taking an oral progestin-only regimen, the patient can switch to Loestrin 24 Fe at any time; she should start taking the Loestrin 24 Fe tablets the day after her last progestin-only tablet. If switching from an implant or an injection, the patient should start Loestrin 24 Fe on the day the implant is removed or the day the next injection would have been administered.

    Oral dosage (monophasic products; e.g., Minastrin 24 Fe chewable tablets)
    Adult and Adolescent females

    1 active hormone chewable tablet (1 mg norethindrone acetate; 0.02 mg ethinyl estradiol) PO once daily for 24 days, followed by 1 iron chewable tablet (75 mg ferrous fumarate) PO once daily for 4 days. Pills should be taken in the order directed on the blister pack. The cycle should be repeated every 28 days. Patients should start the blister pack on the first Sunday after or on which bleeding has started, or alternatively, on day 1 of the menstrual cycle (1st day of menstruation). When switching from another oral contraceptive, patients should start taking this product on the same day that a new pack of the previous oral contraceptive would have been started.

    Oral dosage (monophasic capsule product, i.e., Taytulla)
    Adults and Adolescent females

    1 active hormone capsule (1 mg norethindrone acetate; 0.02 mg ethinyl estradiol) PO once daily for 24 days, followed by 1 iron capsule (75 mg ferrous fumarate) PO once daily for 4 days. Capsules should be taken in the order directed on the blister pack. The cycle should be repeated every 28 days. Patients should start the blister pack on the first Sunday after or on which bleeding has started, or alternatively, on day 1 of the menstrual cycle (1st day of menstruation). When switching from another oral contraceptive, patients should start taking this product on the same day that a new pack of the previous oral contraceptive would have been started.

    Oral dosage (triphasic products; e.g., Estrostep Fe, Tilia Fe, Tri-Legest Fe)
    Adult and Adolescent females

    Phase 1: 1 active hormone tablet (1 mg norethindrone acetate; 0.02 mg ethinyl estradiol) PO once daily for 5 days. Phase 2: 1 active hormone tablet (1 mg norethindrone acetate; 0.03 mg ethinyl estradiol) PO once daily for 7 days. Phase 3: 1 active hormone tablet (1 mg norethindrone acetate; 0.035 mg ethinyl estradiol) PO once daily for 9 days, followed by 1 iron tablet (75 mg ferrous fumarate) PO once daily for 7 days. Pills should be taken in the order directed on the blister pack. The cycle should be repeated every 28 days. Administration of most combination oral contraceptives begins on the first Sunday after or on which bleeding has started. Estrostep products are recommended to be administered according to this Sunday-start regimen.

    Oral dosage (monophasic product with estrogen only phase at cycle end; e.g., Lo Loestrin Fe)
    Adult and Adolescent females

    Phase 1: 1 active hormone tablet (1 mg norethindrone acetate; 0.01 mg ethinyl estradiol) PO once daily for 24 days. Phase 2: 1 active hormone tablet (0.01 mg ethinyl estradiol) PO once daily for 2 days. Phase 3: 1 iron tablet (75 mg ferrous fumarate) PO once daily for 2 days. Pills should be taken in the order directed on the blister pack. The cycle should be repeated every 28 days. Patients should start the blister pack on the first day of menstrual bleeding. When switching from another oral contraceptive, patients should start taking Lo Loestrin Fe tablets on the same day that a new pack of the previous oral contraceptive would have been started.

    For the treatment of moderate acne vulgaris related to sebum overproduction in females who have no known contraindications to oral contraceptives, desire contraception, have achieved menarche, and are unresponsive to topical anti-acne medications.
    Oral dosage (e.g., Estrostep Fe triphasic)
    Adult and Adolescent females

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

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

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

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

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

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    1 tablet/day PO.

    Geriatric

    Not indicated.

    Adolescents

    1 tablet/day PO.

    Children

    Not indicated in prepubescent females.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Hormonal contraceptives are contraindicated for use in the presence of active liver disease or markedly impaired liver function.

    Renal Impairment

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

    ADMINISTRATION

    Hazardous Drugs Classification
    NIOSH 2016 List: Group 2
    NIOSH (Draft) 2020 List: Table 1
    Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
    Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Eye/face and respiratory protection may be needed during preparation and administration.

