Ayuna

INDICATIONS AND USAGE Ayuna is indicated for use by females of reproductive potential to prevent pregnancy.

DOSAGE AND ADMINISTRATION 1. How to Start and Take Ayuna Ayuna is dispensed in a blister pack containing 28 tablets (see HOW SUPPLIED ). Ayuna may be started using either a Day 1 start or a Sunday start (see Table 3). For the first cycle of a Sunday start regimen, an additional method of contraception should be used until after the first 7 consecutive days of administration. Table 3: Instructions for Administration of Ayuna Starting Ayuna in females with no current use of hormonal contraception Day 1 start Take first tablet without regard to meals on the first day of menses Take subsequent tablets once daily at the same time each day Begin each subsequent pack on the same day of the week as the first cycle pack (i.e., on the day after taking the last tablet) Sunday start Take first tablet without regard to meals on the first Sunday after the onset of menstrual period Take subsequent tablets once daily at the same time each day Use additional nonhormonal contraception for the first seven days of product use Begin each subsequent pack on the same day of the week as the first cycle pack (i.e., on the day after taking the last tablet) Switching from another contraceptive method A COC Transdermal patch Vaginal ring Injection Intrauterine contraceptive Implant Start Ayuna: On the day when the new pack of the previous COC would have been started On the day when next application would have been scheduled On the day when next insertion would have been scheduled On the day when next injection would have been scheduled On the day of removal On the day of removal Starting Ayuna after Abortion or Miscarriage First-trimester After a first-trimester abortion or miscarriage, Ayuna may be started immediately. An additional method of contraception is not needed if Ayuna is started immediately. If Ayuna is not started within 5 days after termination of the pregnancy, the patient should use additional non-hormonal contraception (such as condoms or spermicide) for the first seven days of her first cycle of Ayuna. Second-trimester Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start Ayuna following the instructions in Table 3 for Day 1 or Sunday start. Use additional non-hormonal contraception (such as condoms or spermicide) for the first seven days of the patient’s first cycle of Ayuna (see CONTRAINDICATIONS , WARNINGS (1) , PRECAUTIONS (10) and FDA-APPROVED PATIENT LABELING) . Starting Ayuna after Childbirth Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with Ayuna following the instructions in Table 3 for women not currently using hormonal contraception. Ayuna is not recommended for use in lactating women (see PRECAUTIONS (7) and FDA-APPROVED PATIENT LABELING). If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of Ayuna (see CONTRAINDICATIONS , WARNINGS (9) , PRECAUTIONS (6) and FDA-APPROVED PATIENT LABELING) . 2. Dosing Ayuna Instruct patients to take one tablet by mouth at the same time every day. To achieve maximum contraceptive effectiveness, patients must take Ayuna as directed, in the order directed on the blister pack. The failure rate may increase when pills are missed or taken incorrectly. 3. Missed doses Instruct patients about the handling of missed doses (e.g., to take single missed pills as soon as possible) and to follow the dosing instructions provided in the FDA-approved patient labeling. Table 4: Instructions for Missed Ayuna Tablets If one active tablet is missed in Weeks 1, 2, or 3 Take the tablet as soon as possible. Continue taking one tablet a day until the pack is finished. If two active tablets are missed in Week 1 or Week 2 Take the two missed tablets as soon as possible and the next two active tablets the next day. Continue taking one tablet a day until the pack is finished. Additional nonhormonal contraception (such as condoms or spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets. If two active tablets are missed in the third week or three or more active tablets are missed in a row in Weeks 1, 2, or 3 Day 1 start: Throw out the rest of the pack and start a new pack that same day. Sunday start: Continue taking one tablet a day until Sunday, then throw out the rest of the pack and start a new pack that same day. Additional nonhormonal contraception (such as condoms or spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets. 4. Advice in Case of Gastrointestinal Disturbances If vomiting occurs within 3 to 4 hours after taking Ayuna, the patient should proceed as if she missed a tablet. In case of prolonged vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken.

ADVERSE REACTIONS The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: Serious cardiovascular adverse events [see BOXED WARNING and WARNINGS (1) ] Vascular events [see WARNINGS (1) ] Liver disease [see WARNINGS (2) ] Hypertension [see WARNINGS (3) ] Gallbladder disease [see WARNINGS (6) ] Carbohydrate and lipid effects [see WARNINGS (7) ] Headache [see WARNINGS (8) ] Carcinoma of the cervix [see WARNINGS (11) ] Adverse reactions reported by COC users and described elsewhere in the labeling are: Bleeding irregularities and amenorrhea [see WARNINGS (9) ] Mood changes, including depression [see WARNINGS (10) ] Melasma/chloasma which may persist [see WARNINGS (14) ] Edema/fluid retention [see PRECAUTIONS (2) ] Diminution in lactation when given immediately postpartum [see PRECAUTIONS (7) ] Post Marketing Experience Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 to 1.12 (Figure 2). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 2). One of these studies reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19 to 1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8 to 10 years of COC use. Figure 2: Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives RR = relative risk; OR = odds ratio; HR = hazard ratio. “ever COC” are females with current or past COC use; “never COC use” are females that never used COCs. The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related: Breast tenderness, pain, enlargement, secretion; Nausea, vomiting and gastrointestinal symptoms (such as abdominal pain, cramps and bloating); Change in menstrual flow; Temporary infertility after discontinuation of treatment; Change in weight or appetite (increase or decrease); Change in cervical erosion and secretion; Cholestatic jaundice; Rash (allergic); Vaginitis, including candidiasis; Change in corneal curvature (steepening); Intolerance to contact lenses; Mesenteric thrombosis; Decrease in serum folate levels; Exacerbation of systemic lupus erythematosus; Exacerbation of porphyria; Exacerbation of chorea; Aggravation of varicose veins; Anaphylactic/anaphylactoid reactions, including urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms. The following adverse reactions have been reported in users of oral contraceptives, and the association has been neither confirmed nor refuted: Congenital anomalies; Premenstrual syndrome; Cataracts; Optic neuritis, which may lead to partial or complete loss of vision; Cystitis-like syndrome; Nervousness; Dizziness; Hirsutism; Loss of scalp hair; Erythema multiforme; Erythema nodosum; Hemorrhagic eruption; Impaired renal function; Hemolytic uremic syndrome; Budd-Chiari syndrome; Acne; Changes in libido; Colitis; Sickle-cell disease; Cerebral-vascular disease with mitral valve prolapse; Lupus-like syndromes; Pancreatitis; Dysmenorrhea. Figure 2: Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives

