These Highlights Do Not Include All The Information Needed To Use Annovera Safely And Effectively.

Limitations of Use

ANNOVERA has not been adequately studied in females with a BMI >29 kg/m².

ANNOVERA is contraindicated in females who have headaches with focal neurological symptoms or have migraine headaches with aura, and in females over age 35 years who have migraine headaches with or without aura [see Contraindications (4)].

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

Consider discontinuation of ANNOVERA in the case of increased frequency or severity of migraine during CHC use (which may be prodromal of a cerebrovascular event) [see Contraindications (4)].

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.

• 1.
  Dinger, J, Mohner S, Heinemann K. Cardiovascular risk associated with the use of an etonogestrel- containing vaginal ring. Obstetrics & Gynecology 2013; 122(4): 800-808.
• 2.
  Sidney, S, Cheetham TC, Connell FA, Oullet-Hellstrom R, Graham DJ, Davis D,, Recent combined hormonal contraceptives (CHCs) and the risk of thromboembolism and other cardiovascular events in new users. Contraception 2013; 87: 93–100.
• 3.
  Combined hormonal contraceptives (CHCs) and the risk of cardiovascular endpoints. Sidney, S. (primary author) http://www.fda.gov/downloads/Drugs/DrugSafety/UCM277384.pdf, accessed 04- April-2019.

Chloasma may occur with ANNOVERA use, especially in females with a history of chloasma gravidarum. Advise females who tend to develop chloasma to avoid exposure to the sun or ultraviolet radiation while using ANNOVERA.

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: C₂₃H₃₀O₄

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: C₂₀H₂₄O₂

Molecular Weight: 296.4

Physical Form: White to slightly yellowish-white crystalline 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.

Carefully observe females with a history of depression and discontinue ANNOVERA if depression recurs to a serious degree. Data on the association of CHCs with onset of depression or exacerbation of existing depression are limited.

Some females are aware of the vaginal system on occasion during the 21 days of use or during coitus, and partners may feel the vaginal system during coitus.

There is no information on the concomitant use of ANNOVERA with diaphragms, cervical caps, and female condoms.

ANNOVERA may not be suitable for females with conditions that make the vagina more susceptible to vaginal irritation or ulceration. Vaginal and cervical erosion and/or ulceration has been reported in females using other contraceptive vaginal devices. In some cases, the ring adhered to vaginal tissue, which necessitated removal by a healthcare provider.

ANNOVERA is contraindicated in females with uncontrolled hypertension or hypertension with vascular disease [see Contraindications (4)]. For all females, including those with well- controlled hypertension, monitor blood pressure at routine visits and stop ANNOVERA if blood pressure rises significantly.

An increase in blood pressure has been reported in females using CHCs, and this increase is more likely in older females and with extended duration of use. The effect of CHCs on blood pressure may vary according to the progestin in the CHC.

ANNOVERA (segesterone acetate and ethinyl estradiol vaginal system) is a toroidal- shaped (ring), nonbiodegradable, flexible, opaque white vaginal system. The vaginal system body has an overall diameter of 56 mm and a cross-sectional diameter of 8.4 mm. When placed inside the vagina, each ANNOVERA releases an approximate average 0.15 mg/day of segesterone acetate and 0.013 mg/day of ethinyl estradiol over 21-day in-use period of each cycle for up to 13 cycles (total 273 days). Each cycle is 28 days, with 21 days in and 7 days out.

Each ANNOVERA is individually packaged in an aluminum pouch. The pouch consists of a laminate from outside to inside of polyester, aluminum foil, and polyethylene.

First insertion of ANNOVERA must be prior to the date of expiration. Discard one year after first insertions.

A black compact case is provided with the drug product for storage of ANNOVERA by patients during each 7-day vaginal system-out interval.

