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 AMETHIA tablets. Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use.
1. INDICATIONS AND USAGE AMETHIA tablets are indicated for use by women to prevent pregnancy. AMETHIA tablets are an estrogen/progestin COC indicated for use by women to prevent pregnancy. (1)
3. DOSAGE FORMS AND STRENGTHS AMETHIA tablets are available in Extended-Cycle Tablet Dispensers, each containing a 13-week supply of tablets: 84 white tablets, each containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol, and 7 light blue tablets each containing 0.01 mg of ethinyl estradiol. The white tablets are round, flat face beveled edge, unscored tablets with WATSON on one side and 268 on the other side. The light blue tablets are round, flat face beveled edge, unscored tablets with WATSON on one side and 270 on the other side. AMETHIA tablets consists of 84 white tablets containing 0.15 mg levonorgestrel and 0.03 mg ethinyl estradiol, and 7 light blue tablets containing 0.01 mg ethinyl estradiol. (3)
4. CONTRAINDICATIONS Do not prescribe AMETHIA tablets to women who are known to have the following: A high risk of arterial or venous thrombotic diseases. Examples include women who are known to: Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions ( 5.1 )]. Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions ( 5.1 ) ]. Have cerebrovascular disease [see Warnings and Precautions ( 5.1 ) ] . Have coronary artery disease [see Warnings and Precautions ( 5.1 ) ]. 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 ) ]. Have inherited or acquired hypercoagulopathies [see Warnings and Precautions ( 5.1 ) ]. Have uncontrolled hypertension [see Warnings and Precautions ( 5.4 )]. Have diabetes with vascular disease [see Warnings and Precautions ( 5.6 )]. Have headaches with focal neurological symptoms or have migraine headaches with or without aura if over age 35 [see Warnings and Precautions ( 5.7 )]. Undiagnosed abnormal genital bleeding [see Warnings and Precautions ( 5.8 )]. Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see Warnings and Precautions ( 5.2 )]. Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.6 )]. Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and Precautions ( 5.9 ) and Use in Specific Populations ( 8.1 )]. A high risk of arterial or venous thrombotic diseases (4) Undiagnosed abnormal genital bleeding (4) Breast cancer or other estrogen- or progestin-sensitive cancer (4) Liver tumors or liver disease (4) Pregnancy (4)
5. WARNINGS AND PRECAUTIONS Vascular risks: Stop AMETHIA tablets if a thrombotic event occurs. Stop AMETHIA tablets at least 4 weeks before and through 2 weeks after major surgery. Start AMETHIA tablets no earlier than 4 weeks after delivery, in women who are not breastfeeding. (5.1) Liver disease: Discontinue AMETHIA tablets if jaundice occurs. (5.3) High blood pressure: Do not prescribe AMETHIA tablets for women with uncontrolled hypertension or hypertension with vascular disease. (5.4) Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking AMETHIA tablets. Consider an alternate contraceptive method for women with uncontrolled dyslipidemias. (5.6) Headache: Evaluate significant change in headaches and discontinue AMETHIA tablets if indicated. (5.7) Uterine bleeding: Evaluate irregular bleeding or amenorrhea. (5.8) Figure 1. Percent of Women Taking AMETHIA Tablets who Reported Unscheduled Bleeding and/or Spotting or only Unscheduled Bleeding 5.1 Thrombotic and Other Vascular Events Stop AMETHIA tablets 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 AMETHIA tablets 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 AMETHIA 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 AMETHIA tablets no earlier than 4 to 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 AMETHIA tablets 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 AMETHIA tablets 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 AMETHIA tablets if jaundice 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. 5.4 High Blood Pressure For women with well-controlled hypertension, monitor blood pressure and stop AMETHIA tablets 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 AMETHIA tablets. 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. 5.7 Headache If a woman taking AMETHIA tablets develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue AMETHIA tablets 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. 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. When prescribing AMETHIA tablets, 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 Levonorgestrel/ethinyl estradiol tablets and ethinyl estradiol tablets 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 Levonorgestrel/ethinyl estradiol tablets and ethinyl estradiol tablets, 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 Median Q3 Mean Mean 1st 1 4 10 6.9 1.7 4th 0 1 4 3.2 0.8 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 1 4 11 7.4 1.9 4th 0 2 7 4.4 1.1 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 Levonorgestrel/ethinyl estradiol tablets and ethinyl estradiol tablets 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 AMETHIA Tablets 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. 5.9 COC Use Before and 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 ( 8.1 )]. 5.10 Emotional Disorders Women with a history of depression should be carefully observed and AMETHIA tablets discontinued if depression recurs to a serious degree. 5.11 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. 5.12 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 health care. 5.13 Other Conditions 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.
