Limitations of Use

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

2.1 How to Use ANNOVERA

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.

2.2 How to Start ANNOVERA

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

2.3 Deviations from the Recommended Regimen

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].

5.1 Thromboembolic Disorders and Other Vascular Conditions

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)].

Venous Events

The use of CHCs increases the risk of VTE, such as deep vein thrombosis and pulmonary embolism. Risk factors for VTEs include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of CHCs [see Contraindications (4)]. While the increased risk of VTE associated with use of CHCs is well established, the rates of VTE are even greater during pregnancy, and especially during the postpartum period (see Figure 1). The rate of VTE in females using CHCs has been estimated to be 3–12 cases per 10,000 woman-years.

The risk of VTE is highest during the first year of CHC use and when restarting hormonal contraception following a break of 4 weeks or longer. The risk of VTE due to CHCs gradually disappears after use is discontinued.

Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use CHCs, for females who use CHCs, for pregnant females, and for females in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 females who are not pregnant and do not use CHCs are followed for 1 year, between 1 and 5 of these women will develop a VTE.

Figure 1: Likelihood of Developing a VTE

* CHC = combination hormonal contraception

** Pregnancy data based on actual duration of pregnancy in the reference studies. Based on a model assumption that pregnancy duration is 9 months, the rate is 7 to 27 per 10,000 WY.

5.2 Liver Disease

5.3 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with 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.

5.4 Hypertension

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.

5.5 Age-Related Considerations

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

5.6 Gallbladder Disease

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

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

5.7 Adverse Carbohydrate and Lipid Metabolic Effects

5.8 Headache

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)].

5.9 Bleeding Irregularities and Amenorrhea

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.

5.10 Depression

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.

5.11 Malignant Neoplasms

Breast Cancer

Annovera is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4)].

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

Cervical Cancer

Some studies suggest that CHCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings are due to differences in sexual behavior and other factors.

5.12 Effect on Binding Globulins

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.

5.13 Hereditary Angioedema

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

5.14 Chloasma

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.

5.15 Toxic Shock Syndrome (TSS)

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.

5.16 Vaginal Use

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.

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to 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.

6.2 Postmarketing Experience

Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 - 1.12 (Figure 2).

Three studies compared breast cancer risk between current or recent COC users (<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.

7.1 Effects of Other Drugs on Combined Hormonal Contraceptives

7.2 Effects of Combined Hormonal Contraceptives on Other Drugs

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

7.3 Use of Vaginal Products with ANNOVERA

In a drug-drug interaction study with ANNOVERA and the concurrent use of three different formulations of vaginal miconazole, the use of water-based vaginal miconazole cream resulted in no change in exposure to EE or SA from the vaginal system. However, the use of either the 1- day or the 3-day oil-based miconazole suppository was associated with an overall increase in exposure up to 67% for EE and 32% for SA. Considering the potential long-term effect on vaginal system performance, concurrent use of oil-based vaginal suppositories should not occur with ANNOVERA use. If there is a need to treat a vaginal condition, water-based vaginal cream or oral therapy may be used concurrently with the vaginal system [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.

7.4 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation

Do not co-administer ANNOVERA with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Contraindications (4) and Warnings and Precautions (5.3)].

7.5 Interference with Laboratory Tests

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

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

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.

8.5 Geriatric Use

ANNOVERA has not been studied in females who have reached menopause and is not indicated in this population.

8.6 Hepatic Impairment

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)].

8.7 Renal Impairment

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

8.8 Body Mass Index (BMI)/Body Weight

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)].

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

12.3 Pharmacokinetics

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 tmax of about 2 hours in Cycle 1, Cycle 3, and Cycle 13. Concentrations of both components declined after tmax and became more constant after 96 hours post-dose. Over subsequent cycles of use, the peak serum concentrations of SA and EE declined. Serum concentration-time profiles of SA and EE for Cycles 1, 3, and 13 of ANNOVERA use are provided in Figure 2 and Figure 3 with PK parameters summarized in Table 5 and Table 6.

