effect of tinidazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.tipranavirSerious - Use Alternative (1)tipranavir, ethinylestradiol. Other (see comment). Avoid or Use Alternate Drug. Comment: Significant changes (increase or decrease) can occur in estrogen plasma levels. Efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended. .tizanidineMonitor Closely (1)ethinylestradiol will increase the level or effect of tizanidine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor. Monitor for tizanidine adverse effects (eg, hypotension or bradycardia)Minor (1)ethinylestradiol increases levels of tizanidine by unspecified interaction mechanism. Minor/Significance Unknown.tolterodineMonitor Closely (1)ethinylestradiol will increase the level or effect of tolterodine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.topiramateSerious - Use Alternative (2)topiramate will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia). topiramate will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. The efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended.tranexamic acid oralContraindicated (1)tranexamic acid oral, ethinylestradiol. Either increases toxicity of the other by pharmacodynamic synergism. Contraindicated. Coadministration of tranexamic acid oral and combination hormonal contraceptives increases thrombotic risk.trazodoneMinor (1)ethinylestradiol, trazodone. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Oxidative metabolism of TCAs may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Potential for increased TCA adverse effects.triazolamMonitor Closely (1)ethinylestradiol will increase the level or effect of triazolam by Mechanism: decreasing metabolism. Use Caution/Monitor. Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.trimethoprimMonitor Closely (1)trimethoprim will decrease the level or effect of ethinylestradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.trimipramineMinor (1)ethinylestradiol, trimipramine. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Oxidative metabolism of TCAs may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Potential for increased TCA adverse effects.tucatinibSerious - Use Alternative (2)tucatinib will increase the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling. tucatinib will increase the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.ursodiolMonitor Closely (1)ethinylestradiol decreases effects of ursodiol by pharmacodynamic antagonism. Use Caution/Monitor.valoctocogene roxaparvovecMonitor Closely (1)ethinylestradiol and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.valproic acidMonitor Closely (1)ethinylestradiol will decrease the level or effect of valproic acid by increasing elimination. Modify Therapy/Monitor Closely. May lead to increased seizure frequencyvoriconazoleMonitor Closely (1)voriconazole will increase the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.voxelotorSerious - Use Alternative (2)voxelotor will increase the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid. voxelotor will increase the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid. >10% Edema Weakness Anorexia Amenorrhea Breakthrough bleeding Change in menstrual flow Spotting Frequency Not Defined Deep vein thrombosis Thrombophlebitis Depression Dizziness Headache Nervousness Somnolence Breast tenderness Galactorrhea Abdominal pain Nausea Vomiting Weight change Cholestatic jaundice Black Box Warnings Estrogen plus progestin therapy Cardiovascular disorders and dementia risks The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported increased risk of pulmonary embolism (PE), deep vein thrombosis (DVT), stroke, and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women >65 during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo; unknown whether this finding applies to younger postmenopausal women Do not use estrogen plus progestogen therapy for prevention of cardiovascular disease or dementia Breast cancer The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer Only daily oral 0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin substudy of the WHI; therefore, relevance of the WHI findings regarding adverse cardiovascular events, dementia and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestogen products is not known Without such data, it is not possible to definitively exclude these risks or determine extent of these risks for other products Discuss with your patient the benefits and risks of estrogen plus progestogen therapy, taking into account individual risk profile; prescribe estrogens with or without progestogens at lowest effective doses and for shortest duration consistent with treatment goals and risks for individual woman Estrogen alone therapy Endometrial cancer There is increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens; adding a progestogen to estrogen therapy has been shown to reduce risk of endometrial hyperplasia, which may be a precursor to endometrial cancer Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding Cardiovascular disorders and dementia risks The WHI estrogen-alone substudy reported increased risks of stroke and DVT in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral CE (0.625 mg)-alone, relative to placebo The WHIMS estrogen-alone ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo It is unknown whether finding applies to younger postmenopausal women Do not use estrogen-alone therapy for prevention of cardiovascular disease or dementia Only daily oral 0.625 mg CE was studied