REFERENCES SECTION.

REFERENCES. 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.Stadel BV. Oral contraceptives and cardiovascular disease. (Pt. 1). Engl Med 1981; 305:612-618.Stadel BV. Oral contraceptives and cardiovascular disease. (Pt. 2). Engl Med 1981; 305:672-677.Adam SA, Thorogood M. Oral contraception and myocardial infarction revisited: the effects of new preparations and prescribing patterns. Br Obstet Gynecol 1981; 88:838-845.Mann JI, Inman WH. Oral contraceptives and death from myocardial infarction. Br Med 1975; 2(5965):245-248.Mann JI, Vessey MP, Thorogood M, Doll R. Myocardial infarction in young women with special reference to oral contraceptive practice. Br Med 1975; 2(5956):241-245.Royal College of General Practitioners Oral Contraception Study: further analyses of mortality in oral contraceptive users. Lancet 1981; 1:541-546.Slone D, Shapiro S, Kaufman DW, Rosenberg L, Miettinen OS, Stolley PD. Risk of myocardial infarction in relation to current and discontinued use of oral contraceptives. Engl Med 1981; 305:420-424.Vessey MP. Female hormones and vascular disease an epidemiological overview. Br Fam Plann 1980; 6(Supplement):1-12.Russell-Briefel RG, Ezzati TM, Fulwood R, Perlman JA, Murphy RS. Cardiovascular risk status and oral contraceptive use, United States, 1976-80. Prevent Med 1986; 15:352-362.Goldbaum GM, Kendrick JS, Hogelin GC, Gentry EM. The relative impact of smoking and oral contraceptive use on women in the United States. JAMA 1987; 258:1339-1342.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.Knopp RH. Arteriosclerosis risk: the roles of oral contraceptives and postmenopausal estrogens. Reprod Med 1986; 31(9) (Supplement):913-921.Krauss RM, Roy S. Mishell DR, Casagrande J, Pike MC. Effects of two low-dose oral contraceptives on serum lipids and lipoproteins: Differential changes in high-density lipoproteins subclasses. Am Obstet 1983; 145:446-452.Wahl P, Walden C, Knopp R, Hoover J, Wallace R, Heiss G, Rifkind B. Effect of estrogen/progestin potency on lipid/lipoprotein cholesterol. Engl Med 1983; 308:862-867.Wynn V, Niththyananthan R. The effect of progestin in combined oral contraceptives on serum lipids with special reference to high density lipoproteins. Am Obstet Gynecol 1982; 142:766-771.Wynn V, Godsland I. Effects of oral contraceptives on carbohydrate metabolism. Reprod Med 1986; 31(9)(Supplement):892-897.La Rosa JC. Atherosclerotic risk factors in cardiovascular disease. J. Reprod Med 1986; 31(9)(Supplement):906-912.Inman WH, Vessey MP. Investigation of death from pulmonary, coronary, and cerebral thrombosis and embolism in women of child-bearing age. Br Med 1968; 2(5599):193-199.Maguire MG, Tonascia J, Sartwell PE, Stolley PD, Tockman MS. Increased risk of thrombosis due to oral contraceptives: further report. Am Epidemiol 1979; 110(2):188-195.Petitti DB, Wingerd J, Pellegrin F, Ramacharan S. Risk of vascular disease in women: smoking, oral contraceptives, noncontraceptive estrogens, and other factors. JAMA 1979; 242:1150-1154.Vessey MP, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. Br Med 1968; 2(5599):199-205.Vessey MP, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. further report. Br Med 1969; 2(5658):651-657.Porter JB, Hunter JR, Danielson DA, Jick H. Stergachis A. Oral contraceptives and non-fatal vascular disease recent experience. Obstet Gynecol 1982; 59(3):299-302.Vessey M, Doll R, Peto R, Johnson B, Wiggins P. long-term follow-up study of women using different methods of contraception: an interim report. Biosocial Sci 1976; 8:375-427.Royal College of General Practitioners: Oral Contraceptives, venous thrombosis, and varicose veins. Royal Coll Gen Pract 1978; 28:393-399.Collaborative Group for the Study of Stroke in Young Women: Oral contraception and increased risk of cerebral ischemia or thrombosis. Engl Med 1973; 288:871-878.Petitti DB, Wingerd J. Use of oral contraceptives, cigarette smoking, and risk of subarachnoid hemorrhage. Lancet 1978; 2:234-236.Inman WH. Oral contraceptives and fatal subarachnoid hemorrhage. Br Med 1979; 2(6203):1468-1470.Collaborative Group for the Study of Stroke in Young Women: Oral Contraceptives and stroke in young women: associated risk factors. JAMA 1975; 231:718-722.Inman WH, Vessey MP, Westerholm B, Engelund A. Thromboembolic disease and the steroidal content of oral contraceptives. report to the Committee on Safety of Drugs. Br Med 1970; 2:203-209.Meade TW, Greenberg G, Thompson SG. Progestogens and cardiovascular reactions associated with oral contraceptives and comparison of the safety of 50- and 35-mcg estrogen preparations. Br Med 1980; 280(6224):1157-1161.Kay CR. Progestogens and arterial disease-evidence from the Royal College of General Practitioners Study. Am Obstet Gynecol 1982; 142:762-765.Royal College of General Practitioners: Incidence of arterial disease among oral contraceptive users. Royal Coll Gen Pract 1983; 33:75-82.Ory HW. Mortality associated with fertility and fertility control: 1983. Family Planning Perspectives 1983; 15:50-56.The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral contraceptive use and the risk of breast cancer. Engl Med 1986; 315:405-411.Pike MC, Henderson BE, Krailo MD, Duke A, Roy S. Breast cancer in young women and use of oral contraceptives: possible modifying effect of formulation and age at use. Lancet 1983; 2:926-929.Paul C, Skegg DG, Spears GFS, Kaldor JM. Oral contraceptives and breast cancer: national study. Br Med 1986; 293:723-725.Miller DR, Rosenberg L, Kaufman DW, Schottenfeld D, Stolley PD, Shapiro S. Breast cancer risk in relation to early oral contraceptive use. Obstet Gynecol 1986; 68:863-868.Olsson H, Olsson ML, Moller TR, Ranstam J, Holm P. Oral contraceptive use and breast cancer in young women in Sweden (letter). Lancet 1985; (8431): 748-749.McPherson K, Vessey M, Neil A, Doll R, Jones L, Roberts M. Early contraceptive use and breast cancer: Results of another case-control study. Br Cancer 1987; 56:653-660.Huggins GR, Zucker PF. Oral contraceptives and neoplasia: 1987 update. Fertil Steril 1987; 47:733-761.McPherson K, Drife JO. The pill and breast cancer: why the uncertainty Br Med 1986; 293:709-710.Shapiro S. Oral contraceptives time to take stock. Engl Med 1987; 315:450-451.Ory H, Naib Z, Conger SB, Hatcher RA, Tyler CW. Contraceptive choice and prevalence of cervical dysplasia and carcinoma in situ. Am Obstet Gynecol 1976; 124:573-577.Vessey MP, Lawless M, McPherson K, Yeates D. Neoplasia of the cervix uteri and contraception: possible adverse effect of the pill. Lancet 1983; 2:930.Brinton LA, Huggins GR, Lehman HF, Malli K, Savitz DA, Trapido E, Rosenthal J, Hoover R. Long term use of oral contraceptives and risk of invasive cervical cancer. Int Cancer 1986; 38:339-344.WHO Collaborative Study of Neoplasia and Steroid Contraceptives: Invasive cervical cancer and combined oral contraceptives. Br Med 1985; 290:961-965.Rooks JB, Ory HW, Ishak KG, Strauss LT, Greenspan JR, Hill AP, Tyler CW. Epidemiology of hepatocellular adenoma: the role of oral contraceptive use. JAMA 1979; 242:644-648.Bein NN, Goldsmith HS. Recurrent massive hemorrhage from benign hepatic tumors secondary to oral contraceptives. Br Surg 1977; 64:433-435.Klatskin G, Hepatic tumors: possible relationship to use of oral contraceptives. Gastroenterology 1977; 73:386-394.Henderson BE, Preston-Martin S, Edmondson HA, Peters RL, Pike MC. Hepatocellular carcinoma and oral contraceptives. Br Cancer 1983; 48:437-440.Neuberger J, Forman D, Doll R, Williams R. Oral contraceptives and hepatocellular carcinoma. Br Med 1986; 292:1355-1357.Forman D, Vincent TJ, Doll R. Cancer of the liver and oral contraceptives. Br Med 1986; 292:1357-1361.Harlap S, Eldor J. Births following oral contraceptive failures. Obstet Gynecol 1980; 55:447-452.Savolainen E, Saksela E, Saxen L. Teratogenic hazards of oral contraceptives analyzed in national malformation register. Am Obstet Gynecol 1981; 140:521-524.Janerich DT, Piper JM, Glebatis DM. Oral contraceptives and birth defects. Am Epidemiol 1980; 112:73-79.Ferencz C, Matanoski GM, Wilson PD, Rubin JD, Neill CA, Gutberlet R. Maternal hormone therapy and congenital heart disease. Teratology 1980; 21:225-239.Rothman KJ, Fyler DC, Goldblatt A, Kreidberg MB. Exogenous hormones and other drug exposures of children with congenital heart disease. Am Epidemiol 1979; 109:433-439.Boston Collaborative Drug Surveillance Program: Oral contraceptives and venous thromboembolic disease, surgically confirmed gallbladder disease, and breast tumors. Lancet 1973; 1:1399-1404.Royal College of General Practitioners: Oral contraceptives and health. New York, Pittman 1974.Layde PM, Vessey MP, Yeates D. Risk of gallbladder disease: cohort study of young women attending family planning clinics. Epidemiol Community Health 1982; 36:274-278.Rome Group for Epidemiology and Prevention of Cholelithiasis (GREPCO): Prevalence of gallstone disease in an Italian adult female population. Am Epidemiol 1984; 119:796-805.Storm BL, Tamragouri RT, Morse ML, Lazar EL, West SL, Stolley PD, Jones JK. Oral contraceptives and other risk factors for gallbladder disease. Clin Pharmacol Ther 1986; 39:335-341.Wynn V, Adams PW, Godsland IF, Melrose J, Niththyananthan R, Oakley NW, Seedj A. Comparison of effects of different combined oral contraceptive formulations on carbohydrate and lipid metabolism. Lancet 1979; 1:1045-1049.Wynn V. Effect of progesterone and progestins on carbohydrate metabolism. In: Progesterone and Progestin. Bardin CW, Milgrom E, Mauvis-Jarvis P. eds. New York, Raven Press 1983; pp. 395-410.Perlman JA, Roussell-Briefel RG, Ezzati TM, Lieberknecht G. Oral glucose tolerance and the potency of oral contraceptive progestogens. Chronic Dis 1985; 38:857-864.Royal College of General Practitioners Oral Contraception Study: Effect on hypertension and benign breast disease of progestogen component in combined oral contraceptives. Lancet 1977; 1:624.Fisch IR, Frank J. Oral contraceptives and blood pressure. JAMA 1977; 237:2499-2503.Laragh AJ. Oral contraceptive induced hypertension nine years later. Am Obstet Gynecol 1976; 126:141-147.Ramcharan S, Peritz E, Pellegrin FA, Williams WT. Incidence of hypertension in the Walnut Creek Contraceptive Drug Study