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  • CLASSES

    Emergency Contraceptives and Abortifacients
    Extended Cycle Contraceptives
    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 contraceptives (CHCs) 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. Combined hormonal contraceptives have been associated with thromboembolism such as deep venous thrombosis (DVT) and pulmonary embolism (PE). Combined hormonal contraceptives are also generally contraindicated in women who have thrombogenic valvular or thrombogenic rhythm diseases of the heart (e.g., subacute bacterial endocarditis with valvular disease, or atrial fibrillation), or known inherited or acquired hypercoagulopathies (e.g., protein S deficiency, protein C deficiency, Factor V Leiden, prothrombin G20210A mutation, antithrombin deficiency, antiphospholipid antibodies). Because tobacco smoking increases the risk of thromboembolism, DVT, myocardial infarction, stroke and other thromboembolic disease, patients receiving CHCs are strongly advised not to smoke. Risk is especially high for female smokers more than 35 years of age or those who smoke 15 or more cigarettes per day. Therefore, CHCs are 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. Some data suggest that non-cyclic exposure may also increase thromboembolic risk. The overall risk of venous thromboembolism in women using combined hormonal contraceptives 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 CHC therapy or restarting (following a break from therapy 4 weeks or more) with the same or different combination product. The risk of arterial thromboses, such as stroke and myocardial infarction, is especially increased in women with other risk factors for these events. Pre-existing high blood pressure, kidney disease, hypercholesterolemia, diabetes with vascular disease, or patients who are morbidly obese may also increase risk. Levonorgestrel; ethinyl estradiol should be discontinued if an arterial or venous thromboembolic event occurs. After a CHC is discontinued, the increased risk of thromboembolic disease gradually disappears. Because of their association with elevations in blood pressure, CHCs 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 CHCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin. Blood pressure should be monitored closely in individuals with high blood pressure; discontinue the combined hormonal contraceptive if blood pressure rises significantly. CHCs 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) or transdermal contraceptive patch containing levonorgestrel, a progestin with moderate to high androgenic and minimal estrogenic activity, and ethinyl estradiol
    Used for routine contraception in adolescent and adult premenopausal females; extended- and continuous-cycle products allow less withdrawal bleeds per year
    Contains a boxed warning regarding the increased risk for thromboembolism in women who smoke; transdermal patch contraindicated in women with a BMI 30 kg/m2 or more

    COMMON BRAND NAMES

    Afirmelle, Alesse, Altavera, Amethia, Amethia Lo, Amethyst, Ashlyna, Aubra EQ, Aubra-28, Aviane, Camrese, Camrese Lo, Chateal, Chateal EQ, Daysee, Delyla, Enpresse, FALMINA, Fayosim, Introvale, Isibloom, Jolessa, Kurvelo, Lessina, Levlen, Levlite, LEVONEST, Levonorgestrel/Ethinyl Estradiol, Levora, LoSeasonique, Lutera, Lybrel, MARLISSA, Myzilra, Nordette, Orsythia, Portia, Quartette, Quasense, Seasonale, Seasonique, Setlakin, Simpesse, Sronyx, Tri-Levlen, Triphasil, Trivora, Vienva

    HOW SUPPLIED

    Afirmelle/Alesse/Altavera/Amethia/Amethia Lo/Amethyst/Ashlyna/Aubra EQ/Aubra-28/Aviane/Camrese/Camrese Lo/Chateal/Chateal EQ/Daysee/Delyla/Enpresse/Ethinyl Estradiol;Levonorgestrel, Ethinyl Estradiol/FALMINA/Fayosin/Inert;Levonorgestrel, Ethinyl Estradiol/Introvale/Isibloom/Jolessa/Kurvelo/Lessina/Levlen/Levlite/LEVONEST/Levonorgestrel, Ethinyl Estradiol/Levonorgestrel/Ethinyl Estradiol/Levora/LoSeasonique/Lutera/Lybrel/MARLISSA/Myzilra/Nordette/Orsythia/Portia/Quartette/Quasense/Seasonale/Seasonique/Setlakin/Sronyx/Tri-Levlen/Triphasil/Trivora/Vienva Oral Tab: 0.01-0.02-0.025-0.03-0.15-0.01-0.02-0.025-0.03mg, 0.01-0.02-0.1-0.01-0.02mg, 0.01-0.03-0.15-0.01-0.03mg, 0.05-0.075-0.125-0.03-0.04mg, 0.1-0.02mg, 0.15-0.03mg, 90-20mcg

    DOSAGE & INDICATIONS

    For routine contraception.
    For extended-cycle or continuous routine contraception.
    Oral dosage (monophasic extended-cycle regimen; e.g., Seasonale or generic equivalents)
    Adult and Adolescent females

    1 tablet (0.15 mg levonorgestrel; 30 mcg ethinyl estradiol) PO once daily for 84 days. The last 7 days of the 91-day cycle allow withdrawal bleeding to occur. Repeat dosage cycles begin on the eighth day after taking the last hormonally active tablet. Comparable safety and efficacy to standard OC regimens; reduces withdrawal bleeds to 4 per year.

