INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE Levonorgestrel and ethinyl estradiol tablets are indicated for the prevention of pregnancy in women who elect to use oral contraceptives as method of contraception.Oral contraceptives are highly effective for pregnancy prevention. Table lists the typical unintended pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and implants, depend upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.Table 2: Percentage of Women Experiencing an Unintended Pregnancy During The First Year of Typical Use and The First Year of Perfect Use of Contraception and The Percentage Continuing Use at The End of the First Year. United States. of Women Experiencing anUnintended Pregnancywithin the First Year of Use of Women Continuing Useat One Year Method(1) Typical Use (2) Perfect Use (3) (4) Chance 85 85 Spermicides 26 40 Periodic abstinence 25 63 Calendar Ovulation method Sympto-thermal 2 Post-ovulation Cap Parous women 40 26 42 Nulliparous women 20 56 Sponge Parous women 40 20 42 Nulliparous women 20 56 Diaphragm 20 56 Withdrawal 19 Condom Female (Reality(R)) 21 56 Male 14 61 Pill 71 Progestin only 0.5 Combined 0.1 IUD Progesterone 2.0 1.5 81 Copper T380A 0.8 0.6 78 LNg 20 0.1 0.1 81 Depo-Provera(R) 0.3 0.3 70 Levonorgestrel Implants (Norplant(R)) 0.05 0.05 88 Female sterilization 0.5 0.5 100 Male sterilization 0.15 0.10 100Emergency Contraceptive Pills: The FDA has concluded that certain combined oral contraceptives containing ethinyl estradiol and norgestrel or levonorgestrel are safe and effective for use as postcoital emergency contraception. Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.9 Lactation Amenorrhea Method: LAM is highly effective, temporary method of contraception.10 Source: Trussell J. Contraceptive efficacy. In: Hatcher RA, Trussell J, Stewart F, Cates W,Stewart GK, Kowel D, Guest F. Contraceptive Technology: Seventeenth Revised Edition.New York NY: Irvington Publishers; 1998.Among typical couples who initiate use of method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.Among couples who initiate use of method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.Among couples attempting to avoid pregnancy, the percentage who continue to use method for one year.The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether.Foams, creams, gels, vaginal suppositories, and vaginal film.Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases.With spermicidal cream or jelly.Without spermicides.The treatment schedule is one dose within 72 hours after unprotected intercourse, and second dose 12 hours after the first dose. The FDA has declared the following dosage regimens of oral contraceptives to be safe and effective for emergency contraception: for tablets containing 50 mcg of ethinyl estradiol and 500 mcg of norgestrel dose is tablets; for tablets containing 20 mcg of ethinyl estradiol and 100 mcg of levonorgestrel dose is tablets; for tablets containing 30 mcg of ethinyl estradiol and 150 mcg of levonorgestrel dose is tablets.However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches months of age.. Among typical couples who initiate use of method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.. Among couples who initiate use of method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.. Among couples attempting to avoid pregnancy, the percentage who continue to use method for one year.. The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether.. Foams, creams, gels, vaginal suppositories, and vaginal film.. Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases.. With spermicidal cream or jelly.. Without spermicides.. The treatment schedule is one dose within 72 hours after unprotected intercourse, and second dose 12 hours after the first dose. The FDA has declared the following dosage regimens of oral contraceptives to be safe and effective for emergency contraception: for tablets containing 50 mcg of ethinyl estradiol and 500 mcg of norgestrel dose is tablets; for tablets containing 20 mcg of ethinyl estradiol and 100 mcg of levonorgestrel dose is tablets; for tablets containing 30 mcg of ethinyl estradiol and 150 mcg of levonorgestrel dose is tablets.. However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches months of age.. Clinical Studies The efficacy and safety of levonorgestrel and ethinyl estradiol tablets were studied in 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 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 tablets 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 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 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 second supportive study conducted in Europe (315-EU), 641 subjects were randomized to levonorgestrel and ethinyl estradiol tablets (n=323) or the cyclic comparator of 100 mcg levonorgestrel and 20 mcg 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 tablets pill packs and 2,886 cyclic comparator pill packs. There was one pregnancy in the levonorgestrel and ethinyl estradiol tablets group that occurred within 14 days following the last dose. There were three pregnancies in the cyclic comparator group.Inhibition of Menses (Bleeding Profile) The bleeding profile for subjects in Study 313-NA also was assessed. Women with history of unscheduled bleeding and/or spotting were not excluded from the study.In those subjects who provided complete bleeding data, the percentage of patients who were amenorrheic in given cycle and remained amenorrheic through cycle 13 (cumulative amenorrhea rate) was determined (Figure 2).Figure 2: Percentage of Subjects with Cumulative Amenorrhea for Each Pill Pack through Pill Pack 13The 779 subjects with complete data for 13 pill packs were used in this cumulative analysis.Subjects were to begin pill pack on the first day of menses.When prescribing levonorgestrel and ethinyl estradiol tablets, the convenience of having no scheduled menstrual bleeding should be weighed against the inconvenience of unscheduled bleeding and spotting (see WARNINGS, 12). 85b1e02d-figure-03.

