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

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

1. 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.
2. 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.
3. If the woman has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. Discontinue ZAFEMY use if pregnancy is confirmed.

5.1 Thromboembolic Disorders and Other Vascular Conditions

• Stop ZAFEMY if an arterial or venous thromboembolic event (VTE) occurs.
• Stop ZAFEMY if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.
• If feasible, stop ZAFEMY at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE. Discontinue use of ZAFEMY during prolonged immobilization and resume treatment based on clinical judgment.
• Start ZAFEMY no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum VTE decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.
• Before starting ZAFEMY, evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy [see Contraindications (4)].

Arterial Events

The use of CHCs increases the risk of cardiovascular events and cerebrovascular events, such as myocardial infarction and stroke. The risk is greater among older women (> 35 years of age), smokers, and women with hypertension, dyslipidemia, diabetes, or obesity. ZAFEMY is contraindicated in women over 35 years of age who smoke [see Contraindications (4)]. Cigarette smoking increases the risk of serious cardiovascular events from CHC use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked.

Venous Events

The use of CHCs increases the risk of venous thromboembolic events (VTEs), such as deep vein thrombosis and pulmonary embolism. Risk factors for VTEs include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of CHCs. The risk of VTE may be greater with ZAFEMY in women with a BMI ≥ 30 kg/m2 compared to women with a lower BMI [see Contraindications (4)].

While the risk of VTE associated with the use of CHCs is well-established, the rates of VTE are even greater during pregnancy, and especially during the post-partum period (see Figure 1). The frequency of VTE in women using CHCs has been estimated to be 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. This initial higher risk declines during the first year, but users of CHCs remain at an increased risk of VTE compared to non-users of CHCs. Based on results from a few studies, there is some evidence that this is true for non-oral products as well. The risk of thromboembolic disease due to CHCs gradually disappears after CHC use is discontinued.

Figure 1 shows the risk of developing a VTE for women who are not pregnant and do not use CHCs, for women who use CHCs with a range of doses and routes of administration, for pregnant women, and for women in the post-partum period. To put the risk of developing a VTE into perspective: If 10,000 women who are not pregnant and do not use CHCs are followed for one year, between 1 and 5 of these women will develop a VTE.

Figure 1: Likelihood of Developing a VTE Within One Year Among Pregnant and Non-Pregnant Women

*CHC = combination hormonal contraception

**Pregnancy data based on actual duration of pregnancy in the reference studies. Based on a model assumption that pregnancy duration is nine months, the rate is 7 to 27 per 10,000 WY.

5.2 Ethinyl Estradiol Exposure

Higher estrogen exposure may increase the risk of adverse reactions, including venous thromboembolism (VTE). The Area Under the Curve (AUC) for ethinyl estradiol (EE) is approximately 60% higher in women using ZAFEMY compared to oral contraceptives containing EE 35 mcg. In contrast, the peak concentration (Cmax) for EE is approximately 25% lower in women using ZAFEMY [see Clinical Pharmacology (12.3)].

5.3 Liver Disease

Impaired Liver Function

Do not use ZAFEMY in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of liver [see Contraindications (4)]. Discontinue ZAFEMY if jaundice develops. Acute or chronic disturbances of liver function may necessitate the discontinuation of CHC use until markers of liver function return to normal and CHC causation has been excluded.

Liver Tumors

ZAFEMY is contraindicated in women with benign and malignant liver tumors [see Contraindications (4)]. Hepatic adenomas are associated with CHC use. An estimate of the attributable risk is 3.3 cases/100,000 CHC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.

Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) CHC users. However, the risk of liver cancers in CHC users is less than one case per million users.

5.4 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications, such as CHCs. Discontinue ZAFEMY prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4)]. ZAFEMY can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

5.5 High Blood Pressure

ZAFEMY is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see Contraindications (4)]. For women with well-controlled hypertension, monitor blood pressure and stop ZAFEMY if blood pressure rises significantly.

An increase in blood pressure has been reported in women taking hormonal contraceptives, and this increase is more likely in older women with extended duration of use. The incidence of hypertension increases with increasing concentrations of progestin.

