Desogestrel and Ethinyl Estradiol

INDICATIONS AND USAGE Desogestrel 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 1 lists the typical accidental pregnancy rates for users of combined oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and the Norplant System depends upon the reliability with which they are used. Correct and consistent use of these methods can result in lower failure rates. In a clinical trial with desogestrel and ethinyl estradiol tablets 1,195 subjects completed 11,656 cycles and a total of 10 pregnancies were reported. This represents an overall user-efficacy (typical user-efficacy) pregnancy rate of 1.12 per 100 women-years. This rate includes patients who did not take the drug correctly. 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 (4) Method (1) Typical Use a (2) Perfect Use b (3) 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 2.0 1.5 81 Copper T380A 0.8 0.6 78 LNg 20 0.1 0.1 81 Depo-Provera 0.3 0.3 70 Norplant ® and Norplant-2 ® 0.05 0.05 88 Female Sterilization 0.5 0.5 100 Male Sterilization 0.15 0.10 100 Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%. i Lactation Amenorrhea Method: LAM is a highly effective, temporary method of contraception. j Source: Trussel 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. 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 FDA 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), …

DOSAGE AND ADMINISTRATION To achieve maximum contraceptive effectiveness, desogestrel and ethinyl estradiol tablets must be taken exactly as directed and at intervals not exceeding 24 hours. Desogestrel and ethinyl estradiol tablets may be initiated using either a Sunday start or a Day 1 start. NOTE: Each cycle pack dispenser is preprinted with the days of the week, starting with Sunday, to facilitate a Sunday start regimen. Six different “day label stickers” are provided with each cycle pack dispenser in order to accommodate a Day 1 start regimen. In this case, the patient should place the self-adhesive “day label sticker” that corresponds to her starting day over the preprinted days. IMPORTANT: The possibility of ovulation and conception prior to initiation of use of desogestrel and ethinyl estradiol tablets should be considered. DAY 1 START The dosage of desogestrel and ethinyl estradiol tablets for the initial cycle of therapy is one orange "active" tablet administered daily from the 1st day through the 21st day of the menstrual cycle, counting the first day of menstrual flow as "Day 1". Tablets are taken without interruption as follows: One orange "active" tablet daily for 21 days, then one white "reminder" tablet daily for 7 days. After 28 tablets have been taken, a new course is started and a orange "active" tablet is taken the next day. The use of desogestrel and ethinyl estradiol tablets for contraception may be initiated 4 weeks postpartum in women who elect not to breastfeed. When the tablets are administered during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered. (See CONTRAINDICATIONS and WARNINGS concerning thromboembolic disease. See also PRECAUTIONS Nursing Mothers .) If the patient starts on desogestrel and ethinyl estradiol tablets postpartum, and has not yet had a period, she should be instructed to use another method of contraception until a orange "active" tablet has been taken daily for 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered. If the patient misses one (1) orange "active" tablet in Weeks 1, 2, or 3, the orange "active" tablet should be taken as soon as she remembers. If the patient misses two (2) orange "active" tablets in Week 1 or Week 2, the patient should take two (2) orange "active" tablets the day she remembers and two (2) orange "active" tablets the next day; and then continue taking one (1) orange "active" tablet a day until she finishes the pack. The patient should be instructed to use a back-up method of birth control such as condoms or spermicide if she has sex in the seven (7) days after missing pills. If the patient misses two (2) orange "active" tablets in the third week or misses three (3) or more orange "active" tablets in a row, the patient should throw out the rest of the pack and start a new pack that same day. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills. SUNDAY START When taking desogestrel and ethinyl estradiol tablets, the first orange "active" tablet should be taken on the first Sunday after menstruation begins. If the period begins on Sunday, the first orange "active" tablet is taken on that day. If switching directly from another oral contraceptive, the first orange "active" tablet should be taken on the first Sunday after the last ACTIVE tablet of the previous product. Tablets are taken without interruption as follows: One orange "active" tablet daily for 21 days, then one white "reminder" tablet daily for 7 days. After 28 tablets have been taken, a new course is started and a orange "active" tablet is taken the next day (Sunday). When initiating a Sunday start regimen, another method of contraception should be used until after the first 7 consecutive days of administration. The use of desogestrel and ethinyl estradiol tablets for contraception may be i …

