ANNOVERA- segesterone acetate and ethinyl estradiol_ring

CHCs lower the risk of becoming pregnant primarily by suppressing ovulation. Cardiac Electrophysiology The effect of SA on the QTc interval was evaluated in a Phase 1 randomized, placebo and positive controlled, double-blind, single-dose, three-period, crossover thorough QTc study in 44 healthy adult female subjects. At the single intravenous bolus dose which produces 4. 5-fold the therapeutic serum concentrations of SA achieved with ANNOVERA, SA did not prolong the QTc interval to any clinically relevant extent. Absorption The pharmacokinetics (PK) of ANNOVERA were determined in 39 women who used ANNOVERA for up to 13 cycles. Following vaginal administration, SA and EE were absorbed into systemic circulation with median t max max Figure 3: Mean SA and EE Serum Concentrations Delivered by ANNOVERA Over 21 Days of Dosing for Cycles 1, 3, and 13 Figure 4: Mean SA and EE Serum Concentrations Delivered by ANNOVERA Over the First 48 Hours of Dosing for Cycles 1, 3, and 13 Table 5: Mean (SD) PK Parameters for SA following ANNOVERA Administration Cycle AUC 0-21 day AUC 0-1 day C max C avg 1 96. 2) 1,147 (315) 191 (34) 3 65. 6) 363 (133) 131 (29) 13 47. 4) 294 (116) 94 (20) Table 6: Mean (SD) PK Parameters for EE following ANNOVERA Administration Cycle AUC 0-21 day AUC 0-1 day C max C avg 1 22. 7) 129 (39) 44 (19) 3 14. 4) 60 (32) 29 (9) 13 9. 3) 39 (16) 19 (8) Figure 3 Figure 4 Distribution The volume of distribution of SA is 19. SA is approximately 95% bound to human serum proteins and has negligible binding affinity for sex hormone-binding globulin (SHBG). EE is highly protein bound but not specifically bound to serum albumin (98. 5%) and induces an increase in the serum concentrations of SHBG. Metabolism In vitro data show that both SA and EE are metabolized by the cytochrome P450 (CYP) 3A4 isoenzyme. In human serum, two oxidative metabolites (5alpha-dihydro- and 17alpha- hydroxy-5alpha-dihydro metabolites) constitute 50% of exposure relative to SA. Both metabolites are not considered as active metabolites with EC 50 Excretion The mean (SD) half-life of SA is 4. EE is known to be excreted in the urine and feces as glucuronide and sulfate conjugates, and it undergoes enterohepatic recirculation. The mean (SD) half-life of EE is 15. Specific Populations Body Mass Index (BMI) Higher body weight associates with lower systemic exposure of SA and EE. In a PK study conducted in 18 females with BMI <25 (16. 89en dash24. 34) kg/m 2 2 0- 21day Interaction with Vaginal Medications A clinical drug-drug interaction (DDI) study was conducted to evaluate the effect of vaginal antimycotic medication (miconazole nitrate) on the PK of SA and EE in 29 females using ANNOVERA. The results showed that a single-dose vaginal administration of 1,200 mg miconazole suppository on Day 8 of ANNOVERA use increased the systemic exposure of EE (AUC Day8-21 Day8-9 Day8-10, Day8-21 Day8-11 Day8-21 Day8-11 Day8- 21 [see Drug Interactions (7. 3) The in vitro studies suggest that SA is unlikely to inhibit or induce CYP enzymes at the therapeutic dose.

ANNOVERA is indicated for use by females of reproductive potential to prevent pregnancy. ANNOVERA is a progestin/estrogen CHC indicated for use by females of reproductive potential to prevent pregnancy. ( 1 Limitations of Usage Not adequately evaluated in females with a body mass index of >29 kg/m 2 1 Limitations of Use ANNOVERA has not been adequately studied in females with a BMI >29 kg/m 2.

