BOXED WARNING SECTION.


WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs, including levonorgestrel and ethinyl estradiol tablets, are contraindicated in women who are over 35 years of age and smoke [see CONTRAINDICATIONS and WARNINGS (1)].

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

ADVERSE REACTIONS SECTION.


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)] 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.

INDICATIONS & USAGE SECTION.


INDICATIONS AND USAGE Levonorgestrel and ethinyl estradiol tablets, 0.15 mg/30 mcg are indicated for use by females of reproductive potential to prevent pregnancy.

DOSAGE & ADMINISTRATION SECTION.


DOSAGE AND ADMINISTRATION 1. How to Start and Take Levonorgestrel and Ethinyl Estradiol Tablets Levonorgestrel and ethinyl estradiol tablets, 0.15 mg/30 mcg are dispensed in a compact dispenser containing 28 tablets (see HOW SUPPLIED). Levonorgestrel and ethinyl estradiol tablets 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. Starting levonorgestrel and ethinyl estradiol tabletsin females with no current use of hormonal contraception Day 1 start Sunday start Switching from another contraceptive method A COC Transdermal patch Vaginal ring Injection Intrauterine contraceptive Implant Table 3: Instructions for Administration of Levonorgestrel and Ethinyl Estradiol Tablets 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) 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) Start levonorgestrel and ethinyl estradiol tablets: 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 Levonorgestrel and Ethinyl Estradiol Tablets after Abortion or Miscarriage First-trimester After a first-trimester abortion or miscarriage, levonorgestrel and ethinyl estradiol tablets may be started immediately. An additional method of contraception is not needed if levonorgestrel and ethinyl estradiol tablets are started immediately. If levonorgestrel and ethinyl estradiol tablets are 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 levonorgestrel and ethinyl estradiol tablets. Second-trimester Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start levonorgestrel and ethinyl estradiol tablets 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 patients first cycle of levonorgestrel and ethinyl estradiol tablets (see CONTRAINDICATIONS, WARNINGS (1), PRECAUTIONS (10) and FDA-APPROVED PATIENT LABELING). Starting Levonorgestrel and Ethinyl Estradiol Tablets after Childbirth Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with levonorgestrel and ethinyl estradiol tablets following the instructions in Table 3 for women not currently using hormonal contraception. Levonorgestrel and ethinyl estradiol tablets are 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 levonorgestrel and ethinyl estradiol tablets (see CONTRAINDICATIONS, WARNINGS (9), PRECAUTIONS (6) and FDA- APPROVED PATIENT LABELING). 2. Dosing Levonorgestrel and Ethinyl Estradiol Tablets Instruct patients to take one tablet by mouth at the same time every day. To achieve maximum contraceptive effectiveness, patients must take levonorgestrel and ethinyl estradiol tablets 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 Levonorgestrel and Ethinyl Estradiol 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 levonorgestrel and ethinyl estradiol tablets, 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.

SPL UNCLASSIFIED SECTION.


