Twirla

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS and CONTRAINDICATED IN WOMEN WITH A BMI ≥ 30 KG/M 2 Cigarette Smoking and Serious Cardiovascular Events Cigarette smoking increases the risk of serious cardiovascular events from combined hormonal contraceptive (CHC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, CHCs, including TWIRLA, are contraindicated in women who are over 35 years of age and smoke [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )]. Contraindicated in Women with a BMI ≥ 30 kg/m 2 TWIRLA is contraindicated in women with a BMI ≥ 30 kg/m 2 . Compared to women with a lower BMI, women with a BMI ≥ 30 kg/m 2 had reduced effectiveness and may have a higher risk for venous thromboembolism events (VTEs) [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS and CONTRAINDICATED IN WOMEN WITH A BMI ≥ 30 KG/M 2 See full prescribing information for complete boxed warning. TWIRLA is contraindicated in women over 35 years old who smoke. Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive (CHC) use. ( 4 , 5.1 ) TWIRLA is contraindicated in women with a BMI ≥ 30 kg/m 2 . Compared to women with a lower BMI, women with a BMI ≥ 30 kg/m 2 had reduced effectiveness and may have a higher risk for venous thromboembolic events. ( 4 , 5.1 , 8.9 , 14 )

5 WARNINGS AND PRECAUTIONS Vascular Risks : Stop TWIRLA if a thromboembolic event occurs. Stop TWIRLA at least 4 weeks before and through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in women who are not breast-feeding. Consider cardiovascular risk factors before initiating in all women, particularly those over 35 years. ( 5.1 , 5.5 ) Liver Disease : Discontinue TWIRLA if jaundice occurs. ( 5.2 ) Risk of Liver Enzyme Elevations with Concomitant Hepatitis C . ( 5.3 ) Hypertension : If used in women with well-controlled hypertension, monitor blood pressure and stop use if blood pressure rises significantly. ( 5.4 ) Gallbladder Disease : May cause or worsen gallbladder disease. ( 5.6 ) Adverse Carbohydrate and Lipid Metabolic Effect : Monitor glucose in prediabetic and diabetic women using TWIRLA. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. ( 5.7 ) Headache : Evaluate significant change in headaches and discontinue TWIRLA if indicated. ( 5.8 ) Uterine Bleeding : May cause irregular bleeding or amenorrhea. Evaluate for other causes if symptoms persist. ( 5.9 ) 5.1 Thromboembolic Disorders and Other Vascular Conditions Women are at increased risk for a venous thromboembolic event (VTE) when using CHCs, including TWIRLA. The risk of VTE may be greater in women with a BMI ≥ 30 kg/m 2 compared to women with a lower BMI, and TWIRLA is contraindicated in obese patients [see Contraindications ( 4 )] . In the Phase 3 clinical trial, four TWIRLA-treated women experienced a VTE. All of these women had a BMI > 30 kg/m 2 [see Adverse Reactions ( 6.1 )] . Stop TWIRLA if an arterial or venous thromboembolic event occurs. Stop TWIRLA if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. Discontinue TWIRLA during prolonged immobilization and resume treatment based on clinical judgement. If feasible, stop TWIRLA at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism. Start TWIRLA no earlier than four weeks after delivery in women 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 TWIRLA, evaluate any past medical history or family history of thromboembolism or thromboembolic disorders. Consider whether the history suggests an inherited or acquired hypercoagulopathy. TWIRLA is contraindicated in women with a high risk of arterial or venous thromboembolic diseases [see Contraindications ( 4 )] . Arterial Events CHCs increase the risk of cardiovascular events and cerebrovascular events, such as myocardial infarction and stroke. The risk is greater among older women (> 35 years of age), smokers, and women with hypertension, dyslipidemia, diabetes, or obesity. TWIRLA is contraindicated in women 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 women over 35 years of age, and with the number of cigarettes smoked. Venous Events The use of CHCs increases the risk of VTEs, 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. While the increased risk of VTE associated with the use of CHCs is well-established, the rates of VTE are even greater during pregnancy, especially during the postpartum period (see Figure 1 ). The rate of VTE in women using CHCs has been estimated to be 3 to 12 cases per 10,000 woman-years for non-oral CHCs. The risk of VTE is highest during the first year of use of a combined oral contraceptive (COC) and when restarting hormonal contraception after a break of four weeks or longer. This initial higher risk declines during the first year, but users of CHCs remain at an increased risk of VTE compared to non-users of CHCs. Based on results from a few studies, there is some evidence that this is true for non-oral products as well. The risk of thromboembolic disease due to CHCs gradually disappears after CHC use is discontinued. Figure 1 shows the risk of developing a VTE for women who are not pregnant and do not use hormonal contraceptives, for women who use hormonal contraceptives with a range of doses and routes of administration, for pregnant women, and for women in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 women who are not pregnant and do not use hormonal contraceptives are followed for one year, between 1 and 5 of these women will develop a VTE. Figure 1. Likelihood of Developing a VTE Within One Year Among Pregnant and Non-Pregnant Women *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 Elevated Liver Enzymes TWIRLA is contraindicated in women with acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see