Instructions for Use
ANNOVERA registered (segesterone acetate and ethinyl estradiol vaginal system) Read this Instructions for Use carefully before you decide if ANNOVERA is right for you. This information does not take the place of talking with your gynecologist or other healthcare provider who specializes in women''s health. If you have any questions about ANNOVERA, ask your healthcare provider. You should also learn about other birth control methods to choose the one that is best for you. How should I start using ANNOVERA? If you are not currently using hormonal birth control, start using ANNOVERA between Days 2 and 5 of your menstrual period. If your menstrual periods are not regular or if you start using ANNOVERA more than 5 days from when you started your menstrual period, you should use a barrier method of birth control, such as a male condom or spermicide during sexual intercourse for the first 7 days you use ANNOVERA. If you are changing from a birth control pill or patch or monthly disposable contraceptive vaginal ring to ANNOVERA: If you have been using your birth control method correctly and are certain that you are not pregnant, you can change to ANNOVERA any day of your birth control cycle. Do not start ANNOVERA any later than the day you would start your next birth control pill, apply your next patch or insert your next monthly disposable contraceptive vaginal ring. If you are changing from a progestin-only birth control method, such as a minipill, injection, implant or intrauterine system (IUS): You may switch from a minipill on any day. Start using ANNOVERA on the day that you would have taken your next minipill. You should switch from an injectable and start using ANNOVERA on the day when your next injection would be due. You should switch from an implant or the IUS and start using ANNOVERA at the time the implant or IUS is removed. If you are changing from a minipill, injection, implant, or an intrauterine system to ANNOVERA, you should use a barrier method of birth control, such as a male condom or spermicide, during sexual intercourse for the first 7 days you use ANNOVERA. If you start using ANNOVERA after an abortion or miscarriage: Following a first trimester abortion or miscarriage: If you do not start ANNOVERA within 5 days after a first trimester abortion or miscarriage, use a non-hormonal birth control method, such as male condoms or spermicide, while you wait for your menstrual period to start. Start using ANNOVERA between days 2 and 5 of your menstrual period. If you start using ANNOVERA more than 5 days from when you started your menstrual period, you should use a barrier method of birth control, such as a male condom or spermicide during sexual intercourse for the first 7 days you use ANNOVERA. Following a second trimester abortion or miscarriage: If you are starting ANNOVERA after childbirth: You may start using ANNOVERA no sooner than 4 weeks (28 days) after having a baby if you are not breastfeeding. If you have not gotten your menstrual period after childbirth, you should talk to your healthcare provider. You may need a pregnancy test to make sure you are not pregnant before you start using ANNOVERA. Use another birth control method, such as a male condom or spermicide, during sexual intercourse for the first 7 days you use ANNOVERA if you have not yet had a period. If you are breastfeeding, you should not use ANNOVERA. Use other birth control methods until you are no longer breastfeeding. How do I use ANNOVERA? Step 1. Open the package and remove ANNOVERA. Wash your hands with mild soap and water. Dry them well. Take ANNOVERA out of its package (See Figure, Step 1 Wash ANNOVERA with mild soap and water, rinse and pat dry with a clean cloth towel or paper towel. Prepare to insert ANNOVERA. Hold ANNOVERA between your thumb and first (index) finger. Press the sides of ANNOVERA together to make it narrow (See Figure, Step 2 Step 3. Choose a position for insertion of ANNOVERA. Choose the position that is comfortable for you. For example, lying down, squatting, or standing with 1 leg up (See Figures, Steps 3-A 3-B 3-C Step 4. Insert ANNOVERA into your vagina. Gently insert the folded ANNOVERA into your vagina (See Figure, Step 4-A Push ANNOVERA further up into your vagina using your index finger. Push it in as far as you can. It sometimes helps to push down with the muscles in your vagina while you are inserting ANNOVERA. When you insert ANNOVERA, it may be in different positions in your vagina, but ANNOVERA does not have to be in an exact position for it to work. Mark your vaginal system "in day" on your calendar. Note: If you feel the ANNOVERA in your vagina or if it feels uncomfortable, you may not have pushed the ANNOVERA into your vagina far enough. Use your index finger to gently push ANNOVERA as far as you can into your vagina (See Figure, Step 4- B You should not feel ANNOVERA after you have placed it into your vagina. Some women and their partners may be aware of ANNOVERA in the vagina during sexual intercourse. How do I remove ANNOVERA? Wash and dry your hands. Choose the position that is most comfortable for you (See Step 3 Put your index finger into your vagina and hook it through ANNOVERA. Gently pull downward and forward to remove ANNOVERA and pull it out (See Figure, Step 5 Wash the ANNOVERA vaginal system with mild soap and lukewarm water, pat it dry, and store in the case provided. Mark your vaginal system "out day" on your calendar. What else should I know about ANNOVERA? The day of the week when you first insert ANNOVERA (called "Day 1") is your vaginal system change day. This is described further in the Patient Information section entitled "How should I use ANNOVERA?" For each cycle, you put the vaginal system into your vagina and let it stay there 3 weeks (21 full days). Remember You take the vaginal system out on your vaginal system change day (Day 22) and let it stay out for 1 week (7 full days). Note