Introvale

Introvale 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

    WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS

    Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs, including Introvale, are contraindicated in women who are over 35 years of age and smoke

    [see Contraindications (4)and Warnings and Precautions (5.1)].

    WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS

    See full prescribing information for complete boxed warning.

    • Introvale is contraindicated in women over 35 years old who smoke.

    • Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use.

    and

    5.1 Thromboembolic Disorders and Other Vascular Conditions

    • Stop levonorgestrel and ethinyl estradiol tablets if an arterial or venous thrombotic/thromboembolic event occurs.

    • Stop levonorgestrel and ethinyl estradiol tablets if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.

    • Discontinue levonorgestrel and ethinyl estradiol tablets during prolonged immobilization. If feasible, stop levonorgestrel and ethinyl estradiol tablets at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.

    • Start levonorgestrel and ethinyl estradiol tablets no earlier than 4 weeks after delivery in females who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week.

    • Before starting levonorgestrel and ethinyl estradiol tablets evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. Levonorgestrel and ethinyl estradiol tablets are contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases

      [see Contraindications (4)]
      .

    Arterial Events

    COCs 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 females with hypertension, dyslipidemia, diabetes, or obesity.

    Levonorgestrel and ethinyl estradiol tablets are contraindicated in women over 35 years of age who smoke

    [see Contraindications (4)]

    . Cigarette smoking increases the risk of serious cardiovascular events from COC use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked.

    Venous Events

    Use of COCs increases the risk of venous thromboembolic events (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 COCs

    [see Contraindications (4)]

    . While the increased risk of VTE associated with use of COCs 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 COCs has been estimated to be 3 to 9 cases per 10,000 woman years.

    The risk of VTE is highest during the first year of use of a COC and when restarting hormonal contraception after a break of four weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued.

    Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use oral contraceptives, for females who use oral contraceptives, for pregnant females and for females in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 females who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these females will develop a VTE.

    Figure 1: Likelihood of Developing a VTE

    

    Use of levonorgestrel and ethinyl estradiol tablets provides women with more hormonal exposure on a yearly basis than conventional monthly COCs containing the same strength synthetic estrogens and progestins (an additional 9 weeks of exposure per year). In the clinical trial, one case of pulmonary embolism was reported. Postmarketing adverse reactions of VTE have been reported in women who used levonorgestrel and ethinyl estradiol tablets.

    

    ]
    .

  • Have current or history of deep vein thrombosis or pulmonary embolism

    [see

    5.1 Thromboembolic Disorders and Other Vascular Conditions

    • Stop levonorgestrel and ethinyl estradiol tablets if an arterial or venous thrombotic/thromboembolic event occurs.

    • Stop levonorgestrel and ethinyl estradiol tablets if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.

    • Discontinue levonorgestrel and ethinyl estradiol tablets during prolonged immobilization. If feasible, stop levonorgestrel and ethinyl estradiol tablets at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.

    • Start levonorgestrel and ethinyl estradiol tablets no earlier than 4 weeks after delivery in females who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week.

    • Before starting levonorgestrel and ethinyl estradiol tablets evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. Levonorgestrel and ethinyl estradiol tablets are contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases

      [see Contraindications (4)]
      .

    Arterial Events

    COCs 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 females with hypertension, dyslipidemia, diabetes, or obesity.

    Levonorgestrel and ethinyl estradiol tablets are contraindicated in women over 35 years of age who smoke

    [see Contraindications (4)]

    . Cigarette smoking increases the risk of serious cardiovascular events from COC use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked.

    Venous Events

    Use of COCs increases the risk of venous thromboembolic events (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 COCs

    [see Contraindications (4)]

    . While the increased risk of VTE associated with use of COCs 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 COCs has been estimated to be 3 to 9 cases per 10,000 woman years.

    The risk of VTE is highest during the first year of use of a COC and when restarting hormonal contraception after a break of four weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued.

    Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use oral contraceptives, for females who use oral contraceptives, for pregnant females and for females in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 females who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these females will develop a VTE.

    Figure 1: Likelihood of Developing a VTE

    

    Use of levonorgestrel and ethinyl estradiol tablets provides women with more hormonal exposure on a yearly basis than conventional monthly COCs containing the same strength synthetic estrogens and progestins (an additional 9 weeks of exposure per year). In the clinical trial, one case of pulmonary embolism was reported. Postmarketing adverse reactions of VTE have been reported in women who used levonorgestrel and ethinyl estradiol tablets.

