ZAFEMY

6 ADVERSE REACTIONS The following serious adverse reactions with the use of combination hormonal contraceptives, including ZAFEMY, are discussed elsewhere in the labeling: Serious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions (5.1) ] Vascular events, including venous and arterial thromboembolic events [see Warnings and Precautions (5.1) ] Liver disease [see Warnings and Precautions (5.3) ] Adverse reactions commonly reported by users of combination hormonal contraceptives are: Irregular uterine bleeding Nausea Breast tenderness Headache The most frequent adverse reactions reported during clinical trials (≥ 5%) were breast symptoms, nausea/vomiting, headache, application site disorder, abdominal pain, dysmenorrhea, vaginal bleeding and menstrual disorders, and mood, affect and anxiety disorders. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials 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 data described below reflect exposure to ZAFEMY in 3,330 sexually active women (3,322 of whom had safety data) who participated in three Phase 3 clinical trials designed to evaluate contraceptive efficacy and safety. These subjects received six or 13 cycles of contraception (ZAFEMY or an oral contraceptive comparator in 2 of the trials). The women ranged in age from 18 to 45 years and were predominantly white (91%). The most common adverse reactions (≥ 5%) reported during clinical trials were breast symptoms, nausea/vomiting, headache, application site disorder, abdominal pain, dysmenorrhea, vaginal bleeding and menstrual disorders, and mood, affect and anxiety disorders. The most common events leading to discontinuation were application site reaction, breast symptoms (including breast discomfort, engorgement and pain), nausea and/or vomiting, headache and emotional lability. Adverse drug reactions reported by ≥ 2.5% of ZAFEMY-treated subjects in these trials are shown in Table 3. Table 3: Adverse Drug Reactions Reported by ≥ 2.5% of ZAFEMY-treated Subjects in Three Phase 3 Clinical Trials System/Organ Class* Adverse reaction ZAFEMY (n=3,322) Reproductive system and breast disorders Breast symptoms † 22.4% Dysmenorrhea 7.8% Vaginal bleeding and menstrual disorders † 6.4% Gastrointestinal disorders Nausea 16.6% Abdominal pain † 8.1% Vomiting 5.1% Diarrhea 4.2% Nervous system disorders Headache 21.0% Dizziness 3.3% Migraine 2.7% General disorders and administration site conditions Application site disorder † 17.1% Fatigue 2.6% Psychiatric disorders Mood, affect and anxiety disorders † 6.3% Skin and subcutaneous tissue disorders Acne 2.9% Pruritus 2.5% Infections and infestations Vaginal yeast infection † 3.9% Investigations Weight increased 2.7% * MedDRA version 10.0 † Represents a bundle of similar terms Additional adverse drug reactions that occurred in < 2.5% of ZAFEMY-treated subjects in the above clinical trials datasets are: Gastrointestinal disorders: Abdominal distension General disorders and administration site conditions: Fluid retention 1 , malaise Hepatobiliary disorders: Cholecystitis Investigations: Blood pressure increased, lipid disorders 1 Musculoskeletal and connective tissue disorders: Muscle spasms Psychiatric disorders: Insomnia, libido decreased, libido increased Reproductive system and breast disorders: Galactorrhea, genital discharge, premenstrual syndrome, uterine spasm, vaginal discharge, vulvovaginal dryness Respiratory, thoracic and mediastinal disorders: Pulmonary embolism Skin and subcutaneous tissue disorders: Chloasma, dermatitis contact, erythema, skin irritation 1 Represents a bundle of similar terms 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 to 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 to 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 to 10 years of COC use. Figure 2: 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 (Table 4) have been identified during post-approval use of ZAFEMY. 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. Table 4: Alphabetical List of Adverse Drug Reactions Identified During Postmarketing Experience with ZAFEMY by System Organ Class* System Organ Class Adverse Drug Reactions Cardiac disorders Myocardial infarction † Endocrine disorders Hyperglycemia, insulin resistance Eye disorders Contact lens intolerance or complication Gastrointestinal disorders Colitis General disorders and administration site conditions Application site reaction † , edema † Hepatobiliary disorders Blood cholesterol abnormal, cholelithiasis, cholestasis, hepatic lesion, jaundice cholestatic, low density lipoprotein increased Immune system disorders Allergic reaction † , urticaria Investigations Blood glucose abnormal, blood glucose decreased Metabolism and nutrition disorders Increased appetite Neoplasms benign, malignant and unspecified (Incl. cysts and polyps) Breast cancer † , cervix carcinoma, hepatic adenoma, hepatic neoplasm Nervous system disorders Dysgeusia, migraine with aura Psychiatric disorders Anger, emotional disorder, frustration, irritability Reproductive system and breast disorders Breast mass, cervical dysplasia, fibroadenoma of breast, menstrual disorder † , suppressed lactation, uterine leiomyoma Skin and subcutaneous tissues disorders Alopecia, eczema, erythema multiforme, erythema nodosum, photosensitivity reaction, pruritus generalized, rash † , seborrheic dermatitis, skin reaction Vascular disorders Arterial thrombosis † , cerebrovascular accident † , deep vein thrombosis † , hemorrhage intracranial † , hypertension, hypertensive crisis, pulmonary embolism † , thrombosis † * MedDRA version 10.0 † Represents a bundle of similar terms 1

4 CONTRAINDICATIONS ZAFEMY is contraindicated in females who are known to have or develop the following conditions: At high risk of arterial or venous thromboembolic events. Examples include women who: 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 (5.5) ] Have diabetes mellitus with vascular disease [see Warnings and Precautions (5.7) ] Have headaches with focal neurological symptoms or have migraine headaches with aura Women over age 35 with any migraine headaches [see Warnings and Precautions (5.8) ] Body Mass Index ≥ 30 kg/m 2 [see Warnings and Precautions (5.1) ] Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions (5.3) , Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.9) ] Pregnancy, because there is no reason to use hormonal contraceptives during pregnancy [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1) ] Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [see Warnings and Precautions (5.12) ] 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) ] At high risk of arterial or venous thromboembolic events (4) BMI ≥ 30 kg/m 2 (4) Breast cancer or other estrogen- or progestin-sensitive cancer (4) Liver tumors or liver disease (4) Undiagnosed abnormal uterine bleeding (4) Pregnancy (4) Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (4)

11 DESCRIPTION ZAFEMY is a transdermal system with a contact surface area of 12.5 cm 2 . It contains 3.15 mg norelgestromin, USP (NGMN) and 0.289 mg ethinyl estradiol, USP (EE), and its delivery rate is approximately 150 mcg of NGMN, USP and 35 mcg of EE, USP per day. Systemic exposures (as measured by area under the curve [AUC] and steady-state concentration [C ss ]) of NGMN, USP and EE, USP during use of ZAFEMY are higher and the C max is lower than those produced by an oral contraceptive containing norgestimate, USP (NGM) 250 mcg / EE, USP 35 mcg [see Boxed Warning and Clinical Pharmacology (12.3) ] . ZAFEMY is a thin, matrix-type transdermal system consisting of three layers. The backing layer is composed of a tan backing consisting of pigmented polyethylene and polyester. It provides structural support and protects the middle adhesive layer from the environment. The middle layer contains polyisobutylene/polybutene adhesive, polybutene, crospovidone, oleyl alcohol and dipropylene glycol as inactive components. The active components in this layer are the hormones, NGMN, USP and EE, USP. The third layer is the release liner , which protects the adhesive layer during storage and is removed just prior to application. It is a transparent polyethylene terephthalate (PET) film with a silicone coating on the side that is in contact with the middle adhesive layer. The outside of the backing layer is printed with “Norelgestromin and Ethinyl Estradiol 150/35 mcg per day” in brown ink. The structural formulas of the components are: Norelgestromin, USP ethinyl estradiol, USP Molecular weight, NGMN, USP: 327.47 Molecular weight, EE, USP: 296.41 Chemical name for NGMN, USP: 18, 19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-,3-oxime,(17α) Chemical name for EE, USP: 19-Norpregna-1,3,5(10)-trien-20-yne-3, 17-diol,(17α) Structural Formula

