Levonorgestrel and Ethinyl Estradiol (levonorgestrel 90 ug ethinyl estradiol 20 ug) Dailymed

The efficacy and safety of levonorgestrel and ethinyl estradiol were studied in 2 one-year clinical trials of subjects age 18 to 49. There were no exclusions for body mass index (BMI), weight, or bleeding history. The primary efficacy and safety study (313-NA) was a one-year open-label clinical trial that treated 2,134 subjects in North America. Of these subjects 1,213 (56.8%) discontinued prematurely, including 102 (4.8%) discontinued by the Sponsor for early study closure. The mean weight of subjects in this study was 70.38 kg. The efficacy of levonorgestrel and ethinyl estradiol was assessed by the number of pregnancies that occurred after the onset of treatment and within 14 days of the last dose. Among subjects 35 years or less, there were 23 pregnancies (4 of these occurred during the interval 1 to 14 days after the last day of pill use) during 12,572 28-day pill packs of use. The resulting total Pearl Index was 2.38 (95% CI: 1.51, 3.57) and the one-year life table pregnancy rate was 2.39 (95% CI: 1.57, 3.62). Pill pack cycles during which subjects used back-up contraception or were not sexually active were not included in these calculations. Among women 35 years or less who took the pills completely as directed, there were 15 pregnancies (method failures) resulting in a Pearl Index of 1.55 (95% CI: 0.87, 2.56) and the one-year life table pregnancy rate was 1.59 (95% CI: 0.95 to 2.67). In a second supportive study conducted in Europe (315-EU), 641 subjects were randomized to levonorgestrel and ethinyl estradiol (n=323) or the cyclic comparator of 0.1 mg levonorgestrel and 0.02 mg ethinyl estradiol (n=318). The mean weight of subjects in this study was 63.86 kg. The efficacy analysis among women 35 years or less included 2,756 levonorgestrel and ethinyl estradiol pill packs and 2,886 cyclic comparator pill packs. There was one pregnancy in the levonorgestrel and ethinyl estradiol group that occurred within 14 days following the last dose. There were three pregnancies in the cyclic comparator group.

An increased risk of venous thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. The risk of venous thrombotic and thromboembolic events is further increased in women with conditions predisposing for venous thrombosis and thromboembolism. Case control studies have found the relative risk of users compared to non-users to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep-vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization. The approximate incidence of deep-vein thrombosis and pulmonary embolism in users of low dose (<0.05 mg ethinyl estradiol) combination oral contraceptives is up to 4 per 10,000 woman-years compared to 0.5 to 3 per 10,000 woman-years for non-users. However, the incidence is less than that associated with pregnancy (6 per 10,000 woman-years). The excess risk is highest during the first year a woman ever uses a combined oral contraceptive. Venous thromboembolism may be fatal. The risk of thromboembolic disease due to oral contraceptives is not related to length of use and gradually disappears after pill use is stopped.

An increased risk of venous thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. The risk of venous thrombotic and thromboembolic events is further increased in women with conditions predisposing for venous thrombosis and thromboembolism. Case control studies have found the relative risk of users compared to non-users to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep-vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization. The approximate incidence of deep-vein thrombosis and pulmonary embolism in users of low dose (<0.05 mg ethinyl estradiol) combination oral contraceptives is up to 4 per 10,000 woman-years compared to 0.5 to 3 per 10,000 woman-years for non-users. However, the incidence is less than that associated with pregnancy (6 per 10,000 woman-years). The excess risk is highest during the first year a woman ever uses a combined oral contraceptive. Venous thromboembolism may be fatal. The risk of thromboembolic disease due to oral contraceptives is not related to length of use and gradually disappears after pill use is stopped. A post-marketing observational study evaluated the risk of venous thromboembolism with levonorgestrel and ethinyl estradiol use in two large US automated healthcare claims databases. The study was not completed as planned due to low accrual of levonorgestrel and ethinyl estradiol users in these databases and discontinuation of the product from the market due to low usage. At study discontinuation, the crude incidence rate of venous thromboembolism among levonorgestrel and ethinyl estradiol users (n=12,281) was 17.6 per 10,000 person-years, compared to 8.8 per 10,000 person-years among the users of cyclic oral contraceptives containing 20 mcg of ethinyl estradiol and a progestogen, and 5.1 per 10,000 person-years among the users of cyclic oral contraceptives containing the progestin levonorgestrel and 20 mcg of ethinyl estradiol. Adjustment for important risk factors or confounders (such as obesity, cardiovascular disease and other diseases) for venous thromboembolism could not be performed due to the small sample size. Although the study results suggest an elevated risk of venous thromboembolism with current levonorgestrel and ethinyl estradiol use compared to cyclic oral hormonal contraceptive use, reliable interpretation of the results is significantly limited due to the small sample size and concerns over unmeasured and uncontrolled confounding, as well as questions about the suitability of the comparator selection and the validity of the venous thromboembolism definition. A two-to-four fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate post-partum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four weeks after delivery in women who elect not to breastfeed, or after a midtrimester pregnancy termination.

