ETHINYL ESTRADIOL: 309 Adverse Event Reports & Safety Profile

ANNOVERA (segesterone acetate and ethinyl estradiol vaginal system) is a toroidal- shaped (ring), nonbiodegradable, flexible, opaque white vaginal system containing two active components, a progestin, segesterone acetate, and an estrogen, ethinyl estradiol. When placed in the vagina, each ANNOVERA releases an approximate average 0.15 mg/day of segesterone acetate and 0.013 mg/day of ethinyl estradiol over the 21 days in-use period of each cycle for up to 13 cycles (total of 273 days). Each cycle is 28 days, with 21 days in and 7 days out. The inactive ingredients are dibutyltin dilaurate, silicone elastomers, silicone medical adhesive, and titanium dioxide. The elastomers are all methyl siloxane-based polymers. The vaginal system body has an overall diameter of 56 mm and a cross-sectional diameter of 8.4 mm. It contains two channels of approximately 3.0 mm diameter and 27 mm length into which steroid-containing cores are inserted. Each ANNOVERA contains 103 mg of SA distributed throughout both cores and 17.4 mg of EE distributed throughout only one core. The core containing 40% SA and 12% EE of its mass is 3 mm in diameter and 18 mm in length. The core containing 50% SA of its mass is 3 mm in diameter and 11 mm in length. Contact between the cores and the vaginal system body is fixed by coating the channels with silicone medical adhesive before introducing the cores. After insertion of the cores, the channels are sealed with the silicone medical adhesive. The structural formulas, and properties for the active components are shown below: STRUCTURAL FORMULAS: Segesterone Acetate (SA)

Ethinyl

Estradiol (EE) PROPERTIES: Established Name: Segesterone Acetate Chemical Name: 16-methylene-17α-acetoxy-19-nor-pregn-4-ene-3,20-dione Molecular Formula: C 23 H 30 O 4 Molecular Weight:

370.5 Physical Form: White, or yellowish white powder Solubility: Slightly soluble in n-hexane, soluble in ethyl acetate and methanol, freely soluble in acetone (USP classification)

Melting

Point: 173°C–177°C Established Name: Ethinyl Estradiol Chemical Name: 19-Nor-17α -pregna-1,3,5(10)-trien-20-yne-3,17-diol Molecular Formula: C 20 H 24 O 2 Molecular Weight:

296.4 Physical Form: White to slightly ye ll owish-white crysta ll ine powder Solubility: Practically insoluble in water, freely soluble in alcohol, it dissolves in alkaline solution Melting Point: 181°C–185°C The steroids diffuse out of the vaginal system with release rates that vary over time. Based on in vitro data, the daily release rates of SA and EE are higher during each initial 24–48 hours of use achieving a somewhat lower steady-state with continued use over the subsequent days in each cycle. The vaginal system is designed to be used for 13 cycles (1 year) on a 21/7 days in/out schedule. The total in-use time with the 21/7 days in/out schedule over 13 cycles is 273 days. Based on the residual amount of drug in vaginal systems used in clinical trials over 13 cycles, a total of 41.3 mg of SA and 3.4 mg of EE are released over this period. This translates to an approximate average daily dose of 0.15 mg of segesterone acetate and 0.013 mg of ethinyl estradiol with higher release rate expected at the beginning of dosing and a lower release rate toward the end.

Chemical Structure Chemical

Structure

INDICATIONS AND USAGE Levonorgestrel and ethinyl estradiol tablets are indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception. Oral contraceptives are highly effective for pregnancy prevention.

Table

2 lists the typical unintended pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and implants, depend upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

Table

2: Percentage of Women Experiencing an Unintended Pregnancy During The First Year of Typical Use and The First Year of Perfect Use of Contraception and The Percentage Continuing Use at The End of the First Year.

United

States. % of Women Experiencing an Unintended Pregnancy within the First Year of Use % of Women Continuing Use at One Year 3 Method (1)

Typical Use

1 (2)

Perfect Use

2 (3) (4)

Chance

4 85 85 Spermicides 5 26 6 40 Periodic abstinence 25 63 Calendar 9 Ovulation Method 3 Sympto-Thermal 6 2 Post-Ovulation 1 Cap 7 Parous Women 40 26 42 Nulliparous Women 20 9 56 Sponge Parous Women 40 20 42 Nulliparous Women 20 9 56 Diaphragm 7 20 6 56 Withdrawal 19 4 Condom 8 Female (Reality TM ) 21 5 56 Male 14 3 61 Pill 5 71 Progestin only

0.5 Combined

0.1 IUD Progesterone T 2 1.5 81 Copper T380A 0.8 0.6 78 LNg 20 0.1 0.1 81 Depo-Provera ® 0.3 0.3 70 Levonorgestrel Implants (Norplant ®) 0.05 0.05 88 Female Sterilization 0.5 0.5 100 Male Sterilization 0.15 0.10 100 Emergency Contraceptive Pills: The FDA has concluded that certain combined oral contraceptives containing ethinyl estradiol and norgestrel or levonorgestrel are safe and effective for use as postcoital emergency contraception. Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%. 9 Lactation Amenorrhea Method: LAM is a highly effective, temporary method of contraception. 10 Source: Trussell J. Contraceptive efficacy. In: Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowel D, Guest F.

Contraceptive

Technology: Seventeenth Revised Edition.