cohort: In: Pharmacology of steroid contraceptive drugs. Garattini S, Berendes HW. Eds. New York, Raven Press, 1977; pp. 277-288, (Monographs of the Mario Negri Institute for Pharmacological Research Milan).Stockley I. Interactions with oral contraceptives. Pharm 1976; 216:140-143.The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral contraceptive use and the risk of ovarian cancer. JAMA 1983; 249:1596-1599.The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Combination oral contraceptive use and the risk of endometrial cancer. JAMA 1987; 257:796-800.Ory HW. Functional ovarian cysts and oral contraceptives: negative association confirmed surgically. JAMA 1974; 228:68-69.Ory HW, Cole P, MacMahon B, Hoover R. Oral contraceptives and reduced risk of benign breast disease. Engl Med 1976; 294:419-422.Ory HW. The noncontraceptive health benefits from oral contraceptive use. Fam Plann Perspect 1982; 14:182-184.Ory HW, Forrest JD, Lincoln R. Making choices: Evaluating the health risks and benefits of birth control methods. New York, The Alan Guttmacher Institute, 1983; p. 1.Schlesselman J, Stadel BV, Murray P, Lai S. Breast cancer in relation to early use of oral contraceptives. JAMA 1988; 259:1828-1833.Hennekens CH, Speizer FE, Lipnick RJ, Rosner B, Bain C, Belanger C, Stampfer MJ, Willett W, Peto R. case-control study of oral contraceptive use and breast cancer. JNCI 1984; 72:39-42.LaVecchia C, Decarli A, Fasoli M, Franceschi S, Gentile A, Negri E, Parazzini F, Tognoni G. Oral contraceptives and cancers of the breast and of the female genital tract. Interim results from case-control study. Br Cancer 1986; 54:311-317.Meirik O, Lund E, Adami H, Bergstrom R, Christoffersen T, Bergsjo P. Oral contraceptive use and breast cancer in young women. Joint National Case-control study in Sweden and Norway. Lancet 1986; 11:650-654.Kay CR, Hannaford PC. Breast cancer and the pill-A further report from the Royal College of General Practitioners oral contraception study. Br Cancer 1988; 58:675-680.Stadel BV, Lai S, Schlesselman JJ, Murray P. Oral contraceptives and premenopausal breast cancer in nulliparous women. Contraception 1988; 38:287-299.Miller DR, Rosenberg L, Kaufman DW, Stolley P, Warshauer ME, Shapiro S. Breast cancer before age 45 and oral contraceptive use: New Findings. Am Epidemiol 1989; 129:269-280.The UK National Case-Control Study Group, Oral contraceptive use and breast cancer risk in young women. Lancet 1989; 1:973-982.Schlesselman JJ. Cancer of the breast and reproductive tract in relation to use of oral contraceptives. Contraception 1989; 40:1-38.Vessey MP, McPherson K, Villard Mackintosh L, Yeates D. Oral contraceptives and breast cancer: latest findings in large cohort study. Br Cancer 1989; 59: 613-617.Jick SS, Walker AM, Stergachis A, Jick H. Oral contraceptives and breast cancer. Br Cancer 1989; 59:618-621.Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Lancet 1996; 347:1713-1727.Palmer JR, Rosenberg L, Kaufman DW, Warshauer ME, Stolley P, Shapiro S. Oral Contraceptive Use and Liver Cancer. Am Epidemiol 1989; 130:878-882.Improving access to quality care in family planning: Medical eligibility criteria for contraceptive use. Geneva, WHO, Family and Reproductive Health, 1996. Bork K, Fischer B, DeWald G. Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy. Am Med 2003;114:294-298. Van Giersbergen PLM, Halabi A, Dingemanse J. Pharmacokinetic interaction between bosentan and the oral contraceptives norethisterone and ethinyl estradiol. Int Clin Pharmacol Ther 2006;44(3):113-118. Christensen J, Petrenaite V, Atterman J, et al. Oral contraceptives induce lamotrigine metabolism: evidence from double-blind, placebo-controlled trial. Epilepsia 2007;48(3):484-489.Chobanian et al. Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 2003;42;1206-1252.Brown KS, Armstrong IC, Wang A, Walker JR, Noveck RJ, Swearingen D, Allison M, Kissling JC, Kisicki J, Salazar D. Effect of the bile acid sequestrant colesevelam on the pharmacokinetics of pioglitazone, repaglinide, estrogen estradiol, norethindrone, levothyroxine, and glyburide. Clin Pharmacol 2010;50:554-565.Teva Pharmaceuticals USA, Inc.North Wales, PA 19454Rev. 12/2021. 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.. Stadel BV. Oral contraceptives and cardiovascular disease. (Pt. 1). Engl Med 1981; 305:612-618.. Stadel BV. Oral contraceptives and cardiovascular disease. (Pt. 2). Engl Med 1981; 305:672-677.. Adam SA, Thorogood M. Oral contraception and myocardial infarction revisited: the effects of new preparations and prescribing patterns. Br Obstet Gynecol 1981; 88:838-845.. Mann JI, Inman WH. Oral contraceptives and death from myocardial infarction. Br Med 1975; 2(5965):245-248.. Mann JI, Vessey MP, Thorogood M, Doll R. Myocardial infarction in young women with special reference to oral contraceptive practice. Br Med 1975; 2(5956):241-245.. Royal College of General Practitioners Oral Contraception Study: further analyses of mortality in oral contraceptive users. Lancet 1981; 1:541-546.. Slone D, Shapiro S, Kaufman DW, Rosenberg L, Miettinen OS, Stolley PD. Risk of myocardial infarction in relation to current and discontinued use of oral contraceptives. Engl Med 1981; 305:420-424.. Vessey MP. Female hormones and vascular disease an epidemiological overview. Br Fam Plann 1980; 6(Supplement):1-12.. Russell-Briefel RG, Ezzati TM, Fulwood R, Perlman JA, Murphy RS. Cardiovascular risk status and oral contraceptive use, United States, 1976-80. Prevent Med 1986; 15:352-362.. Goldbaum GM, Kendrick JS, Hogelin GC, Gentry EM. The relative impact of smoking and oral contraceptive use on women in the United States. JAMA 1987; 258:1339-1342.. 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.. Knopp RH. Arteriosclerosis risk: the roles of oral contraceptives and postmenopausal estrogens. Reprod Med 1986; 31(9) (Supplement):913-921.. Krauss RM, Roy S. Mishell DR, Casagrande J, Pike MC. Effects of two low-dose oral contraceptives on serum lipids and lipoproteins: Differential changes in high-density lipoproteins subclasses. Am Obstet 1983; 145:446-452.. Wahl P, Walden C, Knopp R, Hoover J, Wallace R, Heiss G, Rifkind B. Effect of estrogen/progestin potency on lipid/lipoprotein cholesterol. Engl Med 1983; 308:862-867.. Wynn V, Niththyananthan R. The effect of progestin in combined oral contraceptives on serum lipids with special reference to high density lipoproteins. Am Obstet Gynecol 1982; 142:766-771.. Wynn V, Godsland I. Effects of oral contraceptives on carbohydrate metabolism. Reprod Med 1986; 31(9)(Supplement):892-897.. La Rosa JC. Atherosclerotic risk factors in cardiovascular disease. J. Reprod Med 1986; 31(9)(Supplement):906-912.. Inman WH, Vessey MP. Investigation of death from pulmonary, coronary, and cerebral thrombosis and embolism in women of child-bearing age. Br Med 1968; 2(5599):193-199.. Maguire MG, Tonascia J, Sartwell PE, Stolley PD, Tockman MS. Increased risk of thrombosis due to oral contraceptives: further report. Am Epidemiol 1979; 110(2):188-195.. Petitti DB, Wingerd J, Pellegrin F, Ramacharan S. Risk of vascular disease in women: smoking, oral contraceptives, noncontraceptive estrogens, and other factors. JAMA 1979; 242:1150-1154.. Vessey MP, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. Br Med 1968; 2(5599):199-205.. Vessey MP, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. further report. Br Med 1969; 2(5658):651-657.. Porter JB, Hunter JR, Danielson DA, Jick H. Stergachis A. Oral contraceptives and non-fatal vascular disease recent experience. Obstet Gynecol 1982; 59(3):299-302.. Vessey M, Doll R, Peto R, Johnson B, Wiggins P. long-term follow-up study of women using different methods of contraception: an interim report. Biosocial Sci 1976; 8:375-427.. Royal College of General Practitioners: Oral Contraceptives, venous thrombosis, and varicose veins. Royal Coll Gen Pract 1978; 28:393-399.. Collaborative Group for the Study of Stroke in Young Women: Oral contraception and increased risk of cerebral ischemia or thrombosis. Engl Med 1973; 288:871-878.. Petitti DB, Wingerd J. Use of oral contraceptives, cigarette smoking, and risk of subarachnoid hemorrhage. Lancet 1978; 2:234-236.. Inman WH. Oral contraceptives and fatal subarachnoid hemorrhage. Br Med 1979; 2(6203):1468-1470.. Collaborative Group for the Study of Stroke in Young Women: Oral Contraceptives and stroke in young women: associated risk factors. JAMA 1975; 231:718-722.. Inman WH, Vessey MP, Westerholm B, Engelund A. Thromboembolic disease and the steroidal content of oral contraceptives. report to the Committee on Safety of Drugs. Br Med 1970; 2:203-209.. Meade TW, Greenberg G, Thompson SG. Progestogens and cardiovascular reactions associated with oral contraceptives and comparison of the safety of 50- and 35-mcg estrogen preparations. Br Med 1980; 280(6224):1157-1161.. Kay CR. Progestogens and arterial disease-evidence from the Royal College of General Practitioners Study. Am Obstet Gynecol 1982; 142:762-765.. Royal College of General Practitioners: Incidence of arterial disease among oral contraceptive users. Royal Coll Gen Pract 1983; 33:75-82.. Ory HW. Mortality associated with fertility and fertility control: 1983. Family Planning Perspectives 1983; 15:50-56.. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral contraceptive use and the risk of breast cancer. Engl Med 1986; 315:405-411.. Pike MC, Henderson BE, Krailo MD, Duke A, Roy S. Breast cancer in young women and use of oral contraceptives: possible modifying effect of formulation and age at use. Lancet 1983; 2:926-929.. Paul C, Skegg DG, Spears GFS, Kaldor JM. Oral contraceptives and breast cancer: national study. Br Med 1986; 293:723-725.. Miller DR, Rosenberg L, Kaufman DW, Schottenfeld D, Stolley PD, Shapiro S. Breast cancer risk in relation to early oral contraceptive use. Obstet Gynecol 1986; 68:863-868.. Olsson H, Olsson ML, Moller TR, Ranstam J, Holm P. Oral contraceptive use and breast cancer in young women in Sweden (letter). Lancet 1985; (8431): 748-749.. McPherson K, Vessey M, Neil A, Doll R, Jones L, Roberts M. Early contraceptive use and breast cancer: Results of another case-control study. Br Cancer 1987; 56:653-660.. Huggins GR, Zucker PF. Oral contraceptives and neoplasia: 1987 update. Fertil Steril 1987; 47:733-761.. McPherson K, Drife JO. The pill and breast cancer: why the uncertainty Br Med 1986; 293:709-710.. Shapiro S. Oral contraceptives time to take stock. Engl Med 1987; 315:450-451.. Ory H, Naib Z, Conger SB, Hatcher RA, Tyler CW. Contraceptive choice and prevalence of cervical dysplasia and carcinoma in situ. Am Obstet Gynecol 1976; 124:573-577.. Vessey MP, Lawless M, McPherson K, Yeates D. Neoplasia of the cervix uteri and contraception: possible adverse effect of the pill. Lancet 1983; 2:930.. Brinton LA, Huggins GR, Lehman HF, Malli K, Savitz DA, Trapido E, Rosenthal J, Hoover R. Long term use of oral contraceptives and risk of invasive cervical cancer. Int Cancer 1986; 38:339-344.. WHO Collaborative Study of Neoplasia and Steroid Contraceptives: Invasive cervical cancer and combined oral contraceptives. Br Med 1985; 290:961-965.. Rooks JB, Ory HW, Ishak KG, Strauss LT, Greenspan JR, Hill AP, Tyler CW. Epidemiology of hepatocellular adenoma: the role of oral contraceptive use. JAMA 1979; 242:644-648.. Bein NN, Goldsmith HS. Recurrent massive hemorrhage from benign hepatic tumors secondary to oral contraceptives. Br Surg 1977; 64:433-435.. Klatskin G, Hepatic tumors: possible relationship to use of oral contraceptives. Gastroenterology 1977; 73:386-394.. Henderson BE, Preston-Martin S, Edmondson HA, Peters RL, Pike MC. Hepatocellular carcinoma and oral contraceptives. Br Cancer 1983; 48:437-440.. Neuberger J, Forman D, Doll R, Williams R. Oral contraceptives and hepatocellular carcinoma. Br Med 1986; 292:1355-1357.. Forman D, Vincent TJ, Doll R. Cancer of the liver and oral contraceptives. Br Med 1986; 292:1357-1361.. Harlap S, Eldor J. Births following oral contraceptive failures. Obstet Gynecol 1980; 55:447-452.. Savolainen E, Saksela E, Saxen L. Teratogenic hazards of oral contraceptives analyzed in national malformation register. Am Obstet Gynecol 1981; 140:521-524.. Janerich DT, Piper JM, Glebatis DM. Oral contraceptives and birth defects. Am Epidemiol 1980; 112:73-79.. Ferencz C, Matanoski GM, Wilson PD, Rubin JD, Neill CA, Gutberlet R. Maternal hormone therapy and congenital heart disease. Teratology 1980; 21:225-239.. Rothman KJ, Fyler DC, Goldblatt A, Kreidberg MB. Exogenous hormones and other drug exposures of children with congenital heart disease. Am Epidemiol 1979; 109:433-439.. Boston Collaborative Drug Surveillance Program: Oral contraceptives and venous thromboembolic disease, surgically confirmed gallbladder disease, and breast tumors. Lancet 1973; 1:1399-1404.. Royal College of General Practitioners: Oral contraceptives and health. New York, Pittman 1974.. Layde PM, Vessey MP, Yeates D. Risk of gallbladder disease: cohort study of young women attending family planning clinics. Epidemiol Community Health 1982; 36:274-278.. Rome Group for Epidemiology and Prevention of Cholelithiasis (GREPCO): Prevalence of gallstone disease in an Italian adult female population. Am Epidemiol 1984; 119:796-805.. Storm BL, Tamragouri RT, Morse ML, Lazar EL, West SL, Stolley PD, Jones JK. Oral contraceptives and other risk factors for gallbladder disease. Clin Pharmacol Ther 1986; 39:335-341.. Wynn V, Adams PW, Godsland IF, Melrose J, Niththyananthan R, Oakley NW, Seedj A. Comparison of effects of different combined oral contraceptive formulations on carbohydrate and lipid metabolism. Lancet 1979; 1:1045-1049.. Wynn V. Effect of progesterone and progestins on carbohydrate metabolism. In: Progesterone and Progestin. Bardin CW, Milgrom E, Mauvis-Jarvis P. eds. New York, Raven Press 1983; pp. 395-410.. Perlman JA, Roussell-Briefel RG, Ezzati TM, Lieberknecht G. Oral glucose tolerance and the potency of oral contraceptive progestogens. Chronic Dis 1985; 38:857-864.. Royal College of General Practitioners Oral Contraception Study: Effect on hypertension and benign breast disease of progestogen component in combined oral contraceptives. Lancet 1977; 1:624.. Fisch IR, Frank J. Oral contraceptives and blood pressure. JAMA 1977; 237:2499-2503.. Laragh AJ. Oral contraceptive induced hypertension nine years later. Am Obstet Gynecol 1976; 126:141-147.. Ramcharan S, Peritz E, Pellegrin FA, Williams WT. Incidence of hypertension in the Walnut Creek Contraceptive Drug Study cohort: In: Pharmacology of steroid contraceptive drugs. Garattini S, Berendes HW. Eds. New York, Raven Press, 1977; pp. 277-288, (Monographs of the Mario Negri Institute for Pharmacological Research Milan).. Stockley I. Interactions with oral contraceptives. Pharm 1976; 216:140-143.. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral contraceptive use and the risk of ovarian cancer. JAMA 1983; 249:1596-1599.. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Combination oral contraceptive use and the risk of endometrial cancer. JAMA 1987; 257:796-800.. Ory HW. Functional ovarian cysts and oral contraceptives: negative association confirmed surgically. JAMA 1974; 228:68-69.. Ory HW, Cole P, MacMahon B, Hoover R. Oral contraceptives and reduced risk of benign breast disease. Engl Med 1976; 294:419-422.. Ory HW. The noncontraceptive health benefits from oral contraceptive use. Fam Plann Perspect 1982; 14:182-184.. Ory HW, Forrest JD, Lincoln R. Making choices: Evaluating the health risks and benefits of birth control methods. New York, The Alan Guttmacher Institute, 1983; p. 1.. Schlesselman J, Stadel BV, Murray P, Lai S. Breast cancer in relation to early use of oral contraceptives. JAMA 1988; 259:1828-1833.. Hennekens CH, Speizer FE, Lipnick RJ, Rosner B, Bain C, Belanger C, Stampfer MJ, Willett W, Peto R. case-control study of oral contraceptive use and breast cancer. JNCI 1984; 72:39-42.. LaVecchia C, Decarli A, Fasoli M, Franceschi S, Gentile A, Negri E, Parazzini F, Tognoni G. Oral contraceptives and cancers of the breast and of the female genital tract. Interim results from case-control study. Br Cancer 1986; 54:311-317.. Meirik O, Lund E, Adami H, Bergstrom R, Christoffersen T, Bergsjo P. Oral contraceptive use and breast cancer in young women. Joint National Case-control study in Sweden and Norway. Lancet 1986; 11:650-654.. Kay CR, Hannaford PC. Breast cancer and the pill-A further report from the Royal College of General Practitioners oral contraception study. Br Cancer 1988; 58:675-680.. Stadel BV, Lai S, Schlesselman JJ, Murray P. Oral contraceptives and premenopausal breast cancer in nulliparous women. Contraception 1988; 38:287-299.. Miller DR, Rosenberg L, Kaufman DW, Stolley P, Warshauer ME, Shapiro S. Breast cancer before age 45 and oral contraceptive use: New Findings. Am Epidemiol 1989; 129:269-280.. The UK National Case-Control Study Group, Oral contraceptive use and breast cancer risk in young women. Lancet 1989; 1:973-982.. Schlesselman JJ. Cancer of the breast and reproductive tract in relation to use of oral contraceptives. Contraception 1989; 40:1-38.. Vessey MP, McPherson K, Villard Mackintosh L, Yeates D. Oral contraceptives and breast cancer: latest findings in large cohort study. Br Cancer 1989; 59: 613-617.. Jick SS, Walker AM, Stergachis A, Jick H. Oral contraceptives and breast cancer. Br Cancer 1989; 59:618-621.. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Lancet 1996; 347:1713-1727.. Palmer JR, Rosenberg L, Kaufman DW, Warshauer ME, Stolley P, Shapiro S. Oral Contraceptive Use and Liver Cancer. Am Epidemiol 1989; 130:878-882.. Improving access to quality care in family planning: Medical eligibility criteria for contraceptive use. Geneva, WHO, Family and Reproductive Health, 1996. Bork K, Fischer B, DeWald G. Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy. Am Med 2003;114:294-298. Van Giersbergen PLM, Halabi A, Dingemanse J. Pharmacokinetic interaction between bosentan and the oral contraceptives norethisterone and ethinyl estradiol. Int Clin Pharmacol Ther 2006;44(3):113-118. Christensen J, Petrenaite V, Atterman J, et al. Oral contraceptives induce lamotrigine metabolism: evidence from double-blind, placebo-controlled trial. Epilepsia 2007;48(3):484-489.. Chobanian et al. Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 2003;42;1206-1252.. Brown KS, Armstrong IC, Wang A, Walker JR, Noveck RJ, Swearingen D, Allison M, Kissling JC, Kisicki J, Salazar D. Effect of the bile acid sequestrant colesevelam on the pharmacokinetics of pioglitazone, repaglinide, estrogen estradiol, norethindrone, levothyroxine, and glyburide. Clin Pharmacol 2010;50:554-565.

SPL PATIENT PACKAGE INSERT SECTION.

BRIEF SUMMARY PATIENT PACKAGE INSERT. Oral contraceptives, also known as birth control pills or the pill, are taken to prevent pregnancy and when taken correctly without missing any pills, have failure rate of approximately 1% per year. The typical failure rate is approximately 5% per year when women who miss pills are included. For most women oral contraceptives are also free of serious or unpleasant side effects. However, forgetting to take pills considerably increases the chances of pregnancy.For the majority of women, oral contraceptives can be taken safely. But there are some women who are at high risk of developing certain serious diseases that can be fatal or may cause temporary or permanent disability. The risks associated with taking oral contraceptives increase significantly if you:smokehave high blood pressure, diabetes, high cholesterolhave or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast or sex organs, jaundice or malignant or benign liver tumors.Although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy, non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women.You should not take the pill if you suspect you are pregnant or have unexplained vaginal bleeding.Do not use Nortrel(R) 0.5/35 and 1/35 if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects (heart and blood vessel problems) from combination oral contraceptives, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke.Most side effects of the pill are not serious. The most common such effects are nausea, vomiting, bleeding between menstrual periods, weight gain, breast tenderness, and difficulty wearing contact lenses. These side effects, especially nausea and vomiting, may subside within the first three months of use.The