levonorgestrel and ethinyl estradiol and ethinyl estradiol

Contraindications, Pregnancy ( 4 ) Removed 01/2023 Warnings and Precautions, Malignant Neoplasms ( 5.11 ) 04/2022

1 INDICATIONS AND USAGE Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are a combination of levonorgestrel, a progestin, and ethinyl estradiol, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy. ( 1 ) Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are indicated for use by females of reproductive potential to prevent pregnancy.

2 DOSAGE AND ADMINISTRATION Take one tablet daily by mouth at the same time every day for 91 days in the order directed on the blister pack. ( 2 ) 2.1 How to Start and Take Levonorgestrel and Ethinyl Estradiol Tablets and Ethinyl Estradiol Tablets Begin levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, take the first white to off-white tablet that day. For each 91-day course, take in the following order: 1. Take one white to off-white tablet daily for 84 consecutive days. Use a non-hormonal back-up method of contraception (such as condoms or spermicide) until a white to off-white has been taken daily for 7 consecutive days. 2. Then take one light peach tablet for 7 consecutive days. A scheduled period should occur during the 7 days that the light peach tablets are taken. Begin the next and all subsequent 91-day cycles without interruption on the same day of the week (Sunday) on which the patient began her first dose of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets, following the same schedule: 84 days taking a white to off-white tablet followed by 7 days taking a light peach tablet. If the patient does not immediately start her next pill pack, instruct her to protect herself from pregnancy by using a non-hormonal back-up method of contraception until she has taken a white to off-white tablet daily for 7 consecutive days. Switching to levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets from another oral hormonal contraceptive or from another contraceptive method (transdermal patch, vaginal ring, injection, intrauterine contraceptive, implant) Start on the Sunday after the patient’s next period starts. Use additional non-hormonal contraceptive (such as condoms and spermicide) until the patient has taken a white to off-white tablet for 7 consecutive days. Starting Levonorgestrel and Ethinyl Estradiol Tablets and Ethinyl Estradiol Tablets after Abortion or Miscarriage First-trimester Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets may be started on the Sunday after an abortion or miscarriage. The patient must use additional non-hormonal contraception (such as condoms and spermicide) until the patient has taken a white to off-white tablet for 7 consecutive days. Second-trimester Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start contraceptive therapy with levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets following the instructions for women not currently using hormonal contraception. Use additional non-hormonal contraception (such as condoms and spermicide) until the patient has taken a white to off-white tablet for 7 consecutive days [see Contraindications (4) and Warnings and Precautions (5.1 )]. Starting Levonorgestrel and Ethinyl Estradiol Tablets 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 and ethinyl estradiol tablets following the instructions for women not currently using hormonal contraception. Use additional non-hormonal contraception (such as condoms and spermicide) until the patient has taken a white to off-white tablet for 7 consecutive days [see Contraindications (4) and Warnings and Precautions (5.1) ]. 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 and ethinyl estradiol tablets [see Warnings and Precautions (5.1), Use in Specific Populations (8.1) ]. 2.2 Dosing Levonorgestrel and Ethinyl Estradiol Tablets and Ethinyl Estradiol Tablets Take one tablet by mouth at the same time every day. The dosage of levonorgestrel and e …

3 DOSAGE FORMS AND STRENGTHS Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets consist of 91 tablets in the following order ( 3 ): • 42 white to off-white tablets containing 0.15 mg levonorgestrel and 0.02 mg ethinyl estradiol, • 21 light peach tablets containing 0.15 mg of levonorgestrel and 0.025 mg ethinyl estradiol, and • 21 bluish green tablets containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol, and • 7 yellow tablets containing 0.01 mg of ethinyl estradiol. ( 3 ) Levonorgestrel and ethinyl estradiol tablets, USP and ethinyl estradiol tablets, USP are available as round, biconvex tablets, packaged in Extended-Cycle Tablet Blister Pack, each containing a 13-week supply of tablets in the following order: • 42 white to off-white tablets, each containing 0.15 mg of levonorgestrel and 0.02 mg ethinyl estradiol: debossed with 72 on one side of the tablet and plain on the other side • 21 light peach tablets containing 0.15 mg of levonorgestrel and 0.025 mg ethinyl estradiol: debossed with 73 on one side of the tablet and plain on the other side • 21 bluish green tablets containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol: debossed with 74 on one side of the tablet and plain on the other side and • 7 yellow tablets containing 0.01 mg of ethinyl estradiol: debossed with 65 on one side of the tablet and plain on the other side