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Postmarketing Experience:Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 to 1.12 (Figure 6).Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 6). One of these studies reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19 to 1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than to 10 years of COC use.Figure 6: Risk of Breast Cancer with Combined Oral Contraceptive UseRR relative risk; OR odds ratio; HR hazard ratio. ever COC are females with current or past COC use; never COC use are females that never used COCs.An increased risk of the following serious adverse reactions (see WARNINGS section for additional information) has been associated with the use of oral contraceptives:Thromboembolic and thrombotic disorders and other vascular problems (including thrombophlebitis and venous thrombosis with or without pulmonary embolism, mesenteric thrombosis, arterial thromboembolism, myocardial infarction, cerebral hemorrhage, cerebral thrombosis, transient ischemic attack)Carcinoma of the reproductive organs and breastsHepatic neoplasia/liver disease (including hepatic adenomas or benign liver tumors)Ocular lesions (including retinal vascular thrombosis)Gallbladder diseaseCarbohydrate and lipid effectsElevated blood pressureHeadache including migraineThe following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug related (alphabetically listed):AcneAmenorrheaAnaphylactic/anaphylactoid reactions, including urticaria, angioedema, and severe reactions with respiratory and circulatory symptomsBreast changes: tenderness, pain, enlargement, secretionBudd-Chiari syndromeCervical erosion and secretion, change inCholestatic jaundiceChorea, exacerbation ofColitisContact lenses, intolerance toCorneal curvature (steepening), change inDizzinessEdema/fluid retentionErythema multiformeErythema nodosumFocal nodular hyperplasiaGastrointestinal symptoms (such as abdominal pain, cramps, and bloating)HirsutismInfertility after discontinuation of treatment, temporaryLactation, diminution in, when given immediately postpartumLibido, change inMelasma/chloasma which may persistMenstrual flow, change inMood changes, including depressionNauseaNervousnessPancreatitisPorphyria, exacerbation ofRash (allergic)Scalp hair, loss ofSerum folate levels, decrease inSpottingSystemic lupus erythematosus, exacerbation ofUnscheduled bleedingVaginitis, including candidiasisVaricose veins, aggravation ofVomitingWeight or appetite (increase or decrease), change inThe following adverse reactions have been reported in users of oral contraceptives:CataractsCystitis-like syndromeDysmenorrheaHemolytic uremic syndromeHemorrhagic eruptionOptic neuritis, which may lead to partial or complete loss of visionPremenstrual syndromeRenal function, impaired. Thromboembolic and thrombotic disorders and other vascular problems (including thrombophlebitis and venous thrombosis with or without pulmonary embolism, mesenteric thrombosis, arterial thromboembolism, myocardial infarction, cerebral hemorrhage, cerebral thrombosis, transient ischemic attack). Carcinoma of the reproductive organs and breasts. Hepatic neoplasia/liver disease (including hepatic adenomas or benign liver tumors). Ocular lesions (including retinal vascular thrombosis). Gallbladder disease. Carbohydrate and lipid effects. Elevated blood pressure. Headache including migraine. Acne. Amenorrhea. Anaphylactic/anaphylactoid reactions, including urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms. Breast changes: tenderness, pain, enlargement, secretion. Budd-Chiari syndrome. Cervical erosion and secretion, change in. Cholestatic jaundice. Chorea, exacerbation of. Colitis. Contact lenses, intolerance to. Corneal curvature (steepening), change in. Dizziness. Edema/fluid retention. Erythema multiforme. Erythema nodosum. Focal nodular hyperplasia. Gastrointestinal symptoms (such as abdominal pain, cramps, and bloating). Hirsutism. Infertility after discontinuation of treatment, temporary. Lactation, diminution in, when given immediately postpartum. Libido, change in. Melasma/chloasma which may persist. Menstrual flow, change in. Mood changes, including depression. Nausea. Nervousness. Pancreatitis. Porphyria, exacerbation of. Rash (allergic). Scalp hair, loss of. Serum folate levels, decrease in. Spotting. Systemic lupus erythematosus, exacerbation of. Unscheduled bleeding. Vaginitis, including candidiasis. Varicose veins, aggravation of. Vomiting. Weight or appetite (increase or decrease), change in. Cataracts. Cystitis-like syndrome. Dysmenorrhea. Hemolytic uremic syndrome. Hemorrhagic eruption. Optic neuritis, which may lead to partial or complete loss of vision. Premenstrual syndrome. Renal function, impaired. figure 6.