    

    ]
    .

  • Have cerebrovascular disease

    [see

    5.1 Thromboembolic Disorders and Other Vascular Conditions

    • Stop levonorgestrel and ethinyl estradiol tablets if an arterial or venous thrombotic/thromboembolic event occurs.

    • Stop levonorgestrel and ethinyl estradiol tablets if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.

    • Discontinue levonorgestrel and ethinyl estradiol tablets during prolonged immobilization. If feasible, stop levonorgestrel and ethinyl estradiol tablets at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.

    • Start levonorgestrel and ethinyl estradiol tablets no earlier than 4 weeks after delivery in females who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week.

    • Before starting levonorgestrel and ethinyl estradiol tablets evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. Levonorgestrel and ethinyl estradiol tablets are contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases

      [see Contraindications (4)]
      .

    Arterial Events

    COCs 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 females with hypertension, dyslipidemia, diabetes, or obesity.

    Levonorgestrel and ethinyl estradiol tablets are contraindicated in women over 35 years of age who smoke

    [see Contraindications (4)]

    . Cigarette smoking increases the risk of serious cardiovascular events from COC use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked.

    Venous Events

    Use of COCs increases the risk of venous thromboembolic events (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 COCs

    [see Contraindications (4)]

    . While the increased risk of VTE associated with use of COCs 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 COCs has been estimated to be 3 to 9 cases per 10,000 woman years.

    The risk of VTE is highest during the first year of use of a COC and when restarting hormonal contraception after a break of four weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued.

    Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use oral contraceptives, for females who use oral contraceptives, for pregnant females and for females in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 females who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these females will develop a VTE.

    Figure 1: Likelihood of Developing a VTE

    

    Use of levonorgestrel and ethinyl estradiol tablets provides women with more hormonal exposure on a yearly basis than conventional monthly COCs containing the same strength synthetic estrogens and progestins (an additional 9 weeks of exposure per year). In the clinical trial, one case of pulmonary embolism was reported. Postmarketing adverse reactions of VTE have been reported in women who used levonorgestrel and ethinyl estradiol tablets.

    

    ]
    .

  • Have coronary artery disease

    [see

    5.1 Thromboembolic Disorders and Other Vascular Conditions

    • Stop levonorgestrel and ethinyl estradiol tablets if an arterial or venous thrombotic/thromboembolic event occurs.

    • Stop levonorgestrel and ethinyl estradiol tablets if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.

    • Discontinue levonorgestrel and ethinyl estradiol tablets during prolonged immobilization. If feasible, stop levonorgestrel and ethinyl estradiol tablets at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.

    • Start levonorgestrel and ethinyl estradiol tablets no earlier than 4 weeks after delivery in females who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week.

    • Before starting levonorgestrel and ethinyl estradiol tablets evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. Levonorgestrel and ethinyl estradiol tablets are contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases

      [see Contraindications (4)]
      .

    Arterial Events

    COCs 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 females with hypertension, dyslipidemia, diabetes, or obesity.

    Levonorgestrel and ethinyl estradiol tablets are contraindicated in women over 35 years of age who smoke

    [see Contraindications (4)]

    . Cigarette smoking increases the risk of serious cardiovascular events from COC use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked.

    Venous Events

    Use of COCs increases the risk of venous thromboembolic events (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 COCs

    [see Contraindications (4)]

    . While the increased risk of VTE associated with use of COCs 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 COCs has been estimated to be 3 to 9 cases per 10,000 woman years.

    The risk of VTE is highest during the first year of use of a COC and when restarting hormonal contraception after a break of four weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued.

    Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use oral contraceptives, for females who use oral contraceptives, for pregnant females and for females in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 females who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these females will develop a VTE.

    Figure 1: Likelihood of Developing a VTE

    

    Use of levonorgestrel and ethinyl estradiol tablets provides women with more hormonal exposure on a yearly basis than conventional monthly COCs containing the same strength synthetic estrogens and progestins (an additional 9 weeks of exposure per year). In the clinical trial, one case of pulmonary embolism was reported. Postmarketing adverse reactions of VTE have been reported in women who used levonorgestrel and ethinyl estradiol tablets.

