Ethynodiol

INDICATIONS AND USAGE Valtya 1/50 is indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception. Oral contraceptive products such as Valtya 1/50, 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. % of women experiencing an unintended pregnancy within the first year of use % of women continuing use at one year (C) Method (1) Typical use (A) (2) Perfect use (B) (3) (4) Chance (D) 85 85 Spermicides (E) 26 6 40 Periodic abstinence 25 63 Calendar 9 Ovulation method 3 Sympto-thermal (F) 2 Post-ovulation 1 Withdrawal 19 4 Cap (G) Parous women 40 26 42 Nulliparous women 20 9 56 Sponge Parous women 40 20 42 Nulliparous women 20 9 56 Diaphragm (G) 20 6 56 Condom (H) Female (Reality ) 21 5 56 Male 14 3 61 Pill 5 71 Progestin only 0.5 Combined 0.1 IUD Progesterone T 2 1.5 81 Copper T 380A 0.8 0.6 78 LNg 20 0.1 0.1 81 Injection (Depo-Provera) 0.3 0.3 70 Implant (Norplant and Norplant-2) 0.05 0.05 88 Female sterilization 0.5 0.5 100 Male sterilization 0.15 0.1 100 Emergency Contraceptive Pills : Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%. (I) Lactational Amenorrhea Method : LAM is a highly effective, temporary method of contraception. (J) 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 (A) 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. (B) 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. (C) Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. (D) 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. (E) Foams, creams, gels, vaginal suppositories, and vaginal film. (F) Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. (G) With spermicidal cream or jelly. (H) Without spermicides. (I) 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).

CLINICAL PHARMACOLOGY Combination oral contraceptives act primarily by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations in the genital tract, including changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which may reduce the likelihood of implantation) may also contribute to contraceptive effectiveness.

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 Valtya 1/50 tablet dispenser contains 21 orange colored active tablets arranged in three numbered rows of 7 tablets each, followed by a fourth row of 7 green inert 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 (orange) is then taken on Day 1. For a SUNDAY START when menstrual flow begins on or before Sunday, the first tablet (orange) is taken on that day. With either a DAY 1 START or SUNDAY START, 1 tablet (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 Sunday, discard the rest of the dispenser and begin a new di

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 of COC use. Figure 2. Risk of Breast Cancer with Combined Oral Contraceptive Use RR = relative risk; OR = odd

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 risk of several serious conditions including venous and arterial thromboembolism, thrombotic and hemorrhagic stroke, myocardial infarction, liver tumors or other liver lesions, and gallbladder disease. The risk of morbidity and mortality increases significantly in the presence of other risk factors such as hypertension, hyperlipidemia, obesity, and diabetes mellitus. Practitioners prescribing oral contraceptives should be familiar with the following information relating to these and other risks. The information contained herein is principally based on studies carried out in patients who used oral contraceptives with formulations containing higher amounts of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lesser amounts of both estrogens and progestogens remains to be determined. Throughout this labeling, epidemiological studies reported are of two types: retrospective case-control studies and prospective cohort studies. Case-control studies provide an estimate of the relative risk of a disease, which is defined as the ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk (or odds ratio) does not provide information about the actual clinical occurrence of a disease. Cohort studies provide a measure of both the relative risk and the attributable risk. The latter is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence or incidence of a disease in the subject 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 associated with oral contraceptive use. 2-21 This increased risk is primarily in smokers or in women with other underlying risk factors for coronary artery disease such as hypertension, obesity, diabetes, and hypercholesterolemia. The relative risk for myocardial infarction in current oral contraceptive users has been estimated to be 2 to 6. The risk is very low under the age of 30. However, there is the possibility of a risk of cardiovascular disease even in very young women who take oral contraceptives. Smoking in combination with oral contraceptive use has been reported to contribute substantially to the risk of myocardial infarction in women in their mid-thirties or older, with smoking accounting for the majority of excess cases. 22 Mortality rates associated with circulatory disease have been shown to increase substantially in smokers, especially in those 35 years of age and older among women who use oral contraceptives (see Figure 1, Table 2). Figure 1. Circulatory disease mortality rates per 100,000 woman-years by age, smoking status, and oral contraceptive use. 14 Adapted from Layde and Beral. 14 Oral contraceptives may compound the effects of well-known cardiovascular risk factors such as hypertension, diabetes, hyperlipidemias, hypercholesterolemia, age, cigarette smoking, and obesity. In particular, some progestogens decrease HDL cholesterol 23-31 and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. 32 Oral contraceptives have been shown to increase blood pressure among some users (see WARNING No. 9 ). Similar effects on risk factors have been associated with an increased risk of heart disease. Graph b. Thromboembolism An increased risk of thromboembolic and thrombotic disease associated with the

CONTRAINDICATIONS Valtya 1/50 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 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).

OVERDOSAGE Serious ill effects have not been reported following acute ingestion 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