    Oral Administration

    Oral contraceptive (OC) formulations:
    Tablets and soft gelatin capsules should be swallowed whole.
    Take at the same time each day to ensure maximum contraceptive efficacy. To minimize nausea, administer with or after the evening meal or at bedtime.
    Absorption may be incomplete in cases of severe vomiting or diarrhea. If these symptoms occur, additional contraceptive measures should be taken. If vomiting occurs within 3 to 4 hours after administration, this can be regarded as a missed dose.
    For multi-phasic products, explanation of tablet or capsule sequencing and different tablet or capsule colors may be needed.
    Contraceptive packs contain iron tablets or capsules. The iron tablets or capsules are included so that the daily dosage cycle can be continuous. This reduces the chance of missed doses. The iron-only doses are taken at the end of the cycle.
     
    OC administration instructions for patients:
    Instruct patient on risks and warnings associated with hormonal contraceptives.
    Missing pills can cause spotting or light bleeding.
    The length of time required for using a second method of contraception after drug initiation is slightly different for each manufacturer. In general, a second, non-hormonal form of contraception should be used until active norethindrone acetate; ethinyl estradiol; ferrous fumarate tablets have been taken for at least 7 consecutive days.
    Each manufacturer has slightly different recommendations for missed pills. Patients should be instructed to review the patient information leaflet that accompanies the prescription each time it is filled.
     
    General recommendations for missed OC doses:
    If one dose is missed, the patient should take it as soon as she remembers and then take the next pill at the regular time as usual. It may be necessary to take 2 tablets or capsules in one day. Some manufacturers recommend that a second method of non-hormonal contraception be used for at least 7 days after restarting the pills.
    If two doses in a row are missed, 2 tablets or capsules should be taken on both the day the missed doses are remembered and the following day. The regular schedule should then be continued. A second method of non-hormonal contraception should be used for at least 7 days after restarting the pills.
    If 3 or more doses in a row are missed, the patient should not take the missed pills. Recommendations for restarting the pills can be found in the patient information leaflet that accompanies the prescription each time it is filled. A second method of contraception should be used for at least 7 days after the pills are restarted.

    Oral Solid Formulations

    Chewable oral contraceptive (OC) tablets (e.g., Minastrin24 Fe):
    The tablets may be chewed and swallowed or swallowed whole. Instruct patient to drink a full glass (8 ounces) of water immediately after swallowing the chewed tablet. Contraceptive pack contains 28 tablets. The first 24 pills contain active hormones; the last 4 tablets contain iron.

    STORAGE

    Aurovela 24 Fe 1/20:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Aurovela Fe:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Blisovi 24 Fe:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Blisovi Fe:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Charlotte 24 Fe:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Estrostep Fe:
    - Product should always be stored in the blister and only removed immediately before use
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Finzala:
    - Avoid extreme temperatures
    - Keep away from heat and flame
    - Protect from direct sunlight
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Gemmily:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Gildess 24 Fe:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Gildess Fe 1.5/30:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Gildess Fe 1/20:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Hailey 24 Fe:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Hailey Fe 1.5/30:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Junel Fe 1.5/30:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Junel Fe 1/20:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Junel Fe 24:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Larin Fe:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Lo Loestrin Fe:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Lo Minastrin Fe:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Loestrin 24 Fe:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Loestrin FE 1.5/30:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Loestrin FE 1/20:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Lomedia 24 Fe:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Melodetta:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Merzee:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Mibelas 24 Fe:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Microgestin 24 Fe:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Microgestin Fe 1.5/30:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Microgestin Fe 1/20:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Minastrin:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Tarina 24 Fe:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Tarina Fe 1/20:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Taysofy:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Taytulla:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Tilia Fe:
    - Product should always be stored in the blister and only removed immediately before use
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Tri-Legest Fe:
    - Product should always be stored in the blister and only removed immediately before use
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Use of norethindrone acetate; ethinyl estradiol; ferrous fumarate products, as with other contraceptive steroids, may result in clinical changes that influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. Specific laboratory test interference has not been reported.

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

    Norethindrone acetate; ethinyl estradiol; ferrous fumarate does not protect against human immunodeficiency virus (HIV) infection or other sexually transmitted disease. Conversely, patients with known HIV infection or acquired immunodeficiency syndrome (AIDS) should be aware that the use of this combined oral hormonal contraceptive (COC) will not prevent the transmission of HIV or other diseases to their partner(s).