in estrogen-alone substudy of the WHI; therefore,the relevance of WHI findings regarding adverse cardiovascular events and dementia to lowerCE doses, other routes of administration, or other estrogen-alone products is not known Without such data, it is not possible to definitively exclude risks or determine extent of these risks for other products; discuss with your patient the benefits and risks of estrogen-alone therapy, taking into account her individual risk profile Prescribe estrogens with or without progestogens at lowest effective doses and for shortest duration consistent with treatment goals and risks for individual woman Contraindications Documented hypersensitivity Active or history of breast cancer Arterial thromboembolic disease (stroke, MI), thrombophlebitis, DVT/PE, thrombogenic valvular disease Estrogen-dependent neoplasia Liver disease, liver tumors Undiagnosed abnormal vaginal bleeding Uncontrolled hypertension Diabetes mellitus with vascular involvement Jaundice with prior oral contraceptive use Cautions Acitretin inhibits contraceptive efficacy of norethindrone preparations Family history of breast cancer and or DVT/PE, current/history of depression, endometriosis, DM, HTN, bone mineral density changes, renal/hepatic impairment, bone metabolic disease, SLE; conditions exacerbated by fluid retention (eg, migraine, asthma, epilepsy) Discontinue if the following develop jaundice, visual problems (may cause contact lens intolerance), any signs of VTE, migraine with unusual severity, significant blood pressure increase, severe depression, increased risk of thromboembolic complications after surgery Carefully observe women with history of depression and discontinue therapy if depression recurs to a serious degree Discontinue 4 week before major surgery or prolonged immobilization Patients on warfarin, oral anticoagulants (increase in anticoagulant dose may be warranted) Increased risk of cervical cancer with OCP use, however HPV remains as main risk factor for this cancer; evidence suggests long-term use of OCPs, 5 or more years, may be associated with increased risk Increased risk of liver cancer with OCP use; risk increases with longer duration of OCP use Some studies suggest that oral contraceptive use has been associated with an increase in risk of cervical intraepithelial neoplasia in some populations of women Benign hepatic adenomas are associated with oral contraceptive use, although incidence is rare in the United States In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema CDC guidelines recommend waiting at least 3 weeks following vaginal birth or 6 weeks after cesarean section to decrease risk for venous thromboembolism before initiating combined hormonal contraceptives; women with additional risk factors for VTE (besides postpartum) should not use combined hormonal contraceptives (MMWR July 7, 2011) Breast cancer Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk; studies do not show an association between ever (current or past) use of COCs and risk of breast cancer Some studies report a small increase in risk of breast cancer among current or recent users(<6 months since last use) and current users with longer duration of COC use A woman's risk depends on conditions where naturally high hormone levels persist for long periods of time including early-onset menstruation before age 12, late-onset menopause, after age 55, first child after age 30, nulliparity Carbohydrates and lipid metabolic effects Oral contraceptives shown to cause glucose intolerance in a significant percentage of users; oral contraceptives containing >75 mcg of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents; however, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives Elevated blood pressure Data from the Royal College of General Practitioners (18) and subsequent randomized trials have shown that incidence of hypertension increases with increasing concentrations of progestogens Women with a history of hypertension or hypertension-related diseases or renal disease should be encouraged to use another method of contraception; if women elect to use oral contraceptives, they should be monitored closely, and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in occurrence of hypertension among ever and never users Cigarette smoking and risk of cardiovascular disease Cigarette smoking increases risk of serious cardiovascular adverse effects from combination hormonal contraceptive use This risk increases with age (>35 yr) and with heavy smoking (15 or more cigarettes/day) Advise women who use hormonal oral contraceptives not to smoke Pregnancy Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy; studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb reduction defects are concerned, when taken inadvertently during early pregnancy Administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy; oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out before continuing oral contraceptive use; if the patient has not adhered to prescribed schedule, possibility of pregnancy should be considered at time of first missed period; oral contraceptive use should be discontinued if pregnancy is confirmed Lactation Small amounts of oral contraceptive steroids identified in the milk of nursing mothers, and a few adverse effects on child reported, including jaundice and breast enlargement; in addition, oral contraceptives given in postpartum period may interfere with lactation by decreasing quantity and quality of breast milk If possible, the nursing