Estetrol

1 INDICATIONS AND USAGE NEXTSTELLIS is indicated for use by females of reproductive potential to prevent pregnancy. NEXTSTELLIS is a combination of drospirenone, a progestin, and estetrol, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy. ( 1 ) Limitations of Use NEXTSTELLIS may be less effective in females with a BMI ≥ 30 kg/m 2 . In females with BMI ≥ 30 kg/m 2 , decreasing effectiveness may be associated with increasing BMI ( 14 ). Limitations of Use NEXTSTELLIS may be less effective in females with a BMI ≥ 30 kg/m 2 . In females with BMI ≥ 30 kg/m 2 , decreasing effectiveness may be associated with increasing BMI [see Clinical Studies (14) ].

12.1 Mechanism of Action CHCs prevent pregnancy primarily by suppressing ovulation.

2 DOSAGE AND ADMINISTRATION Take one tablet by mouth at the same time every day. ( 2.1 ) Take tablets in the order directed on the blister pack. ( 2.1 ) 2.1 Recommended Dosage and Administration Start NEXTSTELLIS using a Day 1 start. Take one tablet by mouth at the same time every day with or without food. 2.2 Additional Administration Information To achieve maximum contraceptive effectiveness, take one tablet every day at about the same time each day. The recommended dosage of NEXTSTELLIS is one tablet daily for 28 consecutive days: one pink active tablet daily during the first 24 days followed by one white inactive tablet daily during the 4 following days (see Table 1 ). Table 1 NEXTSTELLIS Administration Instructions Starting NEXTSTELLIS in females with no current use of hormonal contraception Important: In females with irregular menstrual cycles, pregnancy testing may be necessary prior to initiation of this product. Day 1 Start : Take the first pink active tablet on the first day of menses. Take subsequent pink active tablets once daily at the same time each day for a total of 24 days. Take one white inert tablet daily for 4 days and at the same time of day that active tablets were taken. Begin each subsequent 28-day pack on the same day of the week as the first cycle pack (i.e., on the day after taking the last tablet) If not starting on the first day of menses, use a non-hormonal contraceptive (e.g. condoms and/or spermicide) as back-up until one active tablet has been taken daily for 7 days in a row. Switching to NEXTSTELLIS from another contraceptive method Start NEXTSTELLIS on the day: Combined Oral Contraceptive (COC) When the new pack of the previous COC would have started. Transdermal System When the next application would have been scheduled. Vaginal Insert When the next insertion would have been scheduled. Injection When the next injection would have been scheduled. Intrauterine System (IUS) After removal. Implant After removal. Progestin-only pill After the last tablet was taken. Starting NEXTSTELLIS after delivery (>20 weeks gestation) Must not start earlier than 4 weeks after delivery (due to the increased risk of thromboembolism [see Contraindications (4) and Warnings and Precautions (5.1) ] If menstrual cycles have returned, follow instructions for "Starting NEXTSTELLIS in females with no current use of hormonal contraception". If menstrual cycles have not resumed, consider the possibility of ovulation and pregnancy. If not pregnant, use additional nonhormonal contraception for the first 7 days of NEXTSTELLIS use. Starting NEXTSTELLIS after Abortion or Miscarriage ≤14 weeks gestation Within the first 7 days of complete first trimester abortion or miscarriage, use additional nonhormonal contraception for the next 7 days. After the first 7 days, follow instructions for "Starting NEXTSTELLIS in females with no current use of hormonal contraception". > 14 weeks but ≤ 20 weeks gestation After 4 weeks following second trimester abortion or miscarriage. Consider duration of pregnancy and increased risk of thromboembolism [see Warnings and Precautions (5.1) ] If menstrual cycles have returned, follow instructions for "Starting NEXTSTELLIS in females with no current use of hormonal contraception." If menstrual cycles have not resumed, consider the possibility of ovulation and pregnancy. If not pregnant, use additional nonhormonal contraception for the first 7 days of NEXTSTELLIS use. 2.3 Missed Doses Table 2 Instructions for Missed NEXTSTELLLIS Tablets in a Monthly Dosing Regimen If one pink active tablet is missed Take the missed tablet as soon as possible and take the next tablet at the scheduled time, even if two active tablets are taken in one day. Continue taking one tablet a day until the pack is finished. If two or more pink active tablets are missed in Week 1 or Week 2 Take one missed tablet as soon as possible and take the tablet for the current day (that means taking two tablets in one day) and discard the

