INTROVALE

Warnings and Precautions, Malignant Neoplasms ( 5.11 ) 04/2022

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

2 DOSAGE AND ADMINISTRATION • Take one tablet daily by mouth at the same time every day for 91 days. ( 2.1 ) • Take tablets in the order directed on the Extended-Cycle Blister Cards. ( 2.2 ) 2.1 How to Start Introvale Introvale is dispensed in an Extended-Cycle Blister Card [see How Supplied/Storage and Handling ( 16 )] . Introvale should be started on a Sunday ( see Table 1 ). 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. Instruct patients to take Introvale once a day by mouth at the same time every day for 91 days. To achieve maximum contraceptive effectiveness, Introvale should be taken exactly as directed and at intervals not exceeding 24 hours. For patient instructions regarding missed pills, see FDA-approved patient labeling . 2.2 How to Take Introvale Table 1 Instructions for Administration of Introvale Starting COCs in women not currently using hormonal contraception (Sunday Start) Important: Consider the possibility of ovulation and conception prior to initiation of this product. Tablet Color: Introvale active tablets are peach (Day 1 to Day 84). Introvale inactive tablets are white (Day 85 to Day 91). Sunday Start: For each 91-day course, take in the following order: Take the first peach tablet (0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol) on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, take the tablet on that day. Due to the potential risk of becoming pregnant, use additional non-hormonal contraception (such as condoms or spermicide) for the first 7 days of treatment. Take subsequent peach tablets once daily at the same time each day for a total of 84 days. Take one white tablet (inert) daily for the following 7 days and at the same time of day that active tablets were taken. A scheduled period should occur during the 7 days that the white tablets are taken. Begin the next and all subsequent 91-day courses of Introvale without interruption on the same day of the week (i.e., Sunday) on which the patient began her first dose. Follow the same schedule as the initial 91-day course: a peach tablet once a day for 84 days, and a white tablet once a day for 7 days. 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 peach tablet daily for 7 consecutive days. Switching to Introvale from another oral contraceptive Start on the same day that a new pack of the previous oral contraceptive would have started. Switching from another contraceptive method to Introvale Start Introvale: Transdermal patch On the day when the next application would have been scheduled. Vaginal ring On the day when the next insertion would have been scheduled. Injection On the day when the next injection would have been scheduled. Intrauterine contraceptive (IUD) On the day of removal. If the IUD is not removed on first day of the patient’s menstrual cycle, additional non- hormonal contraception (such as condoms or spermicide) is needed for the first seven days of the first 91-day course. days of the first 91-day course. Implant On the day of removal. Complete instructions to facilitate patient counseling on proper tablet usage are located in the FDA-approved patient labeling. Starting Introvale after Abortion or Miscarriage First-trimester After a first-trimester abortion or miscarriage, Introvale may be started immediately. An additional method of contraception is not needed if Introvale is started immediately. If Introvale 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 91-day course of Introvale. Second-trimester Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased …

3 DOSAGE FORMS AND STRENGTHS Introvale is available as round, biconvex, unscored tablets, packaged in a carton of 3 pouches, each pouch contains Extended-Cycle Tablet Blister Pack of 91 tablets, each containing a 13-week supply of tablets in the following order: 84 white to off-white tablets, each containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol; debossed with 212 on the one side and plain on the other side 7 green inert tablets debossed with 279 on the one side and plain on the other side. Introvale consists of 84 round, white to off-white tablets containing 0.15 mg of levonorgestrel and 0.03 mg of ethinyl estradiol, and 7 round, green inert tablets. ( 3 )