2 DOSAGE AND ADMINISTRATION To achieve maximum contraceptive effectiveness, ZAFEMY must be used exactly as directed. Complete instructions to facilitate patient counseling on proper system usage may be found in the FDA-Approved Patient Labeling. ZAFEMY uses a 28-day (four-week) cycle. Apply a new patch to the upper outer arm, abdomen, buttock or back each week for three weeks (21 total days). Week Four is patch-free. (2.1, 2.3) Apply each new patch on the same day of the week. Wear only one patch at a time. (2.1) Do not cut or alter the patch in any way. (2.1) 2.1 How to Use ZAFEMY The ZAFEMY transdermal system uses a 28-day (four-week) cycle. A new patch is applied each week for three weeks (21 total days). Week Four is patch-free. Withdrawal bleeding is expected during this time. Every new patch should be applied on the same day of the week. This day is known as the “Patch Change Day.” For example, if the first patch is applied on a Monday, all subsequent patches should be applied on a Monday. Only one patch should be worn at a time. Do not cut, damage or alter the ZAFEMY patch in any way. If the ZAFEMY patch is cut, damaged or altered in size, contraceptive efficacy may be impaired. On the day after Week Four ends, a new four-week cycle is started by applying a new patch. Under no circumstances should there be more than a seven-day patch-free interval between dosing cycles. 2.2 How to Start Using ZAFEMY There are multiple options for starting the ZAFEMY patch, and the woman should choose the option that is most appropriate (see Table 1): Table 1: Instructions for Administration Starting ZAFEMY patch in women with no current use of hormonal contraception The woman has two options for starting the patch and she should choose the option that is right for her: First Day Start The woman should apply her first patch during the first 24 hours of her menstrual period. If a patch is applied after the first 24 hours of menstruation, non-hormonal back-up contraception (such as condoms and spermicide, or diaphragm and spermicide) is needed for the first 7 days of the first cycle only. The woman should apply a new patch each week for three weeks (21 total days). Every new patch should be applied on the same day of the week. This day is known as the “Patch Change Day.” For example, if the first patch is applied on a Monday, all subsequent patches should be applied on a Monday. Only one patch should be worn at a time. No patch is worn during Week Four (the “Patch-Free Week”). Withdrawal bleeding is expected during this time. On the day after Week 4 ends, a new 4-week cycle is started by applying a new patch. Under no circumstances should there be more than a 7-day patch-free interval between dosing cycles. Sunday Start The woman should apply her first patch on the first Sunday after her menstrual period begins. With this option, a non-hormonal backup method of birth control, such as a condom and spermicide or diaphragm and spermicide, is needed for the first 7 days of the first cycle only. If her period starts on a Sunday, the first patch should be applied that day, and no backup contraception is needed. Switching from another contraceptive method Oral combination hormonal contraception (oral CHC) If the woman is switching from the pill to ZAFEMY patch, she should complete her current pill cycle and apply the first ZAFEMY patch on the day she would normally start her next pill If she does not get her period within a week after taking the last active pill, she should check with her healthcare professional to be sure that she is not pregnant, but she may go ahead and start ZAFEMY patch for contraception. If the patch is applied more than a week after taking the last active pill, she should use a non-hormonal back-up contraception (such as condoms and spermicide, or diaphragm and spermicide) concurrently for the first 7 days of patch use. Transdermal system If the woman is switching from another contraceptive transdermal system to ZAFEMY patch, she should complete the current transdermal system cycle and apply the first ZAFEMY patch on the day the next transdermal system cycle would normally start. If she does not get her period within a week after removing the last transdermal system, she should check with her healthcare professional to be sure that she is not pregnant, but she may go ahead and start ZAFEMY patch for contraception. If ZAFEMY patch is applied more than a week after removal of the last patch, non-hormonal back-up contraception (such as condoms and spermicide, or diaphragm and spermicide) should be used concurrently for the first 7 days of patch use. Vaginal ring If the woman is switching from the vaginal ring to ZAFEMY patch, she should complete her current vaginal ring cycle and apply the first ZAFEMY patch on the day she would normally insert her next vaginal ring. If she does not get her period within a week after removing the last vaginal ring, she should check with her healthcare professional to be sure that she is not pregnant, but she may go ahead and start ZAFEMY patch for contraception. If the patch is applied more than a week after removal of the last vaginal ring, she should use a non-hormonal back-up contraception (such as condoms and spermicide, or diaphragm and spermicide) concurrently for the first 7 days of patch use. Injection If the woman is switching from an injection contraceptive to ZAFEMY patch, she should apply the first ZAFEMY patch on the day the next injection would normally occur. Intrauterine system (IUS) If the woman is switching from an intrauterine system to ZAFEMY patch, she should apply the first ZAFEMY patch on the day of IUS removal. If the IUS is not removed on the first day of the menstrual cycle, non-hormonal backup contraception (such as condoms and spermicide, or diaphragm and spermicide) should be used concurrently for the first 7 days of patch use. Implant If the woman is switching from an implant to ZAFEMY patch, she should apply the first ZAFEMY patch on the day of implant removal. Progestin-only pill If the woman is switching from a progestin-only pill to ZAFEMY patch, she should apply the first ZAFEMY patch on the day the next progestin-only pill cycle would normally start. Use after Childbirth Start contraceptive therapy with ZAFEMY in women who elect not to breastfeed no sooner than 4 weeks after childbirth due to increased risk of thromboembolism. If a woman begins using ZAFEMY postpartum, and has not yet had a period, consider the possibility of ovulation and conception occurring prior to use of ZAFEMY, and instruct her to use an additional method of contraception, such as a condom and spermicide or diaphragm and spermicide, for the first seven days [see Warnings and Precautions (5.1) and Pregnancy (8.1) ] . Use after Abortion or Miscarriage After an abortion or miscarriage that occurs in the first trimester, ZAFEMY may be started immediately. An additional method of contraception is not needed if ZAFEMY is started immediately. If use of ZAFEMY is not started within 5 days following a first trimester abortion, the woman should follow the instructions for a woman starting ZAFEMY for the first time. In the meantime she should be advised to use a non-hormonal contraceptive method. Ovulation may occur within 10 days of an abortion or miscarriage. Start ZAFEMY no earlier than 4 weeks after a second trimester abortion or miscarriage, due to the increased risk of thromboembolic disease [see Contraindications (4) and Warnings and Precautions (5.1) ] . 