that your vaginal system should be stored in the case provided, away from children, pets, and extreme temperatures. Then you start over again for another 4 weeks. You may not be bleeding when you put the vaginal system in. Always put the vaginal system in or take it out on your vaginal system change day at about the same time of day. For example, if you put your vaginal system in on Monday at 9:00 in the morning, always take it out or put it back in on Monday at about 9:00 in the morning. You do not have to take the vaginal system out when you have sex. If you decide to remove it, remember to reinsert it within 2 hours after removing it or you may not be protected from pregnancy. However, if ANNOVERA is out of your vagina for more than 2 hours at one time or if ANNOVERA is out of your vagina at different times that add up to more than a total of 2 hours over the first 21 days of your cycle, you will need to use another method of birth control Repeat the 4-week cycle for all 13 cycles of the use of the vaginal system. Do not use the vaginal system for more than 13 cycles (1 year). When you take the vaginal system out of your vagina at the end of the 13 cycles, dispose of it. See " How should I dispose of (throw away) ANNOVERA? If you want to continue using ANNOVERA after 13 cycles, you will need to get a new prescription from your healthcare provider to obtain a new vaginal system. Do not to use any vaginal products such as oil-based suppositories, oil-based creams, or oil-based gels while the vaginal system is in your vagina. Do not use any vaginal lubricants that have silicone or oil in them. Water-based lubricants are ok to use. Be sure to read the ingredients on the labels carefully before you buy a vaginal lubricant. First insertion of ANNOVERA must be prior to the date of expiration. Discard one year after first insertion. See " How should I dispose of (throw away) ANNOVERA? Do not take any medicines unless your healthcare provider says it is ok to take them. How do I clean ANNOVERA? After removing ANNOVERA from your vagina, wash it with mild soap and warm water, rinse, and pat it dry with a clean cloth towel or paper towel before you store it. Only use mild soap and warm water to clean. Wash ANNOVERA with mild soap and warm water and pat it dry before you put it back into your vagina. Store ANNOVERA in the case provided. How should I store ANNOVERA? Store ANNOVERA in the supplied case at room temperature between 68°F to 77°F (20°C to 25°C). Protect ANNOVERA from direct sunlight. Do not refrigerate or freeze ANNOVERA. Avoid storing ANNOVERA in extreme heat. Keep ANNOVERA and all medicines out of the reach of children and pets. How should I dispose of (throw away) ANNOVERA? After 13 cycles of use, place ANNOVERA in the case that comes with it. Dispose of ANNOVERA at a drug take-back location, if available. If a drug take-back location is not available, dispose of ANNOVERA in the trash, out of the reach of children and pets. Do not throw away ANNOVERA in the toilet. gov/drugdisposal for more information about disposal of medicines. When does ANNOVERA become effective? ANNOVERA becomes effective on the day it is inserted (Day 1), if it is inserted between Days 2 and 5 of your menstrual period. If ANNOVERA is inserted more than 5 days from when you start your menstrual period, you should use a barrier method of birth control, such as a male condom or spermicide, during sexual intercourse for the first 7 days you use ANNOVERA. Will ANNOVERA interfere during sexual intercourse? If ANNOVERA is placed as high as possible in your vagina, it will not interfere with sexual intercourse. Can I take ANNOVERA out during the first 3 weeks of my cycle? You should leave ANNOVERA in the entire 21 days (3 weeks). If ANNOVERA comes out or if you remove it, put it back in as soon as possible. If you put ANNOVERA back into your vagina before 2 hours has passed, you do not need to use another method of birth control. However, if ANNOVERA is out of your vagina for more than 2 hours at one time or if ANNOVERA is out of your vagina at different times that add up to more than a total of 2 hours over the first 21 days of your cycle, you will need to use another method of birth control What should I do if ANNOVERA comes out of my vagina? ANNOVERA can slip or accidentally come out of your vagina (expelled), for example, during sexual intercourse, bowel movements, or use of tampons. If ANNOVERA slips out of your vagina, wash ANNOVERA with mild soap and warm water, rinse and pat dry with a clean cloth towel or paper towel and put it back in your vagina right away or within 2 hours. See " Can I take ANNOVERA out during the first 3 weeks of my cycle? ANNOVERA can move around and become visible at the opening of your vagina. If this happens follow "Step 4" above for directions on how to push ANNOVERA back to its right position. What if I lose ANNOVERA? Call your healthcare provider right away if you lose ANNOVERA. You should use a back-up method of birth control such as a male condom or spermicide for preventing pregnancy until you get a new ANNOVERA. If you have other questions call your healthcare provider. For information, call Mayne Pharma at 1-844- 825-8500 Distributed by: Mayne Pharma ANNOVERA is a registered trademark of Population Council and licensed under license. The Patient Information and Instructions for Use have been approved by the U. Food and Drug Administration. Revised 08/2024 Figure Figure Figure Figure Figure Figure.">DOSAGE AND ADMINISTRATION