New

York NY: Irvington Publishers; 1998. 1. Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. 2. Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. 3. Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. 4. The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether. 5. Foams, creams, gels, vaginal suppositories, and vaginal film. 6. Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. 7. With spermicidal cream or jelly. 8. Without spermicides. 9. The treatment schedule is one dose within 72 hours after unprotected intercourse and a second dose 12 hours after the first dose. The FDA has declared the following dosage regimens of oral contraceptives to be safe and effective for emergency contraception: for tablets containing 0.05 mg of ethinyl estradiol and 0.5 mg of norgestrel 1 dose is 2 tablets; for tablets containing 0.02 mg of ethinyl estradiol and 0.1 mg of levonorgestrel 1 dose is 5 tablets; for tablets containing 0.03 mg of ethinyl estradiol and 0.15 mg of levonorgestrel 1 dose is 4 tablets. 10. However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches 6 months of age.

Clinical Studies

The efficacy and safety of levonorgestrel and ethinyl estradiol were studied in 2 one-year clinical trials of subjects age 18 to 49. There were no exclusions for body mass index (BMI), weight, or bleeding history. The primary efficacy and safety study (313-NA) was a one-year open-label clinical trial that treated 2,134 subjects in North America. Of these subjects 1,213 (56.8%) discontinued prematurely, including 102 (4.8%) discontinued by the Sponsor for early study closure. The mean weight of subjects in this study was 70.38 kg. The efficacy of levonorgestrel and ethinyl estradiol was assessed by the number of pregnancies that occurred after the onset of treatment and within 14 days of the last dose. Among subjects 35 years or less, there were 23 pregnancies (4 of these occurred during the interval 1 to 14 days after the last day of pill use) during 12,572 28-day pill packs of use. The resulting total Pearl Index was 2.38 (95% CI: 1.51, 3.57) and the one-year life table pregnancy rate was 2.39 (95% CI: 1.57, 3.62). Pill pack cycles during which subjects used back-up contraception or were not sexually active were not included in these calculations. Among women 35 years or less who took the pills completely as directed, there were 15 pregnancies (method failures) resulting in a Pearl Index of 1.55 (95% CI: 0.87, 2.56) and the one-year life table pregnancy rate was 1.59 (95% CI: 0.95 to 2.67). In a second supportive study conducted in Europe (315-EU), 641 subjects were randomized to levonorgestrel and ethinyl estradiol (n=323) or the cyclic comparator of 0.1 mg levonorgestrel and 0.02 mg ethinyl estradiol (n=318). The mean weight of subjects in this study was 63.86 kg. The efficacy analysis among women 35 years or less included 2,756 levonorgestrel and ethinyl estradiol pill packs and 2,886 cyclic comparator pill packs. There was one pregnancy in the levonorgestrel and ethinyl estradiol group that occurred within 14 days following the last dose. There were three pregnancies in the cyclic comparator group. Inhibition of Menses (Bleeding Profile) The bleeding profile for subjects in Study 313-NA also was assessed. Women with a history of unscheduled bleeding and/or spotting were not excluded from the study. In those subjects who provided complete bleeding data, the percentage of patients who were amenorrheic in a given cycle and remained amenorrheic through cycle 13 (cumulative amenorrhea rate) was determined (Figure 2).

Figure

2: Percentage of Subjects with Cumulative Amenorrhea for Each Pill Pack through Pill Pack 13 When prescribing levonorgestrel and ethinyl estradiol, the convenience of having no scheduled menstrual bleeding should be weighed against the inconvenience of unscheduled bleeding and spotting (see WARNINGS , 11 ). fig-2

