WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Thromboembolic Disorders and Other Vascular Problems: Stop Previfem® or Tri-Previfem® if a thrombotic event occurs. Stop at least 4 weeks before and through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in women who are not breastfeeding. (5.1) • Liver disease: Discontinue Previfem® or Tri-Previfem® if jaundice occurs. (5.2) • High blood pressure: If used in women with well-controlled hypertension monitor blood pressure and stop Previfem® or Tri-Previfem® if blood pressure rises significantly. (5.3) • Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking Previfem® or Tri-Previfem®. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. (5.5) • Headache: Evaluate significant change in headaches and discontinue Previfem® or Tri-Previfem® if indicated. (5.6) • Bleeding Irregularities and Amenorrhea: Evaluate irregular bleeding or amenorrhea. (5.7) 5.1 Thromboembolic Disorders and Other Vascular Problems Stop Previfem® or Tri-Previfem® if an arterial thrombotic event or venous thromboembolic (VTE) event occurs. Stop Previfem® or Tri-Previfem® if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately [see Adverse Reactions (6.2)]. If feasible, stop Previfem® or Tri-Previfem® at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE as well as during and following prolonged immobilization. Start Previfem® or Tri-Previfem® no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum VTE decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week. The use of COCs increases the risk of VTE. However, pregnancy increases the risk of VTE as much or more than the use of COCs. The risk of VTE in women using COCs is 3 to 9 cases per 10,000 woman-years. The risk of VTE is highest during the first year of use of COCs and when restarting hormonal contraception after a break of 4 weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after use is discontinued. 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. COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes). This risk increases with age, particularly in women over 35 years of age who smoke. Use COCs with caution in women with cardiovascular disease risk factors. 5.2 Liver Disease Impaired Liver Function Do not use Previfem® or Tri-Previfem® in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of liver [see Contraindications (4) ]. 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. Discontinue Previfem® or Tri-Previfem® if jaundice develops. Liver Tumors Previfem® and Tri-Previfem® are contraindicated in women with benign and malignant liver tumors [see Contraindications (4)]. 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 risk of liver cancers in COC users is less than one case per million users. 5.3 High Blood Pressure Previfem® and Tri-Previfem® are contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see Contraindications (4)]. For women with well-controlled hypertension, monitor blood pressure and stop Previfem® and Tri-Previfem® if blood pressure rises significantly. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women with extended duration of use. The incidence of hypertension increases with increasing concentrations of progestin. 5.4 Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs may worsen existing gallbladder disease. A past history of COC-related cholestasis predicts an increased risk with subsequent COC use. Women with a history of pregnancy-related cholestasis may be at an increased risk for COC related cholestasis. 5.5 Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who take Previfem® or Tri-Previfem®. COCs may decrease glucose tolerance. Consider alternative contraception for women with uncontrolled dyslipidemia. 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. 5.6 Headache If a woman taking Previfem® or Tri-Previfem® develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Previfem® or Tri-Previfem® if indicated. Consider discontinuation of Previfem® or Tri-Previfem® in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event). 5.7 Bleeding Irregularities and Amenorrhea Unscheduled Bleeding and Spotting Unscheduled (breakthrough or intracyclic) bleeding and spotting sometimes occur in patients on COCs, especially during the first three months of use. If bleeding persists or occurs after previously regular cycles, 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 contraceptive product. In clinical trials of norgestimate and ethinyl estradiol tablets 0.25 mg/0.035 mg and norgestimate and ethinyl estradiol tablets 0.18 mg/0.035 mg, 0.215 mg/0.035 mg, 0.25 mg/0.035 mg, the frequency and duration of breakthrough bleeding and/or spotting was assessed in 1,647 patients (21,275 evaluable cycles) and 4,826 patients (35,546 evaluable cycles), respectively. A total of 100 (7.5%) women discontinued norgestimate and ethinyl estradiol tablets 0.25 mg/0.035 mg and 231 (4.8%) women discontinued norgestimate and ethinyl estradiol tablets 0.18 mg/0.035 mg, 0.215 mg/0.035 mg, 0.25 mg/0.035 mg, at least in part, due to bleeding or spotting. Based on data from the clinical trials, 14-34% of women using norgestimate and ethinyl estradiol tablets 0.25 mg/0.035 mg experienced unscheduled bleeding per cycle in the first year; for norgestimate and ethinyl estradiol tablets 0.18 mg/0.035 mg, 0.215 mg/0.035 mg, 0.25 mg/0.035 mg, the respective numbers were 13-38%. The percent of women who experienced breakthrough/unscheduled bleeding tended to decrease over time. Amenorrhea and Oligomenorrhea Women who use Previfem® or Tri-Previfem® may experience amenorrhea. Some women may experience amenorrhea or oligomenorrhea after discontinuation of COCs, especially when such a condition was pre-existent. If scheduled (withdrawal) bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. 5.8 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 oral contraceptives are taken inadvertently during early pregnancy. Discontinue Previfem® or Tri-Previfem® use if pregnancy is confirmed. Administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations (8.1)]. 5.9 Depression Carefully observe women with a history of depression and discontinue Previfem® or Tri-Previfem® if depression recurs to a serious degree. 5.10 Carcinoma of Breast and Cervix Previfem® and Tri-Previfem® are contraindicated in women who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4)]. 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 COC use has been associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. 5.11 Effect on Binding Globulins The estrogen component of COCs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased. 5.12 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. 5.13 Hereditary Angioedema In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. 5.14 Chloasma 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 Tri-Previfem® or Previfem®.