6 ADVERSE REACTIONS The following clinically significant adverse reactions with the use of COCs are discussed elsewhere in labeling: Serious cardiovascular events including venous and arterial thromboembolism [see Boxed Warning and Warnings and Precautions (5.1) ] Hyperkalemia [see Warnings and Precautions (5.2) ] Liver disease [see Warnings and Precautions (5.5) ] Most common adverse reactions (≥2%): bleeding irregularities, mood disturbance, headache, breast symptoms, dysmenorrhea, acne, weight increased, and libido decreased ( 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 Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of one drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data provided reflect the experience with the use of NEXTSTELLIS in two large prospective studies, one in Europe/Russia (C301) and one in North America (C302) (N = 3,632) of NEXTSTELLIS for the prevention of pregnancy in females 16-50 years of age. The mean duration of NEXTSTELLIS exposure was 317 and 257 days for the respective studies. The study population was 27 years of age on average, with a mean BMI of 25 kg/m 2 . The racial distribution was 83% White; 11% Black; 3% Asian; and 3% Other. Table 4 Adverse Reactions Occurring in ≥ 2% of Females Receiving NEXTSTELLIS in Studies C301 and C302 Preferred Term (PT) Participants with Adverse Reaction – US/Canada Phase 3 trial (n [%]) (N = 2073) Represents the safety population of C302 only (US/Canada). Participants with Adverse Reaction – Two Phase 3 trials (n [%]) (N=3632) Represents the safety population of C301/C302 for DRSP/E4. Any adverse reaction Any adverse reaction equals any adverse event ≥ 2%. 1205 (58.1) 2126 (58.5) Mood disturbance Includes PTs: adjustment disorder, affective disorder, agitation, anger, anxiety, depressed mood, depression, depressive symptom, disorientation, emotional disorder, emotional distress, euphoric mood, generalized anxiety disorder, insomnia, irritability, mood altered, mood swings, nervousness, panic attack, panic disorder, performance fear, restlessness, sleep disorder, stress, suicidal ideation, tearfulness. 226 (10.9) 329 (9.1) Bleeding irregularities Includes PTs: abnormal withdrawal bleeding, amenorrhea, cervix hemorrhage uterine, coital bleeding, dysfunctional uterine bleeding, menometrorrhagia, menorrhagia, menstrual disorder, menstruation irregular, metrorrhagia, oligomenorrhea, polymenorrhea, uterine hemorrhage, vaginal hemorrhage. 201 (9.7) 393 (10.8) Breast symptoms Includes PTs: anisomastia, breast cyst, breast discoloration, breast discomfort, breast disorder, breast engorgement, breast enlargement, breast mass, breast edema, breast pain, breast swelling, breast tenderness, fibrocystic breast disease, galactorrhea, gynecomastia, mastoptosis, nipple disorder, nipple pain. 110 (5.3) 197 (5.4) Headache Includes PTs: headache, premenstrual headache, and tension headache. 100 (4.8) 227 (6.3) Dysmenorrhea Includes PTs: adnexa uteri pain, dysmenorrhea, premenstrual cramps, pelvic discomfort, pelvic pain, uterine spasm. 84 (4.1) 133 (3.7) Weight increased Includes PTs: weight increased, weight fluctuation, body mass index increased, weight loss poor, and obesity. 68 (3.3) 108 (3.0) Acne Includes PTs: acne and cystic acne. 66 (3.2) 136 (3.7) Libido decreased/lost Includes PTs: libido decreased and loss of libido. 27 (1.3) 72 (2.0) Adverse Reactions Leading to Study Discontinuation (> 1%) Of 3,632 females in two clinical studies for prevention of pregnancy in females 16-50 years of age, 9.6% discontinued due to an adverse reaction; the most frequent adverse reaction leading to discontinuation was bleeding irregularity (2.8%). Six subjects (0.17%) discontinued study participation due to new

