ZAFEMY: Package Insert and Label Information (Page 2 of 6)

3 DOSAGE FORMS AND STRENGTHS

Transdermal system: 150 mcg/day norelgestromin, USP and 35 mcg/day ethinyl estradiol, USP.

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/m² [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)]

5 WARNINGS AND PRECAUTIONS

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 (C_max ) 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.

Table 2: Unscheduled (Breakthrough) Bleeding/Spotting (Subjects Evaluable for Efficacy)
Treatment Cycle	Pooled data from 3 studies N=3,319
	n	%a
Cycle 1	2,994	18.2
Cycle 2	2,743	11.9
Cycle 3	2,699	11.6
Cycle 4	2,541	10.1
Cycle 5	2,532	9.2
Cycle 6	2,494	8.3
Cycle 7	698	8.3
Cycle 8	692	8.7
Cycle 9	654	8.6
Cycle 10	621	8.7
Cycle 11	631	8.9
Cycle 12	617	6.3
Cycle 13	611	8.0
a Percentage of subjects with breakthrough bleeding/spotting events.

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)].