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 and Warnings and Precautions ( 5.1 )] 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 (≥5%) in clinical trials for Levonorgestrel/ethinyl estradiol tablets and ethinyl estradiol tablets are irregular and/or heavy uterine bleeding, weight gain, and acne. (6) To report SUSPECTED ADVERSE REACTIONS, contact Watson Laboratories, Inc. at 1-800-272-5525 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 Levonorgestrel/ethinyl estradiol tablets and ethinyl estradiol tablets was a 12-month, randomized, multicenter, open-label study, which enrolled women aged 18 to 40, of whom 1,006 took at least one dose of Levonorgestrel/ethinyl estradiol tablets and ethinyl estradiol tablets. Adverse Reactions Leading to Study Discontinuation: 16.3% of the women discontinued from the clinical trial due to an adverse reaction; the most common adverse reactions (≥ 1% of women) leading to discontinuation were irregular and/or heavy uterine bleeding (5.9%), weight gain (2.4%), mood changes (1.5%), and acne (1.0%). Common Treatment-Emergent Adverse Reactions ( ≥ 5% of women): irregular and/or heavy uterine bleeding (17%), weight gain (5%), acne (5%). Serious Adverse Reactions: migraine, cholecystitis, cholelithiasis, pancreatitis, abdominal pain, and major depressive disorder. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Levonorgestrel/ethinyl estradiol tablets and ethinyl estradiol tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal disorders: abdominal distension, vomiting General disorders and administration site conditions: chest pain, fatigue, malaise, edema peripheral, pain Immune system disorders: hypersensitivity reaction Investigations: blood pressure increased Musculoskeletal and connective tissue disorders: muscle spasms, pain in extremity Nervous system disorders: dizziness, loss of consciousness Psychiatric disorders: insomnia Reproductive and breast disorders: dysmenorrhea Respiratory, thoracic and mediastinal disorders: pulmonary embolism, pulmonary thrombosis Skin and subcutaneous tissue disorders: alopecia Vascular disorders: thrombosis
7. DRUG INTERACTIONS No drug-drug interaction studies were conducted with AMETHIA tablets. Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding. Counsel patients to use a back-up method or alternative method of contraception when enzyme inducers are used with COCs. (7.1) 7.1 Changes in Contraceptive Effectiveness Associated with Coadministration of Other Products If a woman on hormonal contraceptives takes a drug or herbal product that induces enzymes, including CYP3A4, that metabolize contraceptive hormones, counsel her to use additional contraception or a different method of contraception. Drugs or herbal products that induce such enzymes may decrease the plasma concentrations of contraceptive hormones, and may decrease the effectiveness of hormonal contraceptives or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include: barbiturates bosentan carbamazepine felbamate griseofulvin oxcarbazepine phenytoin rifampin St. John’s wort topiramate HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant changes (increase or decrease) in the plasma levels of the estrogen and progestin have been noted in some cases of coadministration of HIV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors. Antibiotics: There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids. Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. 7.2 Increase in Plasma Levels of Estradiol Associated with Coadministered Drugs Coadministration of atorvastatin and certain COCs containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels. 7.3 Changes in Plasma Levels of Coadministered Drugs COCs containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations.
8. USE IN SPECIFIC POPULATIONS Nursing Mothers: Not recommended for nursing mothers; can decrease milk production. (8.3) 8.1. Pregnancy 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. 8.3. Nursing Mothers 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. 8.4. Pediatric Use Safety and efficacy of AMETHIA tablets 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 AMETHIA tablets before menarche is not indicated. 8.5. Geriatric Use AMETHIA tablets have not been studied in women who have reached menopause and is not indicated in this population. 8.6 Hepatic Impairment No studies have been conducted to evaluate the effect of hepatic disease on the disposition of AMETHIA tablets. 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 ( 4 ) and Warnings and Precautions ( 5.3 )]. 8.7 Renal Impairment No studies have been conducted to evaluate the effect of renal disease on the disposition of AMETHIA tablets.