Therapy/Monitor Closely. Stiripentol is a CYP3A4 inhibitor and inducer. Monitor CYP3A4 substrates coadministered with stiripentol for increased or decreased effects. CYP3A4 substrates may require dosage adjustment.sugammadex sodiumSerious - Use Alternative (1)sugammadex sodium decreases effects of ethinylestradiol by receptor binding competition. Avoid or Use Alternate Drug. In vitro binding studies showed that sugammadex may bind to progestogen, thereby decreasing progestogen exposure. Therefore, a sugammadex bolus dose is considered to be equivalent to missing dose(s) of hormonal contraceptives containing an estrogen or progestogen. If an oral contraceptive is taken on the same day of sugammadex, or the patient has a transdermal or implant hormonal contraceptive, the patient must use an additional, nonhormonal contraceptive method or back-up method of contraception (eg, condoms and spermicides) for the next 7 days.sulfadiazineMonitor Closely (1)sulfadiazine 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.sulfamethoxazoleMonitor Closely (1)sulfamethoxazole 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.sulfisoxazoleMonitor Closely (1)sulfisoxazole 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.tacrolimusMonitor Closely (1)ethinylestradiol will increase the level or effect of tacrolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.tazemetostatMonitor Closely (2)tazemetostat will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. ethinylestradiol will increase the level or effect of tazemetostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.tecovirimatMonitor Closely (1)tecovirimat will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Tecovirimat is a weak CYP3A4 inducer. Monitor sensitive CYP3A4 substrates for effectiveness if coadministered.teriflunomideMonitor Closely (1)teriflunomide increases levels of ethinylestradiol by unknown mechanism. Use Caution/Monitor.tetracyclineMonitor Closely (1)tetracycline 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.theophyllineMonitor Closely (1)ethinylestradiol will increase the level or effect of theophylline by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.ticarcillinMonitor Closely (1)ticarcillin 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.tigecyclineMonitor Closely (1)tigecycline 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.tinidazoleMonitor Closely (1)ethinylestradiol will increase the level or 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 (1)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 (1)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.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 (1)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. >10% Edema Weakness Amenorrhea Breakthrough bleeding Change in menstrual flow Spotting Anorexia Frequency Not Defined DVT Thrombophlebitis Depression Dizziness Headache Nervousness Somnolence Breast tenderness Galactorrhea Abdominal pain Nausea Vomiting Change in weight Cholestatic jaundice Black Box Warnings cigarette smoking & 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 Contraindications Documented hypersensitivity Active or history of breast cancer Arterial thromboembolic disease (stroke, MI), thrombophlebitis, DVT/PE, thrombogenic valvular disease Estrogen-dependent neoplasia Carcinoma of the endometrium Liver disease, liver tumors Undiagnosed abnormal vaginal bleeding Uncontrolled hypertension Cerebral vascular or coronary artery disease Diabetes mellitus with vascular involvement, jaundice with prior oral contraceptive use Receiving hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir Cautions 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 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 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) May experience spotting, amenorrhea, and unscheduled bleeding, especially during first 3 months of therapy; evaluate unscheduled or breakthrough bleeding that persists or occurs after regular cycles to rule out malignancy or pregnancy; after discontinuing OCP, may experience oligomenorrhea or amenorrhea Sun exposure, combination of hormonal contraceptive, and pregnancy may trigger chloasma; patients should avoid sun exposure or ultraviolet radiation if susceptible to chloasma or at risk Increased risk of cholestasis associated with history of cholestasis with prior OCP use or prior cholestasis of pregnancy Discontinue use and evaluate for retinal thrombosis if unexplained loss of vision, papilledema, proptosis, or diplopia occur Combination hormonal therapy may adversely affect lipid levels, including serum triglycerides; risk of pancreatitis may increase in patients with hypertriglyceridemia or family history of hypertriglyceridemia; in uncontrolled hyperlipidemia, consider alternative contraception Use of combination hormonal contraceptives is associated with hepatic adenomas; fatal intra-abdominal hemorrhage may occur with rupture; rare hepatocellular carcinoma associated with long term use of OCP Therapy not recommended in patients with acute viral hepatitis or during a flare; severity of cirrhotic fibrosis or hepatocellular carcinoma has not been shown to increase with continued use of hormonal combination therapy or to trigger liver failure or hepatic dysfunction Risk of cardiovascular disease may increase in patients at risk, including high LDL, low HDL, high triglycerides, patients who smoke, or with diabetes; use caution Use caution in patients with diabetes; therapy may impair glucose tolerance; therapy may have limited effect on long term effects on diabetes control and insulin needs in patients with nonvascular disease Based on severity of condition, evaluate patients for contraceptive use, if there is concomitant neuropathy, nephropathy, retinopathy, diabetes >20 years, or another vascular disease Combination hormonal contraceptive has been associated with increased risk of gallbladder disease and may also worsen existing disease Hereditary angioedema may become exacerbated in patients with hereditary angioedema Hormonal combination therapy not recommended in patients with complicated organ transplants; limited data suggests serious medical complications, including rejection, graft failure, cardiac allograft vasculopathy, requiring discontinuation of hormonal combination therapy Therapy may increase risk of heart disease, VTE, and stroke in patients with systemic lupus erythematosus (SLE); should not be used in patients with SLE who have positive antiphospholipid antibodies as it may increase risk of arterial and venous thrombosis Discontinue hormonal therapy prior to starting therapy with combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir; may restart approximately 2 weeks following completion of treatment with combination drug regimen 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 Pregnancy There is little or no increased risk of birth defects in children of females who inadvertently use COCs during early pregnancy Discontinue use if pregnancy is confirmed Do not administer COCs to induce withdrawal bleeding as a test for pregnancy; do not use COCs during pregnancy to treat threatened or habitual abortion Animal data Animal data, along with epidemiologic studies, do not show an increased risk of birth defects with use of COCs prior to pregnancy or during early pregnancy Lactation Contraceptive hormones and/or metabolites are present in human milk in small amounts; effects of therapy on breastfed child is unknown; COCs can reduce milk production in lactating women Advise nursing mother to use non-COC contraception, when possible until she has weaned her child; this is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for therapy and any potential adverse effects on breastfed child from the drug or from underlying maternal conditionPregnancy Categories A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk. B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available. Mechanism of Action Ethinylestradiol (EE): Reduces LHRH release from hypothalamus,