serious side effects of the pill occur very infrequently, especially if you are in good health and are young. However, you should know that the following medical conditions have been associated with or made worse by the pill:Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), stoppage or rupture of blood vessel in the brain (stroke), blockage of blood vessels in the heart (heart attack or angina pectoris) or other organs of the body. As mentioned above, smoking increases the risk of heart attacks and strokes and subsequent serious medical consequences.In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, some studies report an increased risk of developing liver cancer. However, liver cancers are rare.High blood pressure, although blood pressure usually returns to normal when the pill is stopped.The symptoms associated with these serious side effects are discussed in the detailed leaflet given to you with your supply of pills. Notify your healthcare professional if you notice any unusual physical disturbances while taking the pill. In addition, drugs such as rifampin, bosentan, as well as some seizure medicines and herbal preparations containing St. Johns wort (Hypericum perforatum) may decrease oral contraceptive effectiveness.Oral contraceptives may interact with lamotrigine (LAMICTAL(R)), seizure medicine used for epilepsy. This may increase the risk of seizures so your healthcare professional may need to adjust the dose of lamotrigine.There may be slight increases in the risk of breast cancer among current users of hormonal birth control pills with longer duration of use of years or more. Some studies have found an increase in the incidence of cancer of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives. There is insufficient evidence to rule out the possibility that the pill may cause such cancers.Taking the combination pill provides some important non-contraceptive benefits. These include less painful menstruation, less menstrual blood loss and anemia, fewer pelvic infections, and fewer cancers of the ovary and the lining of the uterus.Be sure to discuss any medical condition you may have with your healthcare professional. Your healthcare professional will take medical and family history before prescribing oral contraceptives and will examine you. The physical examination may be delayed to another time if you request it and the healthcare professional believes that it is good medical practice to postpone it. You should be reexamined at least once year while taking oral contraceptives. Your pharmacist should have given you the detailed patient information labeling which gives you further information which you should read and discuss with your healthcare professional.This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.HOW TO TAKE THE PILLIMPORTANT POINTS TO REMEMBERBEFORE YOU START TAKING YOUR PILLS:BE SURE TO READ THESE DIRECTIONS:Before you start taking your pills.Anytime you are not sure what to do.THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME.If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant.MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesnt go away, check with your healthcare professional.MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills.On the days you take pills to make up for missed pills, you could also feel little sick to your stomach.IF YOU HAVE VOMITING OR DIARRHEA, or IF YOU TAKE SOME MEDICINES, your pills may not work as well. Use back-up method (such as condom or spermicide) until you check with your healthcare professional.IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your healthcare professional about how to make pill-taking easier or about using another method of birth control.IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your healthcare professional.BEFORE YOU START TAKING YOUR PILLSDECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.It is important to take it at about the same time every day.LOOK AT YOUR PILL PACK TO SEE IF IT HAS 21 OR 28 PILLS.The 21-pill pack has 21 active pills (with hormones) to take for weeks. This is followed by week without pills. The 28-pill pack has 21 active pills (with hormones) to take for weeks. This is followed by week of white reminder pills (without hormones). Nortrel 1/35 (norethindrone and ethinyl estradiol tablets): There are 21 yellow active pills. Nortrel 0.5/35 (norethindrone and ethinyl estradiol tablets): There are 21 light yellow active pills.ALSO FIND: 1) where on the pack to start taking pills, 2) in what order to take the pills. CHECK ADDITIONAL INSTRUCTIONS FOR USING THIS PACKAGE IN THE BRIEF SUMMARY PATIENT PACKAGE INSERT.BE SURE YOU HAVE READY AT ALL TIMES:ANOTHER KIND OF BIRTH CONTROL (such as condom or spermicide) to use as back-up method in case you miss pills.AN EXTRA, FULL PILL PACK.WHEN TO START THE FIRST PACK OF PILLSYou have choice of which day to start taking your first pack of pills. Nortrel 1/35 and 0.5/35 (norethindrone and ethinyl estradiol tablets) are available in the Blister Pack Tablet Dispenser which is preset for Sunday Start. Day Start is also provided. Decide with your healthcare professional which is the best day for you. Pick time of day which will be easy to remember.SUNDAY START:Nortrel 1/35 (norethindrone and ethinyl estradiol tablets): Take the first yellow active pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack the same day.Nortrel 0.5/35 (norethindrone and ethinyl estradiol tablets): Take the first light yellow active pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack the same day.Use another method of birth control such as condom or spermicide as back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). DAY START:Nortrel 1/35 (norethindrone and ethinyl estradiol tablets): Take the first yellow active pill of the first pack during the first 24 hours of your period.Nortrel 0.5/35 (norethindrone and ethinyl estradiol tablets): Take the first light yellow active pill of the first pack during the first 24 hours of your period.You will not need to use back-up method of birth control, since you are starting the pill at the beginning of your period.WHAT TO DO DURING THE MONTHTAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY.Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). Do not skip pills even if you do not have sex very often.WHEN YOU FINISH PACK OR SWITCH YOUR BRAND OF PILLS:21 pills: Wait days to start the next pack. You will probably have your period during that week. Be sure that no more than days pass between 21-day packs.28 pills: Start the next pack on the day after your last white reminder pill. Do not wait any days between packs.WHAT TO DO IF YOU MISS PILLSNortrel 1/35 (norethindrone and ethinyl estradiol tablets):If you MISS yellow active pill:Take it as soon as you remember. Take the next pill at your regular time. This means you may take pills in day.You do not need to use back-up birth control method if you have sex.If you MISS yellow active pills in row in WEEK OR WEEK of your pack:Take pills on the day you remember and pills the next day.Then take pill day until you finish the pack.You COULD BECOME PREGNANT if you have sex in the days after you miss pills. You MUST use another birth control method (such as condom or spermicide) as back-up method for those days.If you MISS yellow active pills in row in THE 3RD WEEK:1a. If you are Sunday Starter: Keep taking pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start new pack of pills that same day.1b. If you are Day Starter: THROW OUT the rest of the pill pack and start new pack that same day.2. You may not have your period this month but this is expected. However, if you miss your period months in row, call your healthcare professional because you might be pregnant.3. You COULD BECOME PREGNANT if you have sex in the days after you miss pills. You MUST use another birth control method (such as condom or spermicide) as back-up method for those days.If you MISS OR MORE yellow active pills in row (during the first weeks):1a. If you are Sunday Starter: Keep taking pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start new pack of pills that same day.1b. If you are Day Starter: THROW OUT the rest of the pill pack and start new pack that same day.2. You may not have your period this month but this is expected. However, if you miss your period months in row, call your doctor or clinic because you might be pregnant.3. You COULD BECOME PREGNANT if you have sex in the days after you miss pills. You MUST use another birth control method (such as condom or spermicide) as back-up method for those days.Nortrel 0.5/35 (norethindrone and ethinyl estradiol tablets):If you MISS light yellow active pill:Take it as soon as you remember. Take the next pill at your regular time. This means you may take pills in day.You do not need to use back-up birth control method if you have sex.If you MISS light yellow active pills in row in WEEK OR WEEK of your pack:Take pills on the day you remember and pills the next day.Then take pill day until you finish the pack.You COULD BECOME PREGNANT if you have sex in the days after you miss pills. You MUST use another birth control method (such as condom or spermicide) as back-up method for those days.If you MISS light yellow active pills in row in THE 3RD WEEK:1a. If you are Sunday Starter: Keep taking pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start new pack of pills that same day.1b. If you are Day Starter: THROW OUT the rest of the pill pack and start new pack that same day.2. You may not have your period this month but this is expected. However, if you miss your period months in row, call your healthcare professional because you might be pregnant.3. You COULD BECOME PREGNANT if you have sex in the days after you miss pills. You MUST use another birth control method (such as condom or spermicide) as back-up method for those days.If you MISS OR MORE light yellow active pills in row (during the first weeks):1a. If you are Sunday Starter: Keep taking pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start new pack of pills that same day.1b. If you are Day Starter: THROW OUT the rest of the pill pack and start new pack that same day.2. You may not have your period this month but this