    

    ]
    .

  • Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation)

    [see

    5.1 Thromboembolic Disorders and Other Vascular Conditions

    • Stop levonorgestrel and ethinyl estradiol tablets if an arterial or venous thrombotic/thromboembolic event occurs.

    • Stop levonorgestrel and ethinyl estradiol tablets if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.

    • Discontinue levonorgestrel and ethinyl estradiol tablets during prolonged immobilization. If feasible, stop levonorgestrel and ethinyl estradiol tablets at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.

    • Start levonorgestrel and ethinyl estradiol tablets no earlier than 4 weeks after delivery in females who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week.

    • Before starting levonorgestrel and ethinyl estradiol tablets evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. Levonorgestrel and ethinyl estradiol tablets are contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases

      [see Contraindications (4)]
      .

    Arterial Events

    COCs 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 females with hypertension, dyslipidemia, diabetes, or obesity.

    Levonorgestrel and ethinyl estradiol tablets are contraindicated in women over 35 years of age who smoke

    [see Contraindications (4)]

    . Cigarette smoking increases the risk of serious cardiovascular events from COC use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked.

    Venous Events

    Use of COCs increases the risk of venous thromboembolic events (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 COCs

    [see Contraindications (4)]

    . While the increased risk of VTE associated with use of COCs 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 COCs has been estimated to be 3 to 9 cases per 10,000 woman years.

    The risk of VTE is highest during the first year of use of a COC and when restarting hormonal contraception after a break of four weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued.

    Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use oral contraceptives, for females who use oral contraceptives, for pregnant females and for females in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 females who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these females will develop a VTE.

    Figure 1: Likelihood of Developing a VTE

    

    Use of levonorgestrel and ethinyl estradiol tablets provides women with more hormonal exposure on a yearly basis than conventional monthly COCs containing the same strength synthetic estrogens and progestins (an additional 9 weeks of exposure per year). In the clinical trial, one case of pulmonary embolism was reported. Postmarketing adverse reactions of VTE have been reported in women who used levonorgestrel and ethinyl estradiol tablets.

    

    ]
    .

  • Have inherited or acquired hypercoagulopathies

    [see

    5.1 Thromboembolic Disorders and Other Vascular Conditions

    • Stop levonorgestrel and ethinyl estradiol tablets if an arterial or venous thrombotic/thromboembolic event occurs.

    • Stop levonorgestrel and ethinyl estradiol tablets if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.

    • Discontinue levonorgestrel and ethinyl estradiol tablets during prolonged immobilization. If feasible, stop levonorgestrel and ethinyl estradiol tablets at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.

    • Start levonorgestrel and ethinyl estradiol tablets no earlier than 4 weeks after delivery in females who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week.

    • Before starting levonorgestrel and ethinyl estradiol tablets evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. Levonorgestrel and ethinyl estradiol tablets are contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases

      [see Contraindications (4)]
      .

    Arterial Events

    COCs 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 females with hypertension, dyslipidemia, diabetes, or obesity.

    Levonorgestrel and ethinyl estradiol tablets are contraindicated in women over 35 years of age who smoke

    [see Contraindications (4)]

    . Cigarette smoking increases the risk of serious cardiovascular events from COC use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked.

    Venous Events

    Use of COCs increases the risk of venous thromboembolic events (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 COCs

    [see Contraindications (4)]

    . While the increased risk of VTE associated with use of COCs 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 COCs has been estimated to be 3 to 9 cases per 10,000 woman years.

    The risk of VTE is highest during the first year of use of a COC and when restarting hormonal contraception after a break of four weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued.

    Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use oral contraceptives, for females who use oral contraceptives, for pregnant females and for females in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 females who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these females will develop a VTE.

    Figure 1: Likelihood of Developing a VTE

    

    Use of levonorgestrel and ethinyl estradiol tablets provides women with more hormonal exposure on a yearly basis than conventional monthly COCs containing the same strength synthetic estrogens and progestins (an additional 9 weeks of exposure per year). In the clinical trial, one case of pulmonary embolism was reported. Postmarketing adverse reactions of VTE have been reported in women who used levonorgestrel and ethinyl estradiol tablets.

    

    ]
    .