    Oral dosage (biphasic extended-cycle regimen; e.g., Seasonique or generic equivalents)
    Adult and Adolescent females

    1 combination tablet (0.15 mg levonorgestrel; 30 mcg ethinyl estradiol) PO once daily for 84 days, then estrogen tablets (10 mcg ethinyl estradiol) PO once daily for 7 days. The last 7 days of the 91-day cycle allow withdrawal bleeding to occur. Repeat dosage cycles begin on the first day after taking the last estrogen tablet. This regimen reduces withdrawal bleeds to 4 per year.

    Oral dosage (lower-dose biphasic extended-cycle regimen; e.g., LoSeasonique or generic equivalents)
    Adult and Adolescent females

    1 combination tablet (0.1 mg levonorgestrel; 20 mcg ethinyl estradiol) PO once daily for 84 days, then estrogen tablets (10 mcg ethinyl estradiol) PO once daily for 7 days. The last 7 days of the 91-day cycle allow withdrawal bleeding to occur. Repeat dosage cycles begin on the first day after taking the last estrogen tablet. This regimen reduces withdrawal bleeds to 4 per year.

    Oral dosage (e.g., quadriphasic extended-cycle regimen; e.g., Quarttete or generic equivalents)
    Adult and Adolescent females

    1 combination tablet (0.15 mg levonorgestrel; 20 mcg ethinyl estradiol) PO once daily for 42 days, then 1 combination tablet (0.15 mg levonorgestrel; 25 mcg ethinyl estradiol) PO once daily for 21 days, then 1 combination tablet (0.15 mg levonorgestrel; 30 mcg ethinyl estradiol) PO once daily for 21 days, then estrogen tablets (10 mcg ethinyl estradiol) PO once daily for 7 days. The last 7 days of the 91-day cycle allow withdrawal bleeding to occur. Repeat dosage cycles begin on the first day after taking the last estrogen tablet. This regimen reduces withdrawal bleeds to 4 per year; the escalating estrogen dose may reduce the incidence of breakthrough bleeding.

    Oral dosage (continuous 365-day monophasic oral contraceptive, e.g., Amethyst or other generic equivalents)
    Adult and Adolescent females

    1 combination tablet (0.09 mg levonorgestrel; 20 mcg ethinyl estradiol) PO once daily while contraception is desired; there is no cycle break to allow for withdrawal bleeding; intended to be taken 365-days of the year. For those not currently using a hormonal contraceptive, initiate on day 1 of the menstrual cycle. For those currently taking 21- or 28-day combination oral contraceptive, initiate on day 1 of the menstrual cycle; initiate no later than 7 days after the last active tablet. For those currently taking a progestin-only pill, initiate the day after taking a progestin-only pill; non-hormonal back-up method of birth control is required for the first 7 days of continuous contraception. For those currently using a hormonal implant, initiate the day of implant removal; a non-hormonal back-up method of birth control is required for the first 7 days of continuous contraception. For those currently using a hormonal injection, initiate the day the next injection is due; non-hormonal back-up method of birth control is required for the first 7 days of continuous contraception.

    Oral dosage (monophasic regimens)
    Adult and Adolescent females

    1 tablet (0.15 mg levonorgestrel; 30 mcg ethinyl estradiol or 0.1 mg levonorgestrel; 20 mcg ethinyl estradiol) PO once daily for 21 days, then a period of 7 days without drug. Repeat dosage cycles begin on the eighth day after taking the last hormonally active tablet. Administration of most combination oral contraceptives (OCs) begins on the first Sunday after or on which bleeding has started. However, some clinicians 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 (triphasic regimens)
    Adult and Adolescent females

    1 tablet PO once daily for 21 days in the order indicated in the pack, then a period of 7 days without drug. Phase 1 contains 6 tablets as a combination of 0.05 mg levonorgestrel and 30 mcg ethinyl estradiol. Phase 2 contains 5 tablets as a combination of 0.075 mg levonorgestrel and 40 mcg ethinyl estradiol. Phase 3 contains 10 tablets as a combination of 0.125 mg levonorgestrel and 30 mcg ethinyl estradiol. Repeat dosage cycles begin on the eighth day after taking the last hormonally active tablet. Administration of most combination OCs begins on the first Sunday after or on which bleeding has started. However, some clinicians 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.