The vaginal system should be placed in the compact case after 13 cycles of use and discarded via a drug take-back option if one is available. If a take-back option is unavailable, then discard in the waste receptacle out of reach of children and pets. The vaginal system should NOT be flushed down the toilet. See www.fda.gov/drugdisposal for more information about disposal of medicines.

Each box contains 1 ANNOVERA vaginal system in a pouch and 1 storage case.

NDC 68308-752-01

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.

The efficacy of ANNOVERA was evaluated in two 1-year multicenter trials enrolling 2,265 females, age 18–40 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/m². At approximately 50% enrollment, women with BMI >29.0 kg/m² were no longer enrolled in the two trials and all women with a BMI >29.0 kg/m² were discontinued from the trials.

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).

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:
  • -
    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 (5.5), (5.7)].
  • -
    Have headaches with focal neurological symptoms, migraine headaches with aura, or are over age 35 with any migraine headaches [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) and 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)].

The following adverse reactions are described elsewhere in other sections of the labeling:

• Serious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions (5.1)]
• Vascular events [see Warnings and Precautions (5.1)]
• Liver disease [see Warnings and Precautions (5.2)]

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.

No studies were conducted in subjects with renal impairment; ANNOVERA is not recommended in patients with renal impairment.

ANNOVERA^® (ann-o-VER-ah)

(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: You may start ANNOVERA within 5 days following a first trimester abortion or miscarriage (the first 12 weeks of pregnancy). You do not need to use an additional birth control method.
  • 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: You may start using ANNOVERA no sooner than 4 weeks (28 days) after a second trimester abortion (after the first 12 weeks of pregnancy).

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?

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 to keep the vaginal system in for the whole 3 weeks (21 full days).
• 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 until ANNOVERA has been in your vagina for 7 days in a row, such as male condoms or spermicides.
• 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?" below.
• 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?" below.
• Do not take any medicines unless your healthcare provider says it is ok to take them.
  
  Tell your healthcare provider when you start a new medicine.

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.
• See www.fda.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 until ANNOVERA has been in your vagina for 7 days in a row, such as male condoms or spermicides.

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?" in the section above.
• 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

Raleigh, NC 27609

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.S. Food and Drug Administration.

Revised 08/2024

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) and Warnings and Precautions (5.2)].

ANNOVERA is indicated for use by females of reproductive potential to prevent pregnancy.

Prior to dispensing ANNOVERA to the user, store ANNOVERA at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Protect ANNOVERA from direct sunlight.

Do not refrigerate or freeze and avoid excessive heat.

Instruct patients that ANNOVERA should be used as directed [see How to Start ANNOVERA (2.2)]. One ANNOVERA should be placed in the vagina. For maximum contraceptive effectiveness, ANNOVERA is to remain in the vagina continuously for 21 days (3 complete weeks). It is removed for a 1-week dose-free interval, and during this time a withdrawal bleed usually occurs. The removed vaginal system should be cleaned with mild soap and warm water, patted dry with a clean cloth towel or paper towel, and placed in its case during the 1-week dose- free interval. At the end of the dose-free interval, the vaginal system should be cleaned prior to being placed back in the vagina for another 21 continuous days (3 complete weeks). This pattern of ANNOVERA use made up of 3-weeks in and 1-week out is a cycle of use; one ANNOVERA vaginal system will provide contraception for 13 cycles.

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.

Studies suggest a small increased relative risk of developing gallbladder disease among CHC users. Use of CHCs may also worsen existing gallbladder disease.

A past history of CHC-related cholestasis predicts an increased risk with subsequent CHC use. Females with a history of pregnancy-related cholestasis may be at an increased risk for CHC- related cholestasis.

CHCs lower the risk of becoming pregnant primarily by suppressing ovulation.

IMPORTANT: Consider the possibility of ovulation and conception prior to the first use of ANNOVERA.

