Levonest

Indications and Usage Oral contraceptives are indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception. Oral contraceptives are highly effective. Table I 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 and the IUD, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates. TABLE I: PERCENTAGE OF WOMEN EXPERIENCING AN UNINTENDED PREGNANCY DURING THE FIRST YEAR OF USE OF A CONTRACEPTIVE METHOD Method Perfect Use Typical Use Levonorgestrel implants 0.05 0.05 Male sterilization 0.1 0.15 Female sterilization 0.5 0.5 Depo-Provera ® (injectable progestogen) 0.3 0.3 Oral contraceptives 5 Combined 0.1 NA Progestin only 0.5 NA IUD Progesterone 1.5 2.0 Copper T 380A 0.6 0.8 Condom (male) without spermicide 3 14 (Female) without spermicide 5 21 Cervical cap Nulliparous women 9 20 Parous women 26 40 Vaginal sponge Nulliparous women 9 20 Parous women 20 40 Diaphragm with spermicidal cream or jelly 6 20 Spermicides alone (foam, creams, jellies, and vaginal suppositories) 6 26 Periodic abstinence (all methods) 1-9* 25 Withdrawal 4 19 No contraception (planned pregnancy) 85 85 NA – not available *Depending on method (calendar, ovulation, symptothermal, post-ovulation) Adapted from Hatcher RA et al, Contraceptive Technology : 17 t h Revised Edition . NY, NY: Ardent Media, Inc., 1998

Dosage and Administration To achieve maximum contraceptive effectiveness, LEVONEST™ Tablets (levonorgestrel and ethinyl estradiol tablets-triphasic regimen) must be taken exactly as directed and at intervals not exceeding 24 hours. LEVONEST™ Tablets (levonorgestrel and ethinyl estradiol tablets-triphasic regimen) are a three-phase preparation plus 7 inert tablets. The dosage of LEVONEST™ Tablets is one tablet daily for 28 consecutive days per menstrual cycle in the following order: 6 yellow tablets (phase 1), followed by 5 green tablets (phase 2), followed by 10 light brown tablets (phase 3), plus 7 white inert tablets, according to the prescribed schedule. It is recommended that LEVONEST™ Tablets be taken at the same time each day, preferably after the evening meal or at bedtime. During the first cycle of medication, the patient should be instructed to take one LEVONEST™ Tablet daily in the order of 6 yellow, 5 green, 10 light brown tablets, and then 7 white inert tablets for twenty-eight (28) consecutive days, beginning on day one (1) of her menstrual cycle. (The first day of menstruation is day one.) Withdrawal bleeding usually occurs within 3 days following the last light brown tablet. (If LEVONEST™ Tablets are first taken later than the first day of the first menstrual cycle of medication or postpartum, contraceptive reliance should not be placed on LEVONEST™ Tablets until after the first 7 consecutive days of administration. The possibility of ovulation and conception prior to initiation of medication should be considered.) When switching from another oral contraceptive, LEVONEST™ Tablets should be started on the first day of bleeding following the last active tablet taken of the previous oral contraceptive. The patient begins her next and all subsequent 28-day courses of LEVONEST™ Tablets on the same day of the week that she began her first course, following the same schedule. She begins taking her yellow tablets on the next day after ingestion of the last white tablet, regardless of whether or not a menstrual period has occurred or is still in progress. Any time a subsequent cycle of LEVONEST™ Tablets is started later than the next day, the patient should be protected by another means of contraception until she has taken a tablet daily for seven consecutive days. If spotting or breakthrough 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 physician. Although the occurrence of pregnancy is highly unlikely if LEVONEST™Tablets are taken according to directions, if withdrawal bleeding does not occur, the possibility of pregnancy must be considered. 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 at the time of the first missed period and appropriate diagnostic measures taken before the medication is resumed. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen. The risk of pregnancy increases with each active (yellow, green, or light brown) tablet missed. For additional patient instructions regarding missed pills, see the " WHAT TO DO IF YOU MISS PILLS " section in the DETAILED PATIENT LABELING below. If breakthrough bleeding occurs following missed active tablets, it will usually be transient and of no consequence. If the patient misses one or more white tablets, she is still protected against pregnancy provided she begins taking yellow tablets again on the proper day. In the nonlactating mother, LEVONEST™ may be initiated postpartum, for contraception. When the tablets are administered in the postpartum period, the increased risk of thromboembolic disease associated with the postpart…

WARNINGS Cigarette smoking increases the risk of serious cardiovascular side effects from oral-contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) 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 myocardial infarction, thromboembolism, stroke, hepatic neoplasia, gallbladder disease, and hypertension, although the risk of serious morbidity and 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 hypertension, hyperlipidemias, obesity, and diabetes.Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks. The information contained in this package insert is based principally on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower formulations 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-contraceptives 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 infarctions 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 (Table II) among women who use oral contraceptives. CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN YEARS BY AGE, SMOKING STATUS AND ORAL-CONTRACEPTIVE USE TABLE 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. TABLE II b. Thromboembolism An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative r…

CONTRAINDICATIONS Levonest™ is contraindicated in females who are known to have or develop the following conditions: Thrombophlebitis or thromboembolic disorders. A past history of deep-vein-thrombophlebitis or thromboembolic disorders. Cerebral-vascular or coronary-artery disease. Current diagnosis or history of breast cancer, which may be hormone sensitive. Undiagnosed abnormal genital bleeding. Cholestatic jaundice of pregnancy or jaundice with prior pill use. Hepatic adenomas and carcinomas. Known or suspected pregnancy. 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 ).

Adverse Reactions To report SUSPECTED ADVERSE REACTIONS, contact Northstar Rx LLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . An increased risk of the following serious adverse reactions has been associated with the use of oral- contraceptives (see “ Warings ” section): Thrombophlebitis. Arterial thromboembolism. Pulmonary embolism. Myocardial infarction. Cerebral hemorrhage. Cerebral thrombosis. Hypertension. Gallbladder disease. Hepatic adenomas or benign liver tumors. 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 1). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 1). 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 8 to 10 years of COC use. Figure 1: Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives 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. There is evidence of an association between the following conditions and the use of oral contraceptives, although additional confirmatory studies are needed: Mesenteric thrombosis. Retinal thrombosis. The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug related: Nausea. Vomiting. Gastrointestinal symptoms (such as abdominal cramps and bloating). Breakthrough bleeding. Spotting. Change in menstrual flow. Amenorrhea. Temporary infertility after discontinuation of treatment. Edema. Melasma which may persist. Breast changes: tenderness, enlargement, secretion. Change in weight (increase or decrease). Change in cervical erosion and secretion. Diminution in lactation when given immediately postpartum. Cholestatic jaundice. Migraine. Rash (allergic). Mental depression. Reduced tolerance to carbohydrates. Vaginal candidiasis. Change in corneal curvature (steepening). Intolerance to contact lenses. The following adverse reactions have been reported in users of oral contraceptives, and the association has been neither confirmed nor refuted: Congenital anomalies. Premenstrual syndrome. Cataracts. Optic neuritis. Changes in appetite. Cystitis-like syndrome. Headache. Nervousness. Dizziness. Hirsutism. Loss of scalp hair. Erythema multiforme. Erythema nodosum. Hemorrhagic eruption. Vaginitis. Porphyria. Impaired renal function. Hemolytic uremic syndrome. Budd-Chiari syndrome. Acne. Changes in libido. Colitis. Sickle-cell disease. Cerebral-vascular disease with mitral valve prolapse. Lupus-like syndromes. Figure 1