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Mode of Action Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).. Pharmacokinetics. Absorption No specific investigation of the absolute bioavailability of levonorgestrel and ethinyl estradiol in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability about 100%) and is not subject to first-pass metabolism. Ethinyl estradiol is rapidly and almost completely absorbed from the gastrointestinal tract but, due to first-pass metabolism in gut mucosa and liver, the bioavailability of ethinyl estradiol is between 38% and 48%.A summary of the single dose and multiple dose levonorgestrel and ethinyl estradiol pharmacokinetic parameters for 18 women under fasting conditions is provided in Table 1. The plasma concentrations of levonorgestrel and ethinyl estradiol reached steady-state by approximately day 14. Levonorgestrel and ethinyl estradiol concentrations did not increase from days 14 to 28, but did increase from days to 28. Table 1: Mean (SD) Pharmacokinetic Parameters of Levonorgestrel and Ethinyl Estradiol Over 28-Day Dosing Period Levonorgestrel Day max (ng/mL) max (h) 1/2 (h) AUC 0-24 (ngoh/mL) 2.4 (0.9) 1.2 (0.4) 16 (8) 14 5.4 (2.1) 1.7 (1.4) 68 (36) 28 5.7 (2.1) 1.3 (0.8) 36 (19) 74 (41) Ethinyl Estradiol Day (pg/mL) (h) (h) (pgoh/mL) 47.7 (20.1) 1.3 (0.5) 378 (140) 14 72.7 (37.2) 1.4 (0.5) 695 (361) 28 74.4 (29.7) 1.4 (0.5) 21 (7) 717 (351)The mean plasma concentrations of levonorgestrel and ethinyl estradiol following single (day 1) and multiple (days 14 and 28) oral administrations of levonorgestrel 90 mcg in combination with ethinyl estradiol 20 mcg to 18 healthy women is provided in Figure 1.Figure 1: Mean Plasma +- SD+ Concentrations of Levonorgestrel and Ethinyl Estradiol Following Single (Day 1) and Multiple (Days 14 and 28) Oral Administrations of Levonorgestrel 90 mcg in Combination with Ethinyl Estradiol 20 mcg to Healthy Women+SD standard deviationThe effect of food on the rate and the extent of levonorgestrel and ethinyl estradiol absorption following oral administration of levonorgestrel and ethinyl estradiol has not been evaluated.Distribution Levonorgestrel in serum is primarily bound to sex hormone-binding globulin (SHBG). Ethinyl estradiol is about 97% bound to serum albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis.Metabolism Levonorgestrel: The most important metabolic pathways are reduction of the 4-3-oxo group and hydroxylation at positions 2, 1, and 16, followed by conjugation. Most of the circulating metabolites are sulfates of 3, 5-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. Some of the parent levonorgestrel also circulates as 17-sulfate. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users.Ethinyl estradiol: Cytochrome P450 enzymes (CYP3A4) in the liver are responsible for the 2-hydroxylation that is the major oxidative reaction. The 2-hydroxy metabolite is further transformed by methylation, sulfation, and glucuronidation prior to urinary and fecal excretion. Levels of CYP3A4 vary widely among individuals and can explain the variation in rates of ethinyl estradiol 2-hydroxylation.Excretion The terminal elimination half-life for levonorgestrel in levonorgestrel and ethinyl estradiol is about 36 hours. Levonorgestrel and its metabolites are excreted in the urine (40% to 68%) and in feces (16% to 48%). The terminal elimination half-life of ethinyl estradiol in levonorgestrel and ethinyl estradiol is about 21 hours.Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates and undergoes enterohepatic recirculation.Special Populations Race No formal studies on the effect of race on the pharmacokinetic parameters of levonorgestrel and ethinyl estradiol were conducted.Hepatic Insufficiency No formal studies have evaluated the effect of hepatic disease on the disposition of levonorgestrel and ethinyl estradiol. However, steroid hormones may be poorly metabolized in patients with impaired liver function.Renal Insufficiency No formal studies have evaluated the effect of renal disease on the disposition of levonorgestrel and ethinyl estradiol.Drug-Drug Interactions See PRECAUTIONS section Drug Interactions.. 85b1e02d-figure-02.