Levonorgestrel and Ethinyl Estradiol Tablets USP, 0.15 mg/30 mcg Important Information about taking levonorgestrel and ethinyl estradiol tablets Take 1 pill every day at the same time. Take the pills in the order directed on your pill pack. Do not skip your pills, even if you do not have sex often. If you miss pills (including starting the pack late) you could get pregnant. The more pills you miss, the more likely you are to get pregnant. If you have trouble remembering to take levonorgestrel and ethinyl estradiol tablets, talk to your healthcare provider. When you first start taking levonorgestrel and ethinyl estradiol tablets, spotting or light bleeding in between your periods may occur. Contact your healthcare provider if this does not go away after a few months. You may feel sick to your stomach (nauseous), especially during the first few months of taking levonorgestrel and ethinyl estradiol tablets. If you feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If your nausea does not go away, call your healthcare provider. Missing pills can also cause spotting or light bleeding, even when you take the missed pills later. On the days you take 2 pills to make up for missed pills (see What should I do if I miss any levonorgestrel and ethinyl estradiol tablets? below), you could also feel a little sick to your stomach. It is not uncommon to miss a period. However, if you miss a period and have not taken levonorgestrel and ethinyl estradiol tablets according to directions, or feel like you may be pregnant, call your healthcare provider. If you have a positive pregnancy test, you should stop taking levonorgestrel and ethinyl estradiol tablets. If you have vomiting or diarrhea within 3-4 hours of taking a white to off-white pill, take another white to off-white pill as soon as possible. Continue taking all your remaining pills in order. Start the first pill of your next pill pack the day after finishing your current pill pack. This will be 1 day earlier than originally scheduled. Continue on your new schedule. If you have vomiting or diarrhea for more than 1 day, your birth control pills may not work as well. Use an additional birth control method, like condoms or spermicide, until you check with your healthcare provider. Stop taking levonorgestrel and ethinyl estradiol tablets at least 4 weeks before you have major surgery and do not restart after the surgery without asking your healthcare provider. Be sure to use other forms of contraception (like condoms or spermicide) during this time period. Before you start taking levonorgestrel and ethinyl estradiol tablets: Decide what time of day you want to take your pill. It is important to take it at the same time every day and in the order as directed on your pill pack. Look at your pill pack. Your pill pack consists of 1 card that holds 28 individually sealed pills. The 28 pills consist of 21 white to off-white pills (3 rows of 7 pills) and 7 green pills (1 row of 7 pills). See Figure A. Also find: oWhere on the card to start taking pills (upper left corner) and oIn what order to take the pills (follow the weeks) Be sure you have ready at all times another kind of birth control (such as condoms or spermicide), to use as a back-up in case you miss pills. When should I start taking levonorgestrel and ethinyl estradiol tablets? If you start taking levonorgestrel and ethinyl estradiol tablets and you have not used a hormonal birth control method before: There are 2 ways to start taking your birth control pills. You can either start on a Sunday (Sunday Start) or on the first day (Day 1) of your natural menstrual period (Day 1 Start). Your healthcare provider should tell you when to start taking your birth control pill. If you use the Sunday Start, use non-hormonal back-up contraception such as condoms or spermicide for the first 7 days that you take levonorgestrel and ethinyl estradiol tablets. You do not need back-up contraception if you use the Day 1 Start. If you start taking levonorgestrel and ethinyl estradiol tablets and you are switching from another birth control pill: Start your new levonorgestrel and ethinyl estradiol tablets pack on the same day that you would start the next pack of your previous birth control method. Do not continue taking the pills from your previous birth control pill pack. If you start taking levonorgestrel and ethinyl estradiol tablets and previously used a vaginal ring: Start using levonorgestrel and ethinyl estradiol tablets on the day you would have started the next ring. If you start taking levonorgestrel and ethinyl estradiol tablets and previously used a transdermal patch: Start using levonorgestrel and ethinyl estradiol tablets on the day you would have started a new cycle (first patch application). If you start taking levonorgestrel and ethinyl estradiol tablets and you are switching from a progestin-only method such as an implant or injection: Start taking levonorgestrel and ethinyl estradiol tablets on the day of removal of your implant, or on the day when you would have had your next injection. If you start taking levonorgestrel and ethinyl estradiol tablets and you are switching from an intrauterine device or system (IUD or IUS): Start taking levonorgestrel and ethinyl estradiol tablets on the day of removal of your IUD or IUS. You do not need back-up contraception if your IUD or IUS is removed on the first day (Day 1) of your period. If your IUD or IUS is removed on any other day, use non-hormonal back-up contraception such as condoms or spermicide for the first 7 days that you take levonorgestrel and ethinyl estradiol tablets. Keep a calendar to track your period: If this is the first time you are taking birth control pills, read, When should I start taking levonorgestrel and ethinyl estradiol tablets? above. Follow these instructions for either a Sunday Start or a Day 1 Start. Instructions for using your levonorgestrel and ethinyl estradiol tablet dispenser: Sunday Start: You will use a Sunday Start if your healthcare provider told you to take your first pill on a Sunday. Take pill 1 on the Sunday after your period starts. To remove your pill from the dispenser, press the pill through the hole in the bottom of the dispenser. If your period starts on a Sunday, take pill "1" that day and refer to Day 1 Start instructions below. Take 1 pill every day in the order on the pill dispenser at the same time each day for 28 days. After taking the last pill on Day 28 from the pill dispenser, start taking the first pill from a new pack, on the same day of the week as the first pack (Sunday). Take the first pill in the new pack whether or not you are having your period. Use non-hormonal back-up contraception such as condoms or spermicide for the first 7 days of the first cycle that you take levonorgestrel and ethinyl estradiol tablets. Day 1 Start: You will use a Day 1 Start if your doctor told you to take your first pill (Day 1) on the first day of your period. Take 1 pill every day in the order of the pill dispenser, at the same time each day, for 28 days. To remove your pill from the dispenser, press the pill through the hole in the bottom of the dispenser. After taking the last pill on Day 28 from the pill dispenser, start taking the first pill from a new pack, on the same day of the week as the first pack. Take the first pill in the new pack whether or not you are having your period. What should I do if I miss any levonorgestrel and ethinyl estradiol tablets? If you miss 1 pill in Weeks 1, 2, or 3, follow these steps: Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. Then continue taking 1 pill every day until you finish the pack. You do not need to use a back-up birth control method if you have sex. If you miss 2 pills in Week 1 or Week 2 of your pack, follow these steps: Take the 2 missed pills as soon as possible and the next 2 pills the next day. Then continue to take 1 pill every day until you finish the pack. Use a non-hormonal birth control method (such as a condom or spermicide) as a back-up if you have sex during the first 7 days after missing your pills. If you miss 2 pills in a row in Week 3, or you miss 3 or more pills in a row during Weeks 1, 2, or 3 of the pack, follow these steps: If you are a Day 1 Starter: oThrow out the rest of the pill pack and start a new pack that same day. oYou may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your healthcare provider because you might be pregnant. oYou could become pregnant if you have sex during the first 7 days after you restart your pills. You MUST use a non-hormonal birth control method (such as a condom or spermicide) as a back-up if you have sex during the first 7 days after you restart your pills. If you are a Sunday Starter: oKeep taking 1 pill every day until Sunday. On Sunday, throw out the rest of the pack and start a new pack of pills that same day. oUse a non-hormonal birth control method (such as a condom or spermicide) as a back-up if you have sex during the first 7 days after you restart your pills. If you have any questions or are unsure about the information in this leaflet, call your healthcare provider. This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Manufactured by: Mylan Laboratories Limited Ahmedabad - 382 213, India Code No.: GUJ-DRUGS/G/28/1297 200014757-003 Revised: 4/2019 FC:A:OT:6550:R6

