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 frequencyverapamilMonitor Closely (1)verapamil will increase the level or effect of etonogestrel by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.voriconazoleMonitor Closely (2)voriconazole will increase the level or effect of etonogestrel by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. 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.zafirlukastMonitor Closely (1)zafirlukast will increase the level or effect of etonogestrel by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. >10% Vaginitis (13.8%) Headache (including migraine) (11.2%) 1-10% Mood changes (6.4%) Device-related events (eg, expulsion/discomfort/foreign body sensation) (6.3%) Nausea/vomiting (5.9%) Vaginal discharge (5.7%) Increased weight (4.9%) Vaginal discomfort (4%) Breast pain/discomfort/tenderness (3.8%) Dysmenorrhea (3.5%) Abdominal pain (3.2%) Acne (2.4%) Decreased libido (2%) Postmarketing Reports Immune system disorders: Hypersensitivity (anaphylaxis and angioedema) Nervous system disorders: Stroke/cerebrovascular accident Vascular disorders: Arterial events (including arterial thromboembolism and myocardial infarction), aggravation of varicose veins Skin and subcutaneous tissue disorders: urticaria, chloasma Reproductive system and breast disorders: penile disorders, including local reactions on penis (in male partners of women using NuvaRing), galactorrhea Injury, poisoning and procedural complications: Vaginal injury (including associated pain, discomfort, and bleeding) associated with ring breakage 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 (ie, ≥15 cigarettes/day) Advise women who use hormonal oral contraceptives not to smoke Contraindications Documented hypersensitivity Arterial thromboembolic disease (stroke, MI), thrombophlebitis, DVT/PE, thrombogenic valvular disease Estrogen-dependent neoplasia (current or history of) Cerebrovascular disease, coronary artery disease Headaches with focal neurological symptoms Liver disease, liver tumors Undiagnosed abnormal vaginal bleeding Uncontrolled hypertension Women >35 years who smoke Major surgery with prolonged immobilization Diabetes mellitus with vascular involvement, jaundice with prior oral contraceptive use Breast cancer or other estrogen-or progestin-sensitive cancer,now or in the past Use of hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations Cautions Avoid using diaphragm concomitantly; may interfere with ring placement Family history of breast cancer and or DVT/PE Use caution in 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) Known risk factors for VTE include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of CHCs; stop use if arterial thrombotic or venous thromboembolic event (VTE) occurs or if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions; evaluate for retinal vein thrombosis immediately The risk of VTE is highest during first year of CHC use and after restarting a CHC following a break of at least four weeks; risk of VTE due to CHCs gradually disappears after use is discontinued Discontinue if the following develop jaundice, visual problems (may cause contact lens intolerance), 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 Discontinue if an arterial thrombotic or venous thromboembolic event occurs Estrogens may cause retinal vascular thrombosis; discontinue therapy if visual disturbances occur including migraine, loss of vision, diplopia, or proptosis 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 Combination of hormonal contraceptives may affect lipoprotein levels and serum triglycerides Use of CHCs may worsen existing gallbladder disease; past history of CHC-related cholestasis predicts an increased risk with subsequent CHC use; women with a history of pregnancy-related cholestasis may be at increased risk for CHC-related cholestasis Use caution in patients with diseases that may be exacerbated by fluid retention including migraine, diabetes, renal dysfunction, and epilepsy CDC guidelines recommend waiting at least 4 weeks following vaginal birth, in women who are not breastfeeding, 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) The risk of postpartum thromboembolism decreases after third postpartum week, whereas risk of ovulation increases after third postpartum week Ring may not be suitable for women with conditions that make vagina more susceptible to vaginal irritation or ulceration; vaginal/cervical erosion or ulceration in women reported; in some cases, the ring adhered to vaginal tissue, necessitating removal by a healthcare provider and in some instances (ie, when tissue had grown over ring), removal was achieved by cutting the ring without incising the overlying vaginal tissue Cases of toxic shock syndrome (TSS) have been reported by NuvaRing users; TSS has been associated with tampons and certain barrier contraceptives, and, in some cases the patients were also using tampons; a causal relationship between use of product and TSS has not been established; if a patient exhibits signs or symptoms of TSS, consider possibility of this diagnosis and initiate appropriate medical evaluation and treatment Do not use product in women with liver disease such as acute viral hepatitis or severe (decompensated) cirrhosis of the liver; acute or chronic disturbances of liver function may necessitate the discontinuation of CHC use until markers of liver function return to normal and CHC causation has been excluded; discontinue use if jaundice develops Risk of liver enzyme elevations with concomitant hepatitis C treatment reported; discontinue use prior to starting therapy with combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir; drug can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen Increase in blood pressure reported in women using CHCs; this increase is more likely in older women and with extended duration of use; incidence of hypertension increases with increasing concentrations of progestin; for women with well-controlled hypertension, monitor blood pressure and stop use if blood pressure rises significantly Hypersensitivity reactions of anaphylaxis and angioedema reported; if anaphylaxis and/or angioedema suspected, discontinue use and administer appropriate treatment Carefully monitor prediabetic and diabetic women who are using product; CHCs may decrease glucose tolerance Consider alternative contraception for women with uncontrolled dyslipidemia; some women will have adverse lipid changes while on CHCs Women with hypertriglyceridemia, or a family history thereof, may be at increased risk of pancreatitis when using CHCs If a woman develops new headaches that are recurrent, persistent, or severe, evaluate cause and discontinue if indicated Consider discontinuation in the case of an increased frequency or severity of migraine during CHC use (which may be prodromal of a cerebrovascular event) 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 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 mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her childPregnancy 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 Ethinyl estradiol (EE): Reduces LHRH release from hypothalamus, reduces gonadotropin release from pituitary; increases synthesis of DNA, RNA, and various proteins in target tissues Etonogestrel: Progestin; inhibits gonadotropin secretion from pituitary; prevents follicular maturation & ovulation, stimulates growth of mammary tissues Pharmacokinetics Half-life: 44.7 hr (ethinyl estradiol); 29.3 hr (etonogestrel) Excretion: Urine, bile, and feces (ethinyl estradiol and etonogestrel) Bioavailability: 56% (ethinyl estraiol); 100% (etonogestrel) Metabolism: Liver (ethinyl estradiol and etonogestrel form metabolites) Protein binding 98% (ethinyl estradiol); 32% (etonogestrel; sex hormone binding globulin and 66% to albumin) Absorption: Rapid (ethinyl estradiol and etonogestrel; tampons do not interfere with absorption) Duration: Serum levels decrease after 3 weeks of continuous use Intravaginal Administration Consider possibility of ovulation and conception before the first use of etonogestrel/ethinyl estradiol intravaginal ring One NuvaRing is inserted in the vagina and is to remain in place continuously for 3 weeks It is removed for a 1-week break, during which a withdrawal bleed usually occurs, THEN A new ring is inserted 1 week after the last ring was removed To prevent loss of contraceptive efficacy, advise women not to deviate from the recommended