ethynodiol diacetate and ethinyl estradiol

INDICATIONS AND USAGE Ethynodiol diacetate and ethinyl estradiol tablets USP, 1 mg/50 mcg are indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception. Oral contraceptive products such as ethynodiol diacetate and ethinyl estradiol tablets, which contain 50 mcg of estrogen, should not be used unless medically indicated. Oral contraceptives are highly effective. Table 1 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 progestogen implants and injections, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates. Table 1. 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. Emergency Contraceptive Pills : Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%. The treatment schedule is one dose within 72 hours after unprotected intercourse and a second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral (1 dose is 2 white pills), Alesse (1 dose is 5 pink pills), Nordette or Levlen (1 dose is 2 light-orange pills), Lo/Ovral (1 dose is 4 white pills), Triphasil or Tri-Levlen (1 dose is 4 yellow pills). Lactational Amenorrhea Method : LAM is a highly effective, temporary method of contraception. 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 six months of age. Source: Trussell J, Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998, in press. 1 % of women experiencing an unintended pregnancy within the first year of use % of women continuing use at one year Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. Method (1) Typical use 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. (2) Perfect use 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. (3) (4) Chance 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. 85 85 Spermicides Foams, creams, gels, vaginal suppositories, and vaginal film. 26 6 40 Periodic abstinence 25 63 Calendar 9 Ovulation method 3 Sympto-thermal Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. 2 Post-ovulation 1 Withdrawal 19 4 Cap With spermicidal cream or jelly. Parous women 40 26 42 Nulliparous women 20 9 56 Sponge Parous women 40 20 42 Nulliparous women 20 9 56 Diaphragm 20 6 56 Condom Without spermicides. Female (Reality ® ) 21 5 …

DOSAGE AND ADMINISTRATION To achieve maximum contraceptive effectiveness, oral contraceptives must be taken exactly as directed and at intervals of 24 hours. IMPORTANT: If the Sunday start schedule is selected, the patient should be instructed to use an additional method of protection until after the first week of administration in the initial cycle. The possibility of ovulation and conception prior to initiation of use should be considered. Dosage Schedules Each ethynodiol diacetate and ethinyl estradiol tablet dispenser contains 21 light orange colored active tablets arranged in three numbered rows of 7 tablets each, followed by a fourth row of 7 green placebo tablets. Days of the week are printed above the tablets, starting with Sunday on the left. 28-Day Schedule: For a DAY 1 START, count the first day of menstrual flow as Day 1 and the first tablet (light orange) is then taken on Day 1. For a SUNDAY START when menstrual flow begins on or before Sunday, the first tablet (light orange) is taken on that day. With either a DAY 1 START or SUNDAY START, 1 tablet (light orange) is taken each day at the same time for 21 days. Then the green tablets are taken for 7 days, whether bleeding has stopped or not. After all 28 tablets have been taken, whether bleeding has stopped or not, the same dosage schedule is repeated beginning on the following day. Special notes Spotting, breakthrough bleeding, or nausea. If spotting (bleeding insufficient to require a pad), breakthrough bleeding (heavier bleeding similar to a menstrual flow), or nausea occurs the patient should continue taking her tablets as directed. The incidence of spotting, breakthrough bleeding or nausea is minimal, most frequently occurring in the first cycle. Ordinarily spotting or breakthrough bleeding will stop within a week. Usually the patient will begin to cycle regularly within two or three courses of tablet-taking. In the event of spotting or breakthrough bleeding organic causes should be borne in mind. (See WARNING No. 11 .) Missed menstrual periods. Withdrawal flow will normally occur 2 or 3 days after the last active tablet is taken. Failure of withdrawal bleeding ordinarily does not mean that the patient is pregnant, providing the dosage schedule has been correctly followed. (See WARNING No. 6 .) If the patient has not adhered to the prescribed dosage regimen, the possibility of pregnancy should be considered after the first missed period, and oral contraceptives should be withheld until pregnancy has been ruled out. 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 first intermenstrual interval after discontinuing the tablets is usually prolonged; consequently, a patient for whom a 28-day cycle is usual might not begin to menstruate for 35 days or longer. Ovulation in such prolonged cycles will occur correspondingly later in the cycle. Post-treatment cycles after the first one, however, are usually typical for the individual woman prior to taking tablets. (See WARNING No. 11 .) Missed tablets. If a woman misses taking one active tablet, the missed tablet should be taken as soon as it is remembered. In addition, the next tablet should be taken at the usual time. If two consecutive active tablets are missed in week 1 or week 2 of the dispenser, the dosage should be doubled for the next 2 days. The regular schedule should then be resumed, but an additional method of protection must be used as backup for the next 7 days if she has sex during that time or she may become pregnant. If two consecutive active tablets are missed in week 3 of the dispenser or three consecutive active tablets are missed during any of the first 3 weeks of the dispenser, direct the patient to do one of the following: Day 1 Starters should discard the rest of the dispenser and begin a new dispenser that same day; Sunday Starters should continue to take 1 tablet daily until Sun …