PRECAUTIONS SECTION.

PRECAUTIONS. 1. General. 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 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 woman using levonorgestrel and ethinyl estradiol, pregnancy test should be performed.. 2. Physical Examination and Follow-Up A periodic personal and family medical history and complete physical examination are appropriate for all women, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen, and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent, or recurrent abnormal vaginal bleeding, appropriate diagnostic measures should be conducted to rule out malignancy. Women with strong family history of breast cancer or who have breast nodules should be monitored with particular care.. 3. Lipid Disorders Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult. (See WARNINGS, 1a., 1d., and 8.)A small proportion of women will have adverse lipid changes while taking oral contraceptives. Nonhormonal contraception should be considered in women with uncontrolled dyslipidemias. Persistent hypertriglyceridemia may occur in small population of combination oral contraceptive users. Elevations of plasma triglycerides may lead to pancreatitis and other complications.. 4. Liver Function If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function.. 5. Fluid Retention Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention.. 6. Emotional Disorders Patients becoming significantly depressed while taking oral contraceptives should stop the medication and use an alternate method of contraception in an attempt to determine whether the symptom is drug related. Women with history of depression should be carefully observed and the drug discontinued if depression recurs to serious degree.. 7. Contact Lenses Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.. 8. Gastrointestinal Diarrhea and/or vomiting may reduce hormone absorption resulting in decreased serum concentrations.. 9. Drug Interactions. Changes in Contraceptive Effectiveness Associated with Coadministration of Other Products: 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 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.Concomitant Use with HCV Combination Therapy Liver Enzyme ElevationDo not coadminister levonorgestrel and ethinyl estradiol tablets with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations (see WARNINGS, Risk of Liver Enzyme Elevations with Concomitant Hepatitis Treatment).Herbal products containing St. Johns Wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in unscheduled bleeding.Increase in Plasma Levels Associated with Coadministered Drugs: Coadministration of atorvastatin and certain oral contraceptives containing ethinyl estradiol increases AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen increase the bioavailability of ethinyl estradiol since these drugs act as competitive inhibitors for sulfation of ethinyl estradiol in the gastrointestinal wall, known pathway of elimination for ethinyl estradiol. CYP 3A4 inhibitors such as indinavir, itraconazole, ketoconazole, fluconazole, and troleandomycin may increase plasma hormone levels. Troleandomycin may also increase the risk of intrahepatic cholestasis during coadministration with combination oral contraceptives.Changes in Plasma Levels of Coadministered Drugs: Combination hormonal contraceptives containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporine, prednisolone and other corticosteroids, and theophylline have been reported with concomitant administration of oral contraceptives. Decreased plasma concentrations of acetaminophen and lamotrigine, and increased clearance of temazepam, salicylic acid, morphine, and clofibric acid, due to induction of conjugation (particularly glucuronidation), have been noted when these drugs were administered with oral contraceptives.The prescribing information of concomitant medications should be consulted to identify potential interactions.. 10. Interactions with Laboratory Tests. Certain endocrine- and liver-function tests and blood components may be affected by oral contraceptives:a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.b. 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.c. Other binding proteins may be elevated in serum i.e., 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.d. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected.e. Glucose tolerance may be decreased.f. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if woman becomes pregnant shortly after discontinuing oral contraceptives.. 11. Carcinogenesis. See WARNINGS section.. 12. Pregnancy. Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS sections.. 13. Nursing Mothers. Small amounts of oral contraceptive steroids and/or metabolites have been identified in the milk of nursing mothers, and 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.. 14. Pediatric Use. Safety and efficacy of levonorgestrel and ethinyl estradiol 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 16 and for users 16 years and older. Use of this product before menarche is not indicated.. 15. Geriatric Use. This product has not been studied in women over 65 years of age and is not indicated in this population.. 16. Information for the Patient. See DETAILED PATIENT LABELING printed below.

SPL PATIENT PACKAGE INSERT SECTION.

