Twirla

Twirla is contraindicated in females who are known to have or develop the following conditions:

• At high risk of arterial or venous thrombotic diseases. Examples include women who
  
  
  • Smoke, if over age 35
    [see Boxed Warning
    and
    Warnings and Precautions (

    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/m²compared to women with a lower BMI, and TWIRLA is contraindicated in obese patients

    [see Contraindications ]

    . In the Phase 3 clinical trial, four TWIRLA-treated women experienced a VTE. All of these women had a BMI > 30 kg/m²

    [see Adverse Reactions ]

    .

    • 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 ]
      .

    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

    ]

    . 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.

    

    )]
  • Have current or history of deep vein thrombosis or pulmonary embolism
    [see Warnings and Precautions (

    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/m²compared to women with a lower BMI, and TWIRLA is contraindicated in obese patients

    [see Contraindications ]

    . In the Phase 3 clinical trial, four TWIRLA-treated women experienced a VTE. All of these women had a BMI > 30 kg/m²

    [see Adverse Reactions ]

    .

    • 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 ]
      .

    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

    ]

    . 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.

    

    )]
  • Have cerebrovascular disease
    [see Warnings and Precautions (

    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/m²compared to women with a lower BMI, and TWIRLA is contraindicated in obese patients

    [see Contraindications ]

    . In the Phase 3 clinical trial, four TWIRLA-treated women experienced a VTE. All of these women had a BMI > 30 kg/m²

    [see Adverse Reactions ]

    .

    • 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 ]
      .

    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

    ]

    . 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.

    

    )]
  • Have coronary artery disease
    [see Warnings and Precautions (

    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/m²compared to women with a lower BMI, and TWIRLA is contraindicated in obese patients

    [see Contraindications ]

    . In the Phase 3 clinical trial, four TWIRLA-treated women experienced a VTE. All of these women had a BMI > 30 kg/m²

    [see Adverse Reactions ]

    .

    • 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 ]
      .

    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

    ]

    . 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.

    

    )]
  • 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 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/m²compared to women with a lower BMI, and TWIRLA is contraindicated in obese patients

    [see Contraindications ]

    . In the Phase 3 clinical trial, four TWIRLA-treated women experienced a VTE. All of these women had a BMI > 30 kg/m²

    [see Adverse Reactions ]

    .

    • 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 ]
      .

    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

    ]

    . 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.

    

    )]
  • Have inherited or acquired hypercoagulopathies
    [see Warnings and Precautions (

    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/m²compared to women with a lower BMI, and TWIRLA is contraindicated in obese patients

    [see Contraindications ]

    . In the Phase 3 clinical trial, four TWIRLA-treated women experienced a VTE. All of these women had a BMI > 30 kg/m²

    [see Adverse Reactions ]

    .

    • 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 ]
      .

    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

    ]

    . 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.

    

    )]
  • Have uncontrolled hypertension or hypertension with vascular disease
    [see Warnings and Precautions (

    5.4 Hypertension

    TWIRLA is contraindicated in women with uncontrolled hypertension or hypertension with vascular disea

    se [see Contraindications ]

    . 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.

    )]
  • 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 (

    5.7 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 ]

    . 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.

    )]
• Have headaches with focal neurological symptoms, migraine headaches with aura
• Women over age 35 with any migraine headaches 
  [see Warnings and Precautions (

  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 ]

  .

  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).

  )]
• BMI ≥ 30 kg/m². Compared to women with a lower BMI, women with a BMI ≥ 30 kg/m² had reduced effectiveness and may have a higher risk for VTEs
  [see Warnings and Precautions (

  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/m²compared to women with a lower BMI, and TWIRLA is contraindicated in obese patients

  [see Contraindications ]

  . In the Phase 3 clinical trial, four TWIRLA-treated women experienced a VTE. All of these women had a BMI > 30 kg/m²

  [see Adverse Reactions ]

  .

  • 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 ]
    .

  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

  ]

  . 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.

  

  ), Use in Specific Populations (

  8.9 Body Mass Index (BMI)

  Compared to women with a lower BMI, women with a BMI ≥ 30 kg/m²had reduced effectiveness and may have a higher risk for VTEs. Therefore, TWIRLA is contraindicated in women with a BMI ≥ 30 kg/m²

  [see Contraindications

  and

  Clinical Studies ]

  .

  TWIRLA has demonstrated reduced efficacy in women with a BMI ≥ 25 and < 30 kg/m²

  [see Clinical Studies ]

  . Consider this before prescribing TWIRLA to women with a BMI ≥ 25 to < 30 kg/m².

