ZAFEMY

Warnings and Precautions ( 5.12 ) 11/2021

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 )

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 pat …

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)

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)

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 Amneal Pharmaceuticals at 1-877-835-5472 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 Experien …

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.

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) ] .

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).

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

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.

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

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.