4 CONTRAINDICATIONS Introvale 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 women who are known to: Smoke, if over age 35 [ see Boxed Warning and Warnings and Precautions ( 5.1 ) ]. Have deep vein thrombosis or pulmonary embolism, now or in the past [ see Warnings and Precautions ( 5.1 ) ]. Have inherited or acquired hypercoagulopathies [ see Warnings and Precautions ( 5.1 ) ]. Have cerebrovascular disease [ see Warnings and Precautions ( 5.1 ) ]. Have coronary artery disease [ see Warnings and Precautions ( 5.1 ) ]. 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 ) ]. Have uncontrolled hypertension [ see Warnings and Precautions ( 5.4 ) ]. Have diabetes mellitus with vascular disease [ see Warnings and Precautions ( 5.6 ) ]. Have headaches with focal neurological symptoms or migraine headaches with aura [ see Warnings and Precautions ( 5.7 ) ]. Women over age 35 with any migraine headaches [ see Warnings and Precautions ( 5.7 ) ]. Liver tumors, benign or malignant, or liver disease [ see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.6 ) ]. Undiagnosed abnormal uterine bleeding [ see Warnings and Precautions ( 5.8 ) ]. Pregnancy, because there is no reason to use COCs during pregnancy [ see Warnings and Precautions (5.9) and Use in Specific Populations ( 8.1 ) ]. Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [see Warnings and Precautions ( 5.11 )]. Use of Hepatitis C drug combination containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations [ see Warnings and Precautions ( 5.3 ) ] A high risk of arterial or venous thrombotic diseases ( 4 ) Liver tumors or liver disease ( 4 ) Undiagnosed abnormal uterine bleeding ( 4 ) Pregnancy ( 4 ) Breast cancer or other estrogen- or progestin-sensitive cancer ( 4 ) Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: • Serious cardiovascular events and stroke [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 )] Adverse reactions commonly reported by COC users are: • Irregular uterine bleeding • Nausea • Breast tenderness • Headache The most common adverse reactions (≥2%) reported during clinical trials were headache, menorrhagia, nausea, dysmenorrhea, acne, migraine, breast tenderness, weight increased, and depression. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Xiromed, LLC at 1-844-XIROMED (1-844-947-6633) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 clinical practice. The clinical trial that evaluated the safety and efficacy of levonorgestrel and ethinyl estradiol was a 12-month, randomized, multicenter, open-label study, which enrolled women aged 18 to 40, of whom 456 took at least one dose of levonorgestrel and ethinyl estradiol (345.14 woman-years of exposure) [see Clinical Studies (14)]. Adverse Reactions Leading to Study Discontinuation: 14.9% of the women discontinued from the clinical trial due to an adverse reaction; the most common adverse reactions (≥1% of women) leading to discontinuation in the levonorgestrel and ethinyl estradiol group were menorrhagia (5.7%), mood swings (1.9%), weight/appetite increase (1.5%), and acne (1.3%). Common Adverse Reactions (≥2% of women): headache (20.6%), menorrhagia (11.6%), nausea (7.5%), dysmenorrhea (5.7%), acne (4.6%), migraine (4.4%), breast tenderness (3.5%), weight increased (3.1%), and depression (2.1%). Serious Adverse Reactions: pulmonary embolus, cholecystitis. 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 A). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure A). 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 A: 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 levonorgestrel and ethinyl estradiol. Because these reactions are reported voluntarily from a population of uncertain size, it is not 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 disorder: hypersensitivity reactions, including itching, rash, and angioedema Investigations: blood pressure increased Musculoskeletal and connective tissue disorders: muscle spasms, pain in extremity Nervous system disorders: dizziness, loss of consciousness Psychiatric disorders: insomnia Reproductive and breast disorders: dysmenorrhea Skin and s …

7 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. Enzyme inducers (e.g., CYP3A4): May decrease the effectiveness of levonorgestrel and ethinyl estradiol tablets or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with levonorgestrel and ethinyl estradiol tablets. ( 7.1 ) 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 5 includes substances that demonstrated an important drug interaction with levonorgestrel and ethinyl estradiol tablets. Table 5: 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 [see Clinical Pharmacology (12.3) ] . 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 certain COCs containing ethinyl estradiol (EE) increase AUC values for EE by approximately 20-25%. Ascorbic acid and acetaminophen may increase systemic exposure of EE possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase systemic exposure of 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] or some HCV protease inhibitors (e.g., boceprevir and telaprevir) and some non-nucleosidase reverse transcriptase inhibitors (e.g., nevirapine). In contrast, significant increases in syst …

8 USE IN SPECIFIC POPULATIONS Pregnancy: Discontinue if pregnancy occurs. ( 8.1 ) Lactation: Advise use of another contraceptive method; levonorgestrel and ethinyl estradiol tablets; 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 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 any potential adverse effects on the breastfed child from levonorgestrel and ethinyl estradiol tablets or the underlying maternal condition. 8.4 Pediatric Use Safety and efficacy of levonorgestrel and ethinyl estradiol tablets have been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 as for users 18 years and older. Use of levonorgestrel and ethinyl estradiol tablets before menarche is not indicated. 8.5 Geriatric Use Levonorgestrel 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 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 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 lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation.

11 DESCRIPTION Introvale (levonorgestrel and ethinyl estradiol tablets) is an extended-cycle combination oral contraceptive consisting of 84 peach active tablets each containing 0.15 mg of levonorgestrel, a synthetic progestin and 0.03 mg of ethinyl estradiol, an estrogen, and 7 white inert tablets (without hormones). The structural formulas for the active components are: Levonorgestrel C 21 H 28 O 2 MW:312.4 Levonorgestrel is chemically 18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-, (17α)-, (-)-. Ethinyl Estradiol C 20 H 24 O 2 MW:296.4 Ethinyl Estradiol is 19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-. Each peach active tablet contains the following inactive ingredients: lactose anhydrous, magnesium stearate, povidone, polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc, iron oxide yellow, iron oxide red and iron oxide black. Each white inert tablet contains the following inactive ingredients: lactose anhydrous, magnesium stearate, povidone, polyvinyl alcohol, polyethylene glycol, talc and titanium dioxide. structure1 structure2

10 OVERDOSAGE There have been no reports of serious ill effects 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 Introvale (Levonorgestrel and Ethinyl Estradiol Tablets, USP) 0.15 mg/0.03 mg is available as round, biconvex, unscored tablets, packaged in a carton of 3 pouches (NDC 70700-208-88); each pouch (NDC 70700-208-87) contains Extended-Cycle Tablet Blister Pack of 91 tablets, each containing a 13-week supply of tablets: 84 white to off-white tablets, each containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol: debossed with 212 on the one side and plain on the other side 7 green inert tablets debossed with 279 on the one side and plain on the other side Carton of 3 pouches NDC 70700-208-88 Storage and Handling Store at 20° to 25° C (68° to 77° F). [See USP Controlled Room Temperature.] Protect from light.