One ANNOVERA is inserted in the vagina. The vaginal system must remain in place continuously for 3 weeks (21 days) followed by a 1-week (7-day) vaginal system-free interval. One vaginal system provides contraception for thirteen 28-day cycles (1 year). ( 2 Instruct patients that ANNOVERA should be used as directed [see How to Start ANNOVERA (2. 2) With clean hands, the user can choose an insertion position that is comfortable, such as lying down, squatting, or standing. The sides of the vaginal system are pressed together for insertion into the vagina. When properly inserted, the vaginal system should be entirely in the vagina and behind the pelvic bone. The day and time of insertion should be noted so that the vaginal system can be removed 3 weeks later on the same day and at about the same time. ANNOVERA can be removed by hooking an index finger into the vaginal system inside the vagina and gently pulling the vaginal system. For patient instructions regarding cleaning the vaginal system, see FDA-approved Patient Information IMPORTANT: Consider the possibility of ovulation and conception prior to the first use of ANNOVERA. No Hormonal Contraceptive Use in the Preceding Cycle and after Copper IUD Removal The woman should insert ANNOVERA between days 2 and 5 of her regular menstrual bleeding; no back-up contraception is needed. If menstrual cycles are irregular or if the start is more than 5 days from the last menstrual bleeding, the woman should use an additional barrier method during coitus, such as a male condom or spermicide, for the first 7 days of ANNOVERA use. Switching from a CHC: A woman who has been using her CHC method consistently and correctly, and who you are reasonably certain is not already pregnant, may switch from her previous CHC to ANNOVERA on any day of the CHC cycle (Day 1-28), without the need for back-up contraception, but no more than 7 hormone-free days should occur before starting ANNOVERA. Switching from a Progestin-Only Method [Progestin-only pills (POP), Progestin Injection, Progestin Implant, Progestin Intrauterine System (IUS)]: If a woman has no contraindications to the use of ethinyl estradiol (EE), she may elect to switch from a progestin-only method to ANNOVERA. If switching from progestin-only pills, she should begin ANNOVERA at the time she would have taken her next POP pill. If switching from an injection, she should begin ANNOVERA at the time of her next scheduled injection. If switching from an implant or an IUS, she should begin ANNOVERA at the time of implant or IUS removal. In all of these cases, the woman should use an additional barrier method during coitus, such as a male condom or spermicide, for the first 7 days of ANNOVERA use. Use after Abortion or Miscarriage: If a woman has no contraindications to the use of EE, ANNOVERA may be initiated for contraception within the first 5 days following a complete first trimester abortion or miscarriage without additional back-up contraception. If more than 5 days have elapsed from the first trimester abortion or miscarriage, then follow the instructions for "No Hormonal Contraceptive Use in the Preceding Cycle" and a barrier method should be used from the time of the first trimester abortion or miscarriage to the initiation of ANNOVERA. ANNOVERA should not be started earlier than 4 weeks after a second trimester abortion or miscarriage due to the increased risk of thromboembolism [see Contraindications (4) Warnings and Precautions (5. 1) Following Childbirth: ANNOVERA should not be started sooner than 4 weeks postpartum and only in females who choose not to breastfeed. Prior to 4 weeks postpartum there is an increased risk of thromboembolism [see Contraindications (4) Warnings and Precautions (5. 1) The initiation of ANNOVERA 4 weeks or more postpartum should be accompanied by an additional method of contraception during coitus, such as male condoms or spermicide, for the first 7 days if the woman has not yet had a period. Consider the possibility of ovulation and conception occurring prior to initiating ANNOVERA. Females who are breastfeeding should not use ANNOVERA until after weaning. Contraceptive efficacy of ANNOVERA may be reduced if a woman deviates from the recommended use. ANNOVERA should remain in the vagina for a continuous period of 21 days (3 weeks); then ANNOVERA should be taken out of the vagina for 7 days. In a 28-day cycle, a deviation that involves ANNOVERA being out of the vagina for less than 7 days will not increase pregnancy risk. In a 28-day cycle, a deviation that involves ANNOVERA being out of the vagina for more than 7 days will increase pregnancy risk and back-up contraception is recommended in these instances. Deviations from the recommended regimen may result in a new vaginal system change day [See FDA- approved Patient Information Inadvertent Removal or Expulsion ANNOVERA can be accidently expelled. Accidental expulsion could occur while removing a tampon, during coitus, or with straining during a bowel movement. If the vaginal system is accidentally expelled once during the 21 days of intravaginal use and is replaced within 2 hours, contraceptive efficacy should not be reduced and no back-up contraception is needed. If the vaginal system is accidently expelled, wash it with mild soap and warm water, rinse and pat dry with a clean cloth towel or paper towel, and replace it as soon as possible. During the 21 days of continuous use, if ANNOVERA is out of the vagina for more than 2 continuous hours or more than 2 cumulative hours (multiple inadvertent removals or expulsions adding up to 2 hours), then back-up contraception, such as male condoms or spermicide, should be used until the vaginal system has been in the vagina for 7 consecutive days. The use of combined hormonal contraceptives (those containing an estrogen) for emergency contraception during use of ANNOVERA is not recommended. Prolonged Vaginal System Free Interval If the vaginal system free interval is prolonged, consider the possibility of pregnancy and have the woman use back-up contraception, such as male condoms or spermicide, during coitus until the vaginal system has been in the vagina for 7 consecutive days. Prolonged Use of ANNOVERA If ANNOVERA is left in the vagina for more than 21 days, it should be removed for 7 days and then reinserted for 21 days to resume a 21/7 schedule.
