Introvale

Product Type: HUMAN PRESCRIPTION DRUG

Route:

Dosage Form:

NDC: 70700-117

Application: ANDA079064

Effective: 20220609

1 INDICATIONS AND USAGE Introvale ® (levonorgestrel and ethinyl estradiol tablets) is indicated for use by females of reproductive potential to prevent pregnancy. Introvale is an estrogen/progestin COC indicated for use by women 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 risk of thromboembolic disease. Start Introvale following the instructions in Table 1 for Sunday start. Use additional non-hormonal contraception (such as condoms or spermicide) for the first seven days of the patient’s first 91-day course of Introvale [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), and FDA-approved Patient Labeling]. Starting Introvale after Childbirth Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with Introvale following the instructions in Table 1 for women not currently using hormonal contraception. Introvale is not recommended for use in lactating women [see Use in Specific Populations ( 8.3 ) 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 Introvale [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.1 and 8.3 ), and FDA-approved Patient Labeling]. Tablet Dispenser Instructions: The Tablet Dispenser consists of a Tri-Fold Blister Card that holds 91 individually sealed pills (a 13-week, or 91-day, cycle). The 91 pills consist of 84 peach pills (active pills with hormones) and 7 white pills (inactive pills without hormone) arranged in 12 rows of 7 tablets each, labeled weeks “START” through “Week 12” (active pills with hormones) followed by 1 row of 7 white pills, labeled “Week 13” (inactive pills without hormone). Advise the patient to remove the first pill in the upper left corner by pushing down on the pill. The pill will come out through a hole in the back of the Tablet Dispenser. Advise the patient to wait 24 hours to take the next pill, and continue to take one pill each day until all the pills have been taken. Advise the patient, after taking the last white pill, to start taking the first peach pill from a new Tablet Dispenser the very next day, regardless of when their period started. image description 2.3 Missed Tablets Table 2 Instructions for Missed Introvale Tablets If one active tablet (peach) is missed in Days1 through 84 Take the tablet as soon as possible. Take the next tablet at the regular time and continue taking one tablet a day until the 91-day course is finished. If two consecutive active tablets (peach) are missed in Days 1 through 84 Take 2 tablets on the day remembered and 2 tablets the next day. Then continue taking one tablet a day until the 91-day course is finished. Additional non-hormonal contraception (such as condoms or spermicide) should be used as back-up if the patient has sex within 7 days after missing 2 tablets. If three or more consecutive active tablets (peach) are missed in Days 1 through 84 Do not take the missed tablets. Continue taking one tablet a day until the 91-day course is finished. Additional non-hormonal contraception (such as condoms or spermicide) must be used as back-up if the patient has sex within 7 days after missing 3 tablets. 2.4 Advice in Case of Gastrointestinal Disturbances In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. If vomiting or diarrhea occurs within 3 to 4 hours after taking a peach tablet, handle this as a missed tablet [see FDA-approved patient labeling].

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 )

Not available.

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 subcutaneous tissue disorders: alopecia Vascular disorders: thrombosis, pulmonary embolism, pulmonary thrombosis image description