INFORMATION FOR THE PATIENT. Brief Summary Patient Package Insert Levonorgestrel and Ethinyl Estradiol Tablets, USP90 mcg/20 mcgRx OnlyThis product (like all oral contraceptives) is intended to prevent pregnancy. 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. Oral contraceptives, also known as birth-control pills or the pill, are taken to prevent pregnancy, and when taken correctly, have failure rate of approximately to 2% per year (1 to pregnancies per 100 women per year of use) when used without missing any pills. The average failure rate of large numbers of pill users is approximately 5% per year (5 pregnancies per 100 women per year of use) when women who miss pills are included. However, forgetting to take pills considerably increases the chances of pregnancy.Levonorgestrel and ethinyl estradiol tablets are birth-control pill that is taken every day. When you take levonorgestrel and ethinyl estradiol tablets the lining of your uterus does not undergo the changes needed for menstruation, and therefore you do not have regular menstrual periods. You are likely to have unscheduled or unplanned bleeding or spotting when you start to use levonorgestrel and ethinyl estradiol tablets. The number of days each month with unscheduled bleeding and spotting usually decreases over time for the majority of women. When using levonorgestrel and ethinyl estradiol tablets the convenience of having no regular menstrual periods should be weighed against the inconvenience of unscheduled or unplanned breakthrough bleeding and spotting. For the majority of women, oral contraceptives can be taken safely. However, there are some women who are at high risk of developing certain serious diseases that can be life-threatening or may cause temporary or permanent disability or death. The risks associated with taking oral contraceptives increase significantly if you:smokehave high blood pressure, diabetes, high cholesterol, or tendency to form blood clots, or are obesehave or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast or sex organs, jaundice, malignant or benign liver tumors, or major surgery with prolonged immobilizationhave headaches with neurological symptomsYou should not take the pill if you suspect you are pregnant or have unexplained vaginal bleeding.Although cardiovascular disease risks may be increased with oral contraceptive use in healthy, nonsmoking women over 40 (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women. Cigarette smoking increases the risk of serious adverse effects on the heart and blood vessels from oral contraceptive use. This risk increases with age and with the amount of smoking (15 or more cigarettes per day has been associated with significantly increased risk) and is quite marked in women over 35 years of age. Women who use oral contraceptives should not smoke. Most side effects of the pill are not serious. The most common such effects are nausea, vomiting, unscheduled bleeding, weight gain, breast tenderness, and difficulty wearing contact lenses. These side effects, especially nausea and vomiting, may subside within the first three months of use.The serious side effects of the pill occur very infrequently, especially if you are in good health and do not smoke. However, you should know that the following medical conditions have been associated with or made worse by the pill:1. Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), stoppage or rupture of blood vessel in the brain (stroke), blockage of blood vessels in the heart (heart attack and angina pectoris) or other organs of the body. As mentioned above, smoking increases the risk of heart attacks and strokes and subsequent serious medical consequences. Women with migraine also may be at increased risk of stroke with pill use.2. Liver tumors, which may rupture and cause severe bleeding. possible, but not definite, association has been found with the pill and liver cancer. However, liver cancers are extremely rare. The chance of developing liver cancer from using the pill is thus even rarer.3. High blood pressure, although blood pressure usually returns to normal when the pill is stopped.The symptoms associated with these serious side effects are discussed in the detailed leaflet given to you with your supply of pills. Notify your health care provider if you notice any unusual physical disturbances while taking the pill. In addition, drugs such as rifampin, as well as some anticonvulsants and some antibiotics, herbal preparations containing St. Johns Wort (Hypericum perforatum), and HIV/AIDS drugs may decrease oral contraceptive effectiveness.There may be slight increases in the risk of breast cancer among current users of hormonal birth control pills with longer duration of use of years or more. Some studies have found an increase in the incidence of cancer of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives.Taking the pill provides some important noncontraceptive benefits. These include less painful menstruation, fewer pelvic infections, and fewer cancers of the ovary and the lining of the uterus.Be sure to discuss any medical condition you may have with your health care provider. Your health care provider will take medical and family history before prescribing oral contraceptives and will examine you. The physical examination may be delayed to another time if you request it, and the health care provider believes that it is appropriate to postpone it. You should be reexamined at least once year while taking oral contraceptives. The detailed patient information leaflet gives you further information which you should read and discuss with your health care provider.What You Should Know About Your Menstrual Cycle When You Use Levonorgestrel and Ethinyl Estradiol Tablets You are likely to have unscheduled or unplanned bleeding or spotting when you start to use levonorgestrel and ethinyl estradiol tablets. The number of days each month with bleeding or spotting usually decreases over time in the majority of women. In study of levonorgestrel and ethinyl estradiol tablets about out of 10 women had or more days of bleeding or spotting while using their third 28-day pill pack of levonorgestrel and ethinyl estradiol