Instructions for Use
ANNOVERA registered (segesterone acetate and ethinyl estradiol vaginal system) Read this Instructions for Use carefully before you decide if ANNOVERA is right for you. This information does not take the place of talking with your gynecologist or other healthcare provider who specializes in women''s health. If you have any questions about ANNOVERA, ask your healthcare provider. You should also learn about other birth control methods to choose the one that is best for you. How should I start using ANNOVERA? If you are not currently using hormonal birth control, start using ANNOVERA between Days 2 and 5 of your menstrual period. If your menstrual periods are not regular or if you start using ANNOVERA more than 5 days from when you started your menstrual period, you should use a barrier method of birth control, such as a male condom or spermicide during sexual intercourse for the first 7 days you use ANNOVERA. If you are changing from a birth control pill or patch or monthly disposable contraceptive vaginal ring to ANNOVERA: If you have been using your birth control method correctly and are certain that you are not pregnant, you can change to ANNOVERA any day of your birth control cycle. Do not start ANNOVERA any later than the day you would start your next birth control pill, apply your next patch or insert your next monthly disposable contraceptive vaginal ring. If you are changing from a progestin-only birth control method, such as a minipill, injection, implant or intrauterine system (IUS): You may switch from a minipill on any day. Start using ANNOVERA on the day that you would have taken your next minipill. You should switch from an injectable and start using ANNOVERA on the day when your next injection would be due. You should switch from an implant or the IUS and start using ANNOVERA at the time the implant or IUS is removed. If you are changing from a minipill, injection, implant, or an intrauterine system to ANNOVERA, you should use a barrier method of birth control, such as a male condom or spermicide, during sexual intercourse for the first 7 days you use ANNOVERA. If you start using ANNOVERA after an abortion or miscarriage: Following a first trimester abortion or miscarriage: If you do not start ANNOVERA within 5 days after a first trimester abortion or miscarriage, use a non-hormonal birth control method, such as male condoms or spermicide, while you wait for your menstrual period to start. Start using ANNOVERA between days 2 and 5 of your menstrual period. If you start using ANNOVERA more than 5 days from when you started your menstrual period, you should use a barrier method of birth control, such as a male condom or spermicide during sexual intercourse for the first 7 days you use ANNOVERA. Following a second trimester abortion or miscarriage: If you are starting ANNOVERA after childbirth: You may start using ANNOVERA no sooner than 4 weeks (28 days) after having a baby if you are not breastfeeding. If you have not gotten your menstrual period after childbirth, you should talk to your healthcare provider. You may need a pregnancy test to make sure you are not pregnant before you start using ANNOVERA. Use another birth control method, such as a male condom or spermicide, during sexual intercourse for the first 7 days you use ANNOVERA if you have not yet had a period. If you are breastfeeding, you should not use ANNOVERA. Use other birth control methods until you are no longer breastfeeding. How do I use ANNOVERA? Step 1. Open the package and remove ANNOVERA. Wash your hands with mild soap and water. Dry them well. Take ANNOVERA out of its package (See Figure, Step 1 Wash ANNOVERA with mild soap and water, rinse and pat dry with a clean cloth towel or paper towel. Prepare to insert ANNOVERA. Hold ANNOVERA between your thumb and first (index) finger. Press the sides of ANNOVERA together to make it narrow (See Figure, Step 2 Step 3. Choose a position for insertion of ANNOVERA. Choose the position that is comfortable for you. For example, lying down, squatting, or standing with 1 leg up (See Figures, Steps 3-A 3-B 3-C Step 4. Insert ANNOVERA into your vagina. Gently insert the folded ANNOVERA into your vagina (See Figure, Step 4-A Push ANNOVERA further up into your vagina using your index finger. Push it in as far as you can. It sometimes helps to push down with the muscles in your vagina while you are inserting ANNOVERA. When you insert ANNOVERA, it may be in different positions in your vagina, but ANNOVERA does not have to be in an exact position for it to work. Mark your vaginal system "in day" on your calendar. Note: If you feel the ANNOVERA in your vagina or if it feels uncomfortable, you may not have pushed the ANNOVERA into your vagina far enough. Use your index finger to gently push ANNOVERA as far as you can into your vagina (See Figure, Step 4- B You should not feel ANNOVERA after you have placed it into your vagina. Some women and their partners may be aware of ANNOVERA in the vagina during sexual intercourse. How do I remove ANNOVERA? Wash and dry your hands. Choose the position that is most comfortable for you (See Step 3 Put your index finger into your vagina and hook it through ANNOVERA. Gently pull downward and forward to remove ANNOVERA and pull it out (See Figure, Step 5 Wash the ANNOVERA vaginal system with mild soap and lukewarm water, pat it dry, and store in the case provided. Mark your vaginal system "out day" on your calendar. What else should I know about ANNOVERA? The day of the week when you first insert ANNOVERA (called "Day 1") is your vaginal system change day. This is described further in the Patient Information section entitled "How should I use ANNOVERA?" For each