2.3 How to Apply ZAFEMY CHOOSING A PLACE ON THE BODY TO PUT THE PATCH The patch may be placed on the upper outer arm, abdomen, buttock or back in a place where it won’t be rubbed by tight clothing. For example, it should not be placed under the waistband of clothing. The patch should not be placed on the breasts, on cut or irritated skin, or on the same location as the previous patch. Before applying the patch: The woman should make sure the skin is clean and dry. She should not use lotions, creams, oils, powders, or make-up at the patch site. It may cause the patch to fail to stick properly or to become loose. HOW TO APPLY THE PATCH The woman should tear open the pouch at the top edge. She should peel open the foil pouch that contains the patch and its clear plastic cover. She should gently remove the patch and its plastic cover together from the pouch, being careful not to separate the patch from the clear plastic cover. Using a fingernail, the woman should peel away half of the clear plastic. She should avoid touching the sticky surface with her fingers. The woman should apply the sticky side of the patch on the skin she has cleaned and dried. She should then remove the other half of the clear plastic and attach the entire patch to her skin. The woman should press firmly on the patch with the palm of her hand for 10 seconds, making sure that the whole patch adheres to her skin. She should run her fingers over the entire surface area to smooth out any “wrinkles” around the outer edges of the patch. The woman should check her patch every day to make sure all edges are sticking correctly. WHEN TO CHANGE THE ZAFEMY PATCH The patch works for seven days (one week). The woman should apply a new patch on the same day each week (her Patch Change Day) for 3 weeks in a row. She must make sure she has removed her old patch prior to applying the new patch. During Week 4, she DOES NOT wear a patch. She must make sure she removes her old patch. (Her period should begin during this week.) Following Week 4, she repeats the cycle of three weekly applications followed by a patch-free week. WHAT IF THE PATCH BECOMES LOOSE OR FALLS OFF? The patch must stick securely to the skin to work properly. If the ZAFEMY patch becomes partially or completely detached and remains detached, insufficient drug delivery occurs. The woman should not try to reapply a patch if it is no longer sticky, if it has become stuck to itself or another surface, or if it has other material stuck to it. If a patch edge lifts up: The woman should press down firmly on the patch with the palm of her hand for 10 seconds, making sure that the whole patch adheres to her skin. She should run her fingers over the entire surface area to smooth out any “wrinkles” around the edges of the patch. If her patch does not stick completely, she should remove it and apply a replacement patch. She should not tape or wrap the patch to her skin or reapply a patch that is partially adhered to clothing. If the patch has been off or partially off: For less than 1 Day, she should try to reapply it. If the patch does not adhere completely, she should apply a new patch immediately. (No backup contraception is needed and her Patch Change Day will stay the same). For more than 1 Day or if she is not sure for how long, she may not be protected from pregnancy. To reduce this risk, she should apply a new patch and start a new 4-week cycle. She will now have a new Patch Change Day and MUST USE NON-HORMONAL BACKUP CONTRACEPTION (such as a condom and spermicide or diaphragm and spermicide) for the first week of her new cycle. IF THE WOMAN FORGETS TO CHANGE HER PATCH at the start of any patch cycle (Week One/Day 1): SHE MAY NOT BE PROTECTED FROM PREGNANCY. She should apply the first patch of her new cycle as soon as she remembers. There is now a new “Patch Change Day” and a new “Day 1.” The woman must use back-up contraception, such as a condom and spermicide or diaphragm and spermicide, for the first week of the new cycle. in the middle of the patch cycle (Week Two/Day 8 or Week Three/Day 15), for one or two days (up to 48 hours), she should apply a new patch immediately. The next patch should be applied on the usual “Patch Change Day.” No back-up contraception is needed. for more than two days (48 hours or more), SHE MAY NOT BE PROTECTED FROM PREGNANCY. She should stop the current contraceptive cycle and start a new four-week cycle immediately by putting on a new patch. There is now a new “Patch Change Day” and a new “Day 1.” The woman must use back-up contraception for one week. at the end of the patch cycle (Week Four/Day 22), If the woman forgets to remove her patch, she should take it off as soon as she remembers. The next cycle should be started on the usual “Patch Change Day,” which is the day after Day 28. No back-up contraception is needed. Under no circumstances should there be more than a seven-day patch-free interval between cycles. If there are more than seven patch-free days, THE WOMAN MAY NOT BE PROTECTED FROM PREGNANCY and back-up contraception, such as a condom and spermicide or diaphragm and spermicide, must be used for seven days. As with combined oral contraceptives, the risk of ovulation increases with each day beyond the recommended drug-free period. If she has had intercourse during such an extended patch-free interval, consider the possibility of pregnancy. Change Day Adjustment If the woman wishes to change her Patch Change Day, she should complete her current cycle, removing the third ZAFEMY patch on the correct day. During the patch-free week, she may select an earlier Patch Day Change by applying a new ZAFEMY patch on the desired day. In no case should there be more than 7 consecutive patch-free days. Breakthrough Bleeding or Spotting In the event of unscheduled or breakthrough bleeding or spotting (bleeding that occurs on the days that ZAFEMY is worn), treatment should be continued. If unscheduled bleeding persists longer than a few cycles, consider causes other than ZAFEMY. If the woman does not have scheduled or withdrawal bleeding (bleeding that should occur during the patch-free week), she should resume treatment on the next scheduled Change Day. If ZAFEMY has been used correctly, the absence of withdrawal bleeding is not necessarily an indication of pregnancy. Nevertheless, consider the possibility of pregnancy, especially if absence of withdrawal bleeding occurs in 2 consecutive cycles. Discontinue ZAFEMY if pregnancy is confirmed. In Case of Skin Irritation If patch use results in uncomfortable irritation, the patch may be removed and a new patch may be applied to a different location until the next Change Day. Only one patch should be worn at a time. Additional Instructions for Dosing Unscheduled bleeding, spotting, and amenorrhea are frequent reasons for patients discontinuing hormonal contraceptives. In case of breakthrough bleeding, as in all cases of irregular bleeding from the vagina, consider nonfunctional causes. In case of undiagnosed persistent or recurrent abnormal bleeding from the vagina, take adequate diagnostic measures to rule out pregnancy or malignancy. If pathology has been excluded, time or a change to another method of contraception may solve the problem. Use of Hormonal Contraceptives in the Event of a Missed Menstrual Period If the woman has not adhered to the prescribed schedule, consider the possibility of pregnancy at the time of the first missed period. Discontinue use of ZAFEMY if pregnancy is confirmed. If the woman has adhered to the prescribed regimen and misses one period, she should continue using her contraceptive patches. However, if she has adhered to the prescribed regimen, misses one period and has symptoms associated with pregnancy, rule out pregnancy. Discontinue ZAFEMY use if pregnancy is confirmed. If the woman has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. Discontinue ZAFEMY use if pregnancy is confirmed. Where to put patch Usage Illustration 1 Usage Illustration 2 Usage Illustration 3 Usage Illustration 4