tablets. The number of women with or more days of bleeding or spotting decreased to out of 10 women during the use of their seventh pill pack. Among women who continued to use levonorgestrel and ethinyl estradiol tablets for one year, about out of 10 women had no bleeding or spotting during their last month of use. Do not stop taking levonorgestrel and ethinyl estradiol tablets because of bleeding or spotting as this will increase your chance of getting pregnant. If the spotting or bleeding continues for more than consecutive days or if the bleeding is heavy, call your health care provider. Can Get Pregnant While Taking Levonorgestrel and Ethinyl Estradiol Tablets You are not likely to get pregnant if you take levonorgestrel and ethinyl estradiol tablets at the same time every day as directed by your health care provider. Because regular monthly bleeding does not occur on levonorgestrel and ethinyl estradiol tablets 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 pregnancy test and you should contact your health care professional. Stop taking levonorgestrel and ethinyl estradiol tablets if you are pregnant. Instructions for the Patient HOW TO TAKE LEVONORGESTREL AND ETHINYL ESTRADIOL TABLETS Important Points to Remember Before You Start Taking Levonorgestrel and Ethinyl Estradiol Tablets: 1. BE SURE TO READ THESE DIRECTIONS:Before you start taking levonorgestrel and ethinyl estradiol tablets. And Anytime you are not sure what to do.2. THE RIGHT WAY TO TAKE LEVONORGESTREL AND ETHINYL ESTRADIOL TABLETS 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 to PACKS OF PILLS.If you feel sick to your stomach, do not stop taking levonorgestrel and ethinyl estradiol tablets. This will usually go away. If it doesnt 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 TABLETS. Do not stop taking your pills even if you are having bleeding or spotting. If the bleeding or spotting lasts for more than 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 pills to make up for missed pills, you could also feel little sick to your stomach.6. IF YOU VOMIT (within 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 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 TABLETS 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 TABLETS1. 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 TABLETS DISPENSER. The pill pack has 28 active white pills (with hormones). 3. ALSO FIND: 1) where on the pack to start taking pills, and 2) in what order to take the pills (follow the arrows).For use of day labels, see WHEN TO START THE FIRST PACK OF LEVONORGESTREL AND ETHINYL ESTRADIOL TABLETS below.4. BE SURE YOU HAVE READY AT ALL TIMES:ANOTHER KIND OF NONHORMONAL BIRTH CONTROL (such as condoms and/or spermicide) to use as back-up in case you miss pills.AN EXTRA, FULL PILL PACK. WHEN TO START THE FIRST PACK OF LEVONORGESTREL AND ETHINYL ESTRADIOL TABLETSDay Start 1. On Day of your period, peel the day label from the sticker sheet which has the corresponding start day of your period printed on the left hand side; place the label on the dispenser in the designated location. Take your pill daily in the order indicated by the arrows on the dispenser card. Pick time of day which will be easy to remember and take your pill at the same time every day.2. Take the first active white pill of the first pack during the first 24 hours of your period. 3. You will not need to use 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 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 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 21 pill pack: Start levonorgestrel and ethinyl estradiol tablets on the first day of your period (withdrawal bleed). Be sure that no more than days pass between the last day of your 21-day pack and your first levonorgestrel and ethinyl estradiol tablets pill. When switching from 28 pill pack (21 active and inactive pills, or 24 active and inactive pills): Start levonorgestrel and ethinyl estradiol tablets on the first day of your period (withdrawal bleed). Be sure that no more than days pass after the last active pill and your first levonorgestrel and ethinyl estradiol tablets pill. IF YOU SWITCH FROM ANOTHER TYPE OF BIRTH CONTROL When switching from other types of birth control such as pills containing only 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 tablets. 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 row What to do when you miss pill(s) 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 pills in day. You COULD BECOME PREGNANT if you have sex during the days after you restart your pills. You MUST use nonhormonal birth-control method (such as condoms and/or spermicide) as back-up for those days. missed pills Take missed pills on the day you remember. The following day you are back on schedule to take pill day. and remembered on the day of the second missed pill For example, you take your pills in the morning and you missed pill on Monday and on Tuesday. On Tuesday evening you remembered that you missed your Monday and Tuesday pills. You take the missed pills on Tuesday evening and on Wednesday morning youre back on schedule and you take pill. You COULD BECOME PREGNANT if you have sex during the days after you restart your pills. You MUST use nonhormonal birth-control method (such as condoms and/or spermicide) as back-up for those days. missed pills Take missed pills on the day you remember. The next day you take pills. The following day you are back on schedule to take your pills. and remembered on the day after the second pill is missed For example, you take your pills in the morning and you missed pill on Monday and on Tuesday. On Wednesday morning you remembered that you missed your Monday and Tuesday pills. You take the missed pills on Wednesday morning and pills on Thursday morning. On Friday morning youre back on schedule and you take pill. You COULD BECOME PREGNANT if you have sex during the days after you restart your pills. You MUST use nonhormonal birth-control method (such as condoms and/or spermicide) as back-up for those days. 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 days after you restart your pills. You MUST use nonhormonal birth-control method (such as condoms and/or spermicide) as back-up for those days.FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED Use 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 tablets. You can get pregnant within days after stopping levonorgestrel and ethinyl estradiol tablets. For additional information see Detailed Patient Labeling.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.Brands listed are the trademarks of their respective owners. Distributed by:Actavis Pharma, Inc.Parsippany, NJ 07054 USA Rev. 11/2021. smoke. have high blood pressure, diabetes, high cholesterol, or tendency to form blood clots, or are obese. have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast or sex organs, jaundice, malignant or benign liver tumors, or major surgery with prolonged immobilization. have headaches with neurological symptoms. FaceCard 1.