cycle, you put the vaginal system into your vagina and let it stay there 3 weeks (21 full days). Remember You take the vaginal system out on your vaginal system change day (Day 22) and let it stay out for 1 week (7 full days). Note that your vaginal system should be stored in the case provided, away from children, pets, and extreme temperatures. Then you start over again for another 4 weeks. You may not be bleeding when you put the vaginal system in. Always put the vaginal system in or take it out on your vaginal system change day at about the same time of day. For example, if you put your vaginal system in on Monday at 9:00 in the morning, always take it out or put it back in on Monday at about 9:00 in the morning. You do not have to take the vaginal system out when you have sex. If you decide to remove it, remember to reinsert it within 2 hours after removing it or you may not be protected from pregnancy. However, if ANNOVERA is out of your vagina for more than 2 hours at one time or if ANNOVERA is out of your vagina at different times that add up to more than a total of 2 hours over the first 21 days of your cycle, you will need to use another method of birth control Repeat the 4-week cycle for all 13 cycles of the use of the vaginal system. Do not use the vaginal system for more than 13 cycles (1 year). When you take the vaginal system out of your vagina at the end of the 13 cycles, dispose of it. See " How should I dispose of (throw away) ANNOVERA? If you want to continue using ANNOVERA after 13 cycles, you will need to get a new prescription from your healthcare provider to obtain a new vaginal system. Do not to use any vaginal products such as oil-based suppositories, oil-based creams, or oil-based gels while the vaginal system is in your vagina. Do not use any vaginal lubricants that have silicone or oil in them. Water-based lubricants are ok to use. Be sure to read the ingredients on the labels carefully before you buy a vaginal lubricant. First insertion of ANNOVERA must be prior to the date of expiration. Discard one year after first insertion. See " How should I dispose of (throw away) ANNOVERA? Do not take any medicines unless your healthcare provider says it is ok to take them. How do I clean ANNOVERA? After removing ANNOVERA from your vagina, wash it with mild soap and warm water, rinse, and pat it dry with a clean cloth towel or paper towel before you store it. Only use mild soap and warm water to clean. Wash ANNOVERA with mild soap and warm water and pat it dry before you put it back into your vagina. Store ANNOVERA in the case provided. How should I store ANNOVERA? Store ANNOVERA in the supplied case at room temperature between 68°F to 77°F (20°C to 25°C). Protect ANNOVERA from direct sunlight. Do not refrigerate or freeze ANNOVERA. Avoid storing ANNOVERA in extreme heat. Keep ANNOVERA and all medicines out of the reach of children and pets. How should I dispose of (throw away) ANNOVERA? After 13 cycles of use, place ANNOVERA in the case that comes with it. Dispose of ANNOVERA at a drug take-back location, if available. If a drug take-back location is not available, dispose of ANNOVERA in the trash, out of the reach of children and pets. Do not throw away ANNOVERA in the toilet. gov/drugdisposal for more information about disposal of medicines. When does ANNOVERA become effective? ANNOVERA becomes effective on the day it is inserted (Day 1), if it is inserted between Days 2 and 5 of your menstrual period. If ANNOVERA is inserted more than 5 days from when you start your menstrual period, you should use a barrier method of birth control, such as a male condom or spermicide, during sexual intercourse for the first 7 days you use ANNOVERA. Will ANNOVERA interfere during sexual intercourse? If ANNOVERA is placed as high as possible in your vagina, it will not interfere with sexual intercourse. Can I take ANNOVERA out during the first 3 weeks of my cycle? You should leave ANNOVERA in the entire 21 days (3 weeks). If ANNOVERA comes out or if you remove it, put it back in as soon as possible. If you put ANNOVERA back into your vagina before 2 hours has passed, you do not need to use another method of birth control. However, if ANNOVERA is out of your vagina for more than 2 hours at one time or if ANNOVERA is out of your vagina at different times that add up to more than a total of 2 hours over the first 21 days of your cycle, you will need to use another method of birth control What should I do if ANNOVERA comes out of my vagina? ANNOVERA can slip or accidentally come out of your vagina (expelled), for example, during sexual intercourse, bowel movements, or use of tampons. If ANNOVERA slips out of your vagina, wash ANNOVERA with mild soap and warm water, rinse and pat dry with a clean cloth towel or paper towel and put it back in your vagina right away or within 2 hours. See " Can I take ANNOVERA out during the first 3 weeks of my cycle? ANNOVERA can move around and become visible at the opening of your vagina. If this happens follow "Step 4" above for directions on how to push ANNOVERA back to its right position. What if I lose ANNOVERA? Call your healthcare provider right away if you lose ANNOVERA. You should use a back-up method of birth control such as a male condom or spermicide for preventing pregnancy until you get a new ANNOVERA. If you have other questions call your healthcare provider. For information, call Mayne Pharma at 1-844- 825-8500 Distributed by: Mayne Pharma ANNOVERA is a registered trademark of Population Council and licensed under license. The Patient Information and Instructions for Use have been approved by the U. Food and Drug Administration. Revised 08/2024 Figure Figure Figure Figure Figure Figure.