One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is less than that associated with childbirth. The observation of a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970's — but not reported until 1983. However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral contraceptive use to women who do not have the various risk factors listed in this labeling.

One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table 3). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is less than that associated with childbirth. The observation of a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970's — but not reported until 1983. However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral contraceptive use to women who do not have the various risk factors uled in this labeling. Because of these changes in practice, and also because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989. The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy nonsmoking women (even with the newer low-dose formulations), there are greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception. Therefore, the Committee recommended that the benefits of oral contraceptive use by healthy nonsmoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective. Table 3: Annual Number of Birth-Related or Method-Related Deaths Associated with Control of Fertility per 100,000 Nonsterile Women, by Fertility-Control Method and According to Age Method of control and outcome 15 to 19 20 to 24 25 to 29 30 to 34 35 to 39 40 to 44 No fertility-control methods* 7 7.4 9.1 14.8 25.7 28.2 Oral contraceptives                nonsmoker** 0.3 0.5 0.9 1.9 13.8 31.6 Oral contraceptives                smoker** 2.2 3.4 6.6 13.5 51.1 117.2 IUD** 0.8 0.8 1 1 1.4 1.4 Condom* 1.1 1.6 0.7 0.2 0.3 0.4 Diaphragm/spermicide* 1.9 1.2 1.2 1.3 2.2 2.8 Periodic abstinence* 2.5 1.6 1.6 1.7 2.9 3.6 * Deaths are birth-related **Deaths are method-related Adapted from H.W. Ory, Family Planning Perspectives, 15:57-63, 1983.

Extensive epidemiological studies have revealed no increased risk of birth defects in infants born to women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy (see section).

Extensive epidemiological studies have revealed no increased risk of birth defects in infants born to women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy (see CONTRAINDICATIONS section). The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion. The possibility of pregnancy should be considered in any patient who may be experiencing symptoms of pregnancy, especially if she has not adhered to the prescribed schedule. Oral-contraceptive use must be discontinued if pregnancy is confirmed.

When prescribing levonorgestrel and ethinyl estradiol, the convenience of having no scheduled menstrual bleeding should be weighed against the inconvenience of unscheduled breakthrough bleeding and spotting. In Study 313-NA, 385/2,134 (18%) of women discontinued prematurely due to bleeding that was reported either as an adverse event or where bleeding was given as one of the reasons for discontinuation (see INDICATIONS AND USAGE, Clinical Studies ). Figure 4 shows the percentage of levonorgestrel and ethinyl estradiol subjects in study 313-NA by pill pack who experienced unscheduled bleeding or spotting only (Defined as “No sanitary protection required”). Figure 4: Percentage of Subjects Reporting Bleeding or Spotting Only per Pill Pack Figure 5 shows the percentage of levonorgestrel and ethinyl estradiol subjects with complete bleeding data in Study 313–NA who had 4 or more and 7 or more days of bleeding and/or spotting during each pill pack cycle. During pill pack 2, 67% of subjects experienced 4 or more days of bleeding and/or spotting and 54% of these subjects experienced 7 or more days of bleeding and/or spotting. During the final cycle of use of levonorgestrel and ethinyl estradiol (pill pack 13), these percentages were 31% and 20%, respectively. Figure 5: Percentage of Subjects Reporting Greater Than or Equal to 4 or 7 Days of Bleeding and/or Spotting per Pill Pack (Study 313-NA) As in any case of bleeding irregularities, nonhormonal causes should be considered and adequate diagnostic measures may be indicated to rule out pregnancy, infection, malignancy, or other conditions. Some women may encounter post-pill amenorrhea or oligomenorrhea (possibly with anovulation), especially when such a condition was preexistent.

Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.

Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.

Patients should be counseled that oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually transmitted diseases (STDs) such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. Scheduled withdrawal bleeding does not occur with the use of levonorgestrel and ethinyl estradiol, therefore, the absence of withdrawal bleeding cannot be used as a sign of an unexpected pregnancy and as such, unexpected pregnancy may be difficult to recognize. Although pregnancy is unlikely if levonorgestrel and ethinyl estradiol is taken as directed, if for any reason, pregnancy is suspected in a woman using levonorgestrel and ethinyl estradiol, a pregnancy test should be performed.

Contraceptive effectiveness may be reduced when hormonal contraceptives are coadministered with antibiotics, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. This could result in unintended pregnancy or unscheduled bleeding. Examples include rifampin, rifabutin, barbiturates, primidone, phenylbutazone, phenytoin, dexamethasone, carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin, and modafinil. In such cases a nonhormonal back-up method of birth control should be considered.