DESCRIPTION SECTION.


DESCRIPTION Levonorgestrel and ethinyl estradiol tablets USP, 0.15 mg/30 mcg are combination oral contraceptives (COC) consisting of 21 white to off-white active tablets, each containing 0.15 mg of levonorgestrel, a synthetic progestin and 30 mcg of ethinyl estradiol, an estrogen, and 7 green inert tablets (without hormones). The structural formulas for the active components are: Levonorgestrel C21H28O2 MW: 312.45 Levonorgestrel is chemically 18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-,(17)-(-)-. Ethinyl Estradiol C20H24O2 MW: 296.40 Ethinyl Estradiol is 19-Nor-17-pregna-1,3,5(10)-trien-20-yne-3, 17-diol. Each white to off-white active tablet contains the following inactive ingredients: lactose monohydrate, magnesium stearate, and polacrilin potassium. Each green inert tablet contains the following inactive ingredients: FD&C Blue No. 1 aluminum lake, lactose monohydrate, magnesium stearate, polacrilin potassium, and yellow oxide of iron.

OVERDOSAGE SECTION.


OVERDOSAGE There have been no reports of serious adverse outcomes from overdose of COCs, including ingestion by children. Overdose may cause uterine bleeding in females and nausea.

PRECAUTIONS SECTION.


