Annovera

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

2 DOSAGE AND ADMINISTRATION One ANNOVERA is inserted in the vagina. The vaginal system must remain in place continuously for 3 weeks (21 days) followed by a 1-week (7-day) vaginal system-free interval. One vaginal system provides contraception for thirteen 28-day cycles (1 year). ( 2 ) 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. No Hormonal Contraceptive Use in the Preceding Cycle and after Copper IUD Removal : The woman should insert ANNOVERA between days 2 and 5 of her regular menstrual bleeding; no back-up contraception is needed. If menstrual cycles are irregular or if the start is more than 5 days from the last menstrual bleeding, the woman should use an additional barrier method during coitus, such as a male condom or spermicide, for the first 7 days of ANNOVERA use. Switching from a CHC: A woman who has been using her CHC method consistently and correctly, and who you are reasonably certain is not already pregnant, may switch from her previous CHC to ANNOVERA on any day of the CHC cycle (Day 1-28), without the need for back-up contraception, but no more than 7 hormone-free days should occur before starting ANNOVERA. Switching from a Progestin-Only Method [Progestin-only pills (POP), Progestin Injection, Progestin Implant, Progestin Intrauterine System (IUS)]: If a woman has no contraindications to the use of ethinyl estradiol (EE), she may elect to switch from a progestin-only method to ANNOVERA. If switching from progestin-only pills, she should begin ANNOVERA at the time she would have taken her next POP pill. If switching from an injection, she should begin ANNOVERA at the time of her next scheduled injection. If switching from an implant or an IUS, she should begin ANNOVERA at the time of implant or IUS removal. In all of these cases, the woman should use an additional barrier method during coitus, such as a male condom or spermicide, for the first 7 days of ANNOVERA use. Use after Abortion or Miscarriage: If a woman has no contraindications to the use of EE, ANNOVERA may be initiated for contraception within the first 5 days following a complete first trimester abortion or miscarriage without additional back-up contraception. If more than 5 days have elapsed from the first trimester abortion or miscarriage, then follow the instructions for "No Hormonal Contraceptive Use…

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 u…

4 CONTRAINDICATIONS 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) ]. A high risk of arterial or venous thrombotic diseases ( 4 ) Breast cancer ( 4 ) Liver tumors, acute hepatitis, or severe (decompensated) cirrhosis ( 4 ) Undiagnosed abnormal uterine bleeding ( 4 ) Hypersensitivity to any of the components of ANNOVERA ( 4 ) Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir ( 4 )

7 DRUG INTERACTIONS The sections below provide information on substances for which data on drug interactions with CHCs are available. There is little information available about the clinical effect of most drug interactions that may affect ANNOVERA. However, based on the known pharmacokinetic effects of these drugs, clinical strategies to minimize any potential adverse effect on contraceptive effectiveness or safety are suggested. Consult the approved product labeling of all concurrently used drugs to obtain further information about interactions with ANNOVERA or the potential for metabolic enzyme or transporter system alterations. Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of ANNOVERA or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with ANNOVERA. ( 7.1 ) 7.1 Effects of Other Drugs on Combined Hormonal Contraceptives Substances Decreasing the Systemic Exposure of CHCs and Potentially Diminishing the Efficacy of ANNOVERA : Table 3 includes substances that demonstrated an important drug interaction with CHCs. Table 3: Significant Drug Interactions Involving Substances That Decrease Systemic Exposure of CHCs Metabolic Enzyme Inducers Clinical effect Concomitant use of CHCs with metabolic enzyme inducers may decrease the systemic concentrations of the estrogen and/or progestin component of CHCs [see Clinical Pharmacology (12.3) ] . Decreased exposure of the estrogen and/or progestin component of CHCs may potentially diminish the effectiveness of CHCs and may lead to contraceptive failure or an increase in breakthrough bleeding. Prevention or management Counsel females to use an alternative method of contraception or a back-up method when enzyme inducers are used with CHCs. Continue back-up contraception for 28 days after discontinuing the enzyme inducer to maintain contraceptive reliability. Examples Aprepitant, barbiturates, bosentan, carbamazepine, efavirenz, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, rifabutin, rufinamide, topiramate, products containing St. John's wort Induction potency of St. John's wort may vary widely based on preparation. , and certain protease inhibitors (see separate section on protease inhibitors below). Substances Increasing the Systemic Exposure of CHCs and Potentially Increasing Exposure to Estrogen and/or Progestin in ANNOVERA : Co- administration of atorvastatin or rosuvastatin and certain CHCs containing EE increase systemic exposure of EE by approximately 20–25%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase systemic exposure of the estrogen and/or progestin component of ANNOVERA. Human Immunodeficiency Virus (HIV)/ Hepatitis C Virus (HCV) Protease Inhibitors and Non-nucleoside Reverse Transcriptase Inhibitors : Significant decreases in systemic exposure of estrogen and/or progestin have been noted when CHCs are co-administered with some HIV protease inhibitors (eg, nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir), some HCV protease inhibitors (eg, boceprevir and telaprevir), and some non-nucleoside reverse transcriptase inhibitors (eg, nevirapine). In contrast, significant increases in systemic exposure of estrogen and/or progestin have been noted when CHCs are co-administered with certain other HIV protease inhibitors (eg, indinavir and atazanavir/ritonavir) and with other non-nucleoside reverse transcriptase inhibitors (eg, etravirine). 7.2 Effects of Combined Hormonal Contraceptives on Other Drugs Table 4 provides significant drug interaction information for drugs co-administered with CHCs. Table 4: Significant Drug Interaction Information for Drugs Co-Administered with CHCs Lamotrigin…

8.1 Pregnancy Risk Summary Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to CHCs before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Discontinue ANNOVERA if pregnancy occurs, because there is no reason to use CHCs during pregnancy. Data Human Data No studies have been conducted of the use of ANNOVERA in pregnant females.

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 ca…