CONTRAINDICATIONS Ethynodiol diacetate and ethinyl estradiol tablets are 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 disease, myocardial infarction, or coronary artery disease, or a past history of these conditions • Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive • Known or suspected carcinoma of the female reproductive organs or suspected estrogen-dependent neoplasia, or a history of these conditions • Undiagnosed abnormal genital bleeding • History of cholestatic jaundice of pregnancy or jaundice with prior oral contraceptive use • Past or present, benign or malignant liver tumors • Known or suspected pregnancy • Are receiving Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations (see Warnings , RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT).

ADVERSE REACTIONS An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS ): • Thrombophlebitis and thrombosis • Arterial thromboembolism • Pulmonary embolism • Myocardial infarction and coronary thrombosis • Cerebral hemorrhage • Cerebral thrombosis • Hypertension • Gallbladder disease • Benign and malignant liver tumors, and other hepatic lesions There is evidence of an association between the following conditions and the use of oral contraceptives, although additional confirmatory studies are needed: • Mesenteric thrombosis • Neuro-ocular lesions (e.g., retinal thrombosis and optic neuritis) 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 during or after use • Temporary infertility after discontinuation of use • Edema • Chloasma or melasma, which may persist • Breast changes: tenderness, enlargement, secretion • Change in weight (increase or decrease) • Change in cervical erosion or 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 or conditions have been reported in users of oral contraceptives and the association has been neither confirmed nor refuted: • Premenstrual syndrome • Cataracts • 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 • Acne • Changes in libido • Colitis • Budd-Chiari syndrome • Endocervical hyperplasia or ectropion 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. Figure 2. Risk of Breast Cancer with Combined Oral Contraceptive 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. Figure 2. Risk of Breast Cancer with Combined Oral Contraceptive Use

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 o …

DESCRIPTION Ethynodiol diacetate and ethinyl estradiol tablets USP, 1 mg/50 mcg. Each orange tablet contains 1 mg of ethynodiol diacetate and 50 mcg of ethinyl estradiol, and the inactive ingredients include lactose monohydrate, povidone K-25, microcrystalline cellulose, polacrilin potassium, magnesium stearate. In addition, the coloring agent is FD&C Yellow No. 6 Aluminum Lake. Each green tablet in the ethynodiol diacetate and ethinyl estradiol tablets USP, 1 mg/50 mcg package is an inert tablet containing no active ingredients, and the inactive ingredients include lactose monohydrate, polacrilin potassium, magnesium stearate, yellow iron oxide and FD&C Blue No. 1 Aluminum Lake. The chemical name for ethynodiol diacetate is 19-Nor-17α-pregn-4-en-20-yne-3β, 17-diol diacetate, and for ethinyl estradiol it is 19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3, 17-diol. The structural formulas are as follows: Therapeutic class: Oral contraceptive. Structure Structure

OVERDOSAGE Serious ill effects have not been reported following acute ingestio n n of large doses of oral contraceptives by young children. 180, 181 Overdosage may cause nausea, and withdrawal bleeding may occur in females. NON-CONTRACEPTIVE HEALTH BENEFITS The following non-contraceptive health benefits related to the use of oral contraceptives are supported by epidemiological studies that largely utilized oral contraceptive formulations containing estrogen doses exceeding 35 mcg of ethinyl estradiol or 50 mcg of mestranol. 148,149 Effects on menses: • Increased menstrual cycle regularity • Decreased blood loss and decreased risk of iron-deficiency anemia • Decreased frequency of dysmenorrhea Effects related to inhibition of ovulation: • Decreased risk of functional ovarian cysts • Decreased risk of ectopic pregnancies Effects from long-term use: • Decreased risk of fibroadenomas and fibrocystic disease of the breast • Decreased risk of acute pelvic inflammatory disease • Decreased risk of endometrial cancer • Decreased risk of ovarian cancer • Decreased risk of uterine fibroids

HOW SUPPLIED Each orange ethynodiol diacetate and ethinyl estradiol tablet USP, 1 mg/50 mcg is round in shape, unscored and debossed with 252 on one side of the tablet and plain on the other side and contains 1 mg of ethynodiol diacetate and 50 mcg of ethinyl estradiol. Ethynodiol diacetate and ethinyl estradiol tablets USP, 1 mg/50 mcg are packaged in cartons of three (NDC 0378-7306-53) tablet dispensers. Each dispenser contains 21 orange tablets and 7 green inert tablets. (Inert tablets are debossed with 302 on one side of the tablet and plain on the other side.) Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]