    Transdermal dosage (Twirla contraceptive patch)
    Adult and Adolescent females

    Apply 1 transdermal system (TDS) (delivering 120 mcg of levonorgestrel and 30 mcg of ethinyl estradiol per 24 hours) topically to the skin. The patch is removed and reapplied once weekly (every 7 days) for 3 weeks, followed by a patch-free period of 1 week. On the day after Week 4 ends, a new 28-day cycle is started by applying a new TDS. Under no circumstances should there be more than a 7-day TDS-free interval between dosing cycles. LIMITATIONS OF USE: Consider the reduced effectiveness of this contraceptive patch in women with a BMI 25 to less than 30 kg/m2. This patch is contraindicated in women with a BMI of 30 kg/m2 or more. NO PRIOR HORMONAL CONTRACEPTIVE USE IN THE PAST MONTH: Apply the first TDS during the first 24 hours of menstruation. If a TDS is applied after the first 24 hours of menstruation, non-hormonal back-up contraception is needed for the first 7 days of the cycle only. SWITCH FROM A COMBINATION ORAL CONTRACEPTIVE, VAGINAL RING, OR PATCH: For patients switching from another oral contraceptive, apply the first TDS on the day the next pill cycle would normally start, the next vaginal ring would normally be inserted, or the next patch cycle would start. If menstrual bleeding does not occur within a week after taking the last active pill, removing the last vaginal ring, or removing the last patch, rule out pregnancy first. If no pregnancy has occurred, the patch may be started for contraception. If the patch is applied more than a week after taking the last active pill has been taken or the ring or patch was removed, nonhormonal back-up contraception should be used concurrently for the first 7 days of patch use. SWITCH FROM AN INJECTION: The woman should apply the first TDS on the day the next injection would normally occur. SWITCH FROM AN INTRAUTERINE SYSTEM (IUS): The woman should apply the first TDS on the day of IUS removal. SWITCH FROM AN IMPLANT: The woman should apply the first TDS on the day of implant removal. SWITCH FROM A PROGESTIN-ONLY METHOD: The woman should apply the first TDS on the day the next progestin-only pill cycle would normally start. POSTPARTUM FOLLOWING DELIVERY or SECOND TRIMESTER ABORTION: Females who elect not to breast-feed should start contraceptive therapy with this patch no sooner than 4 weeks after childbirth. If a woman begins using this drug postpartum and has not yet had a period, the possibility of conception occurring prior to the use of the patch should be considered; instruct the patient to use an additional non-hormonal method of contraception for the first 7 days. Following a first trimester miscarriage or abortion, the patch may be started immediately; an additional method of contraception is not needed. If not started within 5 days following a first-trimester abortion, the woman should follow the instructions for starting the drug for the first time. In the meantime, she should be advised to use a non-hormonal contraceptive method. Ovulation may occur within 10 days of an abortion or miscarriage. Do not start this patch earlier than 4 weeks after a second-trimester abortion or miscarriage. When used postpartum or postabortion, the increased risk of thromboembolic disease must be considered.

    For use as postcoital contraception.
    Oral dosage (e.g., Preven tablets)
    Adult and Adolescent females

    This drug product is discontinued in the U.S. Preven tablets were FDA-approved for emergency contraception. Other non-estrogen containing emergency contraceptives are available and preferred. After the Preven pregnancy test is known to be negative, administer 2 tablets (0.25 mg levonorgestrel and 50 mcg ethinyl estradiol per tablet) as soon as possible after intercourse (preferably within 12 to 24 hours after the event). Although the manufacturer states levonorgestrel; ethinyl estradiol should be administered no later than 72 hours; studies do suggest that efficacy lasts 3 to 5 days after the event. The dose MUST be repeated in 12 hours. If the patient vomits within 1 hour of the initial (first) dose, the dose should be repeated. An antiemetic may be needed for some patients. Other non-estrogen containing emergency contraceptives are available and preferred.

    For the treatment of severe 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
    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 to 12 months may be required; OCs have limited utility when the underlying cause 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. Treatment for 6 to 9 months may be needed to induce endometrial atrophy and reduce symptoms. Combined hormonal contraceptives can reduce endometriosis-associated dyspareunia, dysmenorrhea, and non-menstrual pelvic pain.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Dependent on product used and indication for therapy.

    Geriatric

    Not indicated.

    Adolescents

    Dependent on product used and indication for therapy.

    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

    Products vary in the amount of estrogen and/or progestin; formulations of different hormonal content are not interchangeable.
    Patients should be instructed to review the patient information leaflet that accompanies the prescription each time it is filled.