is expected. However, if you miss your period months in row, call your healthcare professional because you might be pregnant.3. You COULD BECOME PREGNANT if you have sex in the days after you miss pills. You MUST use another birth control method (such as condom or spermicide) as back-up method for those days.A REMINDER FOR THOSE ON 28-DAY PACKSIf you forget any of the white reminder pills in Week 4: THROW AWAY the pills you missed. Keep taking pill each day until the pack is empty. You do not need back-up method.FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED:Use BACK-UP METHOD anytime you have sex.KEEP TAKING ONE ACTIVE PILL EACH DAY until you can reach your healthcare professional.How to Use the Blister Cards for the 21 TabletsThe blister pack comes to you set up for Sunday Start. If your healthcare professional has instructed you to start pill-taking on the SUNDAY after your menstrual period has begun, or if your period begins on Sunday you will take your first pill that very same day. Start with the Sunday pill in row 1. After the Saturday pill has been taken, begin taking the pills in row 2, and so on, until all 21 pills have been taken. You will then take no pills for one week (seven days).If you start pill-taking on day other than SUNDAY, peel the attached sticker by selecting the day of the week you plan to start. Place the sticker over the pre-printed days of the week and make sure it lines up with the pills. This sticker will help to remind you to take your pill every day. Take the yellow pill which corresponds to the day in row for the 1/35 day regimen of the first pack during the first 24 hours of your period.After the last (Saturday) pill in row has been taken, if any remain in the first row, complete your 21-pill schedule by taking one pill daily starting with Sunday in row until all the pills have been taken.When you start taking the pill for the first time, use an additional method of protection until you have taken your first pills.Your tablet dispenser consists of three parts, the foil pouch, wallet, and blister pack containing 21 individually sealed pills. Note that the pills are arranged in three numbered rows of pills each with the days of the week printed above them. All 21 pills are active birth control pills.You must take your pills in order, one pill each day at intervals of 24 hours. To remove pill, push down on the pill with your thumb and forefinger so that the pill releases through the back of the dispenser. See diagram below: Note: Rows 1, and are active pills. Proceed taking one pill each day until all pills have been taken.After you have taken your last pill, wait for days. During this time your period should begin. On the eighth day, start new pack of pills even if your period is not yet over. How to Use the Blister Cards for the 28 TabletsThe blister card comes to you set up for Sunday Start. If your healthcare professional has instructed you to start pill-taking on the SUNDAY after your menstrual period has begun or if your period begins on Sunday you will take your first pill that very same day. Start with the Sunday pill in row 1. Take one active pill daily for 21 days followed by one white placebo pill daily for days.If you start pill-taking on day other than SUNDAY, peel the attached sticker by selecting the day of the week you plan to start. Place the sticker over the pre-printed days of the week and make sure it lines up with the pills. This sticker will help to remind you to take your pill every day. Take the yellow pill which corresponds to the day in row for both the 1/35 day regimen and the 0.5/35 day regimen of the first pack during the first 24 hours of your period. After taking all of the pills at the end of row 3, go back to row and complete the active pills. Once all of the active pills have been taken, proceed to row and take the reminder pills to complete the pack.When you start taking the pill for the first time, use an additional method of protection until you have taken your first pills.Your tablet dispenser consists of three parts, the foil pouch, wallet, and blister pack containing 28 individually sealed pills. Note that the pills are arranged in four numbered rows of pills each with the days of the week printed above them. The 21 colored pills are active birth control pills. The white pills are inactive; their purpose is to help make your pill-taking schedule simple and easy to remember.You must take your pills in order, one pill each day at intervals of 24 hours. Always start with the colored pills in row 1. To remove pill, push down on the pill with your thumb and forefinger so that the pill releases through the back of the dispenser. See diagram below: Note: Rows 1, and are active pills and row contains the reminder pills.After you have taken all 21 pills, take one white pill daily for days: During this time your period should begin.After you have taken all of the pills, start new pack of pills even if your period is not yet over.THREE WAYS TO REMEMBER IN WHAT ORDER TO TAKE THE PILLSFollow the sticker with the days of the week (placed above the pills).Always go from left to right.Always finish your pills.DETAILED PATIENT LABELINGPLEASE NOTE: This labeling is revised from time to time as important new medical information becomes available. Therefore, please review this labeling carefully.The following oral contraceptive products contain combination of an estrogen and progestogen, the two kinds of female hormones:Nortrel 1/35(R) (norethindrone and ethinyl estradiol tablets) (21) Day Regimen and (28) Day Regimen:Each yellow tablet contains mg norethindrone and 0.035 mg ethinyl estradiol. Each white tablet in the 1/35 (28) day regimen contains inert ingredients.Nortrel 0.5/35(R) (norethindrone and ethinyl estradiol tablets) (28) Day Regimen:Each light yellow tablet contains 0.5 mg norethindrone and 0.035 mg ethinyl estradiol. Each white tablet in the 0.5/35 mg (28) day regimen contains inert ingredients.INTRODUCTIONAny woman who considers using oral contraceptives (the birth control pill or the pill) should understand the benefits and risks of using this form of birth control. This patient labeling will give you much of the information you will need to make this decision and will also help you determine if you are at risk of developing any of the serious side effects of the pill. It will tell you how to use the pill properly so that it will be as effective as possible. However, this labeling is not replacement for careful discussion between you and your healthcare professional. You should discuss the information provided in this labeling with him or her, both when you first start taking the pill and during your revisits. You should also follow your healthcare professionals advice with regard to regular check-ups while you are on the pill.EFFECTIVENESS OF ORAL CONTRACEPTIVESOral contraceptives or birth control pills or the pill are used to prevent pregnancy and are more effective than other non-surgical methods of birth control. When they are taken correctly, without missing any pills, the chance of becoming pregnant is approximately 1% (1 pregnancy per 100 women per year of use). Typical failure rates are approximately 5% per year including women who do not always take the pills exactly as directed. The chance of becoming pregnant increases with each missed pill during menstrual cycle.In comparison, typical failure rates for other methods of birth control during the first year of use are as follows:Implant: 1%Male sterilization: <1%Injection: 1%Cervical Cap with spermicides: 20 to 40%IUD: to 2%Condom alone (male): 14%Diaphragm with spermicides: 20%Condom alone (female): 21%Spermicides alone: 26%Periodic abstinence: 25%Vaginal sponge: 20 to 40%Withdrawal: 19%Female sterilization: <1%No methods: 85%WHO SHOULD NOT TAKE ORAL CONTRACEPTIVESDo not use Nortrel(R) 0.5/35 and 1/35 if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects (heart and blood vessel problems) from combination oral contraceptives, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke.Some women should not use the pill. For example, you should not take the pill if you have any of the following conditions:A history of heart attack or strokeBlood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyesA history of blood clots in the deep veins of your legsAn inherited problem that makes your blood clot more than normalChest pain (angina pectoris)Known or suspected breast cancer or cancer of the lining of the uterus, cervix or vagina Unexplained vaginal bleeding (until diagnosis is reached by your healthcare professional)Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or during previous use of the pillLiver tumor (benign or cancerous)Take any Hepatitis drug combination containing ombitasvir/paritaprevir/ ritonavir, with or without dasabuvir. This may increase levels of the liver enzyme alanine aminotransferase (ALT) in the blood.Known or suspected pregnancyValvular heart disease with complicationsSevere hypertensionDiabetes with vascular involvementHeadaches with focal neurological symptomsIf you plan to have surgery with prolonged bed restHypersensitivity to any component of this product.Tell your healthcare professional if you have ever had any of these conditions. Your healthcare professional can recommend safer method of birth control.OTHER CONSIDERATIONS BEFORE TAKING ORAL CONTRACEPTIVESTell your healthcare professional if you have or have had:Breast nodules, fibrocystic disease of the breast, an abnormal breast x-ray or mammogramDiabetesElevated cholesterol or triglyceridesHigh blood pressureMigraine or other headaches or epilepsyMental depressionGallbladder, liver, heart or kidney diseaseHistory of scanty or irregular menstrual periodsWomen with any of these conditions should be checked often by their healthcare professional if they choose to use oral contraceptives.Also, be sure to inform your healthcare professional if you smoke or are on any medications.RISKS OF TAKING ORAL CONTRACEPTIVES1. Risk of developing blood clotsBlood clots and blockage of blood vessels are one of the most serious side effects of taking oral contraceptives and can cause death or serious disability. Serious blood clots can happen especially if you smoke, are