AND ADMINISTRATION To achieve maximum contraceptive effectiveness, norelgestromin and ethinyl estradiol transdermal system 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. Norelgestromin and ethinyl estradiol transdermal system 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 Norelgestromin and Ethinyl Estradiol Transdermal System The norelgestromin and ethinyl estradiol 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 norelgestromin and ethinyl estradiol transdermal patch in any way. If the norelgestromin and ethinyl estradiol transdermal 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 Norelgestromin and Ethinyl Estradiol Transdermal System There are multiple options for starting the norelgestromin and ethinyl estradiol transdermal system, and the woman should choose the option that is most appropriate (see Table 1): Table 1: Instructions for Administration Starting norelgestromin and ethinyl estradiol transdermal system 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 norelgestromin and ethinyl estradiol transdermal system, she should complete her current pill cycle and apply the first norelgestromin and ethinyl estradiol transdermal system 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 norelgestromin and ethinyl estradiol transdermal system 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 norelgestromin and ethinyl estradiol transdermal system, she should complete the current transdermal system cycle and apply the first norelgestromin and ethinyl estradiol transdermal system on the day the next transdermal system cycle would normally start. If she does not get her period within a week after removing the last transdermal system, she should check with her healthcare professional to be sure that she is not pregnant, but she may go ahead and start norelgestromin and ethinyl estradiol transdermal system for contraception. If norelgestromin and ethinyl estradiol transdermal system is applied more than a week after removal of the last patch, non-hormonal back-up contraception (such as condoms and spermicide, or diaphragm and spermicide) should be used concurrently for the first 7 days of patch use. Vaginal ring If the woman is switching from the vaginal ring to norelgestromin and ethinyl estradiol transdermal system, she should complete her current vaginal ring cycle and apply the first norelgestromin and ethinyl estradiol transdermal system on the day she would normally insert her next vaginal ring. If she does not get her period within a week after removing the last vaginal ring, she should check with her healthcare professional to be sure that she is not pregnant, but she may go ahead and start norelgestromin and ethinyl estradiol transdermal system for contraception. If the patch is applied more than a week after removal of the last vaginal ring, she should use a non-hormonal back-up contraception (such as condoms and spermicide, or diaphragm and spermicide) concurrently for the first 7 days of patch use. Injection If the woman is switching from an injection contraceptive to norelgestromin and ethinyl estradiol transdermal system, she should apply the first norelgestromin and ethinyl estradiol transdermal system on the day the next injection would normally occur. Intrauterine system (IUS) If the woman is switching from an intrauterine system to norelgestromin and ethinyl estradiol transdermal system, she should apply the first norelgestromin and ethinyl estradiol transdermal system on the day of IUS removal. If the IUS is not removed on the first day of the menstrual cycle, non-hormonal backup contraception (such as condoms and spermicide, or diaphragm and spermicide) should be used concurrently for the first 7 days of patch use. Implant If the woman is switching from an implant to norelgestromin and ethinyl estradiol transdermal system, she should apply the first norelgestromin and ethinyl estradiol transdermal system on the day of implant removal. Progestin-only pill If the woman is switching from a progestin-only pill to norelgestromin and ethinyl estradiol transdermal system, she should apply the first norelgestromin and ethinyl estradiol transdermal system on the day the next progestin-only pill cycle would normally start. Use after Childbirth Start contraceptive therapy with norelgestromin and ethinyl estradiol transdermal system 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 norelgestromin and ethinyl estradiol transdermal system postpartum, and has not yet had a period, consider the possibility of ovulation and conception occurring prior to use of norelgestromin and ethinyl estradiol transdermal system, 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, norelgestromin and ethinyl estradiol transdermal system may be started immediately. An additional method of contraception is not needed if norelgestromin and ethinyl estradiol transdermal system is started immediately. If use of norelgestromin and ethinyl estradiol transdermal system is not started within 5 days following a first trimester abortion, the woman should follow the instructions for a woman starting norelgestromin and ethinyl estradiol transdermal system 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 norelgestromin and ethinyl estradiol transdermal system 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 Norelgestromin and Ethinyl Estradiol Transdermal System 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 Norelgestromin And Ethinyl Estradiol Transdermal 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 norelgestromin and ethinyl estradiol transdermal 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 norelgestromin and ethinyl estradiol transdermal patch on the correct day. During the patch-free week, she may select an earlier Patch Day Change by applying a new norelgestromin and ethinyl estradiol transdermal 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 norelgestromin and ethinyl estradiol transdermal system is worn), treatment should be continued. If unscheduled bleeding persists longer than a few cycles, consider causes other than norelgestromin and ethinyl estradiol transdermal system. 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 norelgestromin and ethinyl estradiol transdermal system 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 norelgestromin and ethinyl estradiol transdermal system if pregnancy is confirmed.

In

Case of Skin Irritation If patch use results in uncomfortable irritation, the patch may be removed and a new patch may be applied to a different location until the next Change Day. Only one patch should be worn at a time.

Additional

Instructions for Dosing Unscheduled bleeding, spotting, and amenorrhea are frequent reasons for patients discontinuing hormonal contraceptives. In case of breakthrough bleeding, as in all cases of irregular bleeding from the vagina, consider nonfunctional causes. In case of undiagnosed persistent or recurrent abnormal bleeding from the vagina, take adequate diagnostic measures to rule out pregnancy or malignancy. If pathology has been excluded, time or a change to another method of contraception may solve the problem. Use of Hormonal Contraceptives in the Event of a Missed Menstrual Period If the woman has not adhered to the prescribed schedule, consider the possibility of pregnancy at the time of the first missed period. Discontinue use of norelgestromin and ethinyl estradiol transdermal system if pregnancy is confirmed. If the woman has adhered to the prescribed regimen and misses one period, she should continue using her contraceptive patches. However, if she has adhered to the prescribed regimen, misses one period and has symptoms associated with pregnancy, rule out pregnancy. Discontinue norelgestromin and ethinyl estradiol transdermal system use if pregnancy is confirmed. If the woman has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. Discontinue norelgestromin and ethinyl estradiol transdermal system use if pregnancy is confirmed. Where to put patch Usage Illustration 1 Usage Illustration 2 Usage Illustration 3 Usage Illustration 4