• Thrombotic Disorders and Other Vascular Problems: Stop ANNOVERA if a thrombotic or thromboembolic event occurs. Stop ANNOVERA at least 4 weeks before and through 2 weeks after major surgery. Start ANNOVERA no earlier than 4 weeks after delivery, in females who are not breastfeeding. Consider cardiovascular risk factors before initiating in all females, particularly those over 35 years. (5.1, 5.5)
• Liver Disease: Discontinue if jaundice occurs. (5.2)
• Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment: Stop ANNOVERA prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir. ANNOVERA can be restarted 2 weeks following completion of this regimen. (5.3)
• Hypertension: Do not prescribe ANNOVERA for females with uncontrolled hypertension or hypertension with vascular disease. If used in females with well-controlled hypertension, monitor blood pressure and stop use if blood pressure rises significantly. (5.4)
• Carbohydrate and lipid metabolic effects: Monitor glucose in pre-diabetic and diabetic females taking ANNOVERA. Consider an alternate contraceptive method for females with uncontrolled dyslipidemias. (5.7)
• Headache: Evaluate significant change in headaches and discontinue ANNOVERA if indicated. (5.8)
• Bleeding Irregularities and Amenorrhea: May cause irregular bleeding or amenorrhea. Evaluate for other causes if irregular bleeding or amenorrhea persists. (5.9)

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

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)

Vaginal system: Each ANNOVERA releases an approximate average 0.15 mg/day of segesterone acetate (SA) and 0.013 mg/day of ethinyl estradiol (EE) when placed in the vagina over a period of 21 days of each cycle for up to 13 cycles (total of 273 days). Each cycle of use is 28 days with 21 days in and 7 days out.

ANNOVERA (segesterone acetate and ethinyl estradiol vaginal system) is a toroidal- shaped (ring), nonbiodegradable, flexible, opaque white, contraceptive vaginal system containing 103 mg of SA and 17.4 mg EE.

ANNOVERA is 56 mm in overall diameter and 8.4 mm in cross-sectional diameter. It contains 2 channels of approximately 3.0 mm diameter and 27 mm length into which steroid-containing cores are inserted. The cores are 3 mm in diameter with one releasing SA alone and the other releasing both SA and EE.

Each ANNOVERA is designed to be used for up to 13 cycles (1 year).

ANNOVERA is not made with natural rubber latex.

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 (<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: 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.

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.S. (15 sites), and the other two were global studies that included 5 U.S. 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/m² were excluded due to the occurrence of two VTEs in this subgroup. In total, 2,308 females contributed 21,590 cycles of exposure for safety evaluation and 999 completed 13 cycles; there were 209 subjects with BMI >29 kg/m² who contributed 1,254 cycles of exposure with 36 subjects completing 13 cycles. The demographic profile for subjects was: mean age 26.7 years, mean BMI 24.1 (16.0- 41.5) kg/m²; 67% were from the U.S. The racial distribution was 71% Caucasian, 14% African American, 4% Asian, and 11% Other; 30% of the population was Hispanic.

• Pregnancy: Discontinue if pregnancy occurs. (8.1)
• Lactation: Not recommended for nursing mothers; can decrease milk production. (8.2)

The risk for cardiovascular disease and prevalence of risk factors for cardiovascular disease increase with age. Certain conditions, such as smoking and migraine headache without aura, that do not contraindicate CHC use in younger females, are contraindications to use in women over 35 years of age [see Contraindications (4) and Warnings and Precautions (5.1)]. Consider the presence of underlying risk factors that may increase the risk of cardiovascular disease or VTE, particularly before initiating ANNOVERA for women over 35 years, such as:

• Hypertension
• Diabetes
• Dyslipidemia
• Obesity

Cases of TSS have been reported by vaginal ring users. TSS has been associated with tampons and certain barrier contraceptives, and in some TSS cases ring users were also using tampons. Causal relationship between the use of a vaginal ring and TSS has not been established. No cases of TSS occurred in clinical trials with ANNOVERA. If a patient exhibits signs or symptoms of TSS, consider the possibility of this diagnosis, remove ANNOVERA, and initiate appropriate medical evaluation and treatment.

