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 Postmarketing Reports Mood swings Black Box Warnings Cardiovascular risks Estrogens with or without progestins should not be used to prevent cardiovascular disease Estrogens plus progestins: Women’s Health Initiative (WHI) Estrogen Plus Progestin substudy reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis (DVT) in postmenopausal women (aged 50-79 yr) during 5.6 yr of treatment with daily PO conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) compared with placebo Estrogens alone: The estrogen alone substudy of the WHI Study reported increased risks of stroke & DVT in postmenopausal women (aged 50-79 yr) during 6.8 yr of treatment with oral conjugated estrogens (0.625 mg/day) alone compared with placebo Dementia Risks Estrogens with or without progestins should not be used to prevent dementia Women's Health Initiative Memory Study (WHIMS), a substudy of the WHI study, reported increased risk of developing probable dementia in postmenopausal women aged 65 yr or older during 4 yr of treatment w/ daily CE 0.625 mg combined with MPA 2.5 mg, compared with placebo Estrogens alone: A substudy of the WHIMS reported an increased risk of developing probable dementia in postmenopausal women aged 65 yr or older during 5.2 yr of treatment with conjugated estrogens 0.625 mg alone compared with placebo Unknown whether these findings apply to younger postmenopausal women Dose & Duration In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations & dosage forms of estrogens and progestins Because of these risks, estrogens with or without progestins should be prescribed at lowest effective dose and for shortest duration consistent with treatment goals and individual risks 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) The drug is contraindicated in women who are over 35 years of age and smoke Contraindications Liver tumors or liver disease Undiagnosed abnormal uterine bleeding Breast cancer or other estrogen-or progestin-sensitive cancer Pregnancy Receiving hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia Cholestatic jaundice of pregnancy or jaundice with prior pill use Women who currently have the following: High risk of arterial or venous thrombotic diseases, including Smoke, if over age 35 Have cerebrovascular disease Have coronary artery disease Have current or history of deep vein thrombosis or pulmonary embolism Have thrombogenic valvular or thrombogenic rhythm diseases of the heart Have inherited or acquired hypercoagulopathies Have uncontrolled hypertension or hypertension with vascular disease Have headaches with focal neurological symptoms, migraine headaches with aura, or over age 35 with any migraine headaches Have diabetes mellitus and are over age 35, diabetes mellitus with hypertension or with vascular disease or end-organ damage, or diabetes mellitus of > 20 years duration 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, significang blood pressure increase, severe depression, increased risk of thromboembolic complications after surgery If a thrombotic event occurs, stop at least 4 wk before through 2 wk after major surgery; start no earlier than 4 weeks after delivery, in women who are not breastfeeding 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 Steroid hormones may be poorly metabolized in patients with hepatic impairment; acute or chronic disturbances of liver function may necessitate discontinuation of combination oral contraceptive until markers of liver function return to normal and causation by combination oral contraceptive has been excluded 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) Monitor prediabetic and diabetic women taking eithinyl estradiol/ norethindrone; consider alternative contraceptive method for women with uncontrolled dyslipidemia Evaluate significant change in headaches and discontinue therapy if indicated Evaluate irregular bleeding or amenorrhea If used in women with well-controlled hypertension, monitor blood pressure and stop therapy if blood pressure rises significantly 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 In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema Chloasma may occur with therapy, especially in women with a history of chloasma gravidarum; advise women with a history of chloasma to avoid exposure to the sun or ultraviolet radiation while taking the drug 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 Drug interaction overview Significant changes (increase or decrease) in plasma concentrations of estrogen and progestin noted in some cases of co-administration with HIV/HCV protease inhibitors (decrease [eg, nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [eg, indinavir and atazanavir/ritonavir])/HCV protease inhibitors (decrease [eg, boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [eg, nevirapine] or increase [eg, etravirine]) Not for coadministration with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation; a reduction in contraceptive effectiveness and increased incidence of breakthrough bleeding suggested with phenylbutazone COCs containing ethinyl estradiol may inhibit metabolism of other compounds (eg, cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations COCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, temazepam and lamotrigine Significant decrease in plasma concentration of lamotrigine shown, likely due to induction of lamotrigine glucuronidation; this may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentration of thyroid-binding globulin increase with use of COCs Pregnancy There is no use for contraception in pregnancy; therefore, drug should be discontinued during 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 Norethindrone acetate: progestin; inhibits gonadotropin secretion of gonadotropins from pituitary; prevents follicular maturation and ovulation, stimulates growth of mammary tissues Ferrous fumarate: Replacement of iron stores Pharmacokinetics Peak Plasma Time: 8 hr (ethinyl estradiol); 1-2 hr (norethindrone) Protein binding: 80% (ethinyl estradiol); 61% (norethindrone) Both components are metabolized in the liver; estradiol undergoes extensive first-pass metabolism Ethinyl estradiol metabolites: Estriol, estrone Norethindrone metabolites: Sulfate and glucuronide metabolites (inactive) Half-Life: 4-13 hr (norethindrone PO) Excretion Ethinyl estradiol: Urine as conjugates, most estrogens are also excreted in bile and undergo enterohepatic recycling Norethindrone: 33-81% (urine); 35-43% (feces) No images available for this drug. No images available for this drug.A Patient Handout is not currently available for this monograph.Print FormularyPatient DiscountsAdding plans allows you to compare formulary status to other drugs in the same class.To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.Create Your List of PlansAdding plans allows you to:View the formulary and any restrictions for each plan.Manage and view all your plans together – even plans in different states.Compare formulary status to other drugs in the same class.Access your plan list on any device – mobile or desktop. The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information. View explanations for tiers and restrictions Tier Description 1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs. 2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs. 3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs. 4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products. 5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products. 6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products. NC NOT COVERED – Drugs that are not covered by the plan. Code Definition PA Prior Authorization Drugs that require prior authorization. This restriction requires