1 INDICATIONS AND USAGE ZAFEMY ® is indicated for the prevention of pregnancy in women with a body mass index (BMI) < 30 kg/m 2 for whom a combined hormonal contraceptive is appropriate. Limitations of Use: ZAFEMY may be less effective in preventing pregnancy in women who weigh 198 lbs (90 kg) or more. ZAFEMY is contraindicated for use in women with BMI ≥ 30 kg/m 2 [see Contraindications (4) , Warnings and Precautions (5.1) and Clinical Studies (14) ]. ZAFEMY ® is an estrogen/progestin combination hormonal contraceptive (CHC), indicated for the prevention of pregnancy in women with a BMI < 30 kg/m 2 for whom a combined hormonal contraceptive is appropriate. (1) Limitations of Use : ZAFEMY may be less effective in preventing pregnancy in women at or above 198 lbs (90 kg). ( 1 , 4 , 14 )

10 OVERDOSAGE Overdosage may cause nausea and vomiting, and withdrawal bleeding may occur in women. In case of suspected overdose, all ZAFEMY patches should be removed and symptomatic treatment given.

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. Drugs or herbal products that induce certain enzymes (for example CYP3A4) may decrease the effectiveness of CHCs or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with CHCs. (7.1) 7.1 Effects of Other Drugs on Combined Hormonal Contraceptives Substances Decreasing the Plasma Concentrations of CHCs and Potentially Diminishing the Efficacy of CHCs: Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of CHCs and potentially diminish the effectiveness of CHCs 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 CHCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability. Substances Increasing the Plasma Concentrations of CHCs: Co-administration of atorvastatin or rosuvastatin and certain CHCs containing 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 or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]). 7.2 Effects of Combined Hormonal Contraceptives on Other Drugs CHCs containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. CHCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, and temazepam. 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 serum concentration of thyroid-binding globulin increases with use of CHCs [see Warnings and Precautions (5.13) ] . 7.3 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer ZAFEMY with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions (5.4) ] . 7.4 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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action NGMN is the active progestin largely responsible for the progestational activity that occurs in women following application of ZAFEMY. NGMN is also the primary active metabolite produced following oral administration of NGM, the progestin component of some oral contraceptive products. Combination hormonal contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation). 12.2 Pharmacodynamics One clinical trial assessed the return of hypothalamic-pituitary-ovarian axis function post-therapy and found that follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol mean values, though suppressed during therapy, returned to near baseline values during the 6 weeks post therapy. 12.3 Pharmacokinetics Absorption The systemic delivery rate of NGMN and EE from ZAFEMY is approximately 150 mcg of NGMN and 35 mcg of EE per day based on a comparative analysis with intravenous (IV) data. Following a single application of ZAFEMY, both NGMN and EE reach a plateau by approximately 48 hours. Pooled data from the 3 clinical studies have demonstrated that steady-state is reached within 2 weeks of application. In one of the clinical studies, C ss concentrations across all subjects ranged from 0.305 to 1.53 ng/mL for NGMN and from 23 to 137 pg/mL for EE. Absorption of NGMN and EE following application of ZAFEMY to the buttock, upper outer arm, abdomen and upper torso (excluding breast) was examined. While absorption from the abdomen was slightly lower than from other sites, absorption from these anatomic sites was considered to be therapeutically equivalent. The mean (%CV) PK parameters C ss and AUC 0-168 for NGMN and EE following a single buttock application of ZAFEMY are summarized in Table 5. In multiple dose studies, AUC 0-168 for NGMN and EE was found to increase over time (Table 5). In a three-cycle study, these PK parameters reached steady-state conditions during Cycle 3 (Figures 5 and 4). Upon removal of the patch, serum levels of EE and NGMN reach very low or non-measurable levels within 3 days. Table 5: Mean (%CV*) PK Parameters of NGMN and EE Following 3 Consecutive Cycles of ZAFEMY Wear on the Buttock Analyte Parameter Cycle 1 Week 1 Cycle 3 Week 1 Cycle 3 Week 2 Cycle 3 Week 3 NGMN C ss (ng/mL) AUC 0-168 (ng·h/mL) t 1/2 (h) 0.70 (39.4) 107 (44.2) nc 0.70 (41.8) 105 (43.2) nc 0.80 (28.7) 132 (43.4) nc 0.70 (45.3) 120 (43.9) 32.1 (40.3) EE C ss (pg/mL) AUC 0-168 (pg·h/mL) t 1/2 (h) 46.4 (38.5) 6,796 (39.3) nc 47.6 (36.4) 7,160 (40.4) nc 59.0 (42.5) 10,054 (41.8) nc 49.6 (54.4) 8,840 (58.6) 21.0 (43.2) nc = not calculated, *%CV is % of Coefficient of variation = 100 (standard deviation/mean) Figure 3: Mean Serum NGMN Concentrations (ng/mL) in Healthy Female Volunteers Following Application of ZAFEMY on the Buttock for Three Consecutive Cycles (Vertical arrow indicates time of patch removal) Figure 4: Mean Serum EE Concentrations (pg/mL) in Healthy Female Volunteers Following Application of ZAFEMY on the Buttock for Three Consecutive Cycles (Vertical arrow indicates time of patch removal.) The absorption of NGMN and EE following application of ZAFEMY was studied under conditions encountered in a health club (sauna, whirlpool and treadmill) and in a cold water bath. The results indicated that for NGMN, there were no significant treatment effects on C ss or AUC when compared to normal wear. For EE, increased exposures were observed due to sauna, whirlpool and treadmill. There was no significant effect of cold water on these parameters. Results from a study of consecutive ZAFEMY wear for 7 days and 10 days indicated that serum concentrations of NGMN and EE dropped slightly during the first 6 hours after the patch replacement, and recovered within 12 hours. By Day 10 of patch administration, both NGMN and EE concentrations had decreased by approximately 25% when compared to Day 7 concentrations. Metabolism Since norelgestromin and ethinyl estradiol are delivered transdermally, first-pass metabolism (via the gastrointestinal tract and/or liver) of NGMN and EE that would be expected with oral administration does not occur. Hepatic metabolism of NGMN occurs and metabolites include norgestrel, which is highly bound to SHBG, and various hydroxylated and conjugated metabolites. EE is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates. Distribution NGMN and norgestrel (a serum metabolite of NGMN) are highly bound (>97%) to serum proteins. NGMN is bound to albumin and not to SHBG, while norgestrel is bound primarily to SHBG, which limits its biological activity. EE is extensively bound to serum albumin and induces an increase in the serum concentrations of SHBG (see Table 5). Elimination Following removal of patches, the elimination kinetics of NGMN and EE were consistent for all studies with half-life values of approximately 28 hours and 17 hours, respectively. The metabolites of NGMN and EE are eliminated by renal and fecal pathways. Transdermal versus Oral Contraceptives The ZAFEMY transdermal patch delivers EE and NGMN over a seven-day period while oral contraceptives (containing NGM 250 mcg / EE 35 mcg) are administered on a daily basis. Figures 5 and 6 present mean PK profiles for EE and NGMN following administration of an oral contraceptive (containing NGM 250 mcg / EE 35 mcg) compared to the 7-day transdermal ZAFEMY patch (containing NGMN 3.15 mg / EE 0.289 mg) during Cycle 2 in 32 healthy female volunteers. Figure 5: Mean Serum Concentration-Time Profiles of NGMN Following Once-Daily Administration of an Oral Contraceptive for 2 Cycles or Application of ZAFEMY for 2 Cycles to the Buttock in Healthy Female Volunteers. [Oral contraceptive: Cycle 2, Days 15 to 21, ZAFEMY: Cycle 2, Week 3] Figure 6: Mean Serum Concentration-Time Profiles of EE Following Once-Daily Administration of an Oral Contraceptive for 2 Cycles or Application of ZAFEMY for 2 Cycles to the Buttock in Healthy Female Volunteers. [Oral contraceptive: Cycle 2, Days 15 to 21, ZAFEMY: Cycle 2, Week 3] Table 6 provides the mean (%CV) for NGMN and EE pharmacokinetic (PK) parameters. Table 6: Mean (%CV) NGMN and EE Steady-State Pharmacokinetic Parameters Following Application of ZAFEMY and Once-Daily Administration of an Oral Contraceptive (containing NGM 250 mcg / EE 35 mcg) in Healthy Female Volunteers Parameter ZAFEMY* ORAL CONTRACEPTIVE † NGMN ‡ C max (ng/mL) 1.12 (33.6) 2.16 (25.2) AUC 0-168 (ng·h/mL) 145 (36.8) 123 (30.2) § C ss (ng/mL) 0.888 (36.6) 0.732 (30.2) ¶ EE C max (pg/mL) 97.4 (31.6) 133 (27.7) AUC 0-168 (pg·h/mL) 12,971 (33.1) 8,281 (26.9) § C ss (pg/mL) 80.0 (33.5) 49.3 (26.9) ¶ * Cycle 2, Week 3 † Cycle 2, Day 21 ‡ NGM is rapidly metabolized to NGMN following oral administration § Average weekly exposure, calculated as AUC 24 × 7 ¶ C avg In general, overall exposure for NGMN and EE (AUC and C ss ) was higher in subjects treated with ZAFEMY for both Cycle 1 and Cycle 2, compared to that for the oral contraceptive, while C max values were higher in subjects administered the oral contraceptive. Under steady-state conditions, AUC 0-168 and C ss for EE were approximately 55% and 60% higher, respectively, for the transdermal patch, and the C max was about 35% higher for the oral contraceptive, respectively. Inter-subject variability (%CV) for the PK parameters following delivery from ZAFEMY was higher relative to the variability determined from the oral contraceptive. The mean PK profiles are different between the two products and caution should be exercised when making a direct comparison of these PK parameters. In Table 7, percent change in concentrations (%CV) of markers of systemic estrogenic activity (Sex Hormone Binding Globulin [SHBG] and Corticosteroid Binding Globulin [CBG]) from Cycle 1 Day 1 to Cycle 1 Day 22 is presented. Percent change in SHBG concentrations was higher for ZAFEMY users compared to women taking the oral contraceptive; percent change in CBG concentrations was similar for ZAFEMY and oral contraceptive users. Within each group, the absolute values for SHBG were similar for Cycle 1, Day 22 and Cycle 2, Day 22. Table 7: Mean Percent Change (%CV) in SHBG and CBG Concentrations Following Once-Daily Administration of an Oral Contraceptive (containing NGM 250 mcg / EE 35 mcg) for One Cycle and Application of ZAFEMY for One Cycle in Healthy Female Volunteers Parameter ZAFEMY (% change from Day 1 to Day 22) ORAL CONTRACEPTIVE (% change from Day 1 to Day 22) SHBG 334 (39.3) 200 (43.2) CBG 153 (40.2) 157 (33.4) Drug Interactions In a PK drug interaction study, oral administration of tetracycline HCl, 500 mg four times daily for 3 days prior to and 7 days during wear of ZAFEMY did not significantly affect the PK of NGMN or EE. Use in Specific Populations Effects of Age, Body Weight, Body Surface Area and Race The effects of age, body weight, body surface area and race on the PK of NGMN and EE were evaluated in 230 healthy women from nine pharmacokinetic studies of single 7-day applications of ZAFEMY. For both NGMN and EE, increasing age, body weight and body surface area each were associated with slight decreases in C ss and AUC values. However, only a small fraction (10% to 25%) of the overall variability in the PK of NGMN and EE following application of ZAFEMY may be associated with any or all of the above demographic parameters. There was no significant effect of race with respect to Caucasians, Hispanics and Blacks. Figure 3 Figure 4 Figure 5 Figure 6