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

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

The safety and efficacy of ANNOVERA in females with a BMI >29 kg/m² have not been adequately evaluated because this subpopulation was excluded from the clinical trials after 2 VTEs occurred in females with a BMI > 29 kg/m² [see Adverse Reactions (6.1) and Clinical Studies (14)]. Higher body weight is associated with lower systemic exposure of SA and EE [see Clinical Pharmacology (12.3)].

The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

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)].

Bleeding and/or spotting that occurs at any time while the vaginal system is inserted is considered "unscheduled" bleeding/spotting. Bleeding/spotting that occurs during the dose-free week when the vaginal system is out is considered "scheduled" bleeding.

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].

NDC 68308-752-01

Rx only

Annovera^®

(segesterone acetate and

ethinyl estradiol vaginal system)

Delivers 0.15 mg/0.013 mg per day

This product is intended to prevent pregnancy.

It does not protect against HIV infection (AIDS)

and other sexually transmitted diseases.

Keep out of reach of children and pets

For Vaginal Use

CONTAINS 1 VAGINAL SYSTEM

mayne pharma

Females are at increased risk for a venous thrombotic event (VTE) when using ANNOVERA. Limited data are available in females with a BMI >29.0 kg/m² because this subpopulation was excluded from the clinical trials after VTEs were reported.

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

Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive (CHC) use. This risk increases with age, particularly in females over 35 years of age, and with the number of cigarettes smoked. For this reason, CHC should not be used by females who are over 35 years of age and smoke. [See Contraindications (4) and Warnings and Precautions (5.5)].

Table 4 provides significant drug interaction information for drugs co-administered with CHCs.

During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with and 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 females using ethinyl estradiol-containing medications, such as ANNOVERA. Discontinue ANNOVERA prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4)]. ANNOVERA can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

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) and Warnings and Precautions (5.3)].

Limitations of Use

ANNOVERA has not been adequately studied in females with a BMI >29 kg/m².

ANNOVERA is contraindicated in females who have headaches with focal neurological symptoms or have migraine headaches with aura, and in females over age 35 years who have migraine headaches with or without aura [see Contraindications (4)].

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

Consider discontinuation of ANNOVERA in the case of increased frequency or severity of migraine during CHC use (which may be prodromal of a cerebrovascular event) [see Contraindications (4)].

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.

• 1.
  Dinger, J, Mohner S, Heinemann K. Cardiovascular risk associated with the use of an etonogestrel- containing vaginal ring. Obstetrics & Gynecology 2013; 122(4): 800-808.
• 2.
  Sidney, S, Cheetham TC, Connell FA, Oullet-Hellstrom R, Graham DJ, Davis D,, Recent combined hormonal contraceptives (CHCs) and the risk of thromboembolism and other cardiovascular events in new users. Contraception 2013; 87: 93–100.
• 3.
  Combined hormonal contraceptives (CHCs) and the risk of cardiovascular endpoints. Sidney, S. (primary author) http://www.fda.gov/downloads/Drugs/DrugSafety/UCM277384.pdf, accessed 04- April-2019.

Chloasma may occur with ANNOVERA use, especially in females with a history of chloasma gravidarum. Advise females who tend to develop chloasma to avoid exposure to the sun or ultraviolet radiation while using ANNOVERA.

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: C₂₃H₃₀O₄

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: C₂₀H₂₄O₂

Molecular Weight: 296.4

Physical Form: White to slightly yellowish-white crystalline 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.

Carefully observe females with a history of depression and discontinue ANNOVERA if depression recurs to a serious degree. Data on the association of CHCs with onset of depression or exacerbation of existing depression are limited.

Some females are aware of the vaginal system on occasion during the 21 days of use or during coitus, and partners may feel the vaginal system during coitus.