4 CONTRAINDICATIONS A high risk of arterial or venous thrombotic diseases ( 4 ) Undiagnosed abnormal uterine bleeding ( 4 ) Breast cancer ( 4 ) Liver tumors or liver disease, acute viral hepatitis or decompensated cirrhosis ( 4 ) Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir ( 4 ) Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets is contraindicated in females who are known to have or develop the following conditions: A high risk of arterial or venous thrombotic diseases. Examples include females who are known to: ο Smoke, if over age 35 [ see Boxed Warning and Warnings and Precautions ( 5.1 ) ] ο Have current or history of deep vein thrombosis or pulmonary embolism. [ see Warnings and Precautions ( 5.1 ) ] ο Have cerebrovascular disease [ see Warnings and Precautions ( 5.1 ) ] ο Have coronary artery disease [ see Warnings and Precautions ( 5.1 ) ] ο Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [ see Warnings and Precautions ( 5.1 ) ] ο Have inherited or acquired hypercoagulopathies [ see Warnings and Precautions ( 5.1 ) ] ο Have uncontrolled hypertension or hypertension with vascular disease [ see Warnings and Precautions ( 5.5 ) ] ο Have diabetes mellitus and are over age 35, diabetes mellitus with hypertension or with vascular disease or other end-organ damage, or diabetes mellitus of > 20 years duration [ see Warnings and Precautions ( 5.7 ) ] ο Have headaches with focal neurological symptoms, migraine headaches with aura, or over age 35 with any migraine headaches [ see Warnings and Precautions ( 5.8 ) ] Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [ see Warnings and Precautions ( 5.11 ) ] Liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis [ see Warnings and Precautions ( 5.2 ) ]. Undiagnosed abnormal uterine bleeding [ see Warnings and Precautions ( 5.8 ) ] Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations [ see Warnings and Precautions ( 5.4 ) ].

6 ADVERSE REACTIONS The most common adverse reactions (≥2%) in clinical trials for levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets were headaches, heavy/irregular vaginal bleeding, nausea/vomiting, acne, dysmenorrhea, weight increased, mood changes, anxiety/panic attack, breast pain and migraines. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: • Serious cardiovascular events [see Boxed Warning and Warnings and Precautions ( 5.1 )] • Vascular events [see Warnings and Precautions ( 5.1 )] • Liver disease [see Warnings and Precautions ( 5.2 )] 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described below are from a 12-month, US, open-label study, which enrolled women aged 18-40, of whom 3,597 took at least one dose of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets (2,661 woman-years of exposure) [see Clinical Studies ( 14 )] . Adverse Reactions Leading to Study Discontinuation : 13.3% of the women discontinued from the clinical trial due to an adverse reaction; the most common adverse reactions (≥1% of women) leading to discontinuation were heavy/irregular bleeding (5.0%), mood swings/alteration/affect lability (1.4%), headaches/migraines (1.3%), weight increased (1.3%) and acne (1.0%). Common Adverse Reactions (≥2% of women) : headaches (12.2%), heavy/irregular vaginal bleeding (9.7%), nausea/vomiting (8.8%), acne (5.4%), dysmenorrhea (5.4%), weight increased (4.6%), mood changes (depression, depressed mood, crying, major depression, affective disorder, depression suicidal, dysthymic disorder) (2.9%), anxiety/panic attack (2.4%), breast tenderness/pain/discomfort (2.2%), migraine (2.0%). Serious Adverse Reactions (≥2 women): Abortion Spontaneous, Suicide Attempt, Cholecystitis/ Cholelithiasis, Deep Vein Thrombosis, Ectopic Pregnancy. 6.2 Postmarketing 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 - 1.12 (Figure 3). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 3). 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 - 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 8-10 years of COC use. Figure 3: 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 identified during post-approval use of extended-cycle COCs containing levonorgestrel and ethinyl estradiol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal disorders: abdominal distension, vomiting General disorders and administration site conditions: chest pain, fatigue, malaise, edema peripheral, pain Immune system disorders: hypersensitivity reaction Investigations: blood pressure increased Mus …

7 DRUG INTERACTIONS Enzyme inducers (e.g., CYP3A4): May decrease the effectiveness of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablet or increase breakthrough bleeding. Counsel patients to use a back-up method or alternative method of contraception when enzyme inducers are used with levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets. ( 7.1 ) 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 formal drug-drug interaction studies were conducted with levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets. 7.1 Effects of Other Drugs on Combined Oral Contraceptives. Substances Decreasing the Plasma Concentrations of COCs and Potentially Diminishing the Efficacy of COCs: Table 4 includes substances that demonstrated an important drug interaction with levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets. Table 4: Significant Drug Interactions Involving Substances That Affect COCs a Induction potency of St. John's wort may vary widely based on preparation. 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. 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., bocep …