1. Drug Interactions The sections below provide information on substances for which data on drug interactions with COCs are available. There is little information available about the clinical effect of most drug interactions that may affect COCs. However, based on the known pharmacokinetic effects of these drugs, clinical strategies to minimize any potential adverse effect on contraceptive effectiveness or safety are suggested. Consult the approved product labeling of all concurrently used drugs to obtain further information about interactions with COCs or the potential for metabolic enzyme or transporter system alterations . No drug-drug interaction studies were conducted with levonorgestrel and ethinyl estradiol tablets. 4.1 Effects of Other Drugs on Combined Oral Contraceptives Substances Decreasing the Plasma Concentrations of COCs and Potentially Diminishing the Efficacy of COCs: Table 1 includes substances that demonstrated an important drug interaction with levonorgestrel and ethinyl estradiol tablets. Table 1: Significant Drug Interactions Involving Substances That Affect COCs Metabolic Enzyme Inducers Clinical effect Concomitant use of COCs with metabolic enzyme inducers may decrease the plasma concentrations of the estrogen and/or progestin component of COCs. Decreased exposure of the estrogen and/or progestin component of COCs may potentially diminish the effectiveness of COCs and may lead to contraceptive failure or an increase in breakthrough bleeding. Prevention or management Counsel females to use an alternative method of contraception or a backup method when enzyme inducers are used with COCs. Continue backup contraception for 28 days after discontinuing the enzyme inducer to maintain contraceptive reliability. Examples Aprepitant, barbiturates, bosentan, carbamazepine, efavirenz, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, rifabutin, rufinamide, topiramate, products containing St. John’s wort a , and certain protease inhibitors (see separate section on protease inhibitors below). Colesevelam Clinical effect Concomitant use of COCs with colesevelam significantly decreases systemic exposure of ethinyl estradiol. Decreased exposure of the estrogen component of COCs may potentially reduce contraceptive efficacy or result in an increase in breakthrough bleeding, depending on the strength of ethinyl estradiol in the COC. Prevention or management Administer 4 or more hours apart to attenuate this drug interaction. a Induction potency of St. John’s wort may vary widely based on preparation. Substances increasing the systemic exposure of COCs: Co-administration of atorvastatin or rosuvastatin and COCs containing ethinyl estradiol increase systemic exposure of ethinyl estradiol by approximately 20 to 25 percent. Ascorbic acid and acetaminophen may increase systemic exposure of ethinyl estradiol, possibly by inhibition of conjugation. CYP3A inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, 7 or ketoconazole may increase systemic exposure of the estrogen and/or progestin component of COCs. Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant decreases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with some HIV protease inhibitors (e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir), some HCV protease inhibitors (e.g., boceprevir and telaprevir), and some non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine). In contrast, significant increases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with certain other HIV protease inhibitors (e.g., indinavir and atazanavir/ritonavir) and with other non-nucleoside reverse transcriptase inhibitors (e.g., etravirine). 4.2 Effects of Combined Oral Contraceptives on Other Drugs Table 2 provides significant drug interaction information for drugs co-administered with levonorgestrel and ethinyl estradiol tablets. Table 2: Significant Drug Interaction Information for Drugs Co-Administered With COCs Lamotrigine Clinical effect Concomitant use of COCs with lamotrigine may significantly decrease systemic exposure of lamotrigine due to induction of lamotrigine glucuronidation. Decreased systemic exposure of lamotrigine may reduce seizure control. Prevention or management Dose adjustment may be necessary. Consult the approved product labeling for lamotrigine. Thyroid Hormone Replacement Therapy or Corticosteroid Replacement Therapy Clinical effect Concomitant use of COCs with thyroid hormone replacement therapy or corticosteroid replacement therapy may increase systemic exposure of thyroid-binding and cortisol-binding globulin (see Warnings, EFFECT ON BINDING GLOBULINS). Prevention or management The dose of replacement thyroid hormone or cortisol therapy may need to be increased. Consult the approved product labeling for the therapy in use (see Warnings, EFFECT ON BINDING GLOBULINS). Other Drugs Clinical effect Concomitant use of COCs may decrease systemic exposure of acetaminophen, morphine, salicylic acid, and temazepam. Concomitant use with ethinyl estradiol-containing COCs may increase systemic exposure of other drugs (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole). Prevention or management The dosage of drugs that can be affected by this interaction may need to be increased. Consult the approved product labeling for the concomitantly used drug. 4.3 Concomitant Use with Hepatitis C Virus (HCV) Combination Therapy - Liver Enzyme Elevation Do not co-administer levonorgestrel and ethinyl estradiol tablets with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, [see Warnings (5)], and glecaprevir/pibrentasvir due to potential for ALT elevations . 4.4 Effect on Laboratory Tests The use of COCs may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. 5. Carcinogenesis See WARNINGS (11) .