5 WARNINGS AND PRECAUTIONS Thromboembolic Disorders and Other Vascular Problems : Stop NEXTSTELLIS if a thrombotic or thromboembolic event occurs. Start no earlier than 4 weeks after delivery. Consider all cardiovascular risk factors before initiating in any female, particularly in the presence of multiple risk factors. ( 5.1 ) Hyperkalemia : Check serum potassium concentration during the first NEXTSTELLIS treatment cycle in females on long-term treatment with medications that may increase serum potassium concentration. ( 5.2 , 7.2 ) Hypertension : Monitor blood pressure periodically and stop use if blood pressure rises significantly. ( 5.3 ) Migraine : Discontinue if new, recurrent, persistent, or severe migraines occur. ( 5.4 ) Hormonally-Sensitive Malignancy: Discontinue NEXTSTELLIS if a hormonally-sensitive malignancy is diagnosed. ( 5.5 ) Liver Disease : Withhold or permanently discontinue for persistent or significant elevation of liver enzymes. ( 5.6 ) Glucose Tolerance and Hypertriglyceridemia : Monitor glucose in females with prediabetes or diabetes. Consider an alternate contraceptive method for females with hypertriglyceridemia. ( 5.8 ) Gallbladder Disease and Cholestasis : Consider discontinuing NEXTSTELLIS in females with symptomatic gallbladder or cholestatic disease. ( 5.9 ) Bleeding Irregularities and Amenorrhea : May cause irregular bleeding or amenorrhea. Evaluate for other causes if symptoms persist. ( 5.11 ) 5.1 Thromboembolic Disorders and Other Vascular Problems Stop NEXTSTELLIS if an arterial or venous thrombotic/thromboembolic event occurs. Stop NEXTSTELLIS if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately. Discontinue NEXTSTELLIS during prolonged immobilization. Start NEXTSTELLIS no earlier than four weeks after delivery in females who are not breast feeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week. Before starting NEXTSTELLIS, evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. NEXTSTELLIS is contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases [see Contraindications (4) ] . Cardiovascular and Cerebrovascular Events Use of CHCs increases the risk of cardiovascular events and cerebrovascular events, such as myocardial infarction and stroke. The risk is greater among females over age 40, smokers, and females with hypertension, dyslipidemia, diabetes, or obesity. The risk increases with age, particularly in females 35 years of age and older, and with the number of cigarettes smoked. In addition to cigarettes, use of other nicotine-containing products – including cigars, smokeless tobacco, hookah tobacco, e-cigarettes, and nicotine replacement therapy – may also increase the risk of serious cardiovascular events from CHC use. Venous Thromboembolism Use of CHCs also increases the risk of venous thromboembolic events (VTEs), such as deep vein thrombosis and pulmonary embolism. The rate of VTE in females using COCs has been estimated to be 3 to 9 cases per 10,000 woman-years and should be considered in the context of other female of reproductive potential subpopulations who are not taking CHCs [see Adverse Reactions (6.1) ]. Risk factors for VTEs include smoking, obesity, family history of VTE, and prolonged immobilization in addition to other factors that contraindicate use of CHCs [see Contraindications (4) ] . The presence of multiple risk factors for VTE may increase the risk synergistically. The risk of VTE is highest during the first year of CHC use and when restarting hormonal contraception after a break of four weeks or longer. The risk of VTE returns to baseline approximately 3 months after CHC use is disc

4 CONTRAINDICATIONS NEXTSTELLIS is contraindicated in females who are known to have or develop the following conditions: A history of, increased risk for, or current arterial or venous thrombotic/thromboembolic diseases. Examples include females who are known to: - Smoke, if 35 years of age and older [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 (5.1) ] - Have diabetes mellitus with hypertension or end-organ damage; or diabetes mellitus of > 20 years duration [see Warnings and Precautions (5.9) ] - Have migraine headaches with aura [see Warnings and Precautions (5.4) ] Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [see Warnings and Precautions (5.5) ] Hepatic adenoma, hepatocellular carcinoma, acute hepatitis, or severe (decompensated) cirrhosis [see Warnings and Precautions (5.6) ] Use of hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations [see Warnings and Precautions (5.7) ] Abnormal uterine bleeding that has an undiagnosed etiology [see Warnings and Precautions (5.5) ] Renal Impairment [see Warnings and Precautions (5.2) ] Adrenal insufficiency [see Warnings and Precautions (5.2) ] A high risk of arterial or venous thrombotic diseases ( 4 ) Breast cancer or history of breast cancer ( 4 ) Hepatic adenoma, hepatocellular carcinoma, acute hepatitis or decompensated cirrhosis ( 4 ) Co-administration with hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir ( 4 , 7.1 ) Abnormal uterine bleeding that has an undiagnosed etiology ( 4 ) Renal impairment ( 4 ) Adrenal insufficiency ( 4 )

10 OVERDOSAGE Overdosage of CHCs may cause nausea, vomiting, and severe headaches. Individual reports of thromboembolic complications and vaginal bleeding have occurred from overdosage. Pediatric patients with unintended CHC ingestion have reported nausea and vomiting and some developed irritability and drowsiness; rare reports described vaginal bleeding. Overdosage Management Recommendations Consider short-term prophylactic anticoagulation therapy for patients with high risk of VTE. Monitor serum potassium and sodium levels, and for evidence of metabolic acidosis.