The following adverse reactions are described elsewhere in other sections of the labeling: Serious cardiovascular events and stroke [see Boxed Warning Warnings and Precautions (5. 1) Vascular events [see Warnings and Precautions (5. 1) Liver disease [see Warnings and Precautions (5. 2) The most common adverse reactions (>5%) are headache/migraine, nausea/vomiting, vulvovaginal mycotic infection/candidiasis, abdominal pain lower/upper, dysmenorrhea, vaginal discharge, urinary tract infection, breast tenderness/pain/discomfort, bleeding irregularities including metrorrhagia, diarrhea, genital pruritus. ( 6 To report SUSPECTED ADVERSE REACTIONS, contact Mayne Pharma at 1-844-825-8500 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 the rates in the clinical trials of another drug and may not reflect the rates observed in practice. The clinical trials that evaluated the safety of ANNOVERA were obtained from three 13- cycle trials. One trial was conducted entirely in the U. (15 sites), and the other two were global studies that included 5 U. sites and 7 international sites (Australia, Brazil, Chile, Dominican Republic, Finland, Hungary, Sweden). All three trials were open label and enrolled healthy females, desiring contraception, 18 to 40 years of age. At about 50% enrollment, females with BMI >29 kg/m 2 2 2 Most Common Adverse Reactions Table 1 summarizes the most common adverse reactions reported by females using ANNOVERA. This table shows adverse reactions reported in at least 5% of subjects. In addition, 25% of subjects reported at least 1 complete expulsion during their use of ANNOVERA. Table 1: Adverse Drug Reactions Reported by >= 5% of ANNOVERA-treated Subjects Adverse Reactions % Headache, including migraine 38. 6 Nausea/vomiting 25. 0 Vulvovaginal mycotic infection/vaginal candidiasis 14. 5 Abdominal pain/lower/upper 13. 3 Dysmenorrhea 12. 5 Vaginal discharge 11. 8 UTI/cystitis/pyelonephritis/genitourinary tract infection 10. 0 Breast pain/tenderness/discomfort 9. 5 Metrorrhagia/menstrual disorder 7. 5 Diarrhea 7. 2 Genital pruritus 5. 5 Adverse Reactions Leading to Discontinuation Among subjects using ANNOVERA for contraception, 12% discontinued from the clinical trials due to an adverse reaction. Table 2 summarizes the most common adverse reactions leading to discontinuation. In addition, 1. 4% of subjects discontinued ANNOVERA use due to vaginal system expulsions. Table 2: Adverse Reactions Leading to Discontinuation by >= 1% of ANNOVERA treated Subjects Adverse Reactions % Metrorrhagia/menorrhagia 1. 7 Headache, including migraine 1. 3 Vaginal discharge/vulvovaginal mycotic infections 1. 3 Nausea/vomiting 1. 2 Serious Adverse Reactions Serious adverse reactions occurring in >=2 subjects were: VTEs (deep venous thrombosis, cerebral vein thrombosis, pulmonary embolism); psychiatric events; drug hypersensitivity reactions; and spontaneous abortions. 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. 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. 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: Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives RR = relative risk; OR = odds ratio; HR = hazard ratio. "ever COC" are females with current or past COC use; "never COC use" are females who never used COCs.

ANNOVERA is contraindicated in females who are known to have or develop the following conditions: A high risk of arterial or venous thrombotic diseases. Examples include females who are known to: - [see Boxed Warning Warnings and Precautions (5. 1) - [see Warnings and Precautions (5. 4) - [see Warnings and Precautions (5. 7) - [see Warnings and Precautions (5. 8) Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [see Warnings and Precautions (5. 11) Liver tumors, acute hepatitis, or severe (decompensated) cirrhosis [see Warnings and Precautions (5. 2) Use in Specific Populations (8. 6) Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5. 9) Hypersensitivity to any of the components of ANNOVERA. Hypersensitivity reactions reported include: throat constriction, facial edema, urticaria, hives, and wheezing [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 transaminase (ALT) elevations [see Warnings and Precautions (5. 3) A high risk of arterial or venous thrombotic diseases ( 4 Breast cancer ( 4 Liver tumors, acute hepatitis, or severe (decompensated) cirrhosis ( 4 Undiagnosed abnormal uterine bleeding ( 4 Hypersensitivity to any of the components of ANNOVERA ( 4 Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir ( 4.