Twirla is contraindicated in females who are known to have or develop the following conditions: At high risk of arterial or venous thrombotic diseases. Examples include women who Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions ( 5.1 )] Have current or history of deep vein thrombosis or pulmonary embolism [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 inherited or acquired hypercoagulopathies [see Warnings and Precautions ( 5.1 )] Have uncontrolled hypertension or hypertension with vascular disease [see Warnings and Precautions ( 5.4 )] Have diabetes mellitus and are over age 35, diabetes mellitus with hypertension or vascular disease or other end-organ damage, or diabetes mellitus of > 20 years duration [see Warnings and Precautions ( 5.7 )] Have headaches with focal neurological symptoms, migraine headaches with aura Women over age 35 with any migraine headaches [see Warnings and Precautions ( 5.8 )] BMI ≥ 30 kg/m 2 . Compared to women with a lower BMI, women with a BMI ≥ 30 kg/m 2 had reduced effectiveness and may have a higher risk for VTEs [see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.9 ) and Clinical Studies ( 14 )]. Liver tumors (benign or malignant), acute viral hepatitis, or severe (decompensated) cirrhosis, or liver disease [see Warnings and Precautions ( 5.2 )] Undiagnosed abnormal uterine bleeding [see Warnings and Precautions ( 5.9 )] Pregnancy, because there is no reason to use CHCs during pregnancy [see Use in Specific Populations ( 8.1 )] Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [see Warnings and Precautions ( 5.11 )] Hypersensitivity to any components of TWIRLA. Observed reactions include itching and irritation at the TDS application site [see Adverse Reactions ( 6.1 )] Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for alanine aminotransferase (ALT) elevations [see Warnings and Precautions ( 5.3 )] High risk of arterial or venous thrombotic diseases ( 4 ) Breast cancer ( 4 ) BMI ≥ 30 kg/m 2 ( 4 ) Liver tumors, acute viral hepatitis or decompensated cirrhosis ( 4 ) Undiagnosed abnormal uterine bleeding ( 4 ) Pregnancy ( 4 , 8.1 ) Hypersensitivity reactions to components of TWIRLA ( 4 ) Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir ( 4 )

REACTIONS The following serious adverse reactions with the use of combination hormonal contraceptives, including norelgestromin and ethinyl estradiol transdermal system, 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 Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 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 norelgestromin and ethinyl estradiol transdermal system in 3330 sexually active women (3322 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 (norelgestromin and ethinyl estradiol transdermal system 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 norelgestromin and ethinyl estradiol transdermal system-treated subjects in these trials are shown in Table 3.

Table

3: Adverse Drug Reactions Reported by ≥ 2.5% of Norelgestromin and Ethinyl Estradiol Transdermal System-treated Subjects in Three Phase 3 Clinical Trials System/Organ Class * Adverse reaction Norelgestromin and Ethinyl Estradiol Transdermal System (n = 3322) 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 norelgestromin and ethinyl estradiol transdermal system-treated subjects in the above clinical trials datasets are: Gastrointestinal disorders : Abdominal distension General disorders and administration site conditions : Fluid retention 1 , malaise Hepatobiliary disorders : Cholecystitis Investigations : Blood pressure increased, lipid disorders 1 Musculoskeletal and connective tissue disorders : Muscle spasms Psychiatric disorders : Insomnia, libido decreased, libido increased Reproductive system and breast disorders : Galactorrhea, genital discharge, premenstrual syndrome, uterine spasm, vaginal discharge, vulvovaginal dryness Respiratory, thoracic and mediastinal disorders : Pulmonary embolism Skin and subcutaneous tissue disorders : Chloasma, dermatitis contact, erythema, skin irritation 1 Represents a bundle of similar terms

6.2 Postmarketing Experience Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 - 1.12 (Figure 2). Three studies compared breast cancer risk between current or recent COC users (&lt;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 - 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 8-10 years of COC use.

Figure

2: Risk of Breast Cancer with Combined Oral Contraceptive Use RR = relative risk; OR = odds ration; HR = hazard ration. "ever COC" are females with current or past COC use; "never COC use" are fmales that never used COCs. The following adverse reactions (Table 4) have been identified during postapproval use of norelgestromin and ethinyl estradiol transdermal system. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Table

4: Alphabetical List of Adverse Drug Reactions Identified During Postmarketing Experience with Norelgestromin and Ethinyl Estradiol Transdermal System by System Organ Class* System Organ Class Adverse Drug Reactions Cardiac disorders Myocardial infarction † Endocrine disorders Hyperglycemia, insulin resistance Eye disorders Contact lens intolerance or complication Gastrointestinal disorders Colitis General disorders and administration site conditions Application site reaction † , edema † Hepatobiliary disorders Blood cholesterol abnormal, cholelithiasis, cholestasis, hepatic lesion, jaundice cholestatic, low density lipoprotein increased Immune system disorders Allergic reaction † , urticaria Investigations Blood glucose abnormal, blood glucose decreased Metabolism and nutrition disorders Increased appetite Neoplasms benign, malignant and unspecified (Incl. cysts and polyps) Breast cancer † , cervix carcinoma, hepatic adenoma, hepatic neoplasm Nervous system disorders Dysgeusia, migraine with aura Psychiatric disorders Anger, emotional disorder, frustration, irritability Reproductive system and breast disorders Breast mass, cervical dysplasia, fibroadenoma of breast, menstrual disorder † , suppressed lactation, uterine leiomyoma Skin and subcutaneous tissues disorders Alopecia, eczema, erythema multiforme, erythema nodosum, photosensitivity reaction, pruritus generalized, rash † , seborrheic dermatitis, skin reaction Vascular disorders Arterial thrombosis † , cerebrovascular accident † , deep vein thrombosis † , hemorrhage intracranial † , hypertension, hypertensive crisis, pulmonary embolism † , thrombosis † *MedDRA version 10.0 † Represents a bundle of similar terms figure-2

WARNINGS Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with the extent of smoking (in epidemiologic studies, 15 or more cigarettes per day was associated with a significantly increased risk) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke. The use of oral contraceptives is associated with increased risks of several serious conditions including venous and arterial thrombotic and thromboembolic events (such as myocardial infarction, thromboembolism, stroke, and transient ischemic attack), hepatic neoplasia, gallbladder disease, and hypertension, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as certain inherited or acquired thrombophilias, hypertension, hyperlipidemias, obesity, diabetes, and surgery or trauma with increased risk of thrombosis (see CONTRAINDICATIONS ). Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks. The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher doses of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower doses of both estrogens and progestogens remains to be determined. Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population. For further information, the reader is referred to a text on epidemiological methods. 1.