Contraceptive effectiveness may be reduced when hormonal contraceptives are coadministered with antibiotics, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. This could result in unintended pregnancy or unscheduled bleeding. Examples include rifampin, rifabutin, barbiturates, primidone, phenylbutazone, phenytoin, dexamethasone, carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin, and modafinil. In such cases a nonhormonal back-up method of birth control should be considered. Several cases of contraceptive failure and unscheduled bleeding have been reported in the literature with concomitant administration of antibiotics such as ampicillin and other penicillins, and tetracyclines. However, clinical pharmacology studies investigating drug interactions between combined oral contraceptives and these antibiotics have reported inconsistent results. Enterohepatic recirculation of estrogens may also be decreased by substances that reduce gut transit time. Several of the anti-HIV protease inhibitors have been studied with coadministration of oral combination hormonal contraceptives; significant changes (increase and decrease) in the plasma levels of the estrogen and progestin have been noted in some cases. The safety and efficacy of oral contraceptive products may be affected with coadministration of anti-HIV protease inhibitors. Health care professionals should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information. Herbal products containing St. John's Wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in unscheduled bleeding.

Certain endocrine- and liver-function tests and blood components may be affected by oral contraceptives: 1.Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability. 2.Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered. 3.Other binding proteins may be elevated in serum ie, corticosteroid binding globulin (CBG), sex hormone-binding globulins (SHBG) leading to increased levels of total circulating corticosteroids and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. 4.Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected. 5.Glucose tolerance may be decreased. 6.Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.



Small amounts of oral contraceptive steroids and/or metabolites have been identified in the milk of nursing mothers, and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, combination oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use combination oral contraceptives, but to use other forms of contraception until she has completely weaned her child.

Instructions for beginning levonorgestrel and ethinyl estradiol are provided in Table 4 below. Table 4 Current contraceptive therapy Levonorgestrel and ethinyl estradiol start day Nonhormonal back-up method of birth control needed when correctly starting levonorgestrel and ethinyl estradiol? None Day 1 of patient's menstrual cycle (during the first 24 hours of her period) No 21-day COC regimen    OR28-day COC regimen Day 1 of patient's withdrawal bleed, at the latest 7 days after her last active tablet No Progestin-only pill Day after taking a progestin-only pill Yes, for the first 7 days of levonorgestrel and ethinyl estradiol tablet taking Implant Day of implant removal Yes, for the first 7 days of levonorgestrel and ethinyl estradiol tablet taking Injection Day the next injection is due Yes, for the first 7 days of levonorgestrel and ethinyl estradiol tablet taking If spotting or unscheduled bleeding occurs, the patient is instructed to continue on the same regimen. This type of bleeding is usually transient and without significance; however, if the bleeding is persistent or prolonged, the patient is advised to consult her health care professional. The possibility of ovulation increases with each successive day that scheduled brownish peach to light brown tablets are missed. If the patient has not adhered to the prescribed schedule (missed one or more tablets or started taking them on a day later than she should have), the probability of pregnancy should be considered. Hormonal contraception must be discontinued if pregnancy is confirmed. The risk of pregnancy increases with each tablet missed. For additional patient instructions regarding missed tablets, see the WHAT TO DO IF YOU MISS PILLS section in the DETAILED PATIENT LABELING below. Levonorgestrel and ethinyl estradiol may be initiated no earlier than day 28 postpartum in the nonlactating mother or after a second-trimester abortion due to the increased risk for thromboembolism (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS concerning thromboembolic disease). The patient should be advised to use a nonhormonal back-up method for the first 7 days of tablet-taking. However, if intercourse has already occurred, pregnancy should be excluded before the start of combined oral contraceptive use or the patient must wait for her first menstrual period. In the case of first-trimester abortion, if the patient starts levonorgestrel and ethinyl estradiol immediately, additional contraceptive measures are not needed.

You are likely to have unscheduled or unplanned bleeding or spotting when you start to use levonorgestrel and ethinyl estradiol. The number of days each month with bleeding or spotting usually decreases over time in the majority of women. In a study of levonorgestrel and ethinyl estradiol, about 5 out of 10 women had 7 or more days of bleeding or spotting while using their third 28-day pill pack of levonorgestrel and ethinyl estradiol. The number of women with 7 or more days of bleeding or spotting decreased to 3 out of 10 women during the use of their seventh pill pack. Among women who continued to use levonorgestrel and ethinyl estradiol for one year, about 6 out of 10 women had no bleeding or spotting during their last month of use. Do not stop taking levonorgestrel and ethinyl estradiol because of bleeding or spotting as this will increase your chance of getting pregnant. If the spotting or bleeding continues for more than 7 consecutive days or if the bleeding is heavy, call your health care provider.

You are not likely to get pregnant if you take levonorgestrel and ethinyl estradiol at the same time everyday as directed by your health care provider. Because regular monthly bleeding does not occur on levonorgestrel and ethinyl estradiol, it may be difficult to recognize if you get pregnant. If you suspect that you may be pregnant, or if you have symptoms of pregnancy such as nausea/vomiting or unusual breast tenderness, you should have a pregnancy test and you should contact your health care professional. Stop taking levonorgestrel and ethinyl estradiol if you are pregnant.