Pregnancy: Discontinue if pregnancy occurs. 1 Lactation: Not recommended for nursing mothers; can decrease milk production. 2 Risk Summary Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to CHCs before conception or during early pregnancy. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2en dash4% and 15en dash20%, respectively. Discontinue ANNOVERA if pregnancy occurs, because there is no reason to use CHCs during pregnancy. Data Human Data No studies have been conducted of the use of ANNOVERA in pregnant females. Risk Summary Contraceptive hormones and/or metabolites are present in human milk. CHCs can reduce milk production in breastfeeding females. This reduction can occur at any time but is less likely to occur once breastfeeding is well established. Advise the nursing female to use another method of contraception until she discontinues breastfeeding [see Dosage and Administration (2. 2) Data Human Data No studies have been conducted of the use of ANNOVERA in breastfeeding females. Two studies have been conducted in breastfeeding females of segesterone acetate implants delivering lower levels of segesterone acetate than ANNOVERA. Maternal serum levels of up to 141 pg/mL were associated with infant exposure of up to 7 pg/mL. No safety signals in feeding, growth, and development were observed in the infants between the segesterone acetate implant group and the control group. Safety and efficacy of ANNOVERA have been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 as for users 18 years and older. Use of ANNOVERA before menarche is not indicated. ANNOVERA has not been studied in females who have reached menopause and is not indicated in this population. No studies have been conducted to evaluate the effect of hepatic impairment on the disposition of ANNOVERA. However, steroid hormones may be poorly metabolized in patients with hepatic impairment. 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 [see Contraindications (4) Warnings and Precautions (5. 2) No studies were conducted in subjects with renal impairment; ANNOVERA is not recommended in patients with renal impairment. The safety and efficacy of ANNOVERA in females with a BMI >29 kg/m 2 2 [see Adverse Reactions (6. 1) Clinical Studies (14) [see Clinical Pharmacology (12.

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. 1 Substances Decreasing the Systemic Exposure of CHCs and Potentially Diminishing the Efficacy of ANNOVERA 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. separate section on protease inhibitors Substances Increasing the Systemic Exposure of CHCs and Potentially Increasing Exposure to Estrogen and/or Progestin in ANNOVERA Human Immunodeficiency Virus (HIV)/ Hepatitis C Virus (HCV) Protease Inhibitors and Non-nucleoside Reverse Transcriptase Inhibitors 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). 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. 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 [see Clinical Pharmacology (12. 3) 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. Do not co-administer ANNOVERA with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Contraindications (4) Warnings and Precautions (5. 3) The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

OVERDOSAGE
There have been no reports of serious ill effects from overdose of CHCs. Overdosage may cause withdrawal bleeding in females and nausea. In case of suspected overdose, all ANNOVERA vaginal systems should be removed and symptomatic treatment given.
NONCLINICAL TOXICOLOGY
Carcinogenesis In a 2-year carcinogenicity study in rats with subdermal implants releasing 40, 100, and 200 mcg segesterone acetate per day (approximately 17en dash86 times the daily dose of segesterone acetate in females using ANNOVERA, based on body surface area), no drug-related increase in tumor incidence was observed. In a 2-year intravaginal carcinogenicity study in mice, segesterone acetate gel produced an increased incidence of adenocarcinoma and lobular hyperplasia in the breast at a dose of 30 mg/kg/day, approximately 10 times the systemic exposure of segesterone acetate per day in females using ANNOVERA, based on AUC. A dose of 10 mg/kg/day in the mouse, approximately 3 times the systemic exposure of segesterone acetate per day based on AUC, did not result in carcinogenic findings. Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. Mutagenesis Segesterone acetate was neither mutagenic nor clastogenic in the Ames/Salmonella reverse mutation assay, the chromosomal aberration assay in Chinese hamster ovary cells, or in the in vivo mouse micronucleus test. Impairment of Fertility A return to fertility study was conducted with segesterone acetate in rats, using subdermal implants releasing a dose approximately 25 times the anticipated daily vaginal human dose (based on body surface area). Three months of treatment with segesterone acetate suppressed fertility, but 7 weeks after cessation of treatment, there were no adverse effects on ovulation or resulting litter parameters.
CLINICAL STUDIES
The efficacy of ANNOVERA was evaluated in two 1-year multicenter trials enrolling 2,265 females, age 18en dash40 years, who were healthy and sexually active with regular menstrual cycles. The trials were conducted in the U.S., Dominican Republic, Brazil, Chile, Finland, Hungary, Sweden, and Australia, with 67.1% of females from the U.S. The racial/ethnic distribution was Caucasian (71.2%), African-American (14.1%), Asian (3.5%), other/multiple races (11.2%); 28.7% of the study population was Hispanic. The mean age was 26.7 years and the mean (range) BMI was 24.1 (16.0, 41.5) kg/m 2 2 2 Based on pooled data from the two trials, 2,111 females <=35 years of age completed 17,427 evaluable 28-day cycles (cycles in which no back-up contraception was used). The pooled pregnancy rate, evaluated by the Pearl Index (PI), was 2.98 (95% Confidence Interval [2.13, 4.06]) per 100 woman-years of ANNOVERA use. Return to fertility was assessed in 290 of the subjects in the two trials who either desired pregnancy or switched to a nonhormonal method after the trials, and all 290 subjects reported a return to fertility during the 6-month follow-up period (defined as a return of menses or pregnancy).
REFERENCES
1. 2. 3.

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ANNOVERA- segesterone acetate and ethinyl estradiol_ring Product manual source documgent