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

    Combined hormonal contraceptive agents are contraindicated in patients with a current or past history of stroke, cerebrovascular disease, coronary artery disease, coronary thrombosis, myocardial infarction, thrombophlebitis, thromboembolism or thromboembolic disease, or valvular heart disease with complications. Hormonal combined oral contraceptives (COCs) have been associated with thromboembolism such as deep venous thrombosis (DVT) and pulmonary embolism (PE). COCs are also generally contraindicated in women who have thrombogenic valvular or thrombogenic rhythm diseases of the heart (e.g., subacute bacterial endocarditis with valvular disease, or atrial fibrillation), or a known inherited or acquired hypercoagulopathies (e.g., protein S deficiency, protein C deficiency, Factor V Leiden, prothrombin G20210A mutation, antithrombin deficiency, antiphospholipid antibodies). Because tobacco smoking increases the risk of thromboembolism, DVT, myocardial infarction, stroke and other thromboembolic disease, patients receiving COCs are strongly advised not to smoke. Risk is especially high for female smokers over 35 years of age or those who smoke 15 or more cigarettes per day. Therefore, COCs are generally considered contraindicated in women over the age of 35 years who are tobacco smokers. A positive relationship between estrogen dosage and thromboembolic disease has been demonstrated, and oral products containing 50-mcg ethinyl estradiol should not be used unless medically indicated. In addition, certain progestins may increase thromboembolic risk. The overall risk of venous thromboembolism in women using COCs has been estimated to be 3 to 9 per 10,000 woman-years. Preliminary data from a large, prospective cohort safety study suggests that the risk is greatest during the first 6 months after initially starting COC therapy or restarting (following a break from therapy 4 weeks or more) with the same or different combination product. The risk of arterial thromboses, such as stroke and myocardial infarction, is especially increased in women with other risk factors for these events. Pre-existing high blood pressure, kidney disease, hypercholesterolemia, hyperlipidemia, diabetes with vascular disease, and morbidly obese patients may also increase risk. After a COC is discontinued, the risk of thromboembolic disease due to oral contraceptives gradually disappears. Because of their association with elevations in blood pressure, COCs should be used cautiously in patients with mild to moderate hypertension or kidney disease; use is contraindicated in patients with uncontrolled or severe hypertension or hypertension with vascular disease. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin. Blood pressure should be monitored closely in individuals with high blood pressure; discontinue norethindrone acetate; ethinyl estradiol; ferrous fumarate if blood pressure rises significantly. COCs may also cause fluid retention, and patients predisposed to complications from edema, such as those with renal disease or cardiac disease, should be closely monitored.

    Surgery

    Surgery can increase the risk for thromboembolism from combined hormonal contraceptives. If feasible, discontinue norethindrone acetate; ethinyl estradiol; ferrous fumarate products at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism, and during and following any prolonged immobilization.

    Diabetes mellitus

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

    Hyperlipidemia, hypertriglyceridemia

    Women who are being treated for dyslipidemia should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemia more difficult. Females with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.

    Headache, migraine

    Norethindrone acetate; ethinyl estradiol; ferrous fumarate is contraindicated in patients with migraine or other headache that is accompanied by focal neurological symptoms, such as aura, or women over age 35 with any migraine headaches. COCs may cause an exacerbation of migraine or a change in headache patterns and should be used with caution in women with migraine. Patients who complain of migraine with focal neurologic visual changes should be medically evaluated, and in some patients, such changes may indicate cerebrovascular events.

    Contact lenses, retinal thrombosis, visual disturbance

    Consistent with potential thrombotic effects of combined oral hormonal contraceptives (COCs), there have been clinical case reports of retinal thrombosis with COC use. The COC should be discontinued if there is unexplained visual disturbance, partial or complete loss of vision, onset of proptosis or diplopia, papilledema, or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately. Estrogens can increase the curvature of the cornea; patients using contact lenses wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.

    Hereditary angioedema, history of angioedema

    Norethindrone acetate; ethinyl estradiol; ferrous fumarate is contraindicated in patients with hypersensitivity to any of the product components. Ethinyl estradiol is generally contraindicated in patients who have a history of anaphylaxis or history of angioedema to the drug. Cases of both anaphylactic reactions and angioedema have been reported in patients taking estrogens. Events have developed in minutes and have required emergency medical treatment. Exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema, which may be hormonally sensitive.

    Systemic lupus erythematosus (SLE)

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

    Pregnancy

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

    Breast-feeding, obstetric delivery

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

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

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

    Depression

    Mood disorders, like depression, may be aggravated in women taking hormones or combined oral hormonal contraceptives (COCs). Data regarding the association of COCs with onset of depression or exacerbation of existing depression are limited. If significant depression occurs, norethindrone acetate; ethinyl estradiol; ferrous fumarate should be discontinued.