HOW TO TAKE LEVONORGESTREL AND ETHINYL ESTRADIOL TABLETS Important Points to Remember Before You Start Taking levonorgestrel and ethinyl estradiol: 1.BE SURE TO READ THESE DIRECTIONS:Before you start taking levonorgestrel and ethinyl estradiol.AndAnytime you are not sure what to do. 2.THE RIGHT WAY TO TAKE LEVONORGESTREL AND ETHINYL ESTRADIOL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME.If you miss pills, you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. See “WHAT TO DO IF YOU MISS PILLS” below. 3.MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1 to 3 PACKS OF PILLS.If you feel sick to your stomach, do not stop taking levonorgestrel and ethinyl estradiol. This will usually go away. If it doesn't go away, check with your health care professional. 4.MOST WOMEN HAVE SPOTTING OR BLEEDING DURING THE FIRST FEW MONTHS OF TAKING LEVONORGESTREL AND ETHINYL ESTRADIOL. Do not stop taking your pills even if you are having bleeding or spotting. If the bleeding or spotting lasts for more than 7 consecutive days, talk to your health care provider. 5.MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills.On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. 6.IF YOU VOMIT (within 4 hours after you take your pill), you should follow the instructions for WHAT TO DO IF YOU MISS PILLS. IF YOU HAVE DIARRHEA or IF YOU TAKE SOME MEDICINES, including some antibiotics, your pills may not work as well.Use a back-up nonhormonal method (such as condoms and/or spermicide) until you check with your health care professional. 7.IF YOU HAVE TROUBLE REMEMBERING TO TAKE LEVONORGESTREL AND ETHINYL ESTRADIOL, talk to your health care professional about how to make pill-taking easier or about using another method of birth control. 8.IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your health care professional. BEFORE YOU START TAKING LEVONORGESTREL AND ETHINYL ESTRADIOL 1.DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take your pill at the SAME TIME every day. 2.LOOK AT YOUR LEVONORGESTREL AND ETHINYL ESTRADIOL BLISTER. The pill pack has 28 “active” brownish peach to light brown pills (with hormones). 3.Locate the top row of the buler. 4.Pick the day label strip that starts with the first day of your period (this is the day you start bleeding or spotting, even if it is almost midnight when the bleeding begins). 5.Place the day label strip on the tablet buler over the area that has the days of the week (starting with Sunday) imprinted in the plastic. 1.When it comes time to take levonorgestrel and ethinyl estradiol, you will take each pill until the buler is empty. 2.BE SURE YOU HAVE READY AT ALL TIMES:ANOTHER KIND OF NONHORMONAL BIRTH CONTROL (such as condoms and/or spermicide) to use as a back-up in case you miss pills.AN EXTRA, FULL PILL PACK. WHEN TO START THE FIRST PACK OF LEVONORGESTREL AND ETHINYL ESTRADIOL Day 1 Start 1.Take the first “active” brownish peach to light brown pill of the first pack during the first 24 hours of your period. 2.You will not need to use a back-up nonhormonal method of birth control, since you are starting the pill at the beginning of your period. WHAT TO DO DURING THE MONTH 1.TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE BLISTER PACK IS EMPTY. Do not skip pills even if you are spotting or bleeding or feel sick to your stomach (nausea).Do not skip pills even if you do not have sex very often. 2.WHEN YOU FINISH A PACKStart the next pack on the day after your last pill. Do not wait any days between packs. IF YOU SWITCH FROM ANOTHER BRAND OF COMBINATION PILLS: When switching from a 21 pill pack: Start levonorgestrel and ethinyl estradiol on the first day of your period (withdrawal bleed). Be sure that no more than 7 days pass between the last day of your 21-day pack and your first levonorgestrel and ethinyl estradiol pill. When switching from a 28 pill pack (21 active and 7 inactive pills, or 24 active and 4 inactive pills): Start levonorgestrel and ethinyl estradiol on the first day of your period (withdrawal bleed). Be sure that no more than 7 days pass after the last active pill and your first levonorgestrel and ethinyl estradiol pill. IF YOU SWITCH FROM ANOTHER TYPE OF BIRTH CONTROL When switching from other types of birth control such as pills containing only a progestin (progestin only pill or POP), an injection, or an implant, your health care professional will provide you with instructions for when to start levonorgestrel and ethinyl estradiol. WHAT TO DO IF YOU MISS PILLS Combination oral contraceptives may not be as effective if you miss pills. Instructions for what to do if you miss pills are provided in the following table. # of pills missed in a row What to do when you miss a pill(s) 1 missed pill • Take the missed pill as soon as you remember.            THEN • Take the next pill at your regular time. This means you may take 2 pills in 1 day. • You COULD BECOME PREGNANT if you have sex during the 7 days after you restart your pills. You MUST use a nonhormonal birth-control method (such as condoms and/or spermicide) as a back-up for those 7 days. 2 missed pillsand remembered on the day of the second missed pill • Take 2 missed pills on the day you remember. The following day you are back on schedule to take 1 pill a day.For example, you take your pills in the morning and you missed 1 pill on Monday and 1 on Tuesday. On Tuesday evening you remembered that you missed your Monday and Tuesday pills. You take the 2 missed pills on Tuesday evening and on Wednesday morning you're back on schedule and you take 1 pill. • You COULD BECOME PREGNANT if you have sex during the 7 days after you restart your pills. You MUST use a nonhormonal birth-control method (such as condoms and/or spermicide) as a back-up for those 7 days. 2 missed pillsand remembered on the day after the second pill is missed • Take 2 missed pills on the day you remember. The next day you take 2 pills. The following day you are back on schedule to take your pills. For example, you take your pills in the morning and you missed 1 pill on Monday and 1 on Tuesday. On Wednesday morning you remembered that you missed your Monday and Tuesday pills. You take the 2 missed pills on Wednesday morning and 2 pills on Thursday morning. On Friday morning you're back on schedule and you take 1 pill.• You COULD BECOME PREGNANT if you have sex during the 7 days after you restart your pills. You MUST use a nonhormonal birth-control method (such as condoms and/or spermicide) as a back-up for those 7 days. 3 or more missed pills • Contact your health care professional for further advice. Keep taking one pill every day until you reach your health care professional. Do not take the missed pills. • You COULD BECOME PREGNANT if you have sex during the 7 days after you restart your pills. You MUST use a nonhormonal birth-control method (such as condoms and/or spermicide) as a back-up for those 7 days. FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED Use a BACK-UP NONHORMONAL BIRTH-CONTROL METHOD anytime you have sex. PREGNANCY AFTER STOPPING THE PILL If you do not desire pregnancy, you should use another method of birth-control immediately after stopping levonorgestrel and ethinyl estradiol. You can get pregnant within days after stopping levonorgestrel and ethinyl estradiol. For additional information see “Detailed Patient Labeling.”