Thromboembolic

Disorders and Other Vascular Problems Levonorgestrel and ethinyl estradiol is a non-cyclic oral contraceptive that provides a low daily dose of estrogen and progestin; however, levonorgestrel and ethinyl estradiol provides women with more hormonal exposure on a yearly basis (13 additional weeks of hormone intake per year) than conventional cyclic oral contraceptives containing the same strength of synthetic estrogens and similar strength of progestins. a.

Myocardial

Infarction An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary-artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six. The risk is very low under the age of 30. Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarction in women in their mid-thirties or older with smoking accounting for the majority of excess cases. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and nonsmokers over the age of 40 (Figure 3) among women who use oral contraceptives.

Figure

3: Circulatory Disease Mortality Rates per 100,000 Woman Years by Age, Smoking Status and Oral Contraceptive Use Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age, and obesity. In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. Oral contraceptives have been shown to increase blood pressure among users (see section 9 in WARNINGS ). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. fig-3 b.

Venous

Thrombosis and Thromboembolism An increased risk of venous thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. The risk of venous thrombotic and thromboembolic events is further increased in women with conditions predisposing for venous thrombosis and thromboembolism. Case control studies have found the relative risk of users compared to non-users to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep-vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization. The approximate incidence of deep-vein thrombosis and pulmonary embolism in users of low dose (<0.05 mg ethinyl estradiol) combination oral contraceptives is up to 4 per 10,000 woman-years compared to 0.5 to 3 per 10,000 woman-years for non-users. However, the incidence is less than that associated with pregnancy (6 per 10,000 woman-years). The excess risk is highest during the first year a woman ever uses a combined oral contraceptive. Venous thromboembolism may be fatal. The risk of thromboembolic disease due to oral contraceptives is not related to length of use and gradually disappears after pill use is stopped. A post-marketing observational study evaluated the risk of venous thromboembolism with levonorgestrel and ethinyl estradiol use in two large US automated healthcare claims databases. The study was not completed as planned due to low accrual of levonorgestrel and ethinyl estradiol users in these databases and discontinuation of the product from the market due to low usage. At study discontinuation, the crude incidence rate of venous thromboembolism among levonorgestrel and ethinyl estradiol users (n=12,281) was 17.6 per 10,000 person-years, compared to 8.8 per 10,000 person-years among the users of cyclic oral contraceptives containing 20 mcg of ethinyl estradiol and a progestogen, and 5.1 per 10,000 person-years among the users of cyclic oral contraceptives containing the progestin levonorgestrel and 20 mcg of ethinyl estradiol. Adjustment for important risk factors or confounders (such as obesity, cardiovascular disease and other diseases) for venous thromboembolism could not be performed due to the small sample size. Although the study results suggest an elevated risk of venous thromboembolism with current levonorgestrel and ethinyl estradiol use compared to cyclic oral hormonal contraceptive use, reliable interpretation of the results is significantly limited due to the small sample size and concerns over unmeasured and uncontrolled confounding, as well as questions about the suitability of the comparator selection and the validity of the venous thromboembolism definition. A two-to-four fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate post-partum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four weeks after delivery in women who elect not to breastfeed, or after a midtrimester pregnancy termination. c.

Cerebrovascular Diseases

Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes. Transient ischemic attacks have also been associated with oral contraceptive use. In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension. The relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension. The attributable risk is also greater in older women. Oral contraceptives also increase the risk for stroke in women with other underlying risk factors such as certain inherited or acquired thrombophilias. Women with migraine (particularly migraine/headaches with focal neurological symptoms such as aura) who take combination oral contraceptives may be at an increased risk of stroke. (See CONTRAINDICATIONS .) d. Dose-Related Risk of Vascular Disease From Oral Contraceptives A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease. A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents. A decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogen used in the contraceptive. The amount of both hormones should be considered in the choice of an oral contraceptive. Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest estrogen content which is judged appropriate for the individual patient. e. Persistence of Risk of Vascular Disease There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persisted for at least 9 years for women 40 to 49 years who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups. In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small. However, both studies were performed with oral contraceptive formulations containing 0.05 mg or higher of estrogens. 2. Estimates of Mortality From Contraceptive Use One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages ( Table 3 ). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is less than that associated with childbirth. The observation of a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970's — but not reported until 1983. However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral contraceptive use to women who do not have the various risk factors listed in this labeling. Because of these changes in practice, and also because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989.

The

Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy nonsmoking women (even with the newer low-dose formulations), there are greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception. Therefore, the Committee recommended that the benefits of oral contraceptive use by healthy nonsmoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective.