PRECAUTIONS 1. Lipid Disorders Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult [see WARNINGS (7)]. In patients with familial defects of lipoprotein metabolism receiving estrogen-containing preparations, there have been case reports of significant elevations of plasma triglycerides leading to pancreatitis. 2. Fluid Retention Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. 3. Gastrointestinal Motility Diarrhea and/or vomiting may reduce hormone absorption (see DOSAGE AND ADMINISTRATION). 4. 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. Johns wortInduction potency of St. Johns wort may vary widely based on preparation, 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. 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, 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. 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). 6. Pregnancy Risk Summary Levonorgestrel and ethinyl estradiol tablets are contraindicated in pregnancy because there is no reason to use COCs in pregnancy. Discontinue levonorgestrel and ethinyl estradiol tablets 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 COCs before conception or during early pregnancy. Animal studies to evaluate embryo/fetal toxicity were not conducted. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 percent and 15 to 20 percent, respectively. 7. Lactation Risk Summary Contraceptive hormones and/or metabolites are present in human milk. COCs can reduce milk production in breast-feeding females. This reduction can occur at any time but is less likely to occur once breast-feeding is well-established. When possible, advise the nursing female to use other methods of contraception until she discontinues breast-feeding. (see DOSAGE AND ADMINISTRATION). The developmental and health benefits of breast-feeding should be considered along with the mothers clinical need for levonorgestrel and ethinyl estradiol tablets and any potential adverse effects on the breast-fed child from levonorgestrel and ethinyl estradiol tablets or from the underlying maternal condition. 8. Pediatric Use Safety and efficacy of levonorgestrel and ethinyl estradiol tablets have been established in females of reproductive potential. Use of levonorgestrel and ethinyl estradiol tablets before menarche is not indicated. 9. Geriatric Use Levonorgestrel and ethinyl estradiol tablets have not been studied in postmenopausal women and is not indicated in this population. 10. PATIENT COUNSELING INFORMATION Counsel patients that cigarette smoking increases the risk of serious cardiovascular events from COC use, and that women who are over 35 years old and smoke should not use COCs. Counsel patients that this product does not protect against HIV-infection (AIDS) and other sexually transmitted infections. Counsel patients to take one tablet daily by mouth at the same time every day. Instruct patients what to do in the event pills are missed. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs. Counsel patients who are breastfeeding or who desire to breastfeed that COCs may reduce breast milk production. This is less likely to occur if breastfeeding is well established. Counsel any patient who starts levonorgestrel and ethinyl estradiol tablets postpartum, and who has not yet had a period, to use an additional method of contraception until she has taken a white to off-white tablet for 7 consecutive days. Counsel patients that amenorrhea may occur. Pregnancy should be considered in the event of amenorrhea, and should be ruled out if amenorrhea is associated with symptoms of pregnancy, such as morning sickness or unusual breast tenderness.

INSTRUCTIONS FOR USE SECTION.


Instructions For Use

INFORMATION FOR PATIENTS SECTION.


Patient Information

CLINICAL PHARMACOLOGY SECTION.


CLINICAL PHARMACOLOGY Combination oral contraceptives prevent pregnancy primarily by suppressing ovulation.

CONTRAINDICATIONS SECTION.


CONTRAINDICATIONS Levonorgestrel and ethinyl estradiol tablets are contraindicated in females who are known to have the following conditions: A high risk of arterial or venous thrombotic diseases. Examples include women who are known to: -Smoke, if over age 35 [see BOXED WARNING and WARNINGS (1)]. -Have current or history of deep vein thrombosis or pulmonary embolism [see WARNINGS (1)]. -Have cerebrovascular disease [see WARNINGS (1)]. -Have coronary artery disease [see WARNINGS (1)]. -Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see WARNINGS (1)]. -Have inherited or acquired hypercoagulopathies [see (1)]. -Have uncontrolled hypertension or hypertension with vascular disease [see WARNINGS (3)]. -Have diabetes mellitus and are over age 35, diabetes mellitus with hypertension or vascular disease or other end-organ damage, or diabetes mellitus of >20 years duration [see WARNINGS (7)]. -Have headaches with focal neurological symptoms, migraine headaches with aura, or over age 35 with any migraine headaches [see WARNINGS (8)]. Current or history of breast cancer or other estrogen-or progestin-sensitive cancer. Liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis [see WARNINGS (2)]. Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations [see WARNINGS (5)]. Undiagnosed abnormal uterine bleeding [see WARNINGS (9)]. Pregnancy, because there is no reason to use COCs during pregnancy [see PRECAUTIONS (6)].