There is no information on the concomitant use of ANNOVERA with diaphragms, cervical caps, and female condoms.

ANNOVERA may not be suitable for females with conditions that make the vagina more susceptible to vaginal irritation or ulceration. Vaginal and cervical erosion and/or ulceration has been reported in females using other contraceptive vaginal devices. In some cases, the ring adhered to vaginal tissue, which necessitated removal by a healthcare provider.

ANNOVERA is contraindicated in females with uncontrolled hypertension or hypertension with vascular disease [see Contraindications (4)]. For all females, including those with well- controlled hypertension, monitor blood pressure at routine visits and stop ANNOVERA if blood pressure rises significantly.

An increase in blood pressure has been reported in females using CHCs, and this increase is more likely in older females and with extended duration of use. The effect of CHCs on blood pressure may vary according to the progestin in the CHC.

ANNOVERA (segesterone acetate and ethinyl estradiol vaginal system) is a toroidal- shaped (ring), nonbiodegradable, flexible, opaque white vaginal system. The vaginal system body has an overall diameter of 56 mm and a cross-sectional diameter of 8.4 mm. When placed inside the vagina, each ANNOVERA releases an approximate average 0.15 mg/day of segesterone acetate and 0.013 mg/day of ethinyl estradiol over 21-day in-use period of each cycle for up to 13 cycles (total 273 days). Each cycle is 28 days, with 21 days in and 7 days out.

Each ANNOVERA is individually packaged in an aluminum pouch. The pouch consists of a laminate from outside to inside of polyester, aluminum foil, and polyethylene.

First insertion of ANNOVERA must be prior to the date of expiration. Discard one year after first insertions.

A black compact case is provided with the drug product for storage of ANNOVERA by patients during each 7-day vaginal system-out interval.

The vaginal system should be placed in the compact case after 13 cycles of use and discarded via a drug take-back option if one is available. If a take-back option is unavailable, then discard in the waste receptacle out of reach of children and pets. The vaginal system should NOT be flushed down the toilet. See www.fda.gov/drugdisposal for more information about disposal of medicines.

Each box contains 1 ANNOVERA vaginal system in a pouch and 1 storage case.

NDC 68308-752-01

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.

The efficacy of ANNOVERA was evaluated in two 1-year multicenter trials enrolling 2,265 females, age 18–40 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/m². At approximately 50% enrollment, women with BMI >29.0 kg/m² were no longer enrolled in the two trials and all women with a BMI >29.0 kg/m² were discontinued from the trials.

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).

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:
  • -
    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 (5.5), (5.7)].
  • -
    Have headaches with focal neurological symptoms, migraine headaches with aura, or are over age 35 with any migraine headaches [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) and 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)].

The following adverse reactions are described elsewhere in other sections of the labeling:

• Serious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions (5.1)]
• Vascular events [see Warnings and Precautions (5.1)]
• Liver disease [see Warnings and Precautions (5.2)]

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.

No studies were conducted in subjects with renal impairment; ANNOVERA is not recommended in patients with renal impairment.

ANNOVERA^® (ann-o-VER-ah)

(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: You may start ANNOVERA within 5 days following a first trimester abortion or miscarriage (the first 12 weeks of pregnancy). You do not need to use an additional birth control method.
  • 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: You may start using ANNOVERA no sooner than 4 weeks (28 days) after a second trimester abortion (after the first 12 weeks of pregnancy).

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?

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 to keep the vaginal system in for the whole 3 weeks (21 full days).
• 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 until ANNOVERA has been in your vagina for 7 days in a row, such as male condoms or spermicides.
• 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?" below.
• 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?" below.
• Do not take any medicines unless your healthcare provider says it is ok to take them.
  
  Tell your healthcare provider when you start a new medicine.

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.
• See www.fda.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 until ANNOVERA has been in your vagina for 7 days in a row, such as male condoms or spermicides.

