Annovera

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS 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) ]. WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS See full prescribing information for complete boxed warning. Females over 35 years old who smoke should not use ANNOVERA. ( 4 ) Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive (CHC) use. ( 4 )

5 WARNINGS AND PRECAUTIONS 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 ) 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/m 2 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) ] . Arterial Events CHCs increase the risk of cardiovascular events and cerebrovascular events, such as stroke and myocardial infarction. The risk is greater among older females (>35 years of age), smokers, and females with hypertension, dyslipidemia, diabetes, or obesity. ANNOVERA is contraindicated in females over 35 years of age who smoke [see Contraindications (4) ] . Cigarette smoking increases the risk of serious cardiovascular events from CHC use. This risk increases with age, particularly in females over 35 years of age, and with the number of cigarettes smoked. 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. Figure 1 5.2 Liver Disease Impaired Liver Function ANNOVERA is contraindicated in females with acute hepatitis or severe (decompensated) cirrhosis of the liver [see Contraindications (4) ] . Discontinue ANNOVERA if jaundice develops. Acute liver test abnormalities may necessitate the discontinuation of ANNOVERA use until the liver tests return to normal and ANNOVERA causation has been excluded. Liver Tumors ANNOVERA is contraindicated in females with benign or malignant liver tumors [see Contraindications (4) ] . Hepatic adenomas are associated with CHC use. An estimate of the attributable risk is 3.3 cases/100,000 CHC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long- term (>8 years) CHC users. The attributable risk of liver cancers in CHC users is less than one case per million users. 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 Hyperglycemia ANNOVERA is contraindicated in diabetic females over age 35, or females who have diabetes with hypertension, nephropathy, retinopathy, neuropathy, other vascular disease, or females with diabetes of >20 years duration [see Contraindications (4) ] . ANNOVERA may decrease glucose tolerance. Carefully monitor prediabetic and diabetic females who are taking ANNOVERA. Dyslipidemia Consider alternative contraception for females with uncontrolled dyslipidemia. ANNOVERA may cause adverse lipid changes. Females with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using ANNOVERA. 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. Unscheduled and Scheduled Bleeding and Spotting Females using ANNOVERA may experience unscheduled (breakthrough) bleeding and spotting, especially during the first month of use. If unscheduled bleeding persists or occurs after previously regular cycles on ANNOVERA, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different CHC. Based on subject diaries from the two clinical efficacy trials of ANNOVERA [see Clinical Trial Experience (6.1) ] , 5–10% of females experienced unscheduled bleeding per 28-day cycle. The average number of days with unscheduled bleeding and/or spotting, in Treatment Cycles 1 to 13 for those females who experienced unscheduled bleeding and/or spotting, was 1 day or less per cycle. A total of 41 subjects (1.7%) discontinued use due to menstrual disorders including metrorrhagia, menorrhagia, and abnormal withdrawal bleeding. Amenorrhea and Oligomenorrhea Females who are not pregnant and use ANNOVERA may experience amenorrhea. Based on subject diary data from two clinical trials for up to 13 cycles, amenorrhea occurred in 3–5% of females per cycle using ANNOVERA and in 0.9% of females in all 13 cycles. If scheduled bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (removed vaginal system for >2 hours during the first 21 days or does not replace after 7 days of vaginal system- free period), consider the possibility of pregnancy at the time of the first missed period and perform a pregnancy test. If the patient has adhered to the prescribed dosing schedule and misses 2 consecutive periods, perform a pregnancy test to rule out pregnancy. Some females may experience amenorrhea or oligomenorrhea after stopping ANNOVERA, especially when such a condition was pre-existent. 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 ADVERSE REACTIONS 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 most common adverse reactions (>5%) are headache/migraine, nausea/vomiting, vulvovaginal mycotic infection/candidiasis, abdominal pain lower/upper, dysmenorrhea, vaginal discharge, urinary tract infection, breast tenderness/pain/discomfort, bleeding irregularities including metrorrhagia, diarrhea, genital pruritus. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mayne Pharma at 1-844-825-8500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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/m 2 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/m 2 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/m 2 ; 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. Most Common Adverse Reactions Table 1 summarizes the most common adverse reactions reported by females using ANNOVERA. This table shows adverse reactions reported in at least 5% of subjects. In addition, 25% of subjects reported at least 1 complete expulsion during their use of ANNOVERA. Table 1: Adverse Drug Reactions Reported by ≥ 5% of ANNOVERA-treated Subjects Adverse Reactions % (N=2,308) Headache, including migraine 38.6 Nausea/vomiting 25.0 Vulvovaginal mycotic infection/vaginal candidiasis 14.5 Abdominal pain/lower/upper 13.3 Dysmenorrhea 12.5 Vaginal discharge 11.8 UTI/cystitis/pyelonephritis/genitourinary tract infection 10.0 Breast pain/tenderness/discomfort 9.5 Metrorrhagia/menstrual disorder 7.5 Diarrhea 7.2 Genital pruritus 5.5 Adverse Reactions Leading to Discontinuation Among subjects using ANNOVERA for contraception, 12% discontinued from the clinical trials due to an adverse reaction. Table 2 summarizes the most common adverse reactions leading to discontinuation. In addition, 1.4% of subjects discontinued ANNOVERA use due to vaginal system expulsions. Table 2: Adverse Reactions Leading to Discontinuation by ≥ 1% of ANNOVERA treated Subjects Adverse Reactions % (N=2,308) Metrorrhagia/menorrhagia 1.7 Headache, including migraine 1.3 Vaginal discharge/vulvovaginal mycotic infections 1.3 Nausea/vomiting 1.2 Serious Adverse Reactions Serious adverse reactions occurring in ≥2 subjects were: VTEs (deep venous thrombosis, cerebral vein thrombosis, pulmonary embolism); psychiatric events; drug hypersensitivity reactions; and spontaneous abortions. 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. Figure 2

<table width="85%"><caption>Table 1: Adverse Drug Reactions Reported by &#x2265; 5% of ANNOVERA-treated Subjects</caption><col width="75%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" valign="middle">Adverse Reactions</th><th styleCode="Rrule">% (N=2,308)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache, including migraine</td><td styleCode="Rrule">38.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea/vomiting</td><td styleCode="Rrule">25.0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vulvovaginal mycotic infection/vaginal candidiasis</td><td styleCode="Rrule">14.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal pain/lower/upper</td><td styleCode="Rrule">13.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dysmenorrhea</td><td styleCode="Rrule">12.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vaginal discharge</td><td styleCode="Rrule">11.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">UTI/cystitis/pyelonephritis/genitourinary tract infection</td><td styleCode="Rrule">10.0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Breast pain/tenderness/discomfort</td><td styleCode="Rrule">9.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Metrorrhagia/menstrual disorder</td><td styleCode="Rrule">7.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">7.2</td></tr><tr><td styleCode="Lrule Rrule">Genital pruritus</td><td styleCode="Rrule">5.5</td></tr></tbody></table>

<table width="85%"><caption>Table 2: Adverse Reactions Leading to Discontinuation by &#x2265; 1% of ANNOVERA treated Subjects</caption><col width="75%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" valign="middle">Adverse Reactions</th><th styleCode="Rrule">% (N=2,308)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Metrorrhagia/menorrhagia</td><td styleCode="Rrule">1.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache, including migraine</td><td styleCode="Rrule">1.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vaginal discharge/vulvovaginal mycotic infections</td><td styleCode="Rrule">1.3</td></tr><tr><td styleCode="Lrule Rrule">Nausea/vomiting</td><td styleCode="Rrule">1.2</td></tr></tbody></table>