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.warfarinMonitor Closely (1)levonorgestrel transdermal increases effects of warfarin by unspecified interaction mechanism. Use Caution/Monitor. 1-10% Application site disorder (6.2%) Nausea (4.1%) Headache (3.6%) Dysmenorrhea (2.3%) Increased weight (2%) <1% Cholelithiasis Cholecystitis Major depression Suicidal ideation Appendicitis Ectopic pregnancy Pneumonia Gastroenteritis Black Box Warnings Cigarette smoking and serious cardiovascular events Cigarette smoking increases risk of serious cardiovascular events from combined hormonal comtraceptive (CHC) use This risk increases with age, particularly in women aged ≥35 yr, and with the number of cigarettes smoked For this reason, CHCs are contraindicated in women aged ≥35 yr of age who smoke Contraindicated with BMI 30 kg/m2 or greater Contraindicated in women with BMI ≥30 kg/m2 Compared with lower BMI, women with a BMI ≥30 kg/m2 had reduced effectiveness and may have a higher risk for venous thromboembolism events (VTEs) Contraindications Have headaches with focal neurological symptoms, migraine headaches with aura Women aged >35 yr with any migraine headache BMI ≥30 kg/m2; reduced effectiveness and may have higher risk for VTEs compared with women with lower BMI Liver tumors (benign or malignant), acute viral hepatitis, severe (decompensated) cirrhosis, or liver disease Undiagnosed abnormal uterine bleeding Pregnancy, given there is no reason to use CHCs during pregnancy Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past Hypersensitivity to any components; observed reactions include itching and irritation at application site Use of hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, owing to potential for elevated ALT High risk for arterial or VTEs Examples include women who Smoke, if over aged ≥35 yr Have current or history of DVT or PE Have cerebrovascular disease Have coronary artery disease Have thrombogenic valvular or thrombogenic rhythm heart diseases (eg, SBE with valvular disease, atrial fibrillation) Have inherited or acquired hypercoagulopathies Have uncontrolled hypertension or hypertension with vascular disease Have diabetes mellitus and are aged ≥35 yr, diabetes mellitus with hypertension, or vascular disease or other end-organ damage, or diabetes mellitus of >20 years' duration Cautions Contraindicated with benign or malignant liver tumors, acute viral hepatitis, or severe cirrhosis; discontinue if jaundice occurs Increased ALT observed in women taking ethinyl estradiol-containing medications with certain hepatitis C drug regimens (ie, ombitasvir/paritaprevir/ritonavir, with or without dasabuvir) Contraindicated with uncontrolled hypertension or hypertension with vascular disease; if administered to women with well-controlled hypertension, monitor blood pressure; discontinue immediately if blood pressure increases significantly Consider age-related risk factors for CV disease (eg, hypertension, diabetes, dyslipidemia, obesity) Increase risk of gall bladder disease among CHC users Contraindicated in diabetic women aged ≥35 yr, or women who have diabetes with hypertension, nephropathy, retinopathy, or neuropathy, other vascular disease, or women with diabetes >20 yr duration Contraindicated in women who have headaches with focal neurological symptoms or have migraine headaches with aura, and women aged ≥35 yr who have migraine headaches with or without aura Carefully observe women with history of depression; discontinue if depression recurs to a serious degree Some studies suggest that CHCs are associated with increased risk of cervical cancer or intraepithelial neoplasia; controversial whether these findings are caused by CHCs or sexual behavior and other factors Estrogen may raise serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin; dose of replacement thyroid hormone or cortisol therapy may need to be increased Exogenous estrogens may induce or exacerbate symptoms of angioedema Chloasma may occur, especially in women with a history of chloasma gravidarum; avoid sun exposure or ultraviolet radiation Thromboembolic disorders and other vascular conditions Women are at increased risk for VTE when using CHCs VTE risk may be greater with BMI ≥30 