8 USE IN SPECIFIC POPULATIONS • Pregnancy: Discontinue use if pregnancy occurs. ( 8.1 ) • Lactation: Advise use of another method. Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are not recommended for nursing mothers; may decrease milk production. ( 8.2 ) 8.1 Pregnancy Risk Summary There is no use for contraception in pregnancy; therefore, levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets should be discontinued during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb reduction defects) following exposure to COCs before conception or during early pregnancy. 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. 8.2 Lactation Risk Summary Contraceptive hormones and/or metabolites are present in human milk. COCs can reduce milk production in breastfeeding females. This reduction can occur at any time but is less likely to occur once breastfeeding is well-established. When possible, advise the nursing female to use other methods of contraception until she discontinues breastfeeding [See Dosage and Administration (2.1 )] . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets and any potential adverse effects on the breastfed child from levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets or the underlying maternal condition. 8.4 Pediatric Use Safety and efficacy of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 18 as for users 18 years and older. Use of this product before menarche is not indicated. 8.5 Geriatric Use Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets have not been studied in postmenopausal women and is not indicated in this population. 8.6 Hepatic Impairment The pharmacokinetics of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets have not been studied in subjects with hepatic impairment. However, COCs may be poorly metabolized in patients with hepatic impairment. Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are contraindicated in females with acute hepatitis or severe decompensated cirrhosis [see Contraindications (4) and Warnings and Precautions (5.2 )].

8.6 Hepatic Impairment The pharmacokinetics of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets have not been studied in subjects with hepatic impairment. However, COCs may be poorly metabolized in patients with hepatic impairment. Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are contraindicated in females with acute hepatitis or severe decompensated cirrhosis [see Contraindications (4) and Warnings and Precautions (5.2 )].

12.1 Mechanism of Action COCs prevent pregnancy primarily by suppressing ovulation.

11 DESCRIPTION Levonorgestrel and ethinyl estradiol tablets, USP and ethinyl estradiol tablets, USP are an extended-cycle oral contraceptive. Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets consist of 42 white to off-white tablets containing 0.15 mg levonorgestrel and 0.02 mg ethinyl estradiol, 21 light peach tablets containing 0.15 mg levonorgestrel and 0.025 mg ethinyl estradiol, and 21 bluish green tablets containing 0.15 mg levonorgestrel and 0.03 mg ethinyl estradiol, and 7 yellow tablets containing 0.01 mg ethinyl estradiol. Levonorgestrel is a progestin and ethinyl estradiol is an estrogen. The structural formulas, molecular formulas, molecular weights, and chemical names for the active components are shown below: Levonorgestrel is chemically 18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-(17α)-(-)-. Ethinyl Estradiol is 19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-. Each white to off-white tablet contains the following inactive ingredients: lactose monohydrate, polacrilin potassium and magnesium stearate. Each light peach tablet contains the following inactive ingredients: lactose monohydrate, polacrilin potassium, FD&C Yellow No. 6 Aluminum Lake and magnesium stearate. Each bluish green tablet contains the following inactive ingredients: lactose monohydrate, polacrilin potassium, D&C Yellow No.10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake and magnesium stearate. Each yellow tablet contains the following inactive ingredients: anhydrous lactose, microcrystalline cellulose, polacrilin potassium, D&C Yellow No.10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, magnesium stearate, lactose monohydrate, povidone K-25 and dl -α-tocopherol. Meets USP Dissolution Test 2 for Ethinyl Estradiol 0.01 mg Structural Formula Structural Formula

10 OVERDOSAGE There have been no reports of serious ill effects from overdose, from overdose of oral contraceptives including ingestion by children. Overdosage may cause withdrawal bleeding in females and nausea.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Levonorgestrel and Ethinyl Estradiol Tablets, USP (0.1 mg/0.02 mg) and Ethinyl Estradiol Tablets, USP (0.01 mg) are available in Extended-Cycle Wallets, that contains 84 orange tablets each containing 0.1 mg levonorgestrel and 0.02 mg ethinyl estradiol and 7 mustard tablets each containing 0.01 mg of ethinyl estradiol. Orange tablets are round biconvex, film-coated tablets, debossed with "LU" on one side and "T41" on the other side. Mustard tablets are round biconvex, film-coated tablets debossed with "LU" on one side and "V22" on the other side. They are supplied as follows: Levonorgestrel and Ethinyl Estradiol Tablets, USP (0.1 mg/0.02 mg) and Ethinyl Estradiol Tablets, USP (0.01 mg) are available in an extended cycle wallet of 91 tablets which is packed in a pouch (NDC 68180-848-11). Such two pouches are packed in a carton (NDC 68180-848-13). Storage and Handling Store at 25° C (77° F); excursions permitted to 15°to 30° C (59°to 86° F) [see USP Controlled Room Temperature] The tablets should not be removed from the protective blister packaging to avoid damage to the product. The wallet card should be kept in the pouch until dispensed to the patient.