WARNINGS SECTION.

WARNINGS. Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with the extent of smoking (in epidemiologic studies, 15 or more cigarettes per day was associated with significantly increased risk) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke. The use of oral contraceptives is associated with increased risks of several serious conditions including venous and arterial thrombotic and thromboembolic events (such as myocardial infarction, thromboembolism, stroke, and transient ischemic attack), hepatic neoplasia, gallbladder disease, and hypertension, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as certain inherited or acquired thrombophilias, hypertension, hyperlipidemias, obesity, diabetes, and surgery or trauma with increased risk of thrombosis (see CONTRAINDICATIONS).Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks.The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher doses of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower doses of both estrogens and progestogens remains to be determined.Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide measure of the relative risk of disease, namely, ratio of the incidence of disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of disease. Cohort studies provide measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of disease in the population. For further information, the reader is referred to text on epidemiological methods.. 1. Thromboembolic Disorders and Other Vascular Problems Levonorgestrel and ethinyl estradiol tablets are non-cyclic oral contraceptive that provides low daily dose of estrogen and progestin; however, levonorgestrel and ethinyl estradiol tablets provide women with more hormonal exposure on yearly basis (13 additional weeks of hormone intake per year) than conventional cyclic oral contraceptives containing the same strength of synthetic estrogens and similar strength of progestins. a. Myocardial Infarction An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary-artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six. The risk is very low under the age of 30.Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarction in women in their mid-thirties or older with smoking accounting for the majority of excess cases. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and nonsmokers over the age of 40 (Figure 3) among women who use oral contraceptives.Figure 3: Circulatory Disease Mortality Rates per 100,000 Woman Years by Age, Smoking Status and Oral Contraceptive UseAdapted from P.M. Layde and V. Beral, Lancet, 1:541-546, 1981.Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age, and obesity. In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create state of hyperinsulinism. Oral contraceptives have been shown to increase blood pressure among users (see section 10 in WARNINGS). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.. 85b1e02d-figure-04. b. Venous Thrombosis and Thromboembolism 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 for the first episode of superficial venous thrombosis, to 11 for deep-vein thrombosis or pulmonary embolism, and 1.5 to for women with predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower, about 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 per 10,000 woman-years compared to 0.5 to 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 woman ever uses 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 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 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 midtrimester pregnancy termination.. c. Cerebrovascular Diseases Oral contraceptives 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), hypertensive women who also smoke. Hypertension was found to be risk factor for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes. Transient ischemic attacks have also been associated with oral contraceptive use.In large study, the relative risk of thrombotic strokes has been shown to range from for normotensive users to 14 for users with severe hypertension. The relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension. The attributable risk is also greater in older women. Oral contraceptives also increase the risk for stroke in women with other underlying risk factors such as certain inherited or acquired thrombophilias. Women with migraine (particularly migraine/headaches with focal neurological symptoms such as aura) who take combination oral contraceptives may be at an increased risk of stroke. (See CONTRAINDICATIONS).. d. Dose-Related Risk of Vascular Disease from Oral Contraceptives A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease. decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents. decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogen used in the contraceptive. The amount of both hormones should be considered in the choice of an oral contraceptive.Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest estrogen content which is judged appropriate for the individual patient.. e. Persistence of Risk of Vascular Disease There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persisted for at least years for women 40 to 49 years who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups.In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least years after discontinuation of oral contraceptives, although excess risk was very small. However, both studies were performed with oral contraceptive formulations containing 0.05 mg or higher of estrogens.. 