12.1 Mechanism of Action NGMN is the active progestin largely responsible for the progestational activity that occurs in women following application of ZAFEMY. NGMN is also the primary active metabolite produced following oral administration of NGM, the progestin component of some oral contraceptive products. Combination hormonal contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).

12.2 Pharmacodynamics One clinical trial assessed the return of hypothalamic-pituitary-ovarian axis function post-therapy and found that follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol mean values, though suppressed during therapy, returned to near baseline values during the 6 weeks post therapy.

12.3 Pharmacokinetics Absorption The systemic delivery rate of NGMN and EE from ZAFEMY is approximately 150 mcg of NGMN and 35 mcg of EE per day based on a comparative analysis with intravenous (IV) data. Following a single application of ZAFEMY, both NGMN and EE reach a plateau by approximately 48 hours. Pooled data from the 3 clinical studies have demonstrated that steady-state is reached within 2 weeks of application. In one of the clinical studies, C ss concentrations across all subjects ranged from 0.305 to 1.53 ng/mL for NGMN and from 23 to 137 pg/mL for EE. Absorption of NGMN and EE following application of ZAFEMY to the buttock, upper outer arm, abdomen and upper torso (excluding breast) was examined. While absorption from the abdomen was slightly lower than from other sites, absorption from these anatomic sites was considered to be therapeutically equivalent. The mean (%CV) PK parameters C ss and AUC 0-168 for NGMN and EE following a single buttock application of ZAFEMY are summarized in Table 5. In multiple dose studies, AUC 0-168 for NGMN and EE was found to increase over time (Table 5). In a three-cycle study, these PK parameters reached steady-state conditions during Cycle 3 (Figures 5 and 4). Upon removal of the patch, serum levels of EE and NGMN reach very low or non-measurable levels within 3 days. Table 5: Mean (%CV*) PK Parameters of NGMN and EE Following 3 Consecutive Cycles of ZAFEMY Wear on the Buttock Analyte Parameter Cycle 1 Week 1 Cycle 3 Week 1 Cycle 3 Week 2 Cycle 3 Week 3 NGMN C ss (ng/mL) AUC 0-168 (ng·h/mL) t 1/2 (h) 0.70 (39.4) 107 (44.2) nc 0.70 (41.8) 105 (43.2) nc 0.80 (28.7) 132 (43.4) nc 0.70 (45.3) 120 (43.9) 32.1 (40.3) EE C ss (pg/mL) AUC 0-168 (pg·h/mL) t 1/2 (h) 46.4 (38.5) 6,796 (39.3) nc 47.6 (36.4) 7,160 (40.4) nc 59.0 (42.5) 10,054 (41.8) nc 49.6 (54.4) 8,840 (58.6) 21.0 (43.2) nc = not calculated, *%CV is % of Coefficient of variation = 100 (standard deviation/mean) Figure 3: Mean Serum NGMN Concentrations (ng/mL) in Healthy Female Volunteers Following Application of ZAFEMY on the Buttock for Three Consecutive Cycles (Vertical arrow indicates time of patch removal) Figure 4: Mean Serum EE Concentrations (pg/mL) in Healthy Female Volunteers Following Application of ZAFEMY on the Buttock for Three Consecutive Cycles (Vertical arrow indicates time of patch removal.) The absorption of NGMN and EE following application of ZAFEMY was studied under conditions encountered in a health club (sauna, whirlpool and treadmill) and in a cold water bath. The results indicated that for NGMN, there were no significant treatment effects on C ss or AUC when compared to normal wear. For EE, increased exposures were observed due to sauna, whirlpool and treadmill. There was no significant effect of cold water on these parameters. Results from a study of consecutive ZAFEMY wear for 7 days and 10 days indicated that serum concentrations of NGMN and EE dropped slightly during the first 6 hours after the patch replacement, and recovered within 12 hours. By Day 10 of patch administration, both NGMN and EE concentrations had decreased by approximately 25% when compared to Day 7 concentrations. Metabolism Since norelgestromin and ethinyl estradiol are delivered transdermally, first-pass metabolism (via the gastrointestinal tract and/or liver) of NGMN and EE that would be expected with oral administration does not occur. Hepatic metabolism of NGMN occurs and metabolites include norgestrel, which is highly bound to SHBG, and various hydroxylated and conjugated metabolites. EE is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates. Distribution NGMN and norgestrel (a serum metabolite of NGMN) are highly bound (>97%) to serum proteins. NGMN is bound to albumin and not to SHBG, while norgestrel is bound primarily to SHBG, which limits its biological activity. EE is extensively bound to serum albumin and induces an increase in the serum concentrations of SHBG (see Table 5). Elimination Following removal of patches, the elimination kinetics of NGMN and EE were consistent for all studies with half-life values of approximately 28 hours and 17 hours, respectively. The metabolites of NGMN and EE are eliminated by renal and fecal pathways. Transdermal versus Oral Contraceptives The ZAFEMY transdermal patch delivers EE and NGMN over a seven-day period while oral contraceptives (containing NGM 250 mcg / EE 35 mcg) are administered on a daily basis. Figures 5 and 6 present mean PK profiles for EE and NGMN following administration of an oral contraceptive (containing NGM 250 mcg / EE 35 mcg) compared to the 7-day transdermal ZAFEMY patch (containing NGMN 3.15 mg / EE 0.289 mg) during Cycle 2 in 32 healthy female volunteers. Figure 5: Mean Serum Concentration-Time Profiles of NGMN Following Once-Daily Administration of an Oral Contraceptive for 2 Cycles or Application of ZAFEMY for 2 Cycles to the Buttock in Healthy Female Volunteers. [Oral contraceptive: Cycle 2, Days 15 to 21, ZAFEMY: Cycle 2, Week 3] Figure 6: Mean Serum Concentration-Time Profiles of EE Following Once-Daily Administration of an Oral Contraceptive for 2 Cycles or Application of ZAFEMY for 2 Cycles to the Buttock in Healthy Female Volunteers. [Oral contraceptive: Cycle 2, Days 15 to 21, ZAFEMY: Cycle 2, Week 3] Table 6 provides the mean (%CV) for NGMN and EE pharmacokinetic (PK) parameters. Table 6: Mean (%CV) NGMN and EE Steady-State Pharmacokinetic Parameters Following Application of ZAFEMY and Once-Daily Administration of an Oral Contraceptive (containing NGM 250 mcg / EE 35 mcg) in Healthy Female Volunteers Parameter ZAFEMY* ORAL CONTRACEPTIVE † NGMN ‡ C max (ng/mL) 1.12 (33.6) 2.16 (25.2) AUC 0-168 (ng·h/mL) 145 (36.8) 123 (30.2) § C ss (ng/mL) 0.888 (36.6) 0.732 (30.2) ¶ EE C max (pg/mL) 97.4 (31.6) 133 (27.7) AUC 0-168 (pg·h/mL) 12,971 (33.1) 8,281 (26.9) § C ss (pg/mL) 80.0 (33.5) 49.3 (26.9) ¶ * Cycle 2, Week 3 † Cycle 2, Day 21 ‡ NGM is rapidly metabolized to NGMN following oral administration § Average weekly exposure, calculated as AUC 24 × 7 ¶ C avg In general, overall exposure for NGMN and EE (AUC and C ss ) was higher in subjects treated with ZAFEMY for both Cycle 1 and Cycle 2, compared to that for the oral contraceptive, while C max values were higher in subjects administered the oral contraceptive. Under steady-state conditions, AUC 0-168 and C ss for EE were approximately 55% and 60% higher, respectively, for the transdermal patch, and the C max was about 35% higher for the oral contraceptive, respectively. Inter-subject variability (%CV) for the PK parameters following delivery from ZAFEMY was higher relative to the variability determined from the oral contraceptive. The mean PK profiles are different between the two products and caution should be exercised when making a direct comparison of these PK parameters. In Table 7, percent change in concentrations (%CV) of markers of systemic estrogenic activity (Sex Hormone Binding Globulin [SHBG] and Corticosteroid Binding Globulin [CBG]) from Cycle 1 Day 1 to Cycle 1 Day 22 is presented. Percent change in SHBG concentrations was higher for ZAFEMY users compared to women taking the oral contraceptive; percent change in CBG concentrations was similar for ZAFEMY and oral contraceptive users. Within each group, the absolute values for SHBG were similar for Cycle 1, Day 22 and Cycle 2, Day 22. Table 7: Mean Percent Change (%CV) in SHBG and CBG Concentrations Following Once-Daily Administration of an Oral Contraceptive (containing NGM 250 mcg / EE 35 mcg) for One Cycle and Application of ZAFEMY for One Cycle in Healthy Female Volunteers Parameter ZAFEMY (% change from Day 1 to Day 22) ORAL CONTRACEPTIVE (% change from Day 1 to Day 22) SHBG 334 (39.3) 200 (43.2) CBG 153 (40.2) 157 (33.4) Drug Interactions In a PK drug interaction study, oral administration of tetracycline HCl, 500 mg four times daily for 3 days prior to and 7 days during wear of ZAFEMY did not significantly affect the PK of NGMN or EE. Use in Specific Populations Effects of Age, Body Weight, Body Surface Area and Race The effects of age, body weight, body surface area and race on the PK of NGMN and EE were evaluated in 230 healthy women from nine pharmacokinetic studies of single 7-day applications of ZAFEMY. For both NGMN and EE, increasing age, body weight and body surface area each were associated with slight decreases in C ss and AUC values. However, only a small fraction (10% to 25%) of the overall variability in the PK of NGMN and EE following application of ZAFEMY may be associated with any or all of the above demographic parameters. There was no significant effect of race with respect to Caucasians, Hispanics and Blacks. Figure 3 Figure 4 Figure 5 Figure 6