    Oral Administration

    To minimize nausea, administer with or after the evening meal or at bedtime. Take at the same time each day to ensure maximum contraceptive efficacy.
    Ensure patient understanding of product prescribed.
    For biphasic, triphasic, and quadraphasic products, an explanation of tablet sequencing and different tablet colors may be needed.
    Some contraceptive packs contain 28 tablets. For most of these, 21 tablets contain active hormone and 7 contain either iron or inert ingredients so that the daily dosage cycle can be continuous. This reduces the chance of missed doses. The 7 inert or iron tablets are taken at the end of the cycle.
    Seasonale (or generic equivalents) consists of 3 trays containing a total of 91 tablets. For these products, 84 tablets contain active hormone and 7 contain inert ingredients. Seasonique and LoSeasonique (or their generic equivalents) consist of 91 total tablets with 84 tablets containing progestin and estrogen and 7 tablets containing estrogen only. When taken as indicated, these products reduce the number of withdrawal bleeds to 4 per year.
    Amethyst (and other generic equivalents) is a continuous low-dose oral contraceptive, and contains 28 tablets of active hormones. Active tablets are taken every day; these products were designed to eliminate withdrawal bleeding.
     
    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 levonorgestrel; ethinyl estradiol 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 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 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 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.

    Topical Administration
    Transdermal Patch Formulations

    Twirla Transdermal Contraceptive Patch:
    Inform patients regarding the risks and benefits of combined hormonal contraceptives.
    The patch is applied once weekly for 3 weeks. Each patch should be worn for 1 week.
    Establish a 'patch change' day on the same day of the week once weekly.
    How to apply the patch: Apply to clean, dry, intact healthy skin on the buttock, abdomen, upper outer arm or upper torso, in a place where it won't be rubbed by tight clothing. Do not place on skin that is red, irritated or cut, and do not place on the breasts. When applying a new patch, do not apply the new patch directly over the previous patch site. If using the patch results in uncomfortable irritation, the patch may be removed, and a new patch may be applied to a different location until the next 'patch change' day. Only one patch should be worn at a time. Do not cut or alter the patch in any way; the whole patch should be applied.
    Avoid the use of large amounts of body lotions or oils. To prevent interference with the adhesive properties, no makeup, creams, lotions, moisturizers, oils, powders or other topical products should be applied to the skin area where the patch is or will be placed.
    Check the patch for partial or complete detachment daily and after frequent or prolonged water exposure (e.g., swimming).
    If the patch lifts at the edges, reattach by pressing firmly and smoothing down the edges of the system. If the patch comes off completely, try to reapply the patch that detached. If the patch does not adhere completely, apply a new patch immediately.
    Refer to the patient information for complete instructions on how to manage partial or complete patch detachments and late/missed patch applications.
    Once removed, a used patch should be folded to stick to itself and discarded in a waste receptacle out of the reach of children and pets (do not flush in the toilet).

    STORAGE

    Afirmelle:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Alesse:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Altavera:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Amethia :
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Amethia Lo:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Amethyst:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Ashlyna:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Aubra EQ:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Aubra-28:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Aviane :
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Camrese:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Camrese Lo:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Chateal:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Chateal EQ:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Daysee:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Delyla:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Enpresse:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    FALMINA:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Fayosim:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Introvale:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Isibloom:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Jolessa:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Kurvelo:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Lessina:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Levlen:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Levlite:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    LEVONEST:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Levonorgestrel/Ethinyl Estradiol:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Levora:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    LoSeasonique :
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Lutera :
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Lybrel:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    MARLISSA:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Myzilra:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Nordette:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Orsythia:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Portia :
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Quartette:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Quasense :
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Seasonale:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Seasonique:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Setlakin:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Simpesse:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Sronyx:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Tri-Levlen:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Triphasil:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Trivora:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Vienva:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Use of levonorgestrel; ethinyl estradiol, 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