Oral contraceptives or “birth-control pills” or “the pill” are used to prevent pregnancy and are more effective than other nonsurgical methods of birth control. When they are taken correctly, without missing any pills the chance of becoming pregnant is approximately 1-2% per year (1 to 2 pregnancies per 100 women per year of use). Average failure rates are approximately 5% per year (5 pregnancies per 100 women per year of use) when women who miss pills are included. The chance of becoming pregnant increases with each missed pill.

Oral contraceptives or “birth-control pills” or “the pill” are used to prevent pregnancy and are more effective than other nonsurgical methods of birth control. When they are taken correctly, without missing any pills the chance of becoming pregnant is approximately 1-2% per year (1 to 2 pregnancies per 100 women per year of use). Average failure rates are approximately 5% per year (5 pregnancies per 100 women per year of use) when women who miss pills are included. The chance of becoming pregnant increases with each missed pill. In comparison, average failure rates for other methods of birth control during the first year of use are as follows: IUD: 0.1-2% Female condom alone: 21% Depo-Provera® (injectable progestogen): 0.3% Cervical cap Norplant® System (levonorgestrel implants): 0.05%       Never given birth: 20% Diaphragm with spermicides: 20%       Given birth: 40% Spermicides alone: 26% Periodic abstinence: 25% Male condom alone: 14% No methods: 85%

Although cardiovascular disease risks may be increased with oral contraceptive use in healthy, non-smoking women over 40 (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women.

Some women should not use the pill. For example, you should not take the pill if you have any of the following conditions: 1.History of heart attack or stroke. 2.Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes. 3.History of blood clots in the deep veins of your legs. 4.Hereditary or acquired blood clotting disorders 5.Chest pain (angina pectoris). 6.Known or suspected breast cancer or cancer of the lining of the uterus, cervix or vagina, or certain hormonally-sensitive cancers. 7.Unexplained vaginal bleeding (until a diagnosis is reached by your health care professional). 8.Liver tumor (benign or cancerous) or active liver disease. 9.Take any Hepatitis C drug combination containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. This may increase levels of the liver enzyme "alanine aminotransferase" (ALT) in the blood. 10.Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or during previous use of the pill. 11.Known or suspected pregnancy. 12.A need for surgery with prolonged bedrest. 13.Heart valve or heart rhythm disorders that may be associated with formation of blood clots. 14.Diabetes affecting your circulation. 15.Headaches with neurological symptoms such as aura. 16.Uncontrolled high blood pressure. 17.Allergy or hypersensitivity to any of the components of levonorgestrel and ethinyl estradiol tablets Tell your health care professional if you have had any of these conditions. Your health care professional can recommend another method of birth control.