  )
  and
  Clinical Studies (

  14 CLINICAL STUDIES

  The efficacy of TWIRLA was evaluated in one open label, single arm, multicenter trial in the United States (Study 1) (NCT02158572) of one-year duration that enrolled 2,031 women, ranging in age between 18 and 60 years, who were healthy and sexually active with regular menstrual cycles. For the primary efficacy analysis, 1,736 women between the ages 18 and 35 years completed 15,165 evaluable 28-day cycles with TWIRLA, where no back-up contraception was used, and sexual intercourse occurred.

  The racial/ethnic distribution for the primary analysis was White (67%), Black/African American (24%), Asian (4%), American Indian/Alaskan Native (0.5%), Native Hawaiian/Pacific Islander (0.5%), Other/Multiple races (5%); 19% of the study population were Hispanic. The mean age was 26 years.

  The mean BMI in the primary efficacy analysis group was 28.3 kg/m², and 35.3% of subjects had a BMI 30 kg/m². The primary efficacy endpoint was the Pearl Index (PI) defined as the pregnancy rate per 100 woman-years of use. The overall PI for the primary analysis population (TWIRLA-treated patients) was 5.8 (95% CI 4.5, 7.2). There were clear differences in efficacy by BMI category as shown in Table 7 below.

  Table 7: Pearl Index Efficacy Analysis in TWIRLA-Treated Patients by BMI Subgroup in Study 1TWIRLA is contraindicated in women with a BMI ≥ 30 kg/m²

  BMI	Number of evaluable cycles	Pearl Index (95% CI)
  < 25 kg/m2	6007	3.5 (1.8 - 5.2)
  ≥ 25 and < 30 kg/m2	3881	5.7 (3.0 - 8.4)
  ≥ 30 kg/m2	5264	8.6 (5.8 - 11.5)

  Figure 7 shows a model of the rate of pregnancy as BMI increases based on data from Study 1. There is an increase in pregnancy rate (i.e., the number of pregnancies per 100 woman-years), as BMI increased based on the primary analysis population (N = 1,735). TWIRLA is contraindicated in women with a BMI ≥ 30 kg/m²

  [see Indications and Usage and Contraindications ]

  .

  Figure 7. Pregnancy Rates (Estimated*) in TWIRLA-Treated Patients as BMI Increases for Women ≤ 35 Years of Age in Study 1

  

  *Plot is based on Poisson Model with continuous BMI as the predictor (N=1,735); one woman in the primary analysis population had no BMI information. The solid line displays the estimated pregnancy rate, and the shaded area displays the 95% confidence interval for the estimated pregnancy rate.

  Adhesion

  
  
  Based on a Phase 1 study in 78 subjects wearing one TWIRLA on the lower abdomen for 7 days, 77 systems applied (98.7%) exhibited 75% or greater surface area adhesion at all timepoints evaluated (every 24 hours) throughout the wear period. In the Phase 3 trial, 5.0% of all transdermal systems worn during the year-long trial (55,900 transdermal systems) fully detached. Subject-reported adhesion was generally better for the abdomen as compared to the upper torso and buttock. Full detachment rates were higher for transdermal systems exposed to water as compared to transdermal systems with no water exposure.

  

  )].
• Liver tumors (benign or malignant), acute viral hepatitis, or severe (decompensated) cirrhosis, or liver disease 
  [see Warnings and Precautions (

  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 ]

  . 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 ]

  . 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.

  )]
• Undiagnosed abnormal uterine bleeding
  [see Warnings and Precautions (

  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

  and

  Clinical Studies ]

  .

  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

  and

  Clinical Studies ]

  .

  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.

  )]
• Pregnancy, because there is no reason to use CHCs during pregnancy
  [see Use in Specific Populations (

  8.1 Pregnancy

  Risk Summary

  
  
  TWIRLA is contraindicated in pregnancy because there is no reason to use CHCs in pregnancy. Discontinue TWIRLA if pregnancy occurs. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital 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.

  )]
• Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive
  [see Warnings and Precautions (

  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 ]

  .

  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 ].

  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.

  )]
• Hypersensitivity to any components of TWIRLA. Observed reactions include itching and irritation at the TDS application site
  [see Adverse Reactions (

  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 ]

  . Women applied TWIRLA (120 mcg LNG/30 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/m². The BMI of the safety population was widely distributed: 39.4% had a BMI < 25 kg/m², 25.3% had a BMI ≥ 25 kg/m²and < 30 kg/m², and 35.3% had a BMI ≥ 30 kg/m².

  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 disorderRepresents 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.	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%

  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/m²

  [see Contraindications ]

  .

  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.

  )]
• Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for alanine aminotransferase (ALT) elevations
  [see Warnings and Precautions (

  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 ]

  . 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.

  )]