    Levonorgestrel; ethinyl estradiol products do not protect against human immunodeficiency virus (HIV) infection or any other sexually transmitted disease. Patients with known HIV infection or acquired immunodeficiency syndrome (AIDS) should be aware that the use of hormonal contraceptives 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 contraceptives (CHCs) 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. Combined hormonal contraceptives have been associated with thromboembolism such as deep venous thrombosis (DVT) and pulmonary embolism (PE). Combined hormonal contraceptives are also generally contraindicated in women who have thrombogenic valvular or thrombogenic rhythm diseases of the heart (e.g., subacute bacterial endocarditis with valvular disease, or atrial fibrillation), or known inherited or acquired hypercoagulopathies (e.g., protein S deficiency, protein C deficiency, Factor V Leiden, prothrombin G20210A mutation, antithrombin deficiency, antiphospholipid antibodies). Because tobacco smoking increases the risk of thromboembolism, DVT, myocardial infarction, stroke and other thromboembolic disease, patients receiving CHCs are strongly advised not to smoke. Risk is especially high for female smokers more than 35 years of age or those who smoke 15 or more cigarettes per day. Therefore, CHCs are 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. Some data suggest that non-cyclic exposure may also increase thromboembolic risk. The overall risk of venous thromboembolism in women using combined hormonal contraceptives 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 CHC therapy or restarting (following a break from therapy 4 weeks or more) with the same or different combination product. The risk of arterial thromboses, such as stroke and myocardial infarction, is especially increased in women with other risk factors for these events. Pre-existing high blood pressure, kidney disease, hypercholesterolemia, diabetes with vascular disease, or patients who are morbidly obese may also increase risk. Levonorgestrel; ethinyl estradiol should be discontinued if an arterial or venous thromboembolic event occurs. After a CHC is discontinued, the increased risk of thromboembolic disease gradually disappears. Because of their association with elevations in blood pressure, CHCs 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 CHCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin. Blood pressure should be monitored closely in individuals with high blood pressure; discontinue the combined hormonal contraceptive if blood pressure rises significantly. CHCs 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 levonorgestrel; ethinyl estradiol products at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism, and during and following any prolonged immobilization.   

    Diabetes mellitus

    Because of the increased potential for embolic risk, combined hormonal contraceptives (CHCs) containing levonorgestrel; 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 combined hormonal contraceptives (CHCs). 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 CHCs.

    Headache, migraine

    Levonorgestrel; ethinyl estradiol products are contraindicated in patients with migraine or other headache that is accompanied by focal neurological symptoms, such as aura, or women over age 35 with any migraine headaches. CHCs 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.

    50834] 50844
     

    Contact lenses, retinal thrombosis, visual disturbance

    Consistent with potential thrombotic effects of combined hormonal contraceptives (CHCs), there have been clinical case reports of retinal thrombosis with CHC use. The CHC 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

    Levonorgestrel; ethinyl estradiol products are 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 combined hormonal contraceptive (CHC) use in these patients. Avoid CHC use in SLE patients with a history of venous or arterial thrombosis or the presence of a hypercoagulable state. If CHCs 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 contraceptive use has also been reported to induce, unmask, or exacerbate SLE; more data are needed.

    Pregnancy

    Discontinue levonorgestrel; ethinyl estradiol products if pregnancy is detected; there is no reason to continue combined hormonal contraceptives (CHCs) 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 CHCs 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 CHC schedule, consider the possibility of pregnancy at the first missed period. Discontinue CHC use if pregnancy is confirmed.

    Breast-feeding, obstetric delivery

    Manufacturers recommend avoidance of combined hormonal contraceptives (CHCs) if possible during breast-feeding 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 CHCs 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).

    Cholestasis, gallbladder disease, hepatic disease, hepatitis, hepatocellular cancer, jaundice

    Levonorgestrel; ethinyl estradiol products 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 combined hormonal contraceptives (CHCs) in patients with a history of cholestatic jaundice/pruritus of pregnancy or jaundice from prior hormonal contraceptives; these conditions can recur with subsequent hormonal contraceptive use. Discontinue use of levonorgestrel; ethinyl estradiol if jaundice develops during CHC use. Steroid hormones may be poorly metabolized in patients with liver impairment. Acute or chronic disturbances of liver function may necessitate the discontinuation of hormonal contraceptive use until markers of liver function return to normal and hormonal contraceptive 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 hormonal contraceptives. 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 hormonal contraceptives prior to starting hepatitis C therapy with the combination drug regimen ombitasvir; paritaprevir; ritonavir, with or without dasabuvir; hormonal contraceptives can be restarted approximately 2 weeks following completion of treatment with the hepatitis C combination drug regimen. Hepatic adenomas are associated with hormonal contraceptive use. An estimate of the attributable risk is 3.3 cases/100,000 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) CHC users. However, the attributable risk of liver cancers in CHC users is less than 1 case per million users. Use CHCs with caution in patients with pre-existing gallbladder disease; however, recent studies have shown that the relative risk of developing gallbladder disease among CHC 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 hormonal contraceptives (CHCs). Data regarding the association of CHCs with onset of depression or exacerbation of existing depression are limited. If significant depression occurs, levonorgestrel; ethinyl estradiol should be discontinued.