obese, or are older than 35 years of age. Serious blood clots are more likely to happen when you: First start taking birth control pillsRestart the same or different birth control pills after not using them for month or more In particular, clot in the legs can cause thrombophlebitis and clot that travels to the lungs can cause sudden blocking of the vessel carrying blood to the lungs. Rarely, clots occur in the blood vessels of the eye and may cause blindness, double vision, or impaired vision.If you take oral contraceptives and need elective surgery, need to stay in bed for prolonged illness or injury or have recently delivered baby, you may be at risk of developing blood clots. You should consult your healthcare professional about stopping oral contraceptives three to four weeks before surgery and not taking oral contraceptives for two weeks after surgery or during bed rest. You should also not take oral contraceptives soon after delivery of baby. It is advisable to wait for at least four weeks after delivery if you are not breastfeeding or four weeks after second trimester abortion. If you are breastfeeding, you should wait until you have weaned your child before using the pill. (See also the section on Breastfeeding in General Precautions.)The risk of circulatory disease in oral contraceptive users may be higher in users of high-dose pills and may be greater with longer duration of oral contraceptive use. In addition, some of these increased risks may continue for number of years after stopping oral contraceptives. The risk of abnormal blood clotting increases with age in both users and nonusers of oral contraceptives, but the increased risk from the oral contraceptive appears to be present at all ages. For women aged 20 to 44, it is estimated that about in 2,000 using oral contraceptives will be hospitalized each year because of abnormal clotting. Among nonusers in the same age group, about in 20,000 would be hospitalized each year. For oral contraceptive users in general, it has been estimated that in women between the ages of 15 and 34 the risk of death due to circulatory disorder is about in 12,000 per year, whereas for nonusers the rate is about in 50,000 per year. In the age group 35 to 44, the risk is estimated to be about in 2,500 per year for oral contraceptive users and about in 10,000 per year for nonusers.2. Heart attacks and strokesOral contraceptives may increase the tendency to develop strokes (stoppage or rupture of blood vessels in the brain) and angina pectoris and heart attacks (blockage of blood vessels in the heart). Any of these conditions can cause death or serious disability.Smoking greatly increases the possibility of suffering heart attacks and strokes. Furthermore, smoking and the use of oral contraceptives greatly increase the chances of developing and dying of heart disease.3. Gallbladder diseaseOral contraceptive users probably have greater risk than nonusers of having gallbladder disease, although this risk may be related to pills containing high doses of estrogens.4. Liver tumorsIn rare cases, oral contraceptives can cause benign but dangerous liver tumors. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, some studies report an increased risk of developing liver cancer. However, liver cancers are rare.5. Risk of CancerIt is not known if hormonal birth control pills causes breast cancer. Some studies, but not all, suggest that there could be slight increase in the risk of breast cancer among current users with longer duration of use.If you have breast cancer now, or have had it in the past, do not use hormonal birth control because some breast cancers are sensitive to hormones.Some studies have found an increase in the incidence of cancer of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives. There is insufficient evidence to rule out the possibility that the pill may cause such cancers.ESTIMATED RISK OF DEATH FROM BIRTH CONTROL METHOD OR PREGNANCYAll methods of birth control and pregnancy are associated with risk of developing certain diseases which may lead to disability or death. An estimate of the number of deaths associated with different methods of birth control and pregnancy has been calculated and is shown in the following table.ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY CONTROL METHOD ACCORDING TO AGEMethod of control and outcome 15-19 20-24 25-29 30-34 35-39 40-44No fertility control methods1 7.07.4 9.1 14.8 25.7 28.2Oral contraceptives non-smoker2 0.3 0.5 0.9 1.9 13.8 31.6Oral contraceptives smoker2 2.2 3.4 6.6 13.5 51.1 117.2IUD2 0.8 0.8 1.0 1.0 1.4 1.4Condom1 1.1 1.6 0.7 0.2 0.3 0.4Diaphragm/spermicide1 1.9 1.2 1.2 1.3 2.2 2.8Periodic abstinence1 2.5 1.6 1.6 1.7 2.9 3.61. Deaths are birth-related2. Deaths are method-relatedIn the above table, the risk of death from any birth control method is less than the risk of childbirth, except for oral contraceptive users over the age of 35 who smoke and pill users over the age of 40 even if they do not smoke. It can be seen in the table that for women aged 15 to 39, the risk of death was highest with pregnancy (7-26 deaths per 100,000 women, depending on age). Among pill users who do not smoke, the risk of death was always lower than that associated with pregnancy for any age group, although over the age of 40, the risk increases to 32 deaths per 100,000 women, compared to 28 associated with pregnancy at that age. However, for pill users who smoke and are over the age of 35, the estimated number of deaths exceeds those for other methods of birth control. If woman is over the age of 40 and smokes, her estimated risk of death is four times higher (117/100,000 women) than the estimated risk associated with pregnancy (28/100,000 women) in that age group.The suggestion that women over 40 who do not smoke should not take oral contraceptives is based on information from older, higher dose pills. An Advisory Committee of the FDA discussed this issue in 1989 and recommended that the benefits of low dose oral contraceptive use by healthy, non-smoking women over 40 years of age may outweigh the possible risks.WARNING SIGNALSIf any of these adverse effects occur while you are taking oral contraceptives, call your healthcare professional immediately:Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating possible clot in the lung)Pain in the calf (indicating possible clot in the leg)Crushing chest pain or heaviness in the chest (indicating possible heart attack)Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating possible stroke)Sudden partial or complete loss of vision (indicating possible clot in the eye)Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your healthcare professional to show you how to examine your breasts)Severe pain or tenderness in the stomach area (indicating possibly ruptured liver tumor)Difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood (possibly indicating severe depression)Jaundice or yellowing of the skin or eyeballs, accompanied frequently by fever, fatigue, loss of appetite, dark colored urine, or light colored bowel movements (indicating possible liver problems)SIDE EFFECTS OF ORAL CONTRACEPTIVES1. Vaginal bleedingIrregular vaginal bleeding or spotting may occur while you are taking the pills. Irregular bleeding may vary from slight staining between menstrual periods to breakthrough bleeding which is flow much like regular period. Irregular bleeding occurs most often during the first few months of oral contraceptive use, but may also occur after you have been taking the pill for some time. Such bleeding may be temporary and usually does not indicate any serious problems. It is important to continue taking your pills on schedule. If the bleeding occurs in more than one cycle or lasts for more than few days, talk to your healthcare professional.2. Contact lensesIf you wear contact lenses and notice change in vision or an inability to wear your lenses, contact your healthcare professional.3. Fluid retentionOral contraceptives may cause edema (fluid retention) with swelling of the fingers or ankles and may raise your blood pressure. If you experience fluid retention, contact your healthcare professional.4. MelasmaA spotty darkening of the skin is possible, particularly of the face, which may persist.5. Other side effectsOther side effects may include nausea, vomiting and diarrhea, muscle cramps, change in appetite, headache, nervousness, depression, dizziness, loss of scalp hair, rash, vaginal infections, pancreatitis, skin sensitivity to the sun or ultraviolet, and allergic reactions.If any of these side effects bother you, call your healthcare professional.GENERAL PRECAUTIONS1. Missed periods and use of oral contraceptives before or during early pregnancyThere may be times when you may not menstruate regularly after you have completed taking cycle of pills. If you have taken your pills regularly and miss one menstrual period, continue taking your pills for the next cycle but be sure to inform your healthcare professional before doing so. If you have not taken the pills daily as instructed and missed menstrual period, you may be pregnant. If you missed two consecutive menstrual periods, you may be pregnant. Check with your healthcare professional immediately to determine whether you are pregnant. Do not continue to take oral contraceptives until you are sure you are not pregnant, but continue to use another method of contraception.There is no conclusive evidence that oral contraceptive use is associated with an increase in birth defects, when taken inadvertently during early pregnancy. Previously, few studies had reported that oral contraceptives might be associated with birth defects, but these findings have not been seen in more recent studies. Nevertheless, oral contraceptives should not be used during pregnancy. You should check with your healthcare professional about risks to your unborn child of any medication taken during pregnancy.2. While breastfeedingIf you are breastfeeding, consult your healthcare professional before starting oral contraceptives. Some of the drug will be passed on to the child in the milk. few adverse effects on the child have been reported, including yellowing of the skin (jaundice) and breast enlargement. In