BRIELLYN

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 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, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates. TABLE 1: LOWEST EXPECTED AND TYPICAL FAILURE RATES DURING THE FIRST YEAR OF CONTINUOUS USE OF A METHOD % of Women Experiencing an Accidental Pregnancy in the First Year of Continuous Use Method Lowest Expected* Typical** (No contraception) (85) (85) Oral contraceptives combined 0.1 3*** progestin only 0.5 3*** Diaphragm with spermicidal cream or jelly 6 18 Spermicides alone (foam, creams, jellies and vaginal suppositories) 3 21 Vaginal sponge nulliparous 6 18 multiparous 9 28 IUD 0.8-2.0 3# Condom without spermicides 2 12 Periodic abstinence (all methods) 1-9 20 Injectable progestogen 0.3-0.4 0.3-0.4 Implants 6 capsules 0.04 0.04 2 rods 0.03 0.03 Female sterilization 0.2 0.4 Male sterilization 0.1 0.15 Reproduced with permission of the Population Counsil from J. Trusell, et. al: Contraceptive failure in the United States: An update. Studies in Family Planning, 21(1), January-February 1990. * The authors’ best guess of the percentage of women expected to experience an accidental pregnancy among couples who initiate a method (not necessarily for the first time) and who use it consistently and correctly during the first year if they do not stop for any reason other than pregnancy. ** This term represents “typical” couples who initiate use of a method (not necessarily for the first time), who experience an accidental pregnancy during the first year if they do not stop use for any reason other than pregnancy. *** Combined typical rate for both combined and progestin only. # Combined typical rate for both medicated and nonmedicated IUD.

DOSAGE AND ADMINISTRATION The following is a summary of the instructions given to the patient in the “ HOW TO TAKE THE PILL ” section of the DETAILED PATIENT LABELING . The patient is given instructions in five (5) categories: 1. IMPORTANT POINTS TO REMEMBER: The patient is told (a) that she should take one pill every day at the same time, (b) many women have spotting or light bleeding or gastric distress during the first one to three cycles, (c) missing pills can also cause spotting or light bleeding, (d) she should use a back-up method for contraception if she has vomiting or diarrhea or takes some concomitant medications, and/or if she has trouble remembering the pill, (e) if she has any other questions, she should consult her physician. 2. BEFORE SHE STARTS TAKING HER PILLS: She should decide what time of day she wishes to take the pill, check whether her pill pack has 28 pills, and note the order in which she should take the pills (diagrammatic drawings of the pill pack are included in the patient insert). 3. WHEN SHE SHOULD START THE FIRST PACK: The Day-One start is listed as the first choice and the Sunday start (the Sunday after her period starts) is given as the second choice. If she uses the Sunday start she should use a back-up method in the first cycle if she has intercourse before she has taken seven pills. 4. WHAT TO DO DURING THE CYCLE: The patient is advised to take one pill at the same time every day until the pack is empty. If she is on the 28 day regimen, she should start the next pack the day after the last inactive tablet and not wait any days between packs. 5. WHAT TO DO IF SHE MISSES A PILL OR PILLS: The patient is given instructions about what she should do if she misses one, two or more than two pills at varying times in her cycle for both the Day-One and the Sunday start. The patient is warned that she may become pregnant if she has unprotected intercourse in the seven days after missing pills. To avoid this, she must use another birth control method such as condom, foam, or sponge in these seven days.

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 myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, 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 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 principally based 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 a 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. *Adapted from Stadel BB: Oral contraceptives and cardiovascular disease. N Engl J Med, 1981; 305: 612-618, 672-677; with author’s permission. 1. Thromboembolic Disorders and Other Vascular Problems: The physician should be alert to the earliest manifestations of thromboembolic thrombotic disorders as discussed below. Should any of these occur or be suspected the drug should be discontinued immediately. 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 (Figure 1) among women who use oral contraceptives. Layde PM, Beral V: Further analyses of mortality in oral contraceptive users: Royal College of General Practitioners’ oral contraception study. (Table 5) Lancet 1981; 1:541-546. 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 9 in WARNINGS ). Such increases in risk factors have been associated with an increa…

CONTRAINDICATIONS BRIELLYN 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 • Cerebrovascular or coronary artery disease • 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 • 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 ).

8. Drug Interactions: Reduced efficacy and increased incidence of breakthrough bleeding and menstrual irregularities have been associated with concomitant use of rifampin. A similar association, though less marked, has been suggested with barbiturates, phenylbutazone, phenytoin sodium, and possibly with griseofulvin, ampicillin, and tetracyclines. Concomitant Use with HCV Combination Therapy - Liver Enzyme Elevation Do not co-administer BRIELLYN 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 C TREATMENT ).

11. Pregnancy: See CONTRAINDICATIONS and WARNINGS sections.

12. Nursing Mothers: Small amounts of oral contraceptive steroids 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, 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 oral contraceptives but to use other forms of contraception until she has completely weaned her child.

ADVERSE REACTIONS An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS section): • Thrombophlebitis • Arterial thromboembolism • Pulmonary embolism • Myocardial infarction • Cerebral hemorrhage • Cerebral thrombosis • Hypertension • Gallbladder disease • Hepatic adenomas or benign liver tumors 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, and secretion • Change in weight (increase or decrease) • Change in cervical ectropion and secretion • Possible 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: • 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 • Budd-Chiari syndrome • Acne • Changes in libido • Colitis 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 to 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 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 2 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. Figure2.jpg