    Breast cancer

    Norethindrone acetate; ethinyl estradiol; ferrous fumarate is contraindicated in patients with a history of, or known or suspected breast cancer, as breast cancer is a hormonally-sensitive tumor. All women taking combined oral contraceptives (COCs) should receive clinical breast examinations and perform monthly self-examinations as recommended by their health care professional based on patient age, known risk factors, and current standards of care. Epidemiology studies have not found a consistent association between use of COCs and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (less than 6 months since last use) and current users with longer duration of COC use. Several large, well-designed observational studies have provided data regarding the risk of breast cancer with COC use. From one large study published in 2017, the risk of breast cancer was higher among women who currently or recently used contemporary hormonal contraceptives than among women who had never used hormonal contraceptives, and this risk increased with longer durations of use; however, absolute increases in risk were small. The absolute risk of breast cancer associated with any hormonal contraceptive use was 13 per 100,000 women-years, which corresponds to 1 extra case of breast cancer for every 7,690 COC users in 1 year. Moreover, the same study data suggest that any increased risk of breast cancer usually disappears rapidly after an interruption in the use of COCs. There continues to be controversy regarding the risk of COC use in women with a family history of breast cancer (e.g., BRCA mutations). However, evidence does not suggest that the increased risk for breast cancer among women with either a family history of breast cancer or breast cancer susceptibility genes is modified by the use of COCs. Patients should be instructed to perform monthly self-breast examination and report any breast changes, lumps, or discharge to their health care professional. If breast cancer is suspected in a woman who is taking hormonal contraceptives, the contraceptive should be discontinued.

    Cervical cancer

    Norethindrone acetate; ethinyl estradiol; ferrous fumarate is contraindicated in the presence of cervical cancer or other estrogen-responsive tumors. Most cervical cancers are related to the presence of the human papillomavirus (HPV), but hormonal factors influence risk. In women taking COCs, studies have found an increased risk of cervical cancer compared with never-users. The risk appears to increase with duration of use and appears to decline when COCs are discontinued. Clinical surveillance of all women using COCs is important; all women receiving COC treatment should have a pelvic examination and other diagnostic or screening tests, such as cervical cytology, as clinically indicated or as generally recommended based on age, risk factors, and other individual needs.

    Endometrial cancer, ovarian cancer, uterine cancer, vaginal bleeding, vaginal cancer

    In those women with known endometrial cancer or other estrogen-dependent tumors (e.g., vaginal cancer, uterine cancer, ovarian cancer), combined hormonal contraceptives are contraindicated, as such tumors are hormonally sensitive. Hormonal contraceptives are contraindicated in women with undiagnosed vaginal bleeding; evaluate such patients before combined hormonal contraceptive use to determine if a contraindication to use exists.  The use of combined oral contraceptives (COCs) appears to have a protective effect against some cancers. In women using COCs, a meta-analysis of 10 studies indicates a significant trend in decreasing endometrial and ovarian cancer risk with increasing duration of COC use. The beneficial effects of COCs in this regard may persist for 15 years or more after COC use ceases.

    Corticosteroid therapy, hypothyroidism

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

    Chloasma

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

    Obesity

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

    Children

    The safety and efficacy of oral contraceptive products have only been established in females of reproductive age. Safety and efficacy of norethindrone acetate; ethinyl estradiol; ferrous fumarate products is expected to be the same for postpubertal children under the age of 16 and for users 16 years of age and older.

    ADVERSE REACTIONS

    Severe

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

    Moderate

    vaginitis / Delayed / 1.0-10.0
    depression / Delayed / 1.0-10.0
    candidiasis / Delayed / 6.1-6.1
    galactorrhea / Delayed / 0-1.0
    cataracts / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 0-1.0
    jaundice / Delayed / 0-1.0
    hepatitis / Delayed / 0-1.0
    peliosis hepatis / Delayed / 0-1.0
    lactation suppression / Early / Incidence not known
    edema / Delayed / Incidence not known
    hypertension / Early / Incidence not known
    palpitations / Early / Incidence not known
    fluid retention / Delayed / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    migraine / Early / Incidence not known
    peripheral edema / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    hyperlipidemia / Delayed / Incidence not known
    cholelithiasis / Delayed / Incidence not known
    cervical dysplasia / Delayed / Incidence not known
    cystitis / Delayed / Incidence not known