Blood clots and blockage of blood vessels are the most serious side effects of taking oral contraceptives and can cause death or serious disability. In particular, a clot in the legs can cause thrombophlebitis and a clot that travels to the lungs can cause a sudden blocking of the vessel carrying blood to the lungs. Rarely, clots occur in the blood vessels of the eye and may cause blindness, double vision, or impaired vision. Users of combination oral contraceptives have a higher risk of developing blood clots compared to non-users. This risk is highest during the first year of combination oral contraceptive use. If you take oral contraceptives and need elective surgery, need to stay in bed for a prolonged illness or injury, or have recently delivered a baby, you may be at risk of developing blood clots. You should consult your health care professional about stopping oral contraceptives three to four weeks before surgery and not taking oral contraceptives for two weeks after surgery or during bed rest. You should also not take oral contraceptives soon after delivery of a baby or after a midtrimester pregnancy termination. It is advisable to wait for at least four weeks after delivery if you are not breast-feeding. If you are breast-feeding, you should wait until you have weaned your child before using the pill. (See also the section While Breast-Feeding in GENERAL PRECAUTIONS.) The risk of blood clots is greater in users of combination oral contraceptives compared to nonusers. This risk may be higher in users of high-dose pills (those containing 0.05 mg or more of estrogen) and may also be greater with longer use. In addition, some of these increased risks may continue for a number of years after stopping combination oral contraceptives. The risk of abnormal blood clotting increases with age in both users and nonusers of combination oral contraceptives, but the increased risk from the oral contraceptive appears to be present at all ages. The excess risk of blood clots is highest during the first year a woman ever uses a combined oral contraceptive. This increased risk is lower than blood clots associated with pregnancy. The use of combination oral contraceptives also increases the risk of other clotting disorders, including heart attack and stroke. Blood clots in veins cause death in 1% to 2% of cases. The risk of clotting is further increased in women with other conditions. Examples include: smoking, high blood pressure, abnormal lipid levels, certain inherited or acquired clotting disorders, obesity, surgery or injury, recent delivery or second trimester abortion, prolonged inactivity or bedrest. If possible, combination oral contraceptives should be stopped before surgery and during prolonged inactivity or bedrest. Cigarette smoking increases the risk of serious cardiovascular events. This risk increases with age and amount of smoking and is quite pronounced in women over 35. Women who use combination oral contraceptives should be strongly advised not to smoke. If you smoke you should talk to your health care professional before taking combination oral contraceptives.

All methods of birth control and pregnancy are associated with a risk of developing certain diseases which may lead to disability or death. An estimate of the number of deaths associated with different methods of birth control and pregnancy has been calculated and is shown in the following .

All methods of birth control and pregnancy are associated with a risk of developing certain diseases which may lead to disability or death. An estimate of the number of deaths associated with different methods of birth control and pregnancy has been calculated and is shown in the following table. Annual Number of Birth-Related or Method-Related Deaths Associated with Control of Fertility per 100,000 Nonsterile Women, by Fertility-Control Method and According to Age Method of control and outcome 15-19 20-24 25-29 30-34 35-39 40-44 No fertility-control methods* 7.0 7.4 9.1 14.8 25.7 28.2 Oral contraceptives                nonsmoker** 0.3 0.5 0.9 1.9 13.8 31.6 Oral contraceptives                smoker** 2.2 3.4 6.6 13.5 51.1 117.2 IUD** 0.8 0.8 1.0 1.0 1.4 1.4 Condom* 1.1 1.6 0.7 0.2 0.3 0.4 Diaphragm/spermicide* 1.9 1.2 1.2 1.3 2.2 2.8 Periodic abstinence* 2.5 1.6 1.6 1.7 2.9 3.6 * Deaths are birth-related **Deaths are method-related In the above table, the risk of death from any birth-control method is less than the risk of childbirth, except for oral contraceptive users over the age of 35 who smoke and pill users over the age of 40 even if they do not smoke. It can be seen in the table that for women aged 15 to 39, the risk of death was highest with pregnancy (7 to 26 deaths per 100,000 women, depending on age). Among pill users who do not smoke, the risk of death was always lower than that associated with pregnancy for any age group, except for those women over the age of 40, when the risk increases to 32 deaths per 100,000 women, compared to 28 associated with pregnancy at that age. However, for pill users who smoke and are over the age of 35, the estimated number of deaths exceeds those for other methods of birth control. If a woman is over the age of 40 and smokes, her estimated risk of death is four times higher (117/100,000 women) than the estimated risk associated with pregnancy (28/100,000 women) in that age group. The suggestion that women over 40 who do not smoke should not take oral contraceptives is based on information from older high-dose pills. An Advisory Committee of the FDA discussed this issue in 1989 and recommended that the benefits of oral contraceptive use by healthy, nonsmoking women over 40 years of age may outweigh the possible risks. Older women, as all women, who take oral contraceptives, should take an oral contraceptive which contains the least amount of estrogen and progestogen that is compatible with the individual patient needs.

Because regular monthly bleeding does not occur on levonorgestrel and ethinyl estradiol, an unexpected pregnancy may be difficult to recognize. If you suspect you may be pregnant, or if you have symptoms of pregnancy such as nausea/vomiting or unusual breast tenderness, a pregnancy test should be performed and you should contact your health care professional. Stop taking levonorgestrel and ethinyl estradiol if you are pregnant. Pregnancy is unlikely if the pill is taken as directed.