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?" in the section above.
• 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

Raleigh, NC 27609

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.S. Food and Drug Administration.

Revised 08/2024

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) and Warnings and Precautions (5.2)].

ANNOVERA is indicated for use by females of reproductive potential to prevent pregnancy.

Prior to dispensing ANNOVERA to the user, store ANNOVERA at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Protect ANNOVERA from direct sunlight.

Do not refrigerate or freeze and avoid excessive heat.

Instruct patients that ANNOVERA should be used as directed [see How to Start ANNOVERA (2.2)]. One ANNOVERA should be placed in the vagina. For maximum contraceptive effectiveness, ANNOVERA is to remain in the vagina continuously for 21 days (3 complete weeks). It is removed for a 1-week dose-free interval, and during this time a withdrawal bleed usually occurs. The removed vaginal system should be cleaned with mild soap and warm water, patted dry with a clean cloth towel or paper towel, and placed in its case during the 1-week dose- free interval. At the end of the dose-free interval, the vaginal system should be cleaned prior to being placed back in the vagina for another 21 continuous days (3 complete weeks). This pattern of ANNOVERA use made up of 3-weeks in and 1-week out is a cycle of use; one ANNOVERA vaginal system will provide contraception for 13 cycles.

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.

Studies suggest a small increased relative risk of developing gallbladder disease among CHC users. Use of CHCs may also worsen existing gallbladder disease.

A past history of CHC-related cholestasis predicts an increased risk with subsequent CHC use. Females with a history of pregnancy-related cholestasis may be at an increased risk for CHC- related cholestasis.

CHCs lower the risk of becoming pregnant primarily by suppressing ovulation.

IMPORTANT: Consider the possibility of ovulation and conception prior to the first use of ANNOVERA.

• Thrombotic Disorders and Other Vascular Problems: Stop ANNOVERA if a thrombotic or thromboembolic event occurs. Stop ANNOVERA at least 4 weeks before and through 2 weeks after major surgery. Start ANNOVERA no earlier than 4 weeks after delivery, in females who are not breastfeeding. Consider cardiovascular risk factors before initiating in all females, particularly those over 35 years. (5.1, 5.5)
• Liver Disease: Discontinue if jaundice occurs. (5.2)
• Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment: Stop ANNOVERA prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir. ANNOVERA can be restarted 2 weeks following completion of this regimen. (5.3)
• Hypertension: Do not prescribe ANNOVERA for females with uncontrolled hypertension or hypertension with vascular disease. If used in females with well-controlled hypertension, monitor blood pressure and stop use if blood pressure rises significantly. (5.4)
• Carbohydrate and lipid metabolic effects: Monitor glucose in pre-diabetic and diabetic females taking ANNOVERA. Consider an alternate contraceptive method for females with uncontrolled dyslipidemias. (5.7)
• Headache: Evaluate significant change in headaches and discontinue ANNOVERA if indicated. (5.8)
• Bleeding Irregularities and Amenorrhea: May cause irregular bleeding or amenorrhea. Evaluate for other causes if irregular bleeding or amenorrhea persists. (5.9)

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

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)

Vaginal system: Each ANNOVERA releases an approximate average 0.15 mg/day of segesterone acetate (SA) and 0.013 mg/day of ethinyl estradiol (EE) when placed in the vagina over a period of 21 days of each cycle for up to 13 cycles (total of 273 days). Each cycle of use is 28 days with 21 days in and 7 days out.

ANNOVERA (segesterone acetate and ethinyl estradiol vaginal system) is a toroidal- shaped (ring), nonbiodegradable, flexible, opaque white, contraceptive vaginal system containing 103 mg of SA and 17.4 mg EE.

ANNOVERA is 56 mm in overall diameter and 8.4 mm in cross-sectional diameter. It contains 2 channels of approximately 3.0 mm diameter and 27 mm length into which steroid-containing cores are inserted. The cores are 3 mm in diameter with one releasing SA alone and the other releasing both SA and EE.

