Levonorgestrel and Ethinyl Estradiol

INDICATIONS AND USAGE Levonorgestrel and ethinyl estradiol tablets are indicated for the prevention of pregnancy in women who elect to use oral-contraceptives as a method of contraception. Oral-contraceptives are highly effective. Table II lists the typical accidental pregnancy rates for users of combination oral-contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and Norplant ® System, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates. Table II: 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 an Unintended Pregnancy within the First Year of Use % of Women Continuing Use at One Year 3 Method Typical Use 1 Perfect Use 2 (1) (2) (3) (4) Chance 4 85 85 Spermicides 5 26 6 40 Periodic abstinence 25 63 Calendar 9 Ovulation Method 3 Sympto-Thermal 6 2 Post-Ovulation 1 Cap 7 Parous Women 40 26 42 Nulliparous Women 20 9 56 Sponge Parous Women 40 20 42 Nulliparous Women 20 9 56 Diaphragm 7 20 6 56 Withdrawal 19 4 Condom 8 Female (Reality) 21 5 56 Male 14 3 61 Pill 5 71 Progestin only 0.5 Combined 0.1 IUD Progesterone T 2.0 1.5 81 Copper T380A 0.8 0.6 78 LNg 20 0.1 0.1 81 Depo-Provera ® 0.3 0.3 70 Levonorgestrel Implants (Norplant ® ) 0.05 0.05 88 Female Sterilization 0.5 0.5 100 Male Sterilization 0.15 0.10 100 Emergency 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 a 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 a 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 a 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 a 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 a 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 1 dose is 2 tablets; for tablets containing 20 mcg of ethinyl estradiol and 100 mcg of levonorgestrel 1 dose is 5 tablets; for t…

DOSAGE AND ADMINISTRATION To achieve maximum contraceptive effectiveness, levonorgestrel and ethinyl estradiol tablets must be taken exactly as directed and at intervals not exceeding 24 hours. The dosage of levonorgestrel and ethinyl estradiol tablets is one white tablet daily for 21 consecutive days, followed by one peach inert tablet daily for 7 consecutive days, according to the prescribed schedule. It is recommended that levonorgestrel and ethinyl estradiol tablets be taken at the same time each day. During The First Cycle Of Use The possibility of ovulation and conception prior to initiation of medication should be considered. The patient should be instructed to begin taking levonorgestrel and ethinyl estradiol tablets on either the first Sunday after the onset of menstruation (Sunday Start) or on Day 1 of menstruation (Day 1 Start). Sunday start The patient is instructed to begin taking levonorgestrel and ethinyl estradiol tablets on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, the first tablet (white) is taken that day. One white tablet should be taken daily for 21 consecutive days, followed by one peach inert tablet daily for 7 consecutive days. Withdrawal bleeding should usually occur within 3 days following discontinuation of white tablets and may not have finished before the next pack is started. During the first cycle, contraceptive reliance should not be placed on levonorgestrel and ethinyl estradiol tablets until a white tablet has been taken daily for 7 consecutive days, and a nonhormonal back-up method of birth control should be used during those 7 days. Day 1 start During the first cycle of medication, the patient is instructed to begin taking levonorgestrel and ethinyl estradiol tablets during the first 24 hours of her period (day one of her menstrual cycle). One white tablet should be taken daily for 21 consecutive days, followed by one peach inert tablet daily for 7 consecutive days. Withdrawal bleeding should usually occur within 3 days following discontinuation of white tablets and may not have finished before the next pack is started. If medication is begun on day one of the menstrual cycle, no back-up contraception is necessary. If levonorgestrel and ethinyl estradiol tablets are started later than day one of the first menstrual cycle or postpartum, contraceptive reliance should not be placed on levonorgestrel and ethinyl estradiol tablets until after the first 7 consecutive days of administration, and a nonhormonal back-up method of birth control should be used during those 7 days. After the first cycle of use The patient begins her next and all subsequent courses of tablets on the day after taking her last peach tablet. She should follow the same dosing schedule: 21 days on white tablets followed by 7 days on peach tablets. If in any cycle the patient starts tablets later than the proper day, she should protect herself against pregnancy by using a nonhormonal back-up method of birth control until she has taken a white tablet daily for 7 consecutive days. Switching from another hormonal method of contraception When the patient is switching from a 21-day regimen of tablets, she should wait 7 days after her last tablet before she starts levonorgestrel and ethinyl estradiol tablets. She will probably experience withdrawal bleeding during that week. She should be sure that no more than 7 days pass after her previous 21-day regimen. When the patient is switching from a 28-day regimen of tablets, she should start her first pack of levonorgestrel and ethinyl estradiol tablets on the day after her last tablet. She should not wait any days between packs. The patient may switch any day from a progestin only pill and should begin levonorgestrel and ethinyl estradiol tablets the next day. If switching from an implant or injection, the patient should start levonorgestrel and ethinyl estradiol tablets on the day of implant removal or, if using an injection, the day the next …

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 a 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, and stroke), 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 a measure of the relative risk of disease, namely, a ratio of the incidence of a disease among oral-contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a 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 a disease in the population. For further information, the reader is referred to a text on epidemiological methods. 1. Thromboembolic Disorders and Other Vascular Problems 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 II) among women who use oral-contraceptives. FIGURE II: (Adapted 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 a 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. levonorgestrel-ethinyl-estradiol-fig2 b. Venous …

CONTRAINDICATIONS Levonorgestrel and ethinyl estradiol tablets are contraindicated in females who are known to have or develop the following conditions: Thrombophlebitis or thromboembolic disorders A history of deep-vein thrombophlebitis or thromboembolic disorders Cerebrovascular or coronary artery disease (current or past history) Valvular heart disease with thrombogenic complications Thrombogenic rhythm disorders Hereditary or acquired thrombophilias Major surgery with prolonged immobilization Diabetes with vascular involvement Headaches with focal neurological symptoms Uncontrolled hypertension Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia Undiagnosed abnormal genital bleeding Cholestatic jaundice of pregnancy or jaundice with prior pill use Hepatic adenomas or carcinomas, or active liver disease Known or suspected pregnancy Hypersensitivity to any of the components of levonorgestrel and ethinyl estradiol tablets Women who are receiving Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for alanine aminotransferase (ALT) elevations (see WARNINGS, RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT ).

12. Pregnancy 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 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.

ADVERSE REACTIONS Post Marketing 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 - 1.12 (Figure 2). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 2). 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 - 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 8-10 years of COC use. RR = 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), carcinoma of the reproductive organs and breasts, hepatic neoplasia (including hepatic adenomas or benign liver tumors), ocular lesions (including retinal vascular thrombosis), gallbladder disease, carbohydrate and lipid effects, elevated blood pressure, and headache including migraine. The following adverse reactions have been reported in patients receiving oral-contraceptives and are believed to be drug related (alphabetically listed): 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 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 The following adverse reactions have been reported in users of oral-contraceptives: 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-2