20230515

1

3 DOSAGE FORMS AND STRENGTHS Transdermal system: 150 mcg/day norelgestromin, USP and 35 mcg/day ethinyl estradiol, USP. Transdermal system: 150 mcg/day norelgestromin, USP and 35 mcg/day ethinyl estradiol, USP. (3)

ZAFEMY Norelgestromin and Ethinyl Estradiol POLYBUTENE (1400 MW) CROSPOVIDONE OLEYL ALCOHOL DIPROPYLENE GLYCOL NORELGESTROMIN NORELGESTROMIN ETHINYL ESTRADIOL ETHINYL ESTRADIOL

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility See Warnings and Precautions (5.3, 5.12) and Use in Specific Populations (8.1) . Norelgestromin was tested in in vitro mutagenicity assays (bacterial plate incorporation mutation assay, CHO/HGPRT mutation assay, chromosomal aberration assay using cultured human peripheral lymphocytes) and in one in vivo test (rat micronucleus assay) and found to have no genotoxic potential.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility See Warnings and Precautions (5.3, 5.12) and Use in Specific Populations (8.1) . Norelgestromin was tested in in vitro mutagenicity assays (bacterial plate incorporation mutation assay, CHO/HGPRT mutation assay, chromosomal aberration assay using cultured human peripheral lymphocytes) and in one in vivo test (rat micronucleus assay) and found to have no genotoxic potential.

ANDA213950

ZAFEMY

Norelgestromin and Ethinyl Estradiol

42291-930

HUMAN PRESCRIPTION DRUG

TRANSDERMAL

PRINCIPAL DISPLAY PANEL 3 1

Warnings and Precautions ( 5.12 ) 11/2021

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling ( Patient Information and Instructions for Use ) 17.1 General Counsel patients about the following information: Cigarette smoking increases the risk of serious cardiovascular events from combined hormonal contraceptive use, and that women who are over 35 years old and smoke should not use combined hormonal contraceptives. The use of CHCs increases the risk of VTE. However, pregnancy increases the risk of VTE as much or more than the use of CHCs. The risk of VTE in women using CHCs is 3 to 12 cases per 10,000 woman-years. The risk of VTE is highest during the first year of use of CHCs and when restarting hormonal contraception after a break of 4 weeks or longer. The risk of thromboembolic disease due to CHCs gradually disappears after use is discontinued. ZAFEMY does not protect against HIV infection (AIDS) and other sexually transmitted infections. The Warnings and Precautions associated with combined hormonal contraceptives. ZAFEMY is not to be used during pregnancy; if pregnancy occurs during use of ZAFEMY, instruct the patient to stop further use. Apply a single patch the same day every week (Weeks 1 through 3). Instruct patients what to do in the event a patch is missed. See “WHAT IF I FORGET TO CHANGE MY PATCH?” section in FDA-Approved Patient Labeling . Use a back-up or alternative method of contraception when enzyme inducers are used with ZAFEMY. Combined hormonal contraceptives may reduce breast milk production; this is less likely to occur if breastfeeding is well established. Women who start combined hormonal contraceptives postpartum, and who have not yet had a period, should use an additional method of contraception until they have used a patch for 7 consecutive days. Amenorrhea may occur. Consider pregnancy in the event of amenorrhea. Rule out pregnancy in the event of amenorrhea in two or more consecutive cycles, amenorrhea in one cycle if the woman has not adhered to the dosing schedule, or if associated with symptoms of pregnancy, such as morning sickness or unusual breast tenderness. If the ZAFEMY patch becomes partially or completely detached and remains detached, insufficient drug delivery occurs. A patch should not be re-applied if it is no longer sticky, becomes stuck to itself or another surface, has other material stuck to it, or has become loose or fallen off before. If a patch cannot be re-applied, a new patch should be applied immediately. Supplemental adhesives or wraps should not be used. A woman may not be protected from pregnancy if a patch is partially or completely detached for ≥24 hours (or if the woman is not sure how long the patch has been detached). She should start a new cycle immediately by applying a new patch. Back-up contraception, such as a condom and spermicide or diaphragm and spermicide, must be used for the first week of the new cycle. All trademarks are the property of their respective owners. Manufactured for: AvKARE Pulaski, TN 38478 Manufactured by: Amneal Pharmaceuticals LLC Piscataway, NJ 08854 Mfg. Rev. 04-2022-04 AV 04/23