Table

3: Annual Number of Birth-Related or Method-Related Deaths Associated with Control of Fertility per 100,000 Nonsterile Women, by Fertility-Control Method and According to Age Method of control and outcome 15 to 19 20 to 24 25 to 29 30 to 34 35 to 39 40 to 44 No fertility-control methods* 7 7.4 9.1 14.8 25.7

28.2 Oral contraceptives nonsmoker** 0.3 0.5 0.9 1.9 13.8

31.6 Oral contraceptives smoker** 2.2 3.4 6.6 13.5 51.1

117.2 IUD** 0.8 0.8 1 1 1.4

1.4 Condom* 1.1 1.6 0.7 0.2 0.3

0.4 Diaphragm/spermicide* 1.9 1.2 1.2 1.3 2.2

2.8 Periodic abstinence* 2.5 1.6 1.6 1.7 2.9 3.6 * Deaths are birth-related **Deaths are method-related Adapted from H.W. Ory, Family Planning Perspectives, 15 :57-63, 1983. 3.

Malignant

Neoplasms a.

Breast Cancer

Levonorgestrel and ethinyl estradiol is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications ]. 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]. b.

Cervical Cancer

Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia or invasive cervical cancer in some populations of women. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. In spite of many studies of the relationship between combination oral contraceptive use and breast and cervical cancers, a cause-and-effect relationship has not been established. Endometrial biopsies performed in a subset of subjects (Study 1; n = 93) ages 18 to 49 years, after 6 to 12 months of use of levonorgestrel and ethinyl estradiol, did not reveal any hyperplasias or malignancies. Endometrial malignancy is rare in this age group, so change in the risk is unlikely to be detected with a study of this size. 4.

Hepatic Neoplasia

Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of these benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use. Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral contraceptive user. However, these cancers are extremely rare in the U.S. and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users. 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 COCs. Discontinue levonorgestrel and ethinyl estradiol prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications ( 4 )]. Levonorgestrel and ethinyl estradiol can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen. 5.

Ocular Lesions

There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives that may lead to partial or complete loss of vision. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately. 6.

Oral Contraceptive Use

Before or During Early Pregnancy Extensive epidemiological studies have revealed no increased risk of birth defects in infants born to women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy (see CONTRAINDICATIONS section). The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion. The possibility of pregnancy should be considered in any patient who may be experiencing symptoms of pregnancy, especially if she has not adhered to the prescribed schedule. Oral-contraceptive use must be discontinued if pregnancy is confirmed. 7.

Gallbladder Disease

Combination oral contraceptives may worsen existing gallbladder disease and may accelerate the development of this disease in previously asymptomatic women. Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens. More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal. The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens. 8. Carbohydrate and Lipid Metabolic Effects Oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users. Oral contraceptives containing greater than 0.075 mg of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance. Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents. However, in the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives. A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS , 1a . and 1d .; PRECAUTIONS , 3 .), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users. 9.

Elevated Blood

Pressure An increase in blood pressure has been reported in women taking oral contraceptives and this increase is more likely in older oral contraceptive users and with continued use. Data from the Royal College of General Practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing quantities of progestogens. Women with a history of hypertension or hypertension-related diseases, or renal disease should be encouraged to use another method of contraception. If women with hypertension elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued (see CONTRAINDICATIONS section). For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension among ever- and never-users. 10.

Headache

The onset or exacerbation of migraine or development of headache with a new pattern that is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause. (See WARNINGS , 1c . and CONTRAINDICATIONS .) 11.

Bleeding Irregularities

When prescribing levonorgestrel and ethinyl estradiol, the convenience of having no scheduled menstrual bleeding should be weighed against the inconvenience of unscheduled breakthrough bleeding and spotting.

In Study

313-NA, 385/2,134 (18%) of women discontinued prematurely due to bleeding that was reported either as an adverse event or where bleeding was given as one of the reasons for discontinuation (see INDICATIONS AND USAGE, Clinical Studies ).

Figure

4 shows the percentage of levonorgestrel and ethinyl estradiol subjects in study 313-NA by pill pack who experienced unscheduled bleeding or spotting only (Defined as “No sanitary protection required”).

Figure

4: Percentage of Subjects Reporting Bleeding or Spotting Only per Pill Pack Figure 5 shows the percentage of levonorgestrel and ethinyl estradiol subjects with complete bleeding data in Study 313–NA who had 4 or more and 7 or more days of bleeding and/or spotting during each pill pack cycle. During pill pack 2, 67% of subjects experienced 4 or more days of bleeding and/or spotting and 54% of these subjects experienced 7 or more days of bleeding and/or spotting. During the final cycle of use of levonorgestrel and ethinyl estradiol (pill pack 13), these percentages were 31% and 20%, respectively.

Figure

5: Percentage of Subjects Reporting Greater Than or Equal to 4 or 7 Days of Bleeding and/or Spotting per Pill Pack (Study 313-NA) As in any case of bleeding irregularities, nonhormonal causes should be considered and adequate diagnostic measures may be indicated to rule out pregnancy, infection, malignancy, or other conditions. Some women may encounter post-pill amenorrhea or oligomenorrhea (possibly with anovulation), especially when such a condition was preexistent. fig-4 fig-5 12.

Ectopic Pregnancy

Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.

PRECAUTIONS This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity. 1.