Figure 2: Mean SA and EE Serum Concentrations Delivered by ANNOVERA Over 21 Days of Dosing for Cycles 1, 3, and 13

Figure 3: 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	AUC0-21 day (ng*hr/mL)	AUC0-1 day (ng*hr/mL)	Cmax (pg/mL)	Cavg (pg/mL)
1	96.2 (16.9)	15 (3.2)	1,147 (315)	191 (34)
3	65.9 (14.8)	5 (1.6)	363 (133)	131 (29)
13	47.2 (10.1)	3.9 (1.4)	294 (116)	94 (20)

Table 6: Mean (SD) PK Parameters for EE following ANNOVERA Administration

Cycle	AUC0-21 day (ng*hr/mL)	AUC0-1 day (ng*hr/mL)	Cmax (pg/mL)	Cavg (pg/mL)
1	22.2 (9.8)	2.1 (0.7)	129 (39)	44 (19)
3	14.7 (4.7)	0.9 (0.4)	60 (32)	29 (9)
13	9.6 (4.1)	0.7 (0.3)	39 (16)	19 (8)

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

16.1 How Supplied

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.

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 50261-313-01

16.2 Storage Conditions

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.

Cigarette Smoking

Cigarette smoking increases the risk of serious cardiovascular events from CHC use, and females who are over 35 years old and smoke should not use ANNOVERA [see Boxed Warning and Warnings and Precautions (5.1)].

Venous Thromboembolism

Increased risk of VTE compared to nonusers of CHCs is greatest after initially starting a CHC or restarting (following a 4-week or greater dose-free interval) the same or a different CHC [see Warnings and Precautions (5.1)].

Sexually Transmitted Infections

ANNOVERA does not protect against HIV-infection (AIDS) and other sexually transmitted infections. ANNOVERA is compatible with male condoms made with natural rubber latex, polyisoprene, and polyurethane.

Use During Pregnancy

ANNOVERA is not to be used during pregnancy; instruct the patient to remove ANNOVERA if pregnancy is confirmed during treatment [see Use in Specific Populations (8.1)].

ANNOVERA Dosing and Instructions

Advise the woman on proper use of ANNOVERA and what to do if she does not comply with the labeled timing of insertion and removal. The efficacy of ANNOVERA is greatest when ANNOVERA is kept in the vagina continuously for the scheduled 21 consecutive days. Removal of ANNOVERA even briefly during the scheduled 21 days of use can reduce efficacy.

ANNOVERA should be washed with mild soap and water and rinsed and patted dry with a clean cloth towel or paper towel prior to each insertion and at each removal. Prior to initial use, the storage case should be labeled with the discard date to avoid using the product beyond 13 cycles [see Dosage and Administration (2) and FDA-approved Patient Information].

Place the completely used ANNOVERA in the case provided and discard 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. [see How Supplied (16.1)].

Use with Vaginal Products

Water-based vaginal lubricants have no effect on the vaginal system; 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 [see Drug Interactions (7.3)].

Need for Additional Contraception

Use a back-up or alternative method of contraception when:

   Enzyme inducers are used with CHCs [see Drug Interactions (7.1)].

   ANNOVERA has been out for more than 2 hours cumulative during the 21 days of continuous use or the vaginal system-free interval exceeds 7 days [see Dosage and Administration (2.3)].

Postpartum females who have not yet had a period should use an additional method of contraception until ANNOVERA has been in place for 7 consecutive days [see Dosage and Administration (2.2)].

Lactation

ANNOVERA may reduce breast milk production. This is less likely to occur if breastfeeding is well established. Females who are breastfeeding should not use ANNOVERA until after weaning [see Use in Specific Populations (8.2)].

Amenorrhea and Possible Symptoms of Pregnancy

Amenorrhea may occur. Consider pregnancy in the event of amenorrhea and rule out pregnancy if amenorrhea is associated with symptoms of pregnancy, such as morning sickness or unusual breast tenderness [see Warnings and Precautions (5.9)].

Fertility Following Discontinuation of ANNOVERA

Resumption of fertility after discontinuation of ANNOVERA is expected. All women followed for return of fertility experienced a return of fertility by 6 months after discontinuing ANNOVERA [see Clinical Studies (14)].