PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PRINCIPAL DISPLAY PANEL



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INDICATIONS & USAGE SECTION

Highlight: ZAFEMY® is an estrogen/progestin combination hormonal contraceptive (CHC), indicated for the prevention of pregnancy in women with a BMI < 30 kg/m2 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)

1 INDICATIONS AND USAGE

ZAFEMY® is indicated for the prevention of pregnancy in women with a body mass index (BMI) < 30 kg/m2 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/m2 [see Contraindications (4), Warnings and Precautions (5.1) and Clinical Studies (14)].

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DRUG INTERACTIONS SECTION

Highlight: 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 DRUG INTERACTIONS

Consult the labeling of concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.

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.

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USE IN SPECIFIC POPULATIONS SECTION

Highlight: * Nursing mothers: Not recommended; can decrease milk production. (8.3)

8 USE IN SPECIFIC POPULATIONS

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/m2 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)].

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ADVERSE REACTIONS SECTION

Highlight: 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 orwww.fda.gov/medwatch.

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

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.

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 retention1, malaise *Hepatobiliary disorders: Cholecystitis *Investigations: Blood pressure increased, lipid disorders1 *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

1Represents 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.

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NONCLINICAL TOXICOLOGY SECTION

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.

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HOW SUPPLIED SECTION

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 cm2 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 65162-358-03); 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.

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INSTRUCTIONS FOR USE SECTION

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 fromoral hormone birth controlpills, a vaginal contraceptive ringor another contraceptive transdermal patch*to theZAFEMY 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 startingZAFEMY 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 startingZAFEMY 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 occursafter 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

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:

*YourZAFEMY 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 yourZAFEMY 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 yourZAFEMY 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 anearlier "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 yourZAFEMY 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 yourZAFEMY 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 yourZAFEMY 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 yourZAFEMY 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 yourZAFEMY 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 yourZAFEMY 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 yourZAFEMY 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.

Distributed by:
Amneal Pharmaceuticals LLC
****Bridgewater, NJ 08807

Rev. 04-2022-04

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