    Mild

    amenorrhea / Delayed / 22.0-36.0
    breakthrough bleeding / Delayed / 24.0-35.0
    pelvic pain / Delayed / 1.0-10.0
    menstrual irregularity / Delayed / 1.0-10.0
    menorrhagia / Delayed / 1.0-10.0
    breast enlargement / Delayed / 1.0-10.0
    leukorrhea / Delayed / 1.0-10.0
    vaginal discharge / Delayed / 1.0-10.0
    vaginal irritation / Early / 1.0-10.0
    appetite stimulation / Delayed / 1.0-10.0
    asthenia / Delayed / 1.0-10.0
    emotional lability / Early / 1.0-10.0
    fatigue / Early / 1.0-10.0
    libido decrease / Delayed / 1.0-10.0
    anxiety / Delayed / 1.0-10.0
    libido increase / Delayed / 1.0-10.0
    irritability / Delayed / 1.0-10.0
    vomiting / Early / 1.0-10.0
    abdominal pain / Early / 1.0-10.0
    headache / Early / 6.3-6.3
    nausea / Early / 4.6-4.6
    dysmenorrhea / Delayed / 4.4-4.4
    mastalgia / Delayed / 3.4-3.4
    acne vulgaris / Delayed / 2.7-2.7
    weight gain / Delayed / 2.0-2.0
    breast discharge / Delayed / 0-1.0
    diplopia / Early / 0-1.0
    insomnia / Early / Incidence not known
    dizziness / Early / Incidence not known
    malaise / Early / Incidence not known
    rash / Early / Incidence not known
    hirsutism / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    maculopapular rash / Early / Incidence not known
    photosensitivity / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    alopecia / Delayed / Incidence not known
    melasma / Delayed / Incidence not known
    anorexia / Delayed / Incidence not known
    diarrhea / Early / Incidence not known
    weight loss / Delayed / Incidence not known
    dyspepsia / Early / Incidence not known
    back pain / Delayed / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    myalgia / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    gingivitis / Delayed / Incidence not known
    sinusitis / Delayed / Incidence not known
    rhinitis / Early / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing iron if given under fasting conditions. When taken with food, dolutegravir and supplements containing iron can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
    Acarbose: (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis.
    Acetaminophen: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
    Acetaminophen; Aspirin: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Caffeine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
    Acetaminophen; Caffeine; Pyrilamine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
    Acetaminophen; Chlorpheniramine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Codeine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Dextromethorphan: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Diphenhydramine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Hydrocodone: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Oxycodone: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Pentazocine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Propoxyphene: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Pseudoephedrine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    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.
    Acetohydroxamic Acid: (Moderate) Acetohydroxamic acid chelates heavy metals, including iron. Absorption of orally administered iron salts or polysaccharide-iron complex and acetohydroxamic acid from the intestinal lumen may be reduced when both drugs are administered concomitantly. If iron therapy is required in a patient currently taking acetohydroxamic acid, intramuscular iron is recommended.
    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.
    Alendronate: (Moderate) Separate administration of alendronate and iron supplements by at least 30 minutes. Iron will interfere with the absorption of alendronate.
    Alendronate; Cholecalciferol: (Moderate) Separate administration of alendronate and iron supplements by at least 30 minutes. Iron will interfere with the absorption of alendronate.
    Aliskiren; Amlodipine: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Alogliptin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Alogliptin; Metformin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (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: (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 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.
    Alpha-glucosidase Inhibitors: (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Alprazolam: (Minor) Oral contraceptives can increase the effects of alprazolam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to alprazolam.
    Amikacin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Aminoglycosides: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Amlodipine: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Amlodipine; Atorvastatin: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly. (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Amlodipine; Benazepril: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Amlodipine; Celecoxib: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Amlodipine; Olmesartan: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Amlodipine; Valsartan: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Amobarbital: (Major) Women taking both estrogens and barbiturates should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed barbiturates. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of barbiturates. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on barbiturates, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and barbiturate are strong CYP3A4 inducers. Concurrent administration may increase estrogen elimination. (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    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; 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. (Moderate) The bioavailability of oral iron salts is influenced by gastric pH, and the concomitant administration of proton pump inhibitors can decrease iron absorption. The non-heme ferric form of iron needs an acidic intragastric pH to be reduced to ferrous and to be absorbed. Iron salts and polysaccharide-iron complex provide non-heme iron. Proton pump inhibitors have long-lasting effects on the secretion of gastric acid and thus, increase the pH of the stomach. The increase in intragastric pH can interfere with the absorption of iron salts.
    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: (Contraindicated) 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) Oral contraceptives and non-oral combination contraceptives should not be administered with amprenavir. Alternative methods of non-hormonal contraception are recommended. Clinically significant hepatic enzyme (transaminase) elevations may occur with concomitant use. Additionally, hormonal contraceptives, estrogens, and progestins may decrease the serum concentrations of amprenavir, which could lead to loss of virologic response and possible viral resistance. 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 amprenavir, a strong CYP3A inhibitor should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. It is not known if amprenavir 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 the progestin drospirenone, consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors concomitantly.
    Anastrozole: (Contraindicated) Estrogen therapy is not recommended during aromatase inhibitor treatment, due to opposing pharmacologic actions. Estrogens, including those found in horm