  • Have uncontrolled hypertension or hypertension with vascular disease

    [see

    5.4 Hypertension

    Levonorgestrel and ethinyl estradiol tablets are contraindicated in females 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 levonorgestrel and ethinyl estradiol tablets if blood pressure rises significantly.

    An increase in blood pressure has been reported in females taking COCs, and this increase is more likely in older women and with extended duration of use. The effect of COCs on blood pressure may vary according to the progestin in the COC.

    ]
    .

  • Have diabetes mellitus and are over age of 35, diabetes mellitus with hypertension or vascular disease or other end-organ damage, or diabetes mellitus of > 20 years duration

    [see

    5.7 Adverse Carbohydrate and Lipid Metabolic Effects

    Hyperglycemia

    Levonorgestrel and ethinyl estradiol tablets are contraindicated in diabetic women over age 35, or females who have diabetes with hypertension, nephropathy, retinopathy, neuropathy, other vascular disease or females with diabetes of > 20 years of duration

    [see Contraindications (4)]

    . Levonorgestrel and ethinyl estradiol tablets may decrease glucose tolerance. Carefully monitor prediabetic and diabetic females who are using levonorgestrel and ethinyl estradiol tablets.

    Dyslipidemia

    Consider alternative contraception for females with uncontrolled dyslipidemia. Levonorgestrel and ethinyl estradiol tablets may cause adverse lipid changes.

    Females with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using levonorgestrel and ethinyl estradiol tablets, which may increase the risk of pancreatitis.

    ]
    .

  • Have headaches with focal neurological symptoms, migraine headaches with aura, or over age 35 with any migraine headaches

    [see

    5.8 Headache

    Levonorgestrel and ethinyl estradiol tablets are contraindicated in females 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 female taking levonorgestrel and ethinyl estradiol tablets develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue levonorgestrel and ethinyl estradiol tablets if indicated. Consider discontinuation of levonorgestrel and ethinyl estradiol tablets if there is an increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event)

    [see Contraindications (4)]

    .

    ]
    .

• Current diagnosis of, or history of breast cancer, which may be hormone sensitive

  [see

  5.11 Malignant Neoplasms

  Breast Cancer

  Levonorgestrel and ethinyl estradiol tablets are contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive

  [see Contraindications (4)]

  .

  Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use

  [see Postmarketing Experience (6.2)]

  .

  Cervical Cancer

  Some studies suggest that COC are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

  ].

• Liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis

  [see

  5.2 Liver Disease

  Elevated Liver Enzymes

  Levonorgestrel and ethinyl estradiol tablets are contraindicated in females with acute viral hepatitis or severe (decompensated) cirrhosis of the liver

  [see Contraindications (4)]

  . Acute liver test abnormalities may necessitate the discontinuation of levonorgestrel and ethinyl estradiol tablets until the liver tests return to normal and levonorgestrel and ethinyl estradiol tablets causation has been excluded. Discontinue levonorgestrel and ethinyl estradiol tablets if jaundice develops.

  Liver Tumors

  Levonorgestrel and ethinyl estradiol tablets are contraindicated in females with benign and malignant liver tumors

  [see Contraindications (4)]

  . COCs increase the risk of hepatic adenomas. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.

  Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) COC users. The attributable risk of liver cancers in COC users is less than one case per million users.

  and

  8.6 Hepatic Impairment

  The pharmacokinetics of levonorgestrel and ethinyl estradiol tablets have not been studied in subjects with hepatic impairment. However, COCs may be poorly metabolized in patients with hepatic impairment. Levonorgestrel and ethinyl estradiol tablets are contraindicated in females with acute hepatitis or severe decompensated cirrhosis

  [see Contraindications (4)and Warnings and Precautions (5.2)]

  .

  ]
  .

• Undiagnosed abnormal uterine bleeding

  [see

  5.9 Bleeding Irregularities and Amenorrhea

  Bleeding and/or spotting that occurs at any time while taking the first 84 tablets of each extended-cycle regimen is considered “unscheduled” bleeding/spotting. Bleeding that occurs during the time a woman takes the seven green inert tablets is considered “scheduled” bleeding.

  Unscheduled Bleeding and Spotting

  Females using levonorgestrel and ethinyl estradiol tablets may experience unscheduled (breakthrough or intracyclic) bleeding and spotting especially during the first 3 months of use. Bleeding irregularities may resolve over time or by changing to a different contraceptive product. If unscheduled bleeding persists or occurs after previously regular cycles, evaluate for causes such as pregnancy or malignancy.