Because regular monthly bleeding does not occur on levonorgestrel and ethinyl estradiol, an unexpected pregnancy may be difficult to recognize. If you suspect you may be pregnant, or if you have symptoms of pregnancy such as nausea/vomiting or unusual breast tenderness, a pregnancy test should be performed and you should contact your health care professional. Stop taking levonorgestrel and ethinyl estradiol if you are pregnant. Pregnancy is unlikely if the pill is taken as directed. There is no conclusive evidence that oral contraceptive use is associated with an increase in birth defects, when taken inadvertently during early pregnancy. Previously, a few studies had reported that oral contraceptives might be associated with birth defects, but these studies have not been confirmed. Nevertheless, oral contraceptives should not be used during pregnancy. You should check with your health care professional about risks to your unborn child of any medication taken during pregnancy.

If you are breastfeeding, consult your health care professional before starting oral contraceptives. Some of the drug will be passed on to the child in the milk. A few adverse effects on the child have been reported, including yellowing of the skin (jaundice) and breast enlargement. In addition, oral contraceptives may decrease the amount and quality of your milk. If possible, do not use oral contraceptives while breastfeeding. You should use another method of contraception since breastfeeding provides only partial protection from becoming pregnant and this partial protection decreases significantly as you breastfeed for longer periods of time. You should consider starting oral contraceptives only after you have weaned your child completely.

Certain drugs may interact with birth-control pills to make them less effective in preventing pregnancy or cause an increase in unscheduled bleeding. Such drugs include rifampin, drugs used for epilepsy such as barbiturates (for example, phenobarbital) and phenytoin (Dilantin is one brand of this drug), primidone (Mysoline), topiramate (Topamax), carbamazepine (Tegretol is one brand of this drug), phenylbutazone (Butazolidin is one brand), some drugs used for HIV or AIDS such as ritonavir (Norvir), modafinil (Provigil) and possibly certain antibiotics (such as ampicillin and other penicillins, and tetracyclines), and herbal products containing St. John's Wort (Hypericum perforatum). You may also need to use a nonhormonal method of contraception during any pill pack in which you take drugs that can make oral contraceptives less effective.

Certain drugs may interact with birth-control pills to make them less effective in preventing pregnancy or cause an increase in unscheduled bleeding. Such drugs include rifampin, drugs used for epilepsy such as barbiturates (for example, phenobarbital) and phenytoin (Dilantin® is one brand of this drug), primidone (Mysoline®), topiramate (Topamax®), carbamazepine (Tegretol® is one brand of this drug), phenylbutazone (Butazolidin® is one brand), some drugs used for HIV or AIDS such as ritonavir (Norvir®), modafinil (Provigil®) and possibly certain antibiotics (such as ampicillin and other penicillins, and tetracyclines), and herbal products containing St. John's Wort (Hypericum perforatum). You may also need to use a nonhormonal method of contraception during any pill pack in which you take drugs that can make oral contraceptives less effective. You may be at higher risk for a specific type of liver dysfunction if you take troleandomycin and oral contraceptives at the same time. You should inform your health care professional about all medicines you are taking, including nonprescription products.

This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.

You are likely to have unscheduled or unplanned bleeding or spotting when you start to use levonorgestrel and ethinyl estradiol. The number of days each month with bleeding or spotting usually decreases over time in the majority of women. In a study of levonorgestrel and ethinyl estradiol, about 5 out of 10 women had 7 or more days of bleeding or spotting while using their third 28-day pill pack of levonorgestrel and ethinyl estradiol. The number of women with 7 or more days of bleeding or spotting decreased to 3 out of 10 women during the use of their seventh pill pack. Among women who continued to use levonorgestrel and ethinyl estradiol for one year, about 6 out of 10 women had no bleeding or spotting during their last month of use. Do not stop taking levonorgestrel and ethinyl estradiol because of bleeding or spotting as this will increase your chance of getting pregnant. If the spotting or bleeding continues for more than 7 consecutive days or if the bleeding is heavy, call your health care provider.

Important Points to Remember Before You Start Taking levonorgestrel and ethinyl estradiol: 1.BE SURE TO READ THESE DIRECTIONS:Before you start taking levonorgestrel and ethinyl estradiol.AndAnytime you are not sure what to do. 2.THE RIGHT WAY TO TAKE LEVONORGESTREL AND ETHINYL ESTRADIOL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME.If you miss pills, you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. See “WHAT TO DO IF YOU MISS PILLS” below. 3.MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS.If you feel sick to your stomach, do not stop taking levonorgestrel and ethinyl estradiol. This will usually go away. If it doesn't go away, check with your health care professional. 4.MOST WOMEN HAVE SPOTTING OR BLEEDING DURING THE FIRST FEW MONTHS OF TAKING LEVONORGESTREL AND ETHINYL ESTRADIOL. Do not stop taking your pills even if you are having bleeding or spotting. If the bleeding or spotting lasts for more than 7 consecutive days, talk to your health care provider. 5.MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills.On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. 6.IF YOU VOMIT (within 4 hours after you take your pill), you should follow the instructions for WHAT TO DO IF YOU MISS PILLS. IF YOU HAVE DIARRHEA or IF YOU TAKE SOME MEDICINES, including some antibiotics, your pills may not work as well.Use a back-up nonhormonal method (such as condoms and/or spermicide) until you check with your health care professional. 7.IF YOU HAVE TROUBLE REMEMBERING TO TAKE LEVONORGESTREL AND ETHINYL ESTRADIOL, talk to your health care professional about how to make pill-taking easier or about using another method of birth control. 8.IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your health care professional.