General

Patients should be counseled that oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually transmitted diseases (STDs) such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. Scheduled withdrawal bleeding does not occur with the use of DOLISHALE, therefore, the absence of withdrawal bleeding cannot be used as a sign of an unexpected pregnancy and as such, unexpected pregnancy may be difficult to recognize. Although pregnancy is unlikely if DOLISHALE is taken as directed, if for any reason, pregnancy is suspected in a woman using DOLISHALE, a pregnancy test should be performed. 2.

Physical

Examination and Follow-Up A periodic personal and family medical history and complete physical examination are appropriate for all women, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen, and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent, or recurrent abnormal vaginal bleeding, appropriate diagnostic measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care. 3.

Lipid Disorders

Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult. (See WARNINGS , 1a., 1d., and 9.) A small proportion of women will have adverse lipid changes while taking oral contraceptives. Nonhormonal contraception should be considered in women with uncontrolled dyslipidemias. Persistent hypertriglyceridemia may occur in a small population of combination oral contraceptive users. Elevations of plasma triglycerides may lead to pancreatitis and other complications. 4.

Liver

Function If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function. 5.

Fluid Retention

Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. 6.

Emotional Disorders

Patients becoming significantly depressed while taking oral contraceptives should stop the medication and use an alternate method of contraception in an attempt to determine whether the symptom is drug related. Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree. 7.

Contact Lenses

Contact-lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist. 8.

Gastrointestinal

Diarrhea and/or vomiting may reduce hormone absorption resulting in decreased serum concentrations. 9.

Drug Interactions

Changes in Contraceptive Effectiveness Associated with Coadministration of Other Products: Contraceptive effectiveness may be reduced when hormonal contraceptives are coadministered with antibiotics, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. This could result in unintended pregnancy or unscheduled bleeding. Examples include rifampin, rifabutin, barbiturates, primidone, phenylbutazone, phenytoin, dexamethasone, carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin, and modafinil. In such cases a nonhormonal back-up method of birth control should be considered. Several cases of contraceptive failure and unscheduled bleeding have been reported in the literature with concomitant administration of antibiotics such as ampicillin and other penicillins, and tetracyclines. However, clinical pharmacology studies investigating drug interactions between combined oral contraceptives and these antibiotics have reported inconsistent results. Enterohepatic recirculation of estrogens may also be decreased by substances that reduce gut transit time. Several of the anti-HIV protease inhibitors have been studied with coadministration of oral combination hormonal contraceptives; significant changes (increase and decrease) in the plasma levels of the estrogen and progestin have been noted in some cases. The safety and efficacy of oral contraceptive products may be affected with coadministration of anti-HIV protease inhibitors. Health care professionals should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information.

Concomitant

Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer DOLISHALE with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations (see Warnings, RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT ). Herbal products containing St. John's Wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in unscheduled bleeding. Increase in Plasma Levels Associated with Coadministered Drugs: Coadministration of atorvastatin and certain oral contraceptives containing ethinyl estradiol increases AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen increase the bioavailability of ethinyl estradiol since these drugs act as competitive inhibitors for sulfation of ethinyl estradiol in the gastrointestinal wall, a known pathway of elimination for ethinyl estradiol. CYP 3A4 inhibitors such as indinavir, itraconazole, ketoconazole, fluconazole, and troleandomycin may increase plasma hormone levels. Troleandomycin may also increase the risk of intrahepatic cholestasis during coadministration with combination oral contraceptives. Changes in Plasma Levels of Coadministered Drugs: Combination hormonal contraceptives containing some synthetic estrogens (eg, ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporine, prednisolone and other corticosteroids, and theophylline have been reported with concomitant administration of oral contraceptives. Decreased plasma concentrations of acetaminophen and lamotrigine, and increased clearance of temazepam, salicylic acid, morphine, and clofibric acid, due to induction of conjugation (particularly glucuronidation), have been noted when these drugs were administered with oral contraceptives. The prescribing information of concomitant medications should be consulted to identify potential interactions. 10. Interactions with Laboratory Tests Certain endocrine- and liver-function tests and blood components may be affected by oral contraceptives: a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability. b. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T 4 by column or by radioimmunoassay. Free T 3 resin uptake is decreased, reflecting the elevated TBG; free T 4 concentration is unaltered. c. Other binding proteins may be elevated in serum ie, corticosteroid binding globulin (CBG), sex hormone-binding globulins (SHBG) leading to increased levels of total circulating corticosteroids and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. d. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected. e. Glucose tolerance may be decreased. f. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives. 11.

Carcinogenesis

See WARNINGS section. 12.

Pregnancy Pregnancy

Category X. See CONTRAINDICATIONS and WARNINGS sections. 13.

Nursing Mothers

Small amounts of oral contraceptive steroids and/or metabolites have been identified in the milk of nursing mothers, and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, combination oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use combination oral contraceptives, but to use other forms of contraception until she has completely weaned her child. 14.

Pediatric Use

Safety and efficacy of levonorgestrel and ethinyl estradiol tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated. 15.

Geriatric Use

This product has not been studied in women over 65 years of age and is not indicated in this population. 16. Information for the Patient See DETAILED PATIENT LABELING printed below.