  Before prescribing levonorgestrel and ethinyl estradiol tablets, advise the woman to weigh the occurrence of fewer scheduled menses (4 per year instead of 13 per year) against the occurrence of increased unscheduled bleeding and/or spotting.

  The clinical trial of the efficacy of levonorgestrel and ethinyl estradiol tablets (91-day cycles) in preventing pregnancy also assessed scheduled and unscheduled bleeding. The participants in the study were composed primarily of women who had used oral contraceptives previously as opposed to new users. Women with a history of breakthrough bleeding/spotting ≥ 10 consecutive days on oral contraceptives were excluded from the study. More levonorgestrel and ethinyl estradiol tablets subjects, compared to subjects on the comparator 28-day cycle regimen, discontinued prematurely for unacceptable bleeding (7.7% [levonorgestrel and ethinyl estradiol tablets] vs. 1.8% [28-day cycle regimen]).

  Unscheduled bleeding and unscheduled spotting decreased over successive 91-day cycles. Table 3 below presents the number of days with unscheduled bleeding and/or spotting for each respective 91-day cycle.

  Table 3: Number of Unscheduled Bleeding and/or Spotting Days per 91-day Cycle

  Q1=Quartile 1: 25% of women had ≤ this number of days of unscheduled bleeding/spotting Median: 50% of women had ≤ this number of days of unscheduled bleeding/spotting Q3=Quartile 3: 75% of women had ≤ this number of days of unscheduled bleeding/spotting
  Cycle (N)	Days of Unscheduled Bleeding and/or Spotting per 84-Day Interval				Median Days Per Subject- Month
  	Mean	Q1	Median	Q3
  1 (446)	15.1	3.0	12	23.0	3.0
  2 (368)	11.6	2.0	6	17.5	1.5
  3 (309)	10.6	1.0	6	15.0	1.5
  4 (282)	8.8	1.0	4	14.0	1.0

  Table 4 shows the percentages of women with ≥ 7 days and ≥ 20 days of unscheduled spotting and/or bleeding in the levonorgestrel and ethinyl estradiol tablets and the 28-day cycle treatment groups.

  Table 4: Percentage of Subjects with Unscheduled Bleeding and/or Spotting

  Days of unscheduled bleeding and/or spotting	Percentage of Subjectsa
  Levonorgestrel and Ethinyl Estradiol Tablets	Cycle 1 (N=385)	Cycle 4 (N=261)
  ≥ 7 days	65%	42%
  ≥ 20 days	35%	15%
  28-day regimen	Cycles 1-4 (N=194)	Cycles 10-13 (N=158)
  ≥ 7 days	38%	39%
  ≥ 20 days	6%	4%

  ^aBased on spotting and/or bleeding on days 1-84 of a 91 day cycle in the levonorgestrel and ethinyl estradiol tablets subjects and days 1-21 of a 28 day cycle over 4 cycles in the 28-day dosing regimen.

  Total days of bleeding and/or spotting (scheduled plus unscheduled) were similar over one year of treatment for levonorgestrel and ethinyl estradiol tablets subjects and subjects on the 28-day cycle regimen.

  Amenorrhea and Oligomenorrhea

  Females who use levonorgestrel and ethinyl estradiol tablets may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant. Based on data from the clinical trial of levonorgestrel and ethinyl estradiol tablets, amenorrhea occurred in approximately 0.8% of females during Cycle 1, 1.2% of females during Cycle 2, 3.7% of females during Cycle 3, and 3.4% of females during Cycle 4.

  Because females using levonorgestrel and ethinyl estradiol tablets will likely have scheduled bleeding only 4 times per year, rule out pregnancy at the time of any missed menstrual period.

  After discontinuation of levonorgestrel and ethinyl estradiol tablets, amenorrhea or oligomenorrhea may occur, especially if these conditions were pre-existent.

  ]
  .

• Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations

  [see

  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 levonorgestrel and ethinyl estradiol tablets. Discontinue levonorgestrel and ethinyl estradiol tablets prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir

  [see Contraindications (4)]

  . Levonorgestrel and ethinyl estradiol tablets can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

  ]
  .