Contraindications ( 4 )] . Discontinue TWIRLA if jaundice develops. Acute liver test abnormalities may necessitate the discontinuation of CHC use until the liver tests return to normal and CHC causation has been excluded. Liver Tumors TWIRLA is contraindicated in women with benign or malignant liver tumors [see Contraindications ( 4 )] . CHCs increase the risk of hepatic adenomas. An estimate of the attributable risk is 3.3 cases/100,000 CHC users. Rupture of hepatic adenomas may cause death from 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 or 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 women using ethinyl estradiol-containing medications, such as CHCs. CHCs, such as TWIRLA, are contraindicated for use with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications ( 4 )] . Discontinue TWIRLA prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. TWIRLA can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen. 5.4 Hypertension TWIRLA is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see Contraindications ( 4 )] . For all women, including those with well-controlled hypertension, monitor blood pressure at routine visits and stop TWIRLA if blood pressure rises significantly. An increase in blood pressure has been reported in women using CHCs, and this increase is more likely in older women 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 women, 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 a CHC for women over 35 years, such as: Hypertension Diabetes Dyslipidemia Obesity 5.6 Gallbladder Disease Studies suggest an increased 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. Women 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 TWIRLA is contraindicated in diabetic women over age 35, or women who have diabetes with hypertension, nephropathy, retinopathy, neuropathy, other vascular disease, or women with diabetes of > 20 years duration [see Contraindications ( 4 )] . TWIRLA may decrease glucose tolerance. Carefully monitor prediabetic and diabetic women who are using TWIRLA. Dyslipidemia Consider alternative contraception for women with uncontrolled dyslipidemia. TWIRLA may cause adverse lipid changes. Women with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using TWIRLA, which may increase the risk of pancreatitis. 5.8 Headache TWIRLA is contraindicated in women who have headaches with focal neurological symptoms or have migraine headaches with aura, and in women over age 35 years who have migraine headaches with or without aura [see Contraindications ( 4 )] . If a woman using TWIRLA develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue TWIRLA if indicated. Consider discontinuation of TWIRLA if there is any increased frequency or severity of migraines during CHC use (which may be prodromal of a cerebrovascular event). 5.9 Bleeding Irregularities and Amenorrhea Unscheduled and Scheduled Bleeding and Spotting Women using TWIRLA may experience unscheduled (breakthrough or intracyclic) bleeding and spotting, especially during the first three months of use. Bleeding irregularities may resolve over time or by changing to a different contraceptive product. If bleeding persists or occurs after previously regular cycles on TWIRLA, evaluate for causes such as pregnancy or malignancy. Based on women’s electronic diaries from a clinical trial evaluating the safety and efficacy of TWIRLA, the proportion of subjects reporting unscheduled bleeding per 28-day cycle decreased over time. At cycle 1 and 2, 60.4% and 52.6%, respectively reported unscheduled bleeding and/or spotting. At cycle 13, 42.3% of women reported unscheduled bleeding and/or spotting. Women reported a mean number of unscheduled bleeding/spotting days per month that generally decreased over the 13 cycles and was a mean of 1.6 days in Cycle 13. A total of 45 women (2.2%) discontinued the study prematurely due to menstrual disorders including metrorrhagia, vaginal hemorrhage, menorrhagia, dysmenorrhea, irregular menstruation, dysfunctional uterine bleeding, and menstrual disorder [see Clinical Trial Experience ( 6.1 ) and Clinical Studies ( 14 )] . Amenorrhea and Oligomenorrhea Women who use TWIRLA may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant. Based on electronic patient diaries from the clinical trial, the percentages of women with no bleeding and/or spotting days (amenorrhea) in a cycle ranged from 6.3% to 11.9% over 13 cycles [see Clinical Trial Experience ( 6.1 ) and Clinical Studies ( 14 )] . If scheduled bleeding does not occur, consider the possibility of pregnancy. If the woman has not adhered to the prescribed dosing schedule (missed days of active therapy or started her TDS on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and perform appropriate diagnostic measures. If the woman has adhered to the prescribed dosing schedule and misses two consecutive periods, rule out pregnancy. After discontinuation of TWIRLA, amenorrhea or oligomenorrhea may occur, especially if these conditions were pre-existent. 5.10 Depression Carefully observe women with a history of depression and discontinue TWIRLA 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 Twirla 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 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. 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 TWIRLA 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 women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. 5.14 Chloasma Chloasma may occur with TWIRLA use, especially in women with a history of chloasma gravidarum. Advise women with a history of chloasma to avoid exposure to the sun or ultraviolet radiation while using TWIRLA.