kg/m2 compared with lower BMI and CHCs are contraindicated in obese patients Additional information Discontinue if an arterial or VTE occurs Discontinue if unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions occurs; evaluate for retinal vein thrombosis immediately Discontinue during prolonged immobilization and resume treatment based on clinical judgement; if feasible, stop at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism Start no earlier than 4 weeks after delivery in women who are not breastfeeding; risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week Before initiating, evaluate any medical history or family history of thromboembolism or thromboembolic disorders; consider whether the history suggests an inherited or acquired hypercoagulopathy Contraindicated in women with high risk of arterial or VTE, including women aged ≥35 yr who smoke Bleeding irregularities and amenorrhea Bleeding and spotting Women may experience unscheduled (breakthrough or intracyclic) bleeding and spotting, especially during the first 3 months of use Bleeding irregularities may resolve over time or by changing to a different contraceptive product If bleeding persists or occurs after previously regular cycles, evaluate for causes (eg, pregnancy, malignancy) Amenorrhea and oligomenorrhea Women may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant If scheduled bleeding does not occur, consider the possibility of pregnancy Evaluate adherence and rule out pregnancy Drug interaction overview Drugs that decrease systemic exposure of hormonal contraceptives Enzyme inducers: May decrease plasma concentrations of estrogen and/or progestin component of CHCs Colesevelam: Coadministration significantly decreases systemic exposure of ethinyl estradiol HIV protease inhibitors (eg, nelfinavir, ritonavir, darunavir/ritonavir, fosamprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir) and some non-nucleoside reverse transcriptase inhibitors (eg, nevirapine) Drugs that increase systemic exposure of hormonal contraceptives HIV protease inhibitors (eg, indinavir, atazanavir/ritonavir) and with other non-nucleoside reverse transcriptase inhibitors (eg, etravirine) Atorvastatin or rosuvastatin increase systemic exposure of ethinyl estradiol by ~20-25% Ascorbic acid and acetaminophen may increase systemic exposure of ethinyl estradiol, possibly by inhibition of conjugation CYP3A4 inhibitors (eg, itraconazole, voriconazole, fluconazole, grapefruit juice, ketoconazole) may increase systemic exposure of estrogen and/or progestin CHC effect on other drugs Lamotrigine systemic exposure may be significantly decreased owing to induction of lamotrigine glucuronidation; lamotrigine dose adjustment may be required Thyroid hormone: CHCs may increase systemic exposure of thyroid-binding globulin; thyroid hormone dose may need to be increased Corticosteroids: CHCs may increase systemic exposure of cortisol-binding globulin; corticosteroid dose may need to be increased CHCs may decrease systemic exposure of acetaminophen, morphine, salicylic acid, and temazepam CHCs may increase systemic exposure of cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole Pregnancy Contraindicated Discontinue if pregnancy occurs 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 Lactation Contraceptive hormones and/or metabolites are present in human milk CHCs can reduce milk production in breastfeeding women, but this is less likely to occur once breastfeeding is well established Advise breastfeeding women to use another method of contraception until breastfeeding discontinuedPregnancy 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 Combination hormonal contraceptives lower the risk of becoming pregnant primarily by suppressing ovulation Ethinyl estradiol: Reduces LHRH release from hypothalamus and reduces gonadotropin release from pituitary; increases synthesis of DNA, RNA, and various proteins in target tissues; other possible mechanisms include changes in cervical mucus that cause inhibition of sperm penetration and endometrial changes that reduce likelihood of implantation Levonorgestrel transdermal: Synthetic progestin; ovulation is inhibited from a negative feedback mechanism on hypothalamus, leading to