Estarylla

Recent Major Changes Warnings and Precautions (5.11 ) 11/2021

1 INDICATIONS AND USAGE Estarylla (norgestimate and ethinyl estradiol tablets, USP),are an estrogen/progestin COCs, indicated for use by women to prevent pregnancy. ( Error! Hyperlink reference not valid. ) 1.1 Oral Contraceptive Estarylla (norgestimate and ethinyl estradiol tablets) are indicated for use by females of reproductive potential to prevent pregnancy [see CLINICAL STUDIES (14) ] .

2 DOSAGE AND ADMINISTRATION • Take one tablet daily by mouth at the same time every day. ( 2.2 ) • Take tablets in the order directed on the blister pack. ( 2.2 ) • Do not skip or delay tablet intake. ( 2.2 ) 2.1 How to Start Estarylla? EstaryllaTM (norgestimate and ethinyl estradiol tablets), dispensed in a blister pack [see HOW SUPPLIED/STORAGE AND HANDLING ( 16 )]. EstaryllaTM may be started using either a Day 1 start or a Sunday start (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. 2.2 How to Take Estarylla? Table 1: Instructions for Administration of EstaryllaTM Complete instructions to facilitate patient counseling on proper tablet usage are located in the FDA-Approved Patient Labeling. Starting COCs in women not currently using hormonal contraception (Day 1 Start or Sunday Start) Important : Consider the possibility of ovulation and conception prior to initiation of this product. Tablet Color: • EstaryllaTM active tablets are blue (Day 1 to Day 21). • EstaryllaTM has green inactive tablets (Day 22 to Day 28) Day 1 Start: • Take first active tablet without regard to meals on the first day of menses. • Take subsequent active tablets once daily at the same time each day for a total of 21 days. • Take one green inactive tablet daily for 7 days and at the same time of day that active tablets were taken. • Begin each subsequent blister pack on the same day of EstaryllaTM the week as the first cycle blister pack (i.e., on the day after taking the last inactive tablet) Sunday Start: • Take first active tablet without regard to meals on the first Sunday after the onset of menses. Due to the potential risk of becoming pregnant, use additional non-hormonal contraception (such as condoms and spermicide) for the first seven days of the patient's first cycle blister pack of Estarylla TM. • Take subsequent active tablets once daily at the same time each day for a total of 21 days. • Take one green inactive tablet daily for the following 7 days and at the same time of day that active tablets were taken. • Begin each subsequent blister pack on the same day of the week as the first cycle blister pack (i.e., on the Sunday after taking the last inactive tablet) and additional non-hormonal contraceptive is not needed. Switching to Estarylla TM from another oral contraceptive Start on the same day that a new blister pack of the previous oral contraceptive would have started. Switching from another contraceptive method to Estarylla TM Start Estarylla TM: • Transdermal patch On the day when next application would have been scheduled • Vaginal ring • On the day when next insertion would have been scheduled • Injection • On the day when next injection would have been scheduled • Intrauterine contraceptive • On the day of removal • If the IUD is not removed on first day of the patient's menstrual cycle, additional non-hormonal contraceptive (such as condoms and spermicide) is needed for the first seven days of the first cycle blister pack. • Implant • On the day of removal Starting Estarylla TM after Abortion or Miscarriage First-trimester • After a first-trimester abortion or miscarriage, EstaryllaTM may be started immediately. An additional method of contraception is not needed if EstaryllaTM is started immediately. • If EstaryllaTM is not started within 5 days after termination of the pregnancy, the patient should use additional non-hormonal contraception (such as condoms and spermicide) for the first seven days of her first cycle blister pack of EstaryllaTM. Second-trimester • Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start EstaryllaTM, following the instructions in Table 1 for Day 1 or Sunday start, as desired. If using Sunday start, use additional non-hormonal contraception (such as condoms and spermicide) for the first seven day …

3 DOSAGE FORMS AND STRENGTHS • Estarylla is available in blister cards. Each blister pack contains 28 tablets in the following order: • 21 active tablets are blue, round, debossed with SZ on one side and T4 on the other side. • 7 inert tablets are green, round, debossed with SZ on one side and J1 on the other side. Estarylla (norgestimate and ethinyl estradiol tablets, USP) consists of 28 round tablets in the following order ( 3 ): • 21 blue tablets each containing 0.25 mg norgestimate and 0.035 mg ethinyl estradiol • 7 green tablets (inert)