    Breast cancer

    Levonorgestrel; ethinyl estradiol products are 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 hormonal contraceptives (CHCs) 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. There is substantial evidence that use of CHCs does not increase the incidence of breast cancer. Although some past studies have suggested that CHCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings. Several large, well-designed observational studies have provided data regarding the risk of breast cancer with CHC 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 CHCs. There continues to be controversy regarding the risk of CHC use in women with a family history of breast cancer (e.g., BRCA mutations). However, the 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 CHCs. Patients should be instructed to perform a 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

    Levonorgestrel; ethinyl estradiol products are contraindicated in the presence of cervical cancer or other estrogen-responsive tumors. Most cervical cancers are related to the presence of the human papillomavirus (HPV), but hormonal factors influence risk. In women taking combined hormonal contraceptives (CHCs), studies have found a slightly increased risk of cervical cancer compared with never-users. The risk appears to increase with duration of use and appears to decline when CHCs are discontinued. Clinical surveillance of all women using CHCs is important; all women receiving CHC 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 women with known endometrial cancer or other estrogen-dependent tumors (e.g., vaginal cancer, uterine cancer, ovarian cancer), combined hormonal contraceptives (CHCs) are contraindicated, as such tumors are hormonally sensitive. Hormonal contraceptives are contraindicated in women with undiagnosed vaginal bleeding; evaluate such patients before CHC use to determine if a contraindication to use exists.  The use of CHCs appears to have a protective effect against some cancers. In women using CHCs, a meta-analysis of 10 studies indicates a significant trend in decreasing endometrial and ovarian cancer risk with increasing duration of CHC use. The beneficial effects of CHCs in this regard may persist for 15 years or more after CHC 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 hormonal contraceptive (CHC) 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 levonorgestrel; ethinyl estradiol.

    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. The levonorgestrel; ethinyl estradiol contraceptive patch is contraindicated in women with obesity with a BMI of 30 kg/m2 and greater; these women had reduced effectiveness of the contraceptive patch and appeared to have a higher risk for venous thromboembolic events. Limited literature suggests that the effectiveness of other 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, such as the levonorgestrel-EE contraceptive patch) does not seem to be compromised in women who are overweight. Obesity does not seem to reduce the effectiveness of emergency contraceptive products.

    Children

    The safety and efficacy of hormonal contraceptive products have only been established in females of reproductive age. Safety and efficacy of levonorgestrel; ethinyl estradiol products is expected to be the same for postpubertal pediatric patients under the age of 16 and for users 16 years of age and older. Use of hormonal contraceptive products in female children before menarche is not indicated.

    ADVERSE REACTIONS

    Severe

    thrombosis / Delayed / 0-1.0
    thromboembolism / Delayed / 0-1.0
    pulmonary embolism / Delayed / 0-1.0
    stroke / Early / 0-1.0
    myocardial infarction / Delayed / 0-1.0
    papilledema / Delayed / 0-1.0
    optic neuritis / Delayed / 0-1.0
    visual impairment / Early / 0-1.0
    retinal thrombosis / Delayed / 0-1.0
    suicidal ideation / Delayed / 0-1.0
    porphyria / Delayed / 0-1.0
    ectopic pregnancy / Delayed / 0-1.0
    hepatoma / Delayed / 0-0.1
    intracranial bleeding / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    erythema nodosum / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    bowel ischemia / Delayed / Incidence not known
    cholecystitis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known

    Moderate

    candidiasis / Delayed / 1.0-10.0
    vaginitis / Delayed / 1.0-10.0
    galactorrhea / Delayed / 0-1.0
    cataracts / Delayed / 0-1.0
    depression / Delayed / 0-1.0
    jaundice / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 0-1.0
    lactation suppression / Early / Incidence not known
    migraine / Early / Incidence not known
    edema / Delayed / Incidence not known
    fluid retention / Delayed / Incidence not known
    hypertension / Early / Incidence not known
    peliosis hepatis / Delayed / Incidence not known
    hyperlipidemia / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    cholelithiasis / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    cystitis / Delayed / Incidence not known
    cervical dysplasia / Delayed / Incidence not known