reduced secretion of FSH and LH Absorption Concentration at steady-state Cycle 1 Average steady-state concentration, levonorgestrel: 842 pg/mL (week 1); 2009 pg/mL (week 3) Average steady-state concentration, ethinyl estradiol: 31.9 pg/mL (week 1); 34.8 pg/mL (week 3) AUC levonorgestrel: 120 ng⋅h/mL (week 1); 339 ng⋅h/mL (week 3) AUC ethinyl estradiol: 5040 pg⋅h/mL (week 1); 6210 pg⋅h/mL (week 3) Cycle 2 Average steady-state concentration, levonorgestrel: 1389 pg/mL (week 1); 2209 pg/mL (week 3) Average steady-state concentration, ethinyl estradiol: 38.6 pg/mL (week 1); 40.3 pg/mL (week 3) AUC levonorgestrel: 207 ng⋅h/mL (week 1); 378 ng⋅h/mL (week 3) AUC ethinyl estradiol: 6060 pg⋅h/mL (week 1); 7120 pg⋅h/mL (week 3) Distribution Protein bound Levonorgestrel: Primarily bound to sex hormone-binding globulin (SHBG) Ethinyl estradiol: 97% bound to plasma albumin; does not bind to SHBG, but induces SHBG synthesis Metabolism Since it is applied transdermally, first-pass metabolism (via GI tract and/or liver) of levonorgestrel and ethinyl estradiol that would be expected with PO administration does not occur Levonorgestrel The most important hepatic metabolic pathways are reduction of the delta-4-3-oxo group and hydroxylation at positions 2-alpha, 1-beta, and 16-beta, followed by conjugation Most circulating metabolites are sulfates of 3-alpha, 5-beta-tetrahydro-levonorgestrel, while excretion is mostly in the form of glucuronides Ethinyl estradiol CYP3A4 metabolism in the liver is responsible for 2-hydroxylation that is the major oxidative reaction 2-Hydroxy metabolite is further transformed by methylation and glucuronidation before urinary and fecal excretion Elimination Half-life Elimination half-life Levonorgestrel: 38.2 hr (cycle 1, week 3); 40.5 hr (cycle 2, week 3) Ethinyl estradiol: 19.7 hr (cycle 1, week 3); 20.5 hr (cycle 2, week 3) Mean terminal half-life Levonorgestrel: 41 hr Ethinyl estradiol: 21 hr Excretion Levonorgestrel: 40-68% urine; 16-48% feces Ethinyl estradiol: Excreted in urine and feces and glucuronide and sulfate conjugates; undergoes enterohepatic recirculation Transdermal Administration Application For transdermal use only To achieve maximum contraceptive effectiveness, transdermal system (TDS) must be used exactly as directed; failure rate may increase when TDS application is delayed/missed or when TDS is applied incorrectly Apply TDS to clean, dry, and intact skin on abdomen, buttock, or upper torso (excluding breasts) When applying a new TDS, do not apply the new TDS directly over the previous TDS site Do not apply to skin that has been exposed to powder, oil, moisturizer, or lotion Advise women not to routinely use large amounts of body lotions or oils at application sites Prolonged exposure to water may interfere with TDS adherence Do not cut or alter TDS in any way; apply whole TDS; if TDS is cut or damaged or altered in size, contraceptive efficacy may be impaired Discard by folding used TDS so that the adhesive side sticks to itself and safely discard in the trash Used TDS still contains some active hormones; should not be flushed down the toilet TDS edge lifts up Press down firmly on TDS with the palm of the hand for 10 seconds, making sure that the whole TDS is adhered to skin Then run fingers over the entire surface area to smooth out any wrinkles around the edges of the TDS If lifted edge of TDS does not stick completely after attempted readhesion, remove TDS and replace with new TDS Do not tape or wrap TDS to skin or reapply a TDS that is partially adhered to clothing TDS has been off or partially off <1 day Try to reapply TDS; if TDS does not adhere completely, apply new TDS immediately No back-up contraception is needed and the Patch Change Day will stay the same >1 day or unsure of timeframe Woman may not be protected from pregnancy Reduce pregnancy risk by applying new TDS and start a new 4-week cycle The woman will now have a new Patch Change Day and MUST use nonhormonal back-up contraception (eg, condoms and spermicide, diaphragm and spermicide) for the first 7 days of the new cycle Starting in women with no current hormonal contraceptive Day 1 start Apply first TDS during the first 24 hr of menstruation Apply a new TDS each week for 3