Each ANNOVERA is designed to be used for up to 13 cycles (1 year).

ANNOVERA is not made with natural rubber latex.

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 (<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: 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.

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.S. (15 sites), and the other two were global studies that included 5 U.S. 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/m² were excluded due to the occurrence of two VTEs in this subgroup. In total, 2,308 females contributed 21,590 cycles of exposure for safety evaluation and 999 completed 13 cycles; there were 209 subjects with BMI >29 kg/m² who contributed 1,254 cycles of exposure with 36 subjects completing 13 cycles. The demographic profile for subjects was: mean age 26.7 years, mean BMI 24.1 (16.0- 41.5) kg/m²; 67% were from the U.S. The racial distribution was 71% Caucasian, 14% African American, 4% Asian, and 11% Other; 30% of the population was Hispanic.

• Pregnancy: Discontinue if pregnancy occurs. (8.1)
• Lactation: Not recommended for nursing mothers; can decrease milk production. (8.2)

The risk for cardiovascular disease and prevalence of risk factors for cardiovascular disease increase with age. Certain conditions, such as smoking and migraine headache without aura, that do not contraindicate CHC use in younger females, are contraindications to use in women over 35 years of age [see Contraindications (4) and Warnings and Precautions (5.1)]. Consider the presence of underlying risk factors that may increase the risk of cardiovascular disease or VTE, particularly before initiating ANNOVERA for women over 35 years, such as:

• Hypertension
• Diabetes
• Dyslipidemia
• Obesity

Cases of TSS have been reported by vaginal ring users. TSS has been associated with tampons and certain barrier contraceptives, and in some TSS cases ring users were also using tampons. Causal relationship between the use of a vaginal ring and TSS has not been established. No cases of TSS occurred in clinical trials with ANNOVERA. If a patient exhibits signs or symptoms of TSS, consider the possibility of this diagnosis, remove ANNOVERA, and initiate appropriate medical evaluation and treatment.

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

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

The safety and efficacy of ANNOVERA in females with a BMI >29 kg/m² have not been adequately evaluated because this subpopulation was excluded from the clinical trials after 2 VTEs occurred in females with a BMI > 29 kg/m² [see Adverse Reactions (6.1) and Clinical Studies (14)]. Higher body weight is associated with lower systemic exposure of SA and EE [see Clinical Pharmacology (12.3)].

The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

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)].

Bleeding and/or spotting that occurs at any time while the vaginal system is inserted is considered "unscheduled" bleeding/spotting. Bleeding/spotting that occurs during the dose-free week when the vaginal system is out is considered "scheduled" bleeding.

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].

NDC 68308-752-01

Rx only

Annovera^®

(segesterone acetate and

ethinyl estradiol vaginal system)

Delivers 0.15 mg/0.013 mg per day

This product is intended to prevent pregnancy.

It does not protect against HIV infection (AIDS)

and other sexually transmitted diseases.

Keep out of reach of children and pets

For Vaginal Use

CONTAINS 1 VAGINAL SYSTEM

mayne pharma

Females are at increased risk for a venous thrombotic event (VTE) when using ANNOVERA. Limited data are available in females with a BMI >29.0 kg/m² because this subpopulation was excluded from the clinical trials after VTEs were reported.

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

Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive (CHC) use. This risk increases with age, particularly in females over 35 years of age, and with the number of cigarettes smoked. For this reason, CHC should not be used by females who are over 35 years of age and smoke. [See Contraindications (4) and Warnings and Precautions (5.5)].

Table 4 provides significant drug interaction information for drugs co-administered with CHCs.

During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with and 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 females using ethinyl estradiol-containing medications, such as ANNOVERA. Discontinue ANNOVERA prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4)]. ANNOVERA can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

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) and Warnings and Precautions (5.3)].