4 CONTRAINDICATIONS Estarylla 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 )] • • o 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 )] • 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 (5.8) 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 combinations 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 ) • Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive (4) • Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions with the use of COCs are discussed elsewhere in 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 reported during clinical trials (≥2%) were: Norgestimate and ethinyl estradiol: headache/migraine, abdominal/gastrointestinal pain, vaginal infection, genital discharge, breast issues (including breast pain, discharge, and enlargement), mood disorders (including depression and mood altered), flatulence, nervousness, rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Xiromed, LLC. at 1-844-XIROMED (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 rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of norgestimate and ethinyl estradiol was evaluated in 1,647 healthy women of child-bearing potential who participated in 3 clinical trials and received at least 1 dose of norgestimate and ethinyl estradiol for contraception. Two trials were randomized active-controlled trials and 1 was an uncontrolled open-label trial. In all 3 trials, subjects were followed for up to 24 cycles. Common Adverse Reactions (≥ 2% of subjects): The most common adverse reactions reported by at least 2% of the 1,647 women were the following in order of decreasing incidence: headache/migraine (32.9%), abdominal/gastrointestinal pain (7.8%), vaginal infection (8.4%), genital discharge (6.8%), breast issues (including breast pain, discharge, and enlargement) (6.3%), mood disorders (including depression and mood altered) (5%), flatulence (3.2%), nervousness (2.9%), and rash (2.6%). Adverse Reactions Leading to Study Discontinuation: Over the three trials, between 11 to 21% of subjects discontinued the trial due to an adverse reaction. The most common adverse reactions (≥1%) leading to discontinuation were: metrorrhagia (6.9%), nausea/vomiting (5%), headache (4.1%), mood disorders (including depression and mood altered) (2.4%), premenstrual syndrome (1.7%), hypertension (1.4%), breast pain (1.4%), nervousness (1.3%), amenorrhea (1.1%), dysmenorrhea (1.1%), weight increased (1.1%), and flatulence (1.1%). Serious Adverse Reactions: breast cancer (1 subject), mood disorders including depression, irritability, and mood swings (1 subject), myocardial infarction (1 subject), and venous thromboembolic events including pulmonary embolism (1 subject) and deep vein thrombosis (DVT) (1 subject). 6.2 Postmarketing Experience Post Marketing Experience Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 - 1.12 (Figure 2). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 2). One of these studies reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19 - 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 2: Risk of Breast Cancer with Combined Oral Contraceptive Use RR = relative risk; OR = odds ratio; HR = hazard ratio. “ever COC” are females with current or past COC use; “ …

7 DRUG INTERACTIONS Consult the labeling of concurrently used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. No drug-drug interaction studies were conducted with norgestimate and ethinyl estradiol. Drugs or herbal products that induce certain enzymes including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs. ( 7.1 ) 7.1 Effects of Other Drugs on Combined Oral Contraceptives Substances decreasing the plasma concentrations of COCs Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of COCs and potentially diminish the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John's wort. Interactions between hormonal contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability. Colesevelam : Colesevelam, a bile acid sequestrant, given together with a COC, has been shown to significantly decrease the AUC of EE. The drug interaction between the contraceptive and colesevelam was decreased when the two drug products were given 4 hours apart. Substances increasing the plasma concentrations of COCs Co-administration of atorvastatin or rosuvastatin and certain COCs containing ethinyl estradiol (EE) increase AUC values for EE by approximately 20 to 25%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma hormone concentrations. Human immunodeficiency virus (HIV)/Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]). 7.2 Effects of Combined Oral Contraceptives on Other Drugs • COCs containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. • COCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, temazepam and lamotrigine. Significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because the serum concentration of thyroid-binding globulin increases with use of COCs. 7.3 Interference with Laboratory Tests The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. 7.4 Concomitant Use with HCV …

8 USE IN SPECIFIC POPULATIONS Nursing mothers: Not recommended; can decrease milk production. ( 8.3 ) 8.1 Pregnancy There is little or no increased risk of birth defects in women who inadvertently use COCs during early 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 low dose COCs prior to conception or during early pregnancy. Do not administer COCs to induce withdrawal bleeding as a test for pregnancy. Do not use COCs during pregnancy to treat threatened or habitual abortion. 8.3 Nursing Mothers Advise the nursing mother to use other forms of contraception, when possible, until she has weaned her child. COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk. 8.4 Pediatric Use Safety and efficacy of norgestimate and ethinyl estradiol tablets have been established in women of reproductive age. Efficacy is expected to be the same for post-pubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated. 8.5 Geriatric Use Norgestimate and ethinyl estradiol have not been studied in postmenopausal women and are not indicated in this population. 8.6 Hepatic Impairment The pharmacokinetics of norgestimate and ethinyl estradiol has not been studied in subjects with hepatic impairment. However, steroid hormones may be poorly metabolized in patients with hepatic impairment. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded. [See CONTRAINDICATIONS ( 4 ) and WARNINGS AND PRECAUTIONS ( 5.2 ).] 8.7 Renal Impairment The pharmacokinetics of norgestimate and ethinyl estradiol has not been studied in women with renal impairment.

12.1 Mechanism of Action • Oral Contraception 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 Each of the following products is a combination oral contraceptive containing the progestational compound norgestimate and the estrogenic compound ethinyl estradiol. Norgestimate is designated as (18,19-Dinor-17-pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-, oxime,(17α)-(+)-) and ethinyl estradiol is designated as (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol). • Each active blue tablet contains 0.25 mg of norgestimate and 0.035 mg of the ethinyl estradiol. Inactive ingredients include crospovidone, FD & C Blue No.2 Aluminum Lake, lactose anhydrous, magnesium stearate, and pregelatinized starch. • Each green placebo tablet containing only inert ingredients, as follows: crospovidone, D & C Yellow No.10 Aluminum Lake, FD & C Blue No.2 Aluminum Lake, lactose anhydrous, magnesium stearate, and pregelatinized starch. Norgestimate Structure Ethinyl Estradiol Structure

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

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied EstaryllaTM (norgestimate and ethinyl estradiol tablets, USP) are available in blisters containing 28 tablets as follows: Each blister card contains 21 active tablets and 7 inactive tablets. The 21 active tablets are blue, round, debossed with SZ on one side and T4 on the other side. The 7 inert tablets are green, round, debossed with SZ on one side and J1 on the other side. NDC 63629-2349-1, one box containing 3 individual unit cartons 16.2 Storage Conditions Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light. Keep out of reach of children Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504