    Mild

    pelvic pain / Delayed / 1.0-10.0
    menstrual irregularity / Delayed / 1.0-10.0
    menorrhagia / Delayed / 1.0-10.0
    amenorrhea / Delayed / 1.0-10.0
    dysmenorrhea / Delayed / 1.0-10.0
    breast enlargement / Delayed / 1.0-10.0
    mastalgia / 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
    acne vulgaris / Delayed / 1.0-10.0
    vomiting / Early / 1.0-10.0
    abdominal pain / Early / 1.0-10.0
    breast discharge / Delayed / 0-1.0
    diplopia / Early / 0-1.0
    breakthrough bleeding / Delayed / 10.0
    oligomenorrhea / Delayed / 10.0
    headache / Early / 10.0
    nausea / Early / 10.0
    anxiety / Delayed / Incidence not known
    emotional lability / Early / Incidence not known
    fatigue / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    libido decrease / Delayed / Incidence not known
    libido increase / Delayed / Incidence not known
    irritability / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    hirsutism / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    photosensitivity / Delayed / Incidence not known
    xerosis / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    rash / Early / Incidence not known
    skin irritation / Early / Incidence not known
    melasma / Delayed / Incidence not known
    weight gain / Delayed / Incidence not known
    appetite stimulation / Delayed / Incidence not known
    gingivitis / Delayed / Incidence not known
    diarrhea / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    dyspepsia / Early / Incidence not known
    weight loss / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    myalgia / Early / Incidence not known
    back pain / Delayed / Incidence not known
    rhinitis / Early / Incidence not known
    sinusitis / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acarbose: (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis.
    Acetaminophen: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
    Acetaminophen; 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; 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.
    Acitretin: (Major) Acitretin interferes with the contraceptive effect of microdose progestins ('minipill' contraceptive preparations), and may possibly interfere with the effecitivenss of emergency contraceptives like levonorgestrel (e.g., Plan B, Plan B OneStep). It is not known if acitretin also interacts with other progestational contraceptives, such as levonorgestrel implants or IUDs or if these methods are adequate methods of contraception during acitretin therapy. However, female patients should be advised of the possibility that any contraceptive method can fail. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Albiglutide: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as combined hormonal oral contraceptives (OCs). Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. atients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis.
    Aliskiren; Amlodipine: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Alogliptin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Alogliptin; Metformin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) 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.
    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 hormonal contraceptives, could interfere competitively with the pharmacologic action of the aromatase inhibitors such as Anastrozole. The goal of aromatase inhibitor therapy is to decrease circulating estrogen concentrations and inhibit the growth of hormonally-responsive cancers. Aromatase inhibitors exhibit their antiestrogenic effects by reducing the peripheral conversion of adrenally synthesized androgens (e.g., androstenedione) to estrogens through inhibition of the aromatase enzyme.
    Apalutamide: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and apalutamide should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed apalutamide. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on apalutamide, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
    Aprepitant, Fosaprepitant: (Major) If aprepitant, fosaprepitant is coadministered with hormonal contraceptives, including hormonal contraceptive devices (skin patches, implants, and hormonal IUDs), use an alternative or back-up non-hormonal method of contraception (e.g., condoms, spermicides) during treatment and for at least 1 month following the last dose of aprepitant, fosaprepitant. The efficacy of estrogens (including ethinyl estradiol) and/or progestins may be reduced when coadministered with aprepitant, fosaprepitant and for 28 days after the last dose. The exact mechanism for this interaction has not been described. Ethinyl estradiol is a CYP3A4 substrate and aprepitant, fosaprepitant is a CYP3A4 inducer; however, aprepitant, fosaprepitant is also a dose-dependent weak-to-moderate CYP3A4 inhibitor. When administered as an oral 3-day regimen (125mg/80mg/80mg) in combination with ondansetron and dexamethasone, aprepitant decreased trough concentrations of ethinyl estradiol and norethindrone by up to 64% for 3 weeks post-treatment. When ethinyl estradiol and norgestimate were administered on days 1 to 21 and aprepitant (40mg) give as a single dose on day 8, the AUC of ethinyl estradiol decreased by 4% on day 8 and by 29% on day 12; the AUC of norelgestromin increased by 18% on day 8, and decreased by 10% on day 12. Trough concentrations of both ethinyl estradiol and norelgestromin were generally lower after coadministration of aprepitant (40mg) on day 8 compared to administration without aprepitant. Specific studies have not been done with other hormonal contraceptives (e.g., progestins, non-oral combination contraceptives), an alternative or additional non-hormonal method of birth control during treatment and for 28 days after treatment is prudent to avoid potential for contraceptive failure. Additionally, although not specifically studied, because estrogens are CYP3A4 substrates, the efficacy of estrogens or progestins when used for hormone replacement may also be reduced. The clinical significance of this is not known since aprepitant, fosaprepitant is only used intermittently. (Major) If aprepitant, fosaprepitant is coadministered with hormonal contraceptives, including hormonal contraceptive devices (skin patches, implants, and hormonal IUDs), use an alternative or back-up non-hormonal method of contraception (e.g., condoms, spermicides) during treatment and for at least 1 month following the last dose of aprepitant, fosaprepitant. The efficacy of progestins may be reduced when coadministered with aprepitant, fosaprepitant and for 28 days after the last dose. The exact mechanism for this interaction has not been described. Progestins are CYP3A4 substrates and aprepitant, fosaprepitant is a CYP3A4 inducer; however, aprepitant, fosaprepitant is also a dose-dependent weak-to-moderate CYP3A4 inhibitor. When administered as an oral 3-day regimen (125mg/80mg/80mg) in combination with ondansetron and dexamethasone, aprepitant decreased trough concentrations of ethinyl estradiol and norethindrone by up to 64% for 3 weeks post-treatment. When ethinyl estradiol and norgestimate were administered on days 1 to 21 and aprepitant (40mg) give as a single dose on day 8, the AUC of ethinyl estradiol decreased by 4% on day 8 and by 29% on day 12; the AUC of norelgestromin increased by 18% on day 8, and decreased by 10% on day 12. Trough concentrations of both ethinyl estradiol and norelgestromin were generally lower after coadministration of aprepitant (40mg) on day 8 compared to administration without aprepitant. Specific studies have not been done with other hormonal contraceptives (e.g., progestins, non-oral combination contraceptives), an alternative or additional non-hormonal method of birth control during treatment and for 28 days after treatment is prudent to avoid potential for contraceptive failure. The clinical significance of this is not known since aprepitant, fosaprepitant is only used intermittently.