INSTRUCTIONS FOR USE ZAFEMY ® (za fe ʹ my) (n orelgestromin and ethinyl estradiol transdermal system) ZAFEMY is for skin use only. Do not cut, damage, or alter the ZAFEMY patch in any way. How to start using your ZAFEMY patch: Figure A If you are not currently using hormonal birth control, you have 2 ways to begin using your ZAFEMY patch. Choose the way that is best for you: First day start: Apply your first ZAFEMY patch during the first 24 hours of your menstrual period. Sunday start: Apply your first ZAFEMY patch on the first Sunday after your menstrual period begins. Use a non-hormonal contraceptive method of birth control, such as a condom and spermicide or diaphragm and spermicide, for the first 7 days of your first cycle only. If your period starts on Sunday, apply your first ZAFEMY patch that day, and no back-up birth control is needed. If you are changing from oral hormone birth control pills, a vaginal contraceptive ring or another contraceptive transdermal patch to the ZAFEMY patch: Complete your current oral hormone birth control pill cycle, vaginal ring cycle or contraceptive transdermal patch cycle. Apply your first ZAFEMY patch on the day you would normally start your next oral birth control pill, patch or insert your next vaginal ring. If you do not get your period within 1 week after taking your last active pill, removing your last vaginal ring or contraceptive transdermal patch, check with your healthcare provider to make sure you are not pregnant. You may still go ahead and start ZAFEMY patch for contraception. If you apply your ZAFEMY patch more than 1 week after taking your last active oral hormone birth control pill, removing your last vaginal ring or contraceptive transdermal patch, use a non-hormonal contraceptive method, such as a condom and spermicide or diaphragm and spermicide, with the ZAFEMY patch for the first 7 days of patch use. If you are starting ZAFEMY after childbirth: If you are not breastfeeding, wait 4 weeks before using ZAFEMY and use a non-hormonal contraceptive method of birth control, such as a condom and spermicide or diaphragm and spermicide, for the first 7 days of your first cycle only. If you have had sex since your baby was born, wait for your first period, or see your healthcare provider to make sure you are not pregnant before starting ZAFEMY. If you are starting ZAFEMY after a miscarriage or abortion: You may start ZAFEMY immediately after a miscarriage or abortion that occurs in the first 12 weeks (first trimester) of pregnancy. You do not need to use another contraceptive method. If you do not start ZAFEMY within 5 days after a first trimester miscarriage or abortion, use a non-hormonal contraceptive method of birth control, such as a condom and spermicide or diaphragm and spermicide, while you wait for your period to start. You have 2 ways to begin using your ZAFEMY patch. Choose the way that is best for you: First day start: Apply your first ZAFEMY patch during the first 24 hours of your menstrual period. Sunday start: Apply your first ZAFEMY patch on the first Sunday after your menstrual period begins. Use a non-hormonal contraceptive method of birth control, such as a condom and spermicide or diaphragm and spermicide, for the first 7 days of your first cycle only. If your period starts on Sunday, apply your first ZAFEMY patch that day, and no back-up birth control is needed. If you are starting ZAFEMY after a miscarriage or abortion that occurs after the first 12 weeks of pregnancy (second trimester), wait 4 weeks before using ZAFEMY and use a non-hormonal contraceptive method of birth control, such as a condom and spermicide or diaphragm and spermicide, for the first 7 days of your first cycle only. If you have had sex since your miscarriage or abortion, wait for your first period, or see your healthcare provider to make sure you are not pregnant before starting ZAFEMY. Figure B is a picture of the ZAFEMY patch. Figure B Step 1. Choose a place on your body for your ZAFEMY patch The ZAFEMY patch may be placed on your upper outer arm, abdomen, buttock or back in a place where it will not be rubbed by tight clothing. Avoid the waistline because clothing and belts may cause your patch to be rubbed off. Do not apply the patch to your breasts. Apply the ZAFEMY patch only to skin that is clean, dry, and free of any powder, make-up, cream, oil, or lotion. Do not apply the ZAFEMY patch to cut or irritated skin, or in the same location as the previous ZAFEMY patch. Step 2: Apply your ZAFEMY patch Tear open the pouch at the top edge. Peel open the foil pouch that contains the ZAFEMY patch and its clear plastic cover. Gently remove the ZAFEMY patch and its plastic cover together from the pouch, being careful not to separate the patch from the clear plastic cover. Using a fingernail, peel away half of the clear plastic. Avoid touching the sticky surface with your fingers. Apply the sticky side of the ZAFEMY patch to clean, dry skin. Remove the other half of the clear plastic and apply the entire patch to your skin. Press firmly on the ZAFEMY patch with the palm of your hand for 10 seconds, making sure that the whole patch sticks to your skin. Run your fingers over the entire surface area to smooth out any “wrinkles” around the outer edges of the ZAFEMY patch. Check your ZAFEMY patch every day to make sure all edges are sticking correctly. Step 3: Throwing away your ZAFEMY patch To throw away the ZAFEMY patch, fold the sticky side of the patch together, place it in a sturdy child-proof container, and place the container in the trash. Used ZAFEMY patches should not be flushed in the toilet. Important notes: Your ZAFEMY patch must stick securely to your skin to work properly. Do not try to reapply a ZAFEMY patch if it is no longer sticky, if it has become stuck to itself or another surface, or if it has other material stuck to it. Do not tape or wrap the patch to your skin or reapply a patch that is partially adhered to clothing. If your ZAFEMY patch edge lifts up: Press down firmly on the patch with the palm of your hand for 10 seconds, making sure that the whole patch sticks to your skin. Run your fingers over the entire surface area to smooth out any “wrinkles” around the edges of the ZAFEMY patch. If your ZAFEMY patch does not stick completely, remove it and apply a replacement ZAFEMY patch. Do not tape or wrap the ZAFEMY patch to your skin or reapply a ZAFEMY patch that is partially stuck to clothing. If your ZAFEMY patch has been off or partially off: For less than 1 Day, try to reapply it. If the ZAFEMY patch does not stick completely, apply a new ZAFEMY patch immediately. No back-up contraception is needed and your "Patch Change Day" will stay the same. For more than 1 Day or if you are not sure for how long, you could become pregnant. To reduce this chance, apply a new ZAFEMY patch and start a new 4 week cycle. You will now have a new "Patch Change Day." Use a non-hormonal back-up contraception method such as a condom and spermicide or diaphragm and spermicide for the first week of your new 4 week ZAFEMY cycle. Talk to your healthcare provider about a replacement ZAFEMY patch prescription so you will always have an extra ZAFEMY patch available if needed. If you want to move your "Patch Change Day" to a different day of the week, finish your current cycle. Remove your third ZAFEMY patch on the correct day. During week 4, the "Patch Free Week" (Day 22 through Day 28), you may choose an earlier "Patch Change Day" by applying a new patch on the day you prefer. You now have a new Day 1 and a new "Patch Change Day." If your ZAFEMY patch becomes uncomfortable or your application site is red, painful or swollen, change your ZAFEMY patch. Remove your ZAFEMY patch and apply a new patch to a new location until your next "Patch Change Day." If you forget to change or remove your ZAFEMY patch: At the start of any patch cycle (Week 1, Day 1): You could become pregnant. You must use a back-up contraception method for 7 days. Apply the first ZAFEMY patch of your new cycle as soon as you remember. You now have a new "Patch Change Day" and a new Day 1. In the middle of your patch cycle (Week 2 or Week 3): If you forget to change your ZAFEMY patch for 1 or 2 days, apply a new ZAFEMY patch as soon as you remember. Apply your next patch on your normal "Patch Change Day." No back-up contraception method is needed. If you forget to change your ZAFEMY patch for more than 2 days, you could become pregnant. Start a new 4 week cycle as soon as you remember by putting on a new ZAFEMY patch. You now have a different "Patch Change Day" and a new Day 1. You must use a back-up contraception method for the first 7 days of your new cycle. At the end of your patch cycle (Week 4): If you forget to remove your ZAFEMY patch, take it off as soon as you remember. Start your next cycle on your normal "Patch Change Day," the day after Day 28. No back-up contraception method is needed. If you forget to apply your ZAFEMY patch at the start of your next patch cycle, you could become pregnant. Apply the first ZAFEMY patch of your new cycle as soon as you remember. You now have a new "Patch Change Day" and a new Day 1. Use a non-hormonal back-up contraception method such as a condom and spermicide or diaphragm and spermicide for the first 7 days of your new 4 week ZAFEMY cycle. If you have trouble remembering to change your ZAFEMY patch, talk to your healthcare provider about how to make patch changing easier or about using another method of contraception. If you are not sure how to use your ZAFEMY patch: Use a back-up contraception method such as a condom and spermicide or diaphragm and spermicide anytime you have sex. Make sure to have 1 of these non-hormonal contraception methods ready at all times. Talk to your healthcare provider for instructions on using your ZAFEMY patch. This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration. Zafemy is a registered trademark of Amneal Pharmaceuticals LLC Manufactured for: AvKARE Pulaski, TN 38478 Manufactured by: Amneal Pharmaceuticals LLC Piscataway, NJ 08854 Mfg. Rev. 04-2022-04 AV 04/23 Figure A Figure B Where to put patch Usage Illustration 1 Usage Illustration 2 Usage Illustration 3 Usage Illustration 4

