WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (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 should not be used by women who are over 35 years of age and smoke. [See CONTRAINDICATIONS ( 4 ).] WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS See full prescribing information for complete boxed warning Women who are over 35 years old and smoke should not use LoSeasonique. ( 4 ) Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use.
boxed warning
WARNING TO WOMEN WHO SMOKE Do not use LoSeasonique if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects from birth control pills, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke.
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Vascular risks: Stop LoSeasonique if a thrombotic event occurs. Stop LoSeasonique at least 4 weeks before and through 2 weeks after major surgery. Start LoSeasonique no earlier than 4 weeks after delivery, in women who are not breastfeeding. ( 5.1 ) Liver disease: Discontinue LoSeasonique if jaundice occurs. ( 5.3 ) High blood pressure: Do not prescribe LoSeasonique for women with uncontrolled hypertension or hypertension with vascular disease. ( 5.4 ) Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking LoSeasonique. Consider an alternate contraceptive method for women with uncontrolled dyslipidemias. ( 5.6 ) Headache: Evaluate significant change in headaches and discontinue LoSeasonique if indicated. ( 5.7 ) Uterine bleeding: Evaluate irregular bleeding or amenorrhea. ( 5.8 ) 5.1 Vascular Events Stop COCs if an arterial or deep venous thrombotic event occurs. Although use of COCs increases the risk of venous thromboembolism, pregnancy increases the risk of venous thromboembolism as much or more than the use of COCs. The risk of venous thromboembolism in women using COCs is 3 to 9 per 10,000 woman-years. Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. Use of LoSeasonique provides women with more hormonal exposure on a yearly basis than conventional monthly oral contraceptives containing the same strength synthetic estrogens and progestins (an additional 9 and 13 weeks of exposure to progestin and estrogen, respectively, per year.) If feasible, stop COCs at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism. Start COCs no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week. Stop COCs if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. 5.2 Carcinoma of the Breast and Cervix Women who currently have or have had breast cancer should not use COCs because breast cancer may be hormonally sensitive. There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings. Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings are due to differences in sexual behavior and other factors. 5.3 Liver Disease Discontinue COCs if jaundice develops. Steroid hormones may be poorly metabolized in patients with impaired liver function. Hepatic adenomas are associated with COC use. 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. However, the attributable risk of liver cancers in COC users is less than one case per million users. Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis. Women with a history of COC-related cholestasis may have the condition recur with subsequent COC use. 5.4 High Blood Pressure For women with well-controlled hypertension, monitor blood pressure and stop COCs if blood pressure rises significantly. Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin. 5.5 Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder disease among COC users. 5.6 Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who are taking COCs. COCs may decrease glucose tolerance in a dose-related fashion. Consider alternative contraception for women with uncontrolled dyslipidemias. A small proportion of women will have adverse lipid changes while on COCs. 5.7 Headache If a woman taking COCs develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue COCs if indicated. 5.8 Bleeding Irregularities Unscheduled (breakthrough) bleeding and spotting sometimes occur in patients on COCs, especially during the first 3 months of use. If bleeding persists, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COC product. When prescribing LoSeasonique, the convenience of fewer planned menses (4 per year instead of 13 per year) should be weighed against the inconvenience of increased unscheduled bleeding and/or spotting. The clinical trial that evaluated the efficacy of LoSeasonique also assessed unscheduled bleeding. The participants in this 12-month clinical trial (N=2,185) completed the equivalent of over 20,000 28-day cycles of exposure and were composed primarily of women who had used OCs previously (89%), as opposed to new users (11%). A total of 209 subjects (9.6%) discontinued LoSeasonique, at least in part, due to bleeding and/or spotting. Scheduled (withdrawal) bleeding and/or spotting remained fairly constant over time, with an average of 2-3 days of bleeding and/or spotting per each 91-day cycle. Unscheduled bleeding and unscheduled spotting decreased over successive 91-day cycles. Table 1 below presents the number of days with unscheduled bleeding in treatment cycles 1 and 4. Table 2 presents the number of days with unscheduled spotting in treatment cycles 1 and 4. Table 1: Total Number of Days with Unscheduled Bleeding 91-Day Treatment Cycle Days per 84-Day Interval Days per 28-Day Interval Q1 Median Q3 Mean Mean 1st 0 5 11 7.5 2.5 4th 0 0 5 3.5 1.2 Q1=Quartile 1: 25% of women had this number of days of unscheduled bleeding Median: 50% of women had ≤ this number of days of unscheduled bleeding Q3=Quartile 3: 75% of women had ≤ this number of days of unscheduled bleeding Table 2: Total Number of Days with Unscheduled Spotting 91-Day Treatment Cycle Days per 84-Day Interval Days per 28-Day Interval Q1 Median Q3 Mean Mean 1st 3 10 19 14.0 4.7 4th 0 3 10 6.5 2.2 Q1=Quartile 1: 25% of women had ≤ this number of days of unscheduled spotting Median: 50% of women had ≤ this number of days of unscheduled spotting Q3=Quartile 3: 75% of women had ≤ this number of days of unscheduled spotting Figure 1 shows the percentage of LoSeasonique subjects participating in the primary clinical trial with ≥ 7 days or ≥ 20 days of unscheduled bleeding and/or spotting, or just unscheduled bleeding, during each 91-day treatment cycle. Figure 1. Percent of Women Taking LoSeasonique who Reported Unscheduled Bleeding and/or Spotting (Based on Daily Diaries) Amenorrhea sometimes occurs in women who are using COCs. Pregnancy should be ruled out in the event of amenorrhea. Some women may encounter amenorrhea or oligomenorrhea after stopping COCs, especially when such a condition was pre-existent. 5.9 Interference with Laboratory Tests The use of COCs may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid binding globulin increase with use of COCs. 5.10 Monitoring A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare. Chart: Percent of women taking LoSeasonique who reported unscheduled bleeding and/or spotting (based on daily diaries)
6 ADVERSE REACTIONS The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: Serious cardiovascular events and smoking [see BOXED WARNING] Vascular events [see WARNINGS AND PRECAUTIONS ( 5.1 )] Liver disease [see WARNINGS AND PRECAUTIONS ( 5.3 )] Adverse reactions commonly reported by COC users are: Irregular uterine bleeding Nausea Breast tenderness Headache The most common adverse reactions for COCs are irregular uterine bleeding, nausea, breast tenderness, and headaches. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva Women’s Health at 1-800-222-0190 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice. The clinical trial that evaluated the safety and efficacy of LoSeasonique was a 12-month, multicenter, non-comparative open-label study, which enrolled women aged 18-41, of whom 2,185 took at least one dose of LoSeasonique. Adverse Reactions Leading to Study Discontinuation: 11% of the women discontinued from the clinical trial due to an adverse reaction; the most common adverse reactions leading to discontinuation were irregular and/or heavy uterine bleeding, headache, mood changes, nausea, acne, and weight gain. Common Treatment-Emergent Adverse Reactions (≥ 5% of women): headaches (33%); irregular and/or heavy uterine bleeding (13%), dysmenorrhea (11%), nausea and/or vomiting (11%), back pain (8%).