Combination oral contraceptives may not be as effective if you miss pills. Instructions for what to do if you miss pills are provided in the following table. # of pills missed in a row What to do when you miss a pill(s) 1 missed pill • Take the missed pill as soon as you remember.            THEN • Take the next pill at your regular time. This means you may take 2 pills in 1 day. • You COULD BECOME PREGNANT if you have sex during the 7 days after you restart your pills. You MUST use a nonhormonal birth-control method (such as condoms and/or spermicide) as a back-up for those 7 days. 2 missed pillsand remembered on the day of the second missed pill • Take 2 missed pills on the day you remember. The following day you are back on schedule to take 1 pill a day.For example, you take your pills in the morning and you missed 1 pill on Monday and 1 on Tuesday. On Tuesday evening you remembered that you missed your Monday and Tuesday pills. You take the 2 missed pills on Tuesday evening and on Wednesday morning you're back on schedule and you take 1 pill. • You COULD BECOME PREGNANT if you have sex during the 7 days after you restart your pills. You MUST use a nonhormonal birth-control method (such as condoms and/or spermicide) as a back-up for those 7 days. 2 missed pillsand remembered on the day after the second pill is missed • Take 2 missed pills on the day you remember. The next day you take 2 pills. The following day you are back on schedule to take your pills. For example, you take your pills in the morning and you missed 1 pill on Monday and 1 on Tuesday. On Wednesday morning you remembered that you missed your Monday and Tuesday pills. You take the 2 missed pills on Wednesday morning and 2 pills on Thursday morning. On Friday morning you're back on schedule and you take 1 pill.• You COULD BECOME PREGNANT if you have sex during the 7 days after you restart your pills. You MUST use a nonhormonal birth-control method (such as condoms and/or spermicide) as a back-up for those 7 days. 3 or more missed pills • Contact your health care professional for further advice. Keep taking one pill every day until you reach your health care professional. Do not take the missed pills. • You COULD BECOME PREGNANT if you have sex during the 7 days after you restart your pills. You MUST use a nonhormonal birth-control method (such as condoms and/or spermicide) as a back-up for those 7 days. FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED Use a BACK-UP NONHORMONAL BIRTH-CONTROL METHOD anytime you have sex. KEEP TAKING ONE PILL EACH DAY until you can reach your health care professional.

The incidence of pill failure resulting in pregnancy is approximately 1-2% per year (1 to 2 pregnancies per 100 women per year of use) if taken every day as directed, but the average failure rate is approximately 5% per year (5 pregnancies per 100 women per year of use) including women who do not always take the pill exactly as directed without missing any pills. If you do become pregnant, the risk to the fetus is minimal, but you should stop taking your pills and discuss the pregnancy with your health care professional.

levonorgestrel and ethinyl estradiolA pregnancy can occur within days after stopping levonorgestrel and ethinyl estradiol.

If you do not desire pregnancy, you should use another method of birth-control immediately after stopping levonorgestrel and ethinyl estradiol. A pregnancy can occur within days after stopping levonorgestrel and ethinyl estradiol. There does not appear to be any increase in birth defects in newborn babies when pregnancy occurs soon after stopping the pill. There may be some delay in becoming pregnant after you stop using oral contraceptives, especially if you had irregular menstrual cycles before you used oral contraceptives. It may be advisable to postpone conception until you begin menstruating regularly once you have stopped taking the pill and desire pregnancy.

In addition to preventing pregnancy, some information suggests that the use of oral contraceptives provide certain other benefits. The benefits are:

In addition to preventing pregnancy, some information suggests that the use of oral contraceptives provide certain other benefits. The benefits are: 1.Decreased blood loss, and less iron may be lost. Therefore, anemia due to iron deficiency is less likely to occur. 2.Pain or other cycle-related symptoms may occur less frequently. 3.Ovarian cysts may occur less frequently. 4.Ectopic (tubal) pregnancy may occur less frequently. 5.Noncancerous cysts or lumps in the breast may occur less frequently. 6.Acute pelvic inflammatory disease may occur less frequently. 7.Oral contraceptive use may provide some protection against developing two forms of cancer: cancer of the ovaries and cancer of the lining of the uterus. If you want more information about birth-control pills, ask your health care professional or pharmacist. They have a more technical leaflet called the Professional Labeling which you may wish to read.