2. Estimates of Mortality from Contraceptive Use One study gathered data from 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 possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970s -- 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.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 AGE 15 to 19 20 to 24 25 to 29 30 to 34 35 to 39 40 to 44 Deaths are birth-related Deaths are method-related Adapted from H.W. Ory, Family Planning Perspectives, 15:57-63, 1983. 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. 3. Malignant Neoplasms Breast CancerLevonorgestrel and ethinyl estradiol tablets are contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive (see CONTRAINDICATIONS).Epidemiology studies have not found consistent association between use of combined oral contraceptives (COCs) and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use (see Postmarketing Experience).Cervical CancerSome studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia or invasive cervical cancer in some populations of women. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. In spite of many studies of the relationship between combination oral contraceptive use and breast and cervical cancers, cause-and-effect relationship has not been established. Endometrial biopsies performed in subset of subjects (Study 1; = 93) ages 18 to 49 years, after to 12 months of use of levonorgestrel and ethinyl estradiol tablets did not reveal any hyperplasias or malignancies. Endometrial malignancy is rare in this age group, so change in the risk is unlikely to be detected with study of this size. 4. Hepatic Neoplasia Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of these benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, risk that increases after four or more years of use. Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral contraceptive user. However, these cancers are extremely rare in the U.S. and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users.. 5. Risk of Liver Enzyme Elevations with Concomitant Hepatitis Treatment During clinical trials with the Hepatitis combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications such as COCs. Discontinue levonorgestrel and ethinyl estradiol tablets prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (see CONTRAINDICATIONS). Levonorgestrel and ethinyl estradiol tablets can be restarted approximately weeks following completion of treatment with the combination drug regimen.. 6. Ocular Lesions. There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives that may lead to partial or complete loss of vision. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately. 7. Oral Contraceptive Use Before or During Early Pregnancy 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 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 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.. 8. Gallbladder Disease Combination oral contraceptives may worsen existing gallbladder disease and may accelerate the development of this disease in previously asymptomatic women. Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens. More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal. The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.. 9. Carbohydrate and Lipid Metabolic Effects Oral contraceptives have been shown to cause glucose intolerance in significant percentage of users. Oral contraceptives containing greater than 0.075 mg of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance. Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents. However, in the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives.A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS, 1a. and 1d.; PRECAUTIONS, 3.), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.. 10. Elevated Blood Pressure An increase in blood pressure has been reported in women taking oral contraceptives and this increase is more likely in older oral contraceptive users and with continued use. Data from the Royal College of General Practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing quantities of progestogens.Women with history of hypertension or hypertension-related diseases, or renal disease should be encouraged to use another method of contraception. If women with hypertension elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued (see CONTRAINDICATIONS section). For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension among ever- and never-users.. 11. Headache The onset or exacerbation of migraine or development of headache with new pattern that is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause. (See WARNINGS, 1c. and CONTRAINDICATIONS).. 12. Bleeding Irregularities When prescribing levonorgestrel and ethinyl estradiol tablets 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 shows the percentage of levonorgestrel and ethinyl estradiol tablets 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: The for each pill pack is the number of subjects with 28 days of data.Bleeding required sanitary protection; spotting only did not require sanitary protection.Figure shows the percentage of levonorgestrel and ethinyl estradiol tablets subjects with complete bleeding data in Study 313-NA who had or more and or more days of bleeding and/or spotting during each pill pack cycle. During pill pack 2, 67% of subjects experienced or more days of bleeding and/or spotting and 54% of these subjects experienced or more days of bleeding and/or spotting. During the final cycle of use of levonorgestrel and ethinyl estradiol tablets (pill pack 13), these percentages were 31% and 20%, respectively.Figure 5: Percentage of Subjects Reporting Greater than or Equal to or Days of Bleeding and/or Spotting per Pill Pack (Study 313-NA): The for each pill pack is the number of subjects with 28 days of data.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 condition was preexistent.. 85b1e02d-figure-05. 85b1e02d-figure-06. 13. Ectopic Pregnancy Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.