6 ADVERSE REACTIONS The following serious adverse reactions with the use of CHCs, including TWIRLA, are discussed elsewhere in the labeling: Thromboembolic Disorders and Other Vascular Conditions [see Warnings and Precautions ( 5.1 )] Liver disease [see Warnings and Precautions ( 5.3 )] The most common adverse reactions (≥ 2%) in clinical trials for TWIRLA are application site disorders, nausea, headache, dysmenorrhea, and increased weight. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Exeltis USA, Inc. at 1-877-324-9349 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 one product cannot be directly compared to rates in the clinical trials of another product and may not reflect the rates observed in practice. The safety of TWIRLA was evaluated in a 12-month, multicenter, open-label, single-arm clinical trial (NCT02158572) conducted in the United States [see Clinical Studies ( 14 )] . Women applied TWIRLA (40 mcg LNG/10 mcg EE) for 13 28-day treatment cycles. One treatment cycle is defined as three consecutive weeks that one TWIRLA TDS is applied for seven-day wear followed by one week that TWIRLA is not applied. The safety population for this clinical trial was composed of 2,031 women that contributed 18,841 treatment cycles of exposure. Of these 2,031 women, 989 women completed 13 treatment cycles. The mean age was 27.5 years. The mean BMI for the safety population was 28.3 kg/m 2 . The BMI of the safety population was widely distributed: 39.4% had a BMI < 25 kg/m 2 , 25.3% had a BMI ≥ 25 kg/m 2 and < 30 kg/m 2 , and 35.3% had a BMI ≥ 30 kg/m 2 . For women who received TWIRLA, the most common reasons for discontinuation from the study were a womans decision (15.3%) and lost to follow-up (11.3%). Discontinuation due to an adverse reaction occurred in 10.9% of women. The most common (≥ 2%) adverse reactions leading to discontinuation were application site disorder (3.1%) and any bleeding irregularities (2.2%). The most common adverse reactions that occurred in ≥ 2% of the 2,031 women that used TWIRLA are shown in Table 3. Table 3: Adverse Drug Reactions Reported by 2% of TWIRLA-Treated Women in One Phase 3 Clinical Trial Adverse reaction TWIRLA (n=2,031) General disorders and administration site conditions Application site disorder* 6.2% Gastrointestinal disorders Nausea 4.1% Nervous system disorders Headache 3.6% Reproductive system and breast disorder Dysmenorrhoea 2.3% Investigations Weight increased 2.0% *Represents a bundle of similar terms that include the following adverse reactions: application site acne, hemorrhage, pustules, dermatitis, hypersensitivity, rash, discoloration, induration, reaction, dryness, irritation, ulcer, erosion, pain, urticaria, erythema, papules, vesicles, exfoliation, pruritis. Venous Thromboembolic Events (VTEs) A total of four VTEs (including pulmonary embolism and deep vein thrombosis) in TWIRLA-treated patients were identified in the clinical trial. Of these, all were in women with a BMI > 30 kg/m 2 [see Contraindications ( 4 )] . Other Serious Adverse Reactions The following serious adverse reactions occurred in < 1% of women who received TWIRLA: cholelithiasis, cholecystitis, major depression, suicidal ideation, appendicitis, ectopic pregnancy, pneumonia, and gastroenteritis. 6.2 Postmarketing Experience Five studies that compared breast cancer risk between ever-users (current or past use) of combined oral contraceptives (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 that never used COCs. image description

<table border="1"><caption>Table 3: Adverse Drug Reactions Reported by 2% of TWIRLA-Treated Women in One Phase 3 Clinical Trial</caption><tbody><tr><td><content styleCode="bold">Adverse reaction</content></td><td><paragraph><content styleCode="bold">TWIRLA (n=2,031)</content></paragraph></td></tr><tr><td><content styleCode="bold">General disorders and administration site conditions</content> Application site disorder* </td><td>6.2%</td></tr><tr><td><content styleCode="bold">Gastrointestinal disorders</content> Nausea </td><td>4.1%</td></tr><tr><td><content styleCode="bold">Nervous system disorders</content> Headache </td><td>3.6%</td></tr><tr><td><content styleCode="bold">Reproductive system and breast disorder</content> Dysmenorrhoea </td><td>2.3%</td></tr><tr><td><content styleCode="bold">Investigations</content> Weight increased </td><td>2.0%</td></tr></tbody></table>