Included as part of the PRECAUTIONS section.
Thrombotic and Other Vascular Events
Stop Seasonique (levonorgestrel, ethinyl estradiol) if an arterial or deep venous thrombotic event occurs. Although the 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. The excess risk is highest during the first year of use of a COC. 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. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued.
Use of Seasonique (levonorgestrel, ethinyl estradiol) 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 Seasonique (levonorgestrel, ethinyl estradiol) at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.
Start Seasonique (levonorgestrel, ethinyl estradiol) no earlier than 4-6 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.
COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years of age), and hypertensive women who also smoke. COCs also increase the risk for stroke in women with other underlying risk factors.
Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.
Stop Seasonique (levonorgestrel, ethinyl estradiol) if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.
Carcinoma of the Breast and Cervix
Women who currently have or have had breast cancer should not use Seasonique (levonorgestrel, ethinyl estradiol) 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.
Discontinue Seasonique (levonorgestrel, ethinyl estradiol) ifjaundice develops. Steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded.
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.
High Blood Pressure
For women with well-controlled hypertension, monitor blood pressure and stop Seasonique (levonorgestrel, ethinyl estradiol) 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.
Studies suggest a small increased relative risk of developing gallbladder disease among COC users.
Carbohydrate and Lipid Metabolic Effects
Carefully monitor prediabetic and diabetic women who are taking Seasonique (levonorgestrel, ethinyl estradiol) . 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.
Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.
If a woman taking Seasonique (levonorgestrel, ethinyl estradiol) develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Seasonique (levonorgestrel, ethinyl estradiol) if indicated.
An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC.
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.
When prescribing Seasonique (levonorgestrel, ethinyl estradiol) , 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 primary clinical trial (PSE-301) that evaluated the efficacy of Seasonique (levonorgestrel, ethinyl estradiol) also assessed unscheduled bleeding. The participants in the 12-month clinical trial (N=1,006) completed the equivalent of 8,681 28-day cycles of exposure and were composed primarily of women who had used oral contraceptives previously (89%) as opposed to new users (11%). A total of 82 (8.2%) of the women discontinued Seasonique (levonorgestrel, ethinyl estradiol) , at least in part, due to bleeding or spotting.
Scheduled (withdrawal) bleeding and/or spotting remained fairly constant over time, with an average of 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=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=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 Seasonique (levonorgestrel, ethinyl estradiol) subjects participating in trial PSE-301 with ≥ 7 days or ≥ 20 days of unscheduled bleeding and/or spotting, or only unscheduled bleeding, during each 91-day treatment cycle.
Figure 1. Percent of Women Taking Seasonique (levonorgestrel, ethinyl estradiol) who Reported Unscheduled Bleeding and/or Spotting or only Unscheduled Bleeding
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.
COC Use Before or During Early Pregnancy
Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy. Oral contraceptive use should be discontinued if pregnancy is confirmed.
The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations].
Women with a history of depression should be carefully observed and Seasonique (levonorgestrel, ethinyl estradiol) discontinued if depression recurs to a serious degree.
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.
A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated health care.
In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking COCs.
Carcinogenesis, Mutagenesis, Impairment of Fertility
[See WARNINGS AND PRECAUTIONS].
Use In Specific Populations
There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. 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 low dose COCs prior to conception or during early pregnancy.
The administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy. COCs should not be used during pregnancy to treat threatened or habitual abortion.
Women who do not breastfeed may start COCs no earlier than four to six weeks postpartum.
When possible, advise the nursing mother to use other forms of contraception until she has weaned her child. Estrogen-containing COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk.
Safety and efficacy of Seasonique (levonorgestrel, ethinyl estradiol) have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 18 as for users 18 years and older. Use of Seasonique (levonorgestrel, ethinyl estradiol) before menarche is not indicated.
Seasonique (levonorgestrel, ethinyl estradiol) has not been studied in women who have reached menopause and is not indicated in this population.
No studies have been conducted to evaluate the effect of hepatic disease on the disposition of Seasonique (levonorgestrel, ethinyl estradiol) . However, steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. [See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].
No studies have been conducted to evaluate the effect of renal disease on the disposition of Seasonique (levonorgestrel, ethinyl estradiol) .