WARNINGS SECTION.


WARNINGS 1. Thromboe mbolic Disorders and Other Vascular Conditions Stop levonorgestrel and ethinyl estradiol tablets if an arterial or venous thrombotic/thromboembolic event occurs. Stop levonorgestrel and ethinyl estradiol tablets if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately. Discontinue levonorgestrel and ethinyl estradiol tablets during prolonged immobilization. If feasible, stop levonorgestrel and ethinyl estradiol tablets at least four weeks before and through two weeks after major surgery, or other surgeries known to have an elevated risk of thromboembolism. Start levonorgestrel and ethinyl estradiol tablets no earlier than four weeks after delivery in females who are not breast-feeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week. Before starting levonorgestrel and ethinyl estradiol tablets evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. Levonorgestrel and ethinyl estradiol tablets are contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases (see CONTRAINDICATIONS). Arterial Events COCs increase the risk of cardiovascular events and cerebrovascular events, such as myocardial infarction and stroke. The risk is greater among older women (> 35 years of age), smokers, and females with hypertension, dyslipidemia, diabetes, or obesity. Levonorgestrel and ethinyl estradiol tablets are contraindicated in women over 35 years of age who smoke (see CONTRAINDICATIONS). Cigarette smoking increases the risk of serious cardiovascular events from COC use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. Venous Events Use of COCs increases the risk of venous thromboembolic events (VTEs), such as deep vein thrombosis and pulmonary embolism. Risk factors for VTEs include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of COCs (see CONTRAINDICATIONS). While the increased risk of VTE associated with use of COCs is well-established, the rates of VTE are even greater during pregnancy, and especially during the postpartum period (see Figure 1). The rate of VTE in females using COCs has been estimated to be 3 to 9 cases per 10,000 woman-years. The risk of VTE is highest during the first year of use of a COC and when restarting hormonal contraception after a break of four weeks or longer. Based on results from a few studies, there is some evidence that this is true for non-oral products as well. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued. Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use oral contraceptives, for females who use oral contraceptives, for pregnant females, and for females in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 females who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these females will develop a VTE. Figure 1 Likelihood of Developing a VTE 2. Liver Disease Elevated Liver Enzymes Levonorgestrel and ethinyl estradiol tablets are contraindicated in females with acute viral hepatitis or severe (decompensated) cirrhosis of liver (see CONTRAINDICATIONS). Discontinue levonorgestrel and ethinyl estradiol tablets if jaundice develops. Acute liver test abnormalities may necessitate the discontinuation of COC use until the liver tests return to normal and COC causation has been excluded. Liver Tumors Levonorgestrel and ethinyl estradiol tablets are contraindicated in females with benign or malignant liver tumors (see CONTRAINDICATIONS). COCs increase the risk of hepatic adenomas. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death from abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) COC users. The attributable risk of liver cancers in COC users is less than one case per million users. 3. Hypertension Levonorgestrel and ethinyl estradiol tablets are contraindicated in females with uncontrolled hypertension or hypertension with vascular disease (see CONTRAINDICATIONS). For all females, including those with well-controlled hypertension, monitor blood pressure at routine visits and stop levonorgestrel and ethinyl estradiol tablets if blood pressure rises significantly. An increase in blood pressure has been reported in females using COCs, and this increase is more likely in older women with extended duration of use. The effect of COCs on blood pressure may vary according to the progestin in the COC. 4. Age-related Considerations The risk for cardiovascular disease and prevalence of risk factors for cardiovascular disease increase with age. Certain conditions, such as smoking and migraine headache without aura, that do not contraindicate COC use in younger females, are contraindications to use in women over 35 years of age [see CONTRAINDICATIONS and WARNINGS (1)]. Consider the presence of underlying risk factors that may increase the risk of cardiovascular disease or VTE, particularly before initiating a COC for women over 35 years, such as: Hypertension Diabetes Dyslipidemia Obesity 5. Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications such as COCs. Discontinue levonorgestrel and ethinyl estradiol tablets prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (see CONTRAINDICATIONS). Levonorgestrel and ethinyl estradiol tablets can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen. 6. Gallbladder Disease Studies suggest an increased risk of developing gallbladder disease among COC users. Use of COCs may also worsen existing gallbladder disease. A past history of COC-related cholestasis predicts an increased risk with subsequent COC use. Females with a history of pregnancy-related cholestasis may be at an increased risk for COC-related cholestasis. 7. Adverse Carbohydrate and Lipid Metabolic Effects Hyperglycemia Levonorgestrel and ethinyl estradiol tablets are contraindicated in diabetic women over age 35, or females who have diabetes with hypertension, nephropathy, retinopathy, neuropathy, other vascular disease, or females with diabetes of > 20 years duration (see CONTRAINDICATIONS). Levonorgestrel and ethinyl estradiol tablets may decrease glucose tolerance. Carefully monitor prediabetic and diabetic females who are using levonorgestrel and ethinyl estradiol tablets. Dyslipidemia Consider alternative contraception for females with uncontrolled dyslipidemia. Levonorgestrel and ethinyl estradiol tablets may cause adverse lipid changes. Females with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using levonorgestrel and ethinyl estradiol tablets which may increase the risk of pancreatitis. 8. Headache Levonorgestrel and ethinyl estradiol tablets are contraindicated in females who have headaches with focal neurological symptoms or have migraine headaches with aura, and in women over age 35 years who have migraine headaches with or without aura (see CONTRAINDICATIONS). If a woman using levonorgestrel and ethinyl estradiol tablets develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue levonorgestrel and ethinyl estradiol tablets if indicated. Consider discontinuation of levonorgestrel and ethinyl estradiol tablets if there is an increased frequency or severity of migraines during COC use (which may be prodromal of a cerebrovascular event). 9. Bleeding Irregularities and Amenorrhea Unscheduled Bleeding and Spotting Females using levonorgestrel and ethinyl estradiol tablets may experience unscheduled (breakthrough or intracyclic) bleeding and spotting, especially during the first three 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 such as pregnancy or malignancy. In two clinical trials of levonorgestrel and ethinyl estradiol tablets (1084 subjects reporting for a total of 8186 treatment cycles and 238 subjects reporting for a total of 1102 treatment cycles), breakthrough bleeding occurred in 6.9% and 8.1% of reported cycles, and spotting occurred in 8.6% and 7.9% of reported cycles over the total study duration, respectively. In the two trials, intermenstrual bleeding (i.e., breakthrough bleeding and/or spotting) occurred in 13.1% and 12.9% of reported cycles over the total study duration, respectively. In one trial, 33 subjects out of 1084 (3.0%) discontinued due to bleeding irregularities (i.e., breakthrough bleeding and spotting); in the other trial, 6 subjects out of 238 (2.5%) discontinued due to bleeding irregularities. Amenorrhea and Oligomenorrhea Females who use levonorgestrel and ethinyl estradiol tablets may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant. In two clinical trials of levonorgestrel and ethinyl estradiol tablets, one including 8186 reported treatment cycles, and the other including 1102 reported treatment cycles, amenorrhea occurred in 1.5% of treatment cycles in each trial. If scheduled bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or two active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and perform appropriate diagnostic measures. If the patient has adhered to the prescribed dosing schedule and misses two consecutive periods, rule out pregnancy. After discontinuation of a COC, amenorrhea or oligomenorrhea may occur, especially if these conditions were pre-existent. 10. Depression Carefully observe females with a history of depression and discontinue levonorgestrel and ethinyl estradiol tablets if depression recurs to a serious degree. Data on the association of COCs with onset of depression or exacerbation of existing depression are limited. 11. Cervical Cancer Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. There is controversy about the extent to which these findings are due to differences in sexual behavior and other factors. 12. Effect on Binding Globulins The estrogen component of levonorgestrel and ethinyl estradiol tablets may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased. 13. Hereditary Angioedema In females with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. 14. Chloasma Chloasma may occur with levonorgestrel and ethinyl estradiol tablets use, especially in females with a history of chloasma gravidarum. Advise females with a history of chloasma to avoid exposure to the sun or ultraviolet radiation while using levonorgestrel and ethinyl estradiol tablets.