    Armodafinil: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estradiol, ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation. (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estrogens and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Artemether; Lumefantrine: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including oral contraceptives. This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended. (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including progestin contraceptives (i.e. levonorgestrel). Additional use of a non-hormonal method of birth control is recommended.
    Ascorbic Acid, Vitamin C: (Minor) Ascorbic acid, vitamin C acts as a competitive inhibitor of the sulfation of ethinyl estradiol in the gastrointestinal tract wall and may increase the bioavailability by 50%. Patients who ingest ascorbic acid supplements may experience an increase in estrogen related side effects.
    Aspirin, ASA; Butalbital; Caffeine: (Major) 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. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) 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. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
    Aspirin, ASA; Caffeine: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
    Aspirin, ASA; Caffeine; Orphenadrine: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
    Atazanavir: (Major) If ethinyl estradiol is administered with atazanavir boosted with ritonavir, it is recommended that the dose of ethinyl estradiol be at least 35 mcg. However, the dose of ethinyl estradiol should be no more than 30 mcg when administered with atazanavir that is NOT boosted by ritonavir. The mean exposure and minimum serum concentrations of ethinyl estradiol are increased when administered with atazanavir; but if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased. Data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of atazanavir with levonorgestrel have not been conducted; therefore, an alternative method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of levonorgestrel. 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 atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
    Atazanavir; Cobicistat: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with levonorgestrel. 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) If ethinyl estradiol is administered with atazanavir boosted with ritonavir, it is recommended that the dose of ethinyl estradiol be at least 35 mcg. However, the dose of ethinyl estradiol should be no more than 30 mcg when administered with atazanavir that is NOT boosted by ritonavir. The mean exposure and minimum serum concentrations of ethinyl estradiol are increased when administered with atazanavir; but if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased. Data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of atazanavir with levonorgestrel have not been conducted; therefore, an alternative method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of levonorgestrel. 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 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) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
    Atorvastatin: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
    Atorvastatin; Ezetimibe: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
    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) 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.
    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) 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.
    Belzutifan: (Major) Women taking both estrogens and belzutifan should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on belzutifan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
    Benzhydrocodone; 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.
    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. (Major) Women taking both estrogens and bexarotene should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed bexarotene. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of bexarotene. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on bexarotene, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and bexarotene is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Blinatumomab: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as ethinyl estradiol. The dose of the concomitant drug may need to be adjusted.
    Boceprevir: (Major) Boceprevir reduces the Cmax of norethindrone by 17%, which may be sufficient to decrease the effectiveness of combined oral contraceptives containing less than 1 mg of norethindrone (ethinyl estradiol; norethindrone, ethinyl estradiol; norethindrone acetate, mestranol; norethindrone); concurrent use of these products are contraindicated. Instead, the manufacturer recommends use of contraceptives that contain ethinyl estradiol and at least 1 mg of norethindrone. Boceprevir recipients and their partners are also required to use a second, non-hormonal, form of birth control while on therapy and for at least 6 months after treatment. (Major) Close clinical monitoring for signs of estrogen deficiency is advised when administering ethinyl estradiol in combination with boceprevir. When used concurrently, ethinyl estradiol plasma concentrations may be decreased, potentially resulting in impaired efficacy. If ethinyl estradiol dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment.
    Bosentan: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary. (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use two acceptable contraception methods during treatment and for one month after discontinuation of bosentan therapy. The patient may choose one highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or two barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on bosentan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and bosentan is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
    Bromocriptine: (Minor) Bromocriptine is used to restore ovulation and ovarian function in amenorrheic women. Estrogens and progestins can cause amenorrhea and