CONTRAINDICATIONS Desogestrel 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 • Known thrombophilic conditions • Cerebral vascular or coronary artery disease (current or history) • Valvular heart disease with complications • Persistent blood pressure values of ≥ 160 mm Hg systolic or ≥ 100 mm Hg diastolic 102 • Diabetes with vascular involvement • Headaches with focal neurological symptoms • Major surgery with prolonged immobilization • 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 • Acute or chronic hepatocellular disease with abnormal liver function • Hepatic adenomas or carcinomas • Known or suspected pregnancy • Hypersensitivity to any component of this product • 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 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: 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. An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS ). • Thrombophlebitis and venous thrombosis with or without embolism • 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: • 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 • Allergic reaction, including rash, urticaria, and angioedema • 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 a causal association has been neither confirmed nor refuted: • Pre-menstrual 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 desogeefig2

8. Drug Interactions Consult the labeling of concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. Effects of Other Drugs on Combined Hormonal Contraceptives Substances decreasing the plasma concentrations of COCs and potentially diminishing the efficacy of COCs: Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of COCs and potentially diminish the effectiveness of CHCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John's wort. Interactions between hormonal contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with CHCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability. Substances increasing the plasma concentrations of COCs: Co-administration of atorvastatin or rosuvastatin and certain COCs containing EE increase AUC values for EE by approximately 20 to 25%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma hormone concentrations. Human immunodeficiency virus (HIV)/ Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir]) /HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]). Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation: Do not co-administer desogestrel and ethinyl estradiol tablets with HCV drug combinations containing ombitasvir/ paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations (see section 5 in WARNINGS ), Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment). Colesevelam: Colesevelam, a bile acid sequestrant, given together with a combination oral hormonal contraceptive, has been shown to significantly decrease the AUC of EE. A drug interaction between the contraceptive and colesevelam was decreased when the two drug products were given 4 hours apart. Effects of Combined Hormonal Contraceptives on Other Drugs COCs containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. COCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, temazepam and lamotrigine. Significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increases with use of COCs.

DESCRIPTION Desogestrel and ethinyl estradiol tablets, USP provide an oral contraceptive regimen of 21 orange tablets each containing 0.15 mg desogestrel (13-ethyl-11-methylene-18,19-dinor-17 alpha-pregn-4-en-20-yn-17-ol), and 0.03 mg ethinyl estradiol (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne-3,17, diol). Each "active" orange tablet with "S3" debossed on one side contains the following inactive ingredients: lactose monohydrate, pregelatinized corn starch, povidone, stearic acid, vitamin E, HPMC/hypromellose, titanium dioxide, macrogol/polyethylene glycol, D&C Yellow #10 Aluminum Lake, FD&C Yellow #6 Aluminium Lake, Iron Oxide Yellow, FD&C Red #40 Aluminum Lake, FD&C Blue #2 Aluminum Lake. Each "inactive" reminder white, biconvex, round tablets with "P" debossed on one side and " N " on the other side contains the following inactive ingredients: titanium dioxide, polydextrose, hypromellose, triacetin, polyethylene glycol, lactose, magnesium stearate, and pregelatinized corn starch. The 21 orange tablets meet USP Dissolution Test 2. image-01

OVERDOSAGE Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. 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 combined oral contraceptives are supported by epidemiological studies which largely utilized oral contraceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg mestranol. 73–78 Effects on menses: ● increased menstrual cycle regularity ● decreased blood loss and decreased incidence of iron deficiency anemia ● decreased incidence of dysmenorrhea Effects related to inhibition of ovulation: ● decreased incidence of functional ovarian cysts ● decreased incidence of ectopic pregnancies Effects from long-term use: ● decreased incidence of fibroadenomas and fibrocystic disease of the breast ● decreased incidence of acute pelvic inflammatory disease ● decreased incidence of endometrial cancer ● decreased incidence of ovarian cancer

HOW SUPPLIED Desogestrel and ethinyl estradiol tablets, USP 0.15 mg/0.03 mg are available in a blister pack (NDC 79929-006-05). The blister pack contains 28 tablets, as follows: 21 light orange, round, biconvex, beveled edged, film coated tablets, debossed with “EY” on one side and “1” on other side containing 0.15 mg desogestrel together with 0.03 mg ethinyl estradiol, and 7 green, round, biconvex, beveled edged, film coated tablets, debossed with “EY” on one side and “2” on other side containing inert ingredients. Desogestrel and ethinyl estradiol tablets USP 0.15 mg/0.03 mg are packaged in a carton containing 3 blister pack. STORAGE Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). ® The brands listed are trademarks of their respective owners.