5.6 Gallbladder Disease

Studies suggest a small increased relative risk of developing gallbladder disease among CHC users. Use of CHCs may also worsen existing gallbladder disease. A past history of CHC-related cholestasis predicts an increased risk with subsequent CHC use. Women with a history of pregnancy-related cholestasis may be at an increased risk for CHC-related cholestasis.

5.7 Carbohydrate and Lipid Metabolic Effects

Carefully monitor prediabetic and diabetic women who take ZAFEMY. CHCs may decrease glucose tolerance in a dose-related fashion. In a 6-cycle clinical trial with ZAFEMY patch there were no clinically significant changes in fasting blood glucose from baseline to end of treatment.

Consider alternative contraception for women with uncontrolled dyslipidemia. A small proportion of women will have adverse lipid changes while on hormonal contraceptives.

Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using hormonal contraceptives.

5.8 Headache

If a woman taking ZAFEMY develops new headaches that are recurrent, persistent or severe, evaluate the cause and discontinue ZAFEMY if indicated.

Consider discontinuation of ZAFEMY in the case of increased frequency or severity of migraine during hormonal contraceptive use (which may be prodromal of a cerebrovascular event).

5.9 Bleeding Irregularities

Unscheduled Bleeding and Spotting

Unscheduled (breakthrough) bleeding and spotting sometimes occur in women using ZAFEMY. Consider non-hormonal causes and take adequate diagnostic measures to rule out malignancy, other pathology, or pregnancy in the event of unscheduled bleeding, as in the case of any abnormal vaginal bleeding. If pathology and pregnancy have been excluded, time or a change to another contraceptive product may resolve the bleeding.

In the clinical trials, most women started their scheduled (withdrawal) bleeding on the fourth day of the drug-free interval, and the median duration of withdrawal bleeding was 5 to 6 days. On average, 26% of women per cycle had 7 or more total days of bleeding and/or spotting (this includes both scheduled and unscheduled bleeding and/or spotting). Three clinical studies of the efficacy of ZAFEMY in preventing pregnancy assessed scheduled and unscheduled bleeding [see Clinical Studies (14)] in 3,330 women who completed 22,155 cycles of exposure. A total of 36 (1.1%) of the women discontinued ZAFEMY at least in part, due to bleeding or spotting.

Table 2 summarizes the proportion of subjects who experienced unscheduled (breakthrough) bleeding/spotting by treatment cycle.

Amenorrhea and Oligomenorrhea

In the event of amenorrhea, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one patch or started the patch on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy.

Some women may encounter amenorrhea or oligomenorrhea after discontinuation of hormonal contraceptive use, especially when such a condition was pre-existent.

5.10 Hormonal Contraceptive Use Before or During Early Pregnancy

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. Discontinue ZAFEMY use if pregnancy is confirmed.

Administration of CHCs should not be used as a test for pregnancy [see Use in Specific Populations (8.1)].

5.11 Depression

Carefully observe women with a history of depression and discontinue ZAFEMY if depression recurs to a serious degree.

5.12 Malignant Neoplasms

Breast Cancer

ZAFEMY is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4)]. Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use [see Postmarketing Experience (6.2)].

Cervical Cancer

Some studies suggest that combination oral contraceptive use has been associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

5.13 Effect on Binding Globulins

The estrogen component of CHCs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased.

5.14 Monitoring

A woman who is taking hormonal contraceptive should have routine visits with her healthcare provider for a blood pressure check and for other indicated healthcare.

5.15 Hereditary Angioedema

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

5.16 Chloasma

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while using ZAFEMY.

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.

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.

8.1 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)].

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, Css 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 Css and AUC0-168 for NGMN and EE following a single buttock application of ZAFEMY are summarized in Table 5.

In multiple dose studies, AUC0-168 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.

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 Css 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.

In general, overall exposure for NGMN and EE (AUC and Css) was higher in subjects treated with ZAFEMY for both Cycle 1 and Cycle 2, compared to that for the oral contraceptive, while Cmax values were higher in subjects administered the oral contraceptive. Under steady-state conditions, AUC0-168 and Css for EE were approximately 55% and 60% higher, respectively, for the transdermal patch, and the Cmax 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.

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 Css 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.

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.

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.

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.

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Distributed by:
Amneal Pharmaceuticals LLC
Bridgewater, NJ 08807

Rev. 04-2022-04