14 CLINICAL STUDIES In 3 large clinical trials lasting 12 months, in North America, Europe and South Africa, 3,330 women (ages 18 to 45) completed 22,155 cycles of ZAFEMY patch use, the pregnancy rate in women aged 18 to 35 years was 1.07 (95% confidence interval 0.60, 1.76) per 100 woman-years of ZAFEMY patch use. The racial distribution was 91% Caucasian, 4.9% Black, 1.6% Asian, and 2.4% Other. With respect to weight, 5 of the 15 pregnancies reported with ZAFEMY patch use were among women with a baseline body weight ≥ 198 lbs., which constituted < 3% of the study population. The greater proportion of pregnancies among women at or above 198 lbs. was statistically significant and suggests that ZAFEMY patch may be less effective in these women. Patch Adhesion In the clinical trials with ZAFEMY patch, approximately 2% of the cumulative number of patches completely detached and 3% partially detached. The proportion of subjects with at least 1 patch that completely detached ranged from 2% to 6%, with a reduction from Cycle 1 (6%) to Cycle 13 (2%). For instructions on how to manage detachment of patches, refer to Dosage and Administration (2) .

8.5 Geriatric Use ZAFEMY has not been studied in postmenopausal women and is not indicated in this population.

8.3 Nursing Mothers The effects of ZAFEMY in nursing mothers have not been evaluated and are unknown. When possible, advise the nursing mother to use other forms of contraception until she has completely weaned her child. Estrogen-containing CHCs 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 contraceptive steroids and/or metabolites are present in breast milk.

8.4 Pediatric Use Safety and efficacy of ZAFEMY 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.

8.1 Pregnancy There is little or no increased risk of birth defects in women who inadvertently use hormonal contraceptives 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 hormonal contraceptives prior to conception or during early pregnancy. The administration of hormonal contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Hormonal contraceptives should not be used during pregnancy to treat threatened or habitual abortion.

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 hormonal contraceptives 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 hormonal contraceptives prior to conception or during early pregnancy. The administration of hormonal contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Hormonal contraceptives should not be used during pregnancy to treat threatened or habitual abortion. 8.3 Nursing Mothers The effects of ZAFEMY in nursing mothers have not been evaluated and are unknown. When possible, advise the nursing mother to use other forms of contraception until she has completely weaned her child. Estrogen-containing CHCs 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 contraceptive steroids and/or metabolites are present in breast milk. 8.4 Pediatric Use Safety and efficacy of ZAFEMY 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 ZAFEMY has not been studied in postmenopausal women and is not indicated in this population. 8.6 Hepatic Impairment No studies with ZAFEMY have been conducted in women with hepatic impairment. However, steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of combined hormonal contraceptive use until markers of liver function return to normal and combined hormonal contraceptive causation has been excluded [see Contraindications (4) and Warnings and Precautions (5.3) ] . 8.7 Renal Impairment No studies with ZAFEMY have been conducted in women with renal impairment. 8.8 BMI and Weight Considerations ZAFEMY is contraindicated in women with a BMI ≥ 30 kg/m 2 because of the potential increased risk of VTE [see Contraindications (4) and Warnings and Precautions (5.1) ] . ZAFEMY may be less effective in preventing pregnancy in women who weigh 198 lbs or more [see Clinical Studies (14) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied ZAFEMY (norelgestromin and ethinyl estradiol transdermal system) is available in one strength of 150 mcg/day NGMN, USP and 35 mcg/day EE, USP. ZAFEMY is a 12.5 cm 2 system with rounded corners with tan backing printed with “Norelgestromin and Ethinyl Estradiol 150/35 mcg per day” in brown ink, protected with a removable translucent oversized dimple slit-release liner. Each patch contains 3.15 mg of norelgestromin, USP and 0.289 mg of ethinyl estradiol, USP. Each transdermal system is packaged in a protective pouch. ZAFEMY is available in folding cartons of 1 cycle each (NDC 42291-930-03); each cycle contains 3 systems. 16.2 Special Precautions for Storage and Disposal Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Store patches in their protective pouches. Apply immediately upon removal from the protective pouch. Do not store in the refrigerator or freezer. Used patches still contain some active hormones. The sticky sides of the patch should be folded together and the folded patch placed in a sturdy container, preferably with a child-resistant cap, and the container thrown in the trash. Used patches should not be flushed down the toilet. For more information, go to www.avkare.com or call 1-855-361-3993

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS and CONTRAINDICATED IN WOMEN WITH A BMI ≥ 30 kg/m2 Cigarette Smoking and Serious Cardiovascular Events Cigarette smoking increases the risk of serious cardiovascular events from hormonal contraceptive use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, CHCs, including ZAFEMY, are contraindicated in women who are over 35 years of age and smoke [see Contraindications (4) and Warnings and Precautions (5.1) ] . Contraindicated in Women with a BMI ≥ 30 kg/m 2 ZAFEMY is contraindicated in women with a BMI ≥ 30 kg/m 2 . The risk of VTE may be greater with ZAFEMY in women with a BMI > 30 kg/m 2 compared to women with a lower BMI [see Contraindications (4) and Warnings and Precautions (5.1) ] . WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS and CONTRAINDICATED IN WOMEN WITH A BMI ≥ 30 kg/m 2 See full prescribing information for complete boxed warning. ZAFEMY is contraindicated in women over 35 years old who smoke. Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive (CHC) use. ( 4 , 5.1 ) ZAFEMY is contraindicated for use in women with a BMI ≥ 30 kg/m 2 . Women with a BMI ≥ 30 kg/m 2 who use ZAFEMY may have a higher risk of venous thromboembolic events compared with women with a lower BMI. ( 4 , 5.1 , 8.8 )