INTERACTIONS The sections below provide information on substances for which data on drug interactions with CHCs are available. There is little information available about the clinical effect of most drug interactions that may affect ANNOVERA. However, based on the known pharmacokinetic effects of these drugs, clinical strategies to minimize any potential adverse effect on contraceptive effectiveness or safety are suggested. Consult the approved product labeling of all concurrently used drugs to obtain further information about interactions with ANNOVERA or the potential for metabolic enzyme or transporter system alterations. Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of ANNOVERA or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with ANNOVERA. ( 7.1 )

7.1 Effects of Other Drugs on Combined Hormonal Contraceptives Substances Decreasing the Systemic Exposure of CHCs and Potentially Diminishing the Efficacy of ANNOVERA : Table 3 includes substances that demonstrated an important drug interaction with CHCs.

Table

3: Significant Drug Interactions Involving Substances That Decrease Systemic Exposure of CHCs Metabolic Enzyme Inducers Clinical effect Concomitant use of CHCs with metabolic enzyme inducers may decrease the systemic concentrations of the estrogen and/or progestin component of CHCs [see Clinical Pharmacology (12.3) ] . Decreased exposure of the estrogen and/or progestin component of CHCs may potentially diminish the effectiveness of CHCs and may lead to contraceptive failure or an increase in breakthrough bleeding. Prevention or management Counsel females to use an alternative method of contraception or a back-up method when enzyme inducers are used with CHCs. Continue back-up contraception for 28 days after discontinuing the enzyme inducer to maintain contraceptive reliability.

Examples

Aprepitant, barbiturates, bosentan, carbamazepine, efavirenz, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, rifabutin, rufinamide, topiramate, products containing St. John's wort Induction potency of St. John's wort may vary widely based on preparation. , and certain protease inhibitors (see separate section on protease inhibitors below).

Substances

Increasing the Systemic Exposure of CHCs and Potentially Increasing Exposure to Estrogen and/or Progestin in ANNOVERA : Co- administration of atorvastatin or rosuvastatin and certain CHCs containing EE increase systemic exposure of EE by approximately 20–25%. 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 systemic exposure of the estrogen and/or progestin component of ANNOVERA.

Human Immunodeficiency

Virus (HIV)/ Hepatitis C Virus (HCV)

Protease

Inhibitors and Non-nucleoside Reverse Transcriptase Inhibitors : Significant decreases in systemic exposure of estrogen and/or progestin have been noted when CHCs are co-administered with some HIV protease inhibitors (eg, nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir), some HCV protease inhibitors (eg, boceprevir and telaprevir), and some non-nucleoside reverse transcriptase inhibitors (eg, nevirapine). In contrast, significant increases in systemic exposure of estrogen and/or progestin have been noted when CHCs are co-administered with certain other HIV protease inhibitors (eg, indinavir and atazanavir/ritonavir) and with other non-nucleoside reverse transcriptase inhibitors (eg, etravirine).

7.2 Effects of Combined Hormonal Contraceptives on Other Drugs Table 4 provides significant drug interaction information for drugs co-administered with CHCs.

Table

4: Significant Drug Interaction Information for Drugs Co-Administered with CHCs Lamotrigine Clinical effect Concomitant use of CHCs with lamotrigine may significantly decrease systemic exposure of lamotrigine due to induction of lamotrigine glucuronidation. Prevention or management Dose adjustment for lamotrigine may be necessary. Consult the approved product labeling for lamotrigine.

Thyroid Hormone Replacement

Therapy or Corticosteroid Replacement Therapy Clinical effect Concomitant use of CHCs with thyroid hormone replacement therapy or corticosteroid replacement therapy may increase systemic exposure of thyroid-binding and cortisol-binding globulin [see Warnings and Precautions (5.12) ] . Prevention or management The dose of replacement thyroid hormone or cortisol therapy may need to be increased. Consult the approved product labeling for the therapy in use [see Warnings and Precautions (5.12) ] .

Other Drugs

Clinical effect Concomitant use of CHCs may decrease systemic exposure of acetaminophen, morphine, salicylic acid, and temazepam. Concomitant use with ethinyl estradiol-containing CHCs may increase systemic exposure of other drugs (eg, cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole). Prevention or management The dosage of drugs that can be affected by this interaction may need to be increased or decreased. Consult the approved product labeling for the concomitantly used drug.

7.3 Use of Vaginal Products with ANNOVERA In a drug-drug interaction study with ANNOVERA and the concurrent use of three different formulations of vaginal miconazole, the use of water-based vaginal miconazole cream resulted in no change in exposure to EE or SA from the vaginal system. However, the use of either the 1- day or the 3-day oil-based miconazole suppository was associated with an overall increase in exposure up to 67% for EE and 32% for SA. Considering the potential long-term effect on vaginal system performance, concurrent use of oil-based vaginal suppositories should not occur with ANNOVERA use. If there is a need to treat a vaginal condition, water-based vaginal cream or oral therapy may be used concurrently with the vaginal system <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Lubricants: Water-based vaginal lubricants have no effect on ANNOVERA; however, oil- based (including silicone-based) vaginal lubricants will alter the vaginal system and/or exposure to EE and SA and should not be used. ANNOVERA use is compatible with male condoms made with natural rubber latex, polyisoprene, and polyurethane. The effect of tampon use on the systemic exposure of SA and EE from ANNOVERA has not been studied.

7.4 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer ANNOVERA with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations <span class="opacity-50 text-xs">[see Contraindications (4) and Warnings and Precautions (5.3) ]</span> .

7.5 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.