addition, combined oral contraceptives may decrease the amount and quality of your milk. If possible, do not use combined oral contraceptives while breastfeeding. You should use another method of contraception since breastfeeding provides only partial protection from becoming pregnant and this partial protection decreases significantly as you breastfeed for longer periods of time. You should consider starting combined oral contraceptives only after you have weaned your child completely.3. Laboratory testsIf you are scheduled for any laboratory tests, tell your healthcare professional you are taking birth control pills. Certain blood tests may be affected by birth control pills.4. Drug interactionsTell your healthcare provider about all medicines and herbal products that you take.Some medicines and herbal products may make hormonal birth control less effective, including, but not limited to:certain seizure medicines (carbamazepine, felbamate, oxcarbazepine, phenytoin, rufinamide, and topiramate)aprepitantbarbituratesbosentancolesevelamgriseofulvincertain combinations of HIV medicines (nelfinavir, ritonavir, ritonavir-boosted protease inhibitors)certain non nucleoside reverse transcriptase inhibitors (nevirapine)rifampin and rifabutinSt. Johns wortUse another birth control method (such as condom and spermicide or diaphragm and spermicide) when you take medicines that may make Nortrel 0.5/35 or 1/35 less effective.Some medicines and grapefruit juice may increase your level of the hormone ethinyl estradiol if used together, including:acetaminophenascorbic acidmedicines that affect how your liver breaks down other medicines (itraconazole, ketoconazole, voriconazole, and fluconazole)certain HIV medicines (atazanavir, indinavir)atorvastatinrosuvastatinetravirineHormonal birth control methods may interact with lamotrigine, seizure medicine used for epilepsy. This may increase the risk of seizures, so your healthcare provider may need to adjust the dose of lamotrigine.Women on thyroid replacement therapy may need increased doses of thyroid hormone.Know the medicines you take. Keep list of them to show your doctor and pharmacist when you get new medicine.5. Sexually transmitted diseasesThis product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.HOW TO TAKE THE PILLIMPORTANT POINTS TO REMEMBERBEFORE YOU START TAKING YOUR PILLS:BE SURE TO READ THESE DIRECTIONS:Before you start taking your pills.Anytime you are not sure what to do.THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME.If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant.MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesnt go away, check with your healthcare professional.MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills.On the days you take pills to make up for missed pills, you could also feel little sick to your stomach.IF YOU HAVE VOMITING OR DIARRHEA, or IF YOU TAKE SOME MEDICINES, your pills may not work as well. Use back-up method (such as condom or spermicide) until you check with your healthcare professional.IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your healthcare professional about how to make pill-taking easier or about using another method of birth control.IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your healthcare professional.BEFORE YOU START TAKING YOUR PILLSDECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day.LOOK AT YOUR PILL PACK TO SEE IF IT HAS 21 OR 28 PILLS. The 21-pill pack has 21 active pills (with hormones) to take for weeks. This is followed by week without pills. The 28-pill pack has 21 active pills (with hormones) to take for weeks. This is followed by week of white reminder pills (without hormones). Nortrel 1/35 (norethindrone and ethinyl estradiol tablets): There are 21 yellow active pills. Nortrel 0.5/35 (norethindrone and ethinyl estradiol tablets): There are 21 light yellow active pills.ALSO FIND: 1) where on the pack to start taking pills, 2) in what order to take the pills. CHECK ADDITIONAL INSTRUCTIONS FOR USING THIS PACKAGE IN THE BRIEF SUMMARY PATIENT PACKAGE INSERT.BE SURE YOU HAVE READY AT ALL TIMES: ANOTHER KIND OF BIRTH CONTROL (such as condom or spermicide) to use as back-up method in case you miss pills. AN EXTRA, FULL PILL PACK.WHEN TO START THE FIRST PACK OF PILLSYou have choice of which day to start taking your first pack of pills. Nortrel 1/35 and 0.5/35 (norethindrone and ethinyl estradiol tablets) are available in the Blister Pack Tablet Dispenser which is preset for Sunday Start. Day Start is also provided. Decide with your healthcare professional which is the best day for you. Pick time of day which will be easy to remember.SUNDAY START:Nortrel 1/35 (norethindrone and ethinyl estradiol tablets): Take the first yellow active pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack the same day.Nortrel 0.5/35 (norethindrone and ethinyl estradiol tablets): Take the first light yellow active pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack the same day.Use another method of birth control such as condom or spermicide as back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). DAY START:Nortrel 1/35 (norethindrone and ethinyl estradiol tablets): Take the first yellow active pill of the first pack during the first 24 hours of your period.Nortrel 0.5/35 (norethindrone and ethinyl estradiol tablets): Take the first light yellow active pill of the first pack during the first 24 hours of your period.You will not need to use back-up method of birth control, since you are starting the pill at the beginning of your period.WHAT TO DO DURING THE MONTHTAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY.Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). Do not skip pills even if you do not have sex very often.WHEN YOU FINISH PACK OR SWITCH YOUR BRAND OF PILLS:21 pills: Wait days to start the next pack. You will probably have your period during that week. Be sure that no more than days pass between 21-day packs.28 pills: Start the next pack on the day after your last white reminder pill. Do not wait any days between packs.WHAT TO DO IF YOU MISS PILLSNortrel 1/35 (norethindrone and ethinyl estradiol tablets):If you MISS yellow active pill:Take it as soon as you remember. Take the next pill at your regular time. This means you may take pills in day. You do not need to use back-up birth control method if you have sex.If you MISS yellow active pills in row in WEEK OR WEEK of your pack:Take pills on the day you remember and pills the next day. Then take pill day until you finish the pack. You COULD BECOME PREGNANT if you have sex in the days after you miss pills. You MUST use another birth control method (such as condom or spermicide) as back-up method for those days.If you MISS yellow active pills in row in THE 3RD WEEK:1a. If you are Sunday Starter: Keep taking pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start new pack of pills that same day.1b. If you are Day Starter: THROW OUT the rest of the pill pack and start new pack that same day.2. You may not have your period this month but this is expected. However, if you miss your period months in row, call your healthcare professional because you might be pregnant.3. You COULD BECOME PREGNANT if you have sex in the days after you miss pills. You MUST use another birth control method (such as condom or spermicide) as back-up method for those days.If you MISS OR MORE yellow active pills in row (during the first weeks):1a. If you are Sunday Starter: Keep taking pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start new pack of pills that same day.1b. If you are Day Starter: THROW OUT the rest of the pill pack and start new pack that same day.2. You may not have your period this month but this is expected. However, if you miss your period months in row, call your healthcare professional because you might be pregnant.3. You COULD BECOME PREGNANT if you have sex in the days after you miss pills. You MUST use another birth control method (such as condom or spermicide) as back-up method for those days.Nortrel 0.5/35 (norethindrone and ethinyl estradiol tablets):If you MISS light yellow active pill:Take it as soon as you remember. Take the next pill at your regular time. This means you may take pills in day. You do not need to use back-up birth control method if you have sex.If you MISS light yellow active pills in row in WEEK OR WEEK of your pack:Take pills on the day you remember and pills the next day. Then take pill day until you finish the pack. You COULD BECOME PREGNANT if you have sex in the days after you miss pills. You MUST use another birth control method (such as condom or spermicide) as back-up method for those days.If you MISS light yellow active pills in row in THE 3RD WEEK:1a. If you are Sunday Starter: Keep taking pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start new pack of pills that same day.1b. If you are Day Starter: THROW OUT the rest of the pill pack and start new pack that same day.2. You may not have your period this month but this is expected. However, if you miss your period months in row, call your healthcare professional because you might be pregnant.3. You COULD BECOME PREGNANT if you have sex in the days after you miss pills. You MUST use another birth control method (such as condom or spermicide) as back-up method for those days.If you MISS OR MORE light yellow active pills in row (during the first weeks):1a. If you are Sunday Starter: Keep taking pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start new pack of pills that same day.1b. If you are Day Starter: THROW OUT the rest of the pill pack and start new pack that same day.2. You may not have your period this month but this is expected. However, if you miss your period months in row, call your healthcare professional because you might be pregnant.3. You COULD BECOME PREGNANT if you have sex in the days after you miss pills. You MUST use another birth control method (such as condom or spermicide) as back-up method for those days.A REMINDER FOR THOSE ON 28-DAY PACKSIf you forget any of the white reminder pills in Week 4: THROW AWAY the pills you missed. Keep taking pill each day until the pack is empty. You do not need back-up method.FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSEDUse BACK-UP METHOD anytime you have sex.KEEP TAKING ONE ACTIVE PILL EACH DAY until you can reach your healthcare professional.PREGNANCY DUE TO PILL FAILURECombined Oral ContraceptivesThe incidence of pill failure resulting in pregnancy is approximately one percent (i.e., one pregnancy per 100 women per year) if taken every day as directed, but more typical failure rates are 5%. If failure does occur, the risk to the fetus is minimal.PREGNANCY AFTER STOPPING THE PILLThere may be some delay in becoming pregnant after you stop using oral contraceptives, especially if you had irregular menstrual cycles before you used oral contraceptives. It may be advisable to postpone conception until you begin menstruating regularly once you have stopped taking the pill and desire pregnancy.There does not appear to be any increase in birth defects in newborn babies when pregnancy occurs soon after stopping the pill.OVERDOSAGESerious ill effects have not been reported following ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea and withdrawal bleeding in females. In case of overdosage, contact your healthcare professional or pharmacist.OTHER INFORMATIONYour healthcare professional will take medical and family history before prescribing oral contraceptives and will examine you. The physical examination may be delayed to another time if you request it and the healthcare professional believes that it is good medical practice to postpone it. You should be reexamined at least once year. Be sure to inform your healthcare professional if there is family history of any of the conditions listed previously in this leaflet. Be sure to keep all appointments with your healthcare professional, because this is time to determine if there are early signs of side effects of oral contraceptive use.Do not use the drug for any condition other than the one for which it was prescribed. This drug has been prescribed specifically for you; do not give it to others who may want birth control pills.HEALTH BENEFITS FROM ORAL CONTRACEPTIVESIn addition to preventing pregnancy, use of combined oral contraceptives may provide certain benefits. They are:menstrual cycles may become more regularblood flow during menstruation may be lighter and less iron may be lost. Therefore, anemia due to iron deficiency is less likely to occur.pain or other symptoms during menstruation may be encountered less frequentlyectopic (tubal) pregnancy may occur less frequentlynoncancerous cysts or lumps in the breast may occur less frequentlyacute pelvic inflammatory disease may occur less frequentlyoral contraceptive use may provide some protection against developing two forms of cancer: cancer of the ovaries and cancer of the lining of the uterus.If you want more information about birth control pills, ask your healthcare professional or pharmacist. They have more technical leaflet called the Professional Labeling, which you may wish to read.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.Store at 20 to 25C (68 to 77F).KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.All brand names listed are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA.Teva Pharmaceuticals USA, Inc.North Wales, PA 19454Rev. 12/2021. smoke. have high blood pressure, diabetes, high cholesterol. have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast or sex organs, jaundice or malignant or benign liver tumors.. Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), stoppage or rupture of blood vessel in the brain (stroke), blockage of blood vessels in the heart (heart attack or angina pectoris) or other organs of the body. As mentioned above, smoking increases the risk of heart attacks and strokes and subsequent serious medical consequences.. In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, some studies report an increased risk of developing liver cancer. However, liver cancers are rare.. High blood pressure, although blood pressure usually returns to normal when the pill is stopped.. BE SURE TO READ THESE DIRECTIONS:Before you start taking your pills.Anytime you are not sure what to do.. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME.If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant.. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesnt go away, check with your healthcare professional.. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills.On the days you take pills to make up for missed pills, you could also feel little sick to your stomach.. IF YOU HAVE VOMITING OR DIARRHEA, or IF YOU TAKE SOME MEDICINES, your pills may not work as well. Use back-up method (such as condom or spermicide) until you check with your healthcare professional.. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your healthcare professional about how to make pill-taking easier or about using another method of birth control.. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your healthcare professional.. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.It is important to take it at about the same time every day.. LOOK AT YOUR PILL PACK TO SEE IF IT HAS 21 OR 28 PILLS.The 21-pill pack has 21 active pills (with hormones) to take for weeks. This is followed by week without pills. The 28-pill pack has 21 active pills (with hormones) to take for weeks. This is followed by week of white reminder pills (without hormones). Nortrel 1/35 (norethindrone and ethinyl estradiol tablets): There are 21 yellow active pills. Nortrel 0.5/35 (norethindrone and ethinyl estradiol tablets): There are 21 light yellow active pills.. ALSO FIND: 1) where on the pack to start taking pills, 2) in what order to take the pills. CHECK ADDITIONAL INSTRUCTIONS FOR USING THIS PACKAGE IN THE BRIEF SUMMARY PATIENT PACKAGE INSERT.. BE SURE YOU HAVE READY AT ALL TIMES:ANOTHER KIND OF BIRTH CONTROL (such as condom or spermicide) to use as back-up method in case you miss pills.AN EXTRA, FULL PILL PACK.. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY.Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). Do not skip pills even if you do not have sex very often.. WHEN YOU FINISH PACK OR SWITCH YOUR BRAND OF PILLS:21 pills: Wait days to start the next pack. You will probably have your period during that week. Be sure that no more than days pass between 21-day packs.28 pills: Start the next pack on the day after your last white reminder pill. Do not wait any days between packs.. Take it as soon as you remember. Take the next pill at your regular time. This means you may take pills in day.. You do not need to use back-up birth control method if you have sex.. Take pills on the day you remember and pills the next day.. Then take pill day until you finish the pack.. You COULD BECOME PREGNANT if you have sex in the days after you miss pills. You MUST use another birth control method (such as condom or spermicide) as back-up method for those days.. Take it as soon as you remember. Take the next pill at your regular time. This means you may take pills in day.. You do not need to use back-up birth control method if you have sex.. Take pills on the day you remember and pills the next day.. Then take pill day until you finish the pack.. You COULD BECOME PREGNANT if you have sex in the days after you miss pills. You MUST use another birth control method (such as condom or spermicide) as back-up method for those days.. The blister pack comes to you set up for Sunday Start. If your healthcare professional has instructed you to start pill-taking on the SUNDAY after your menstrual period has begun, or if your period begins on Sunday you will take your first pill that very same day. Start with the Sunday pill in row 1. After the Saturday pill has been taken, begin taking the pills in row 2, and so on, until all 21 pills have been taken. You will then take no pills for one week (seven days).. If you start pill-taking on day other than SUNDAY, peel the attached sticker by selecting the day of the week you plan to start. Place the sticker over the pre-printed days of the week and make sure it lines up with the pills. This sticker will help to remind you to take your pill every day. Take the yellow pill which corresponds to the day in row for the 1/35 day regimen of the first pack during the first 24 hours of your period.. After the last (Saturday) pill in row has been taken, if any remain in the first row, complete your 21-pill schedule by taking one pill daily starting with Sunday in row until all the pills have been taken.. When you start taking the pill for the first time, use an additional method of protection until you have taken your first pills.. Your tablet dispenser consists of three parts, the foil pouch, wallet, and blister pack containing 21 individually sealed pills. Note that the pills are arranged in three numbered rows of pills each with the days of the week printed above them. All 21 pills are active birth control pills.. You must take your pills in order, one pill each day at intervals of 24 hours. To remove pill, push down on the pill with your thumb and forefinger so that the pill releases through the back of the dispenser. See diagram below: Note: Rows 1, and are active pills. Proceed taking one pill each day until all pills have been taken.. After you have taken your last pill, wait for days. During this time your period should begin. On the eighth day, start new pack of pills even if your period is not yet over. The blister card comes to you set up for Sunday Start. If your healthcare professional has instructed you to start pill-taking on the SUNDAY after your menstrual period has begun or if your period begins on Sunday you will take your first pill that very same day. Start with the Sunday pill in row 1. Take one active pill daily for 21 days followed by one white placebo pill daily for days.. If you start pill-taking on day other than SUNDAY, peel the attached sticker by selecting the day of the week you plan to start. Place the sticker over the pre-printed days of the week and make sure it lines up with the pills. This sticker will help to remind you to take your pill every day. Take the yellow pill which corresponds to the day in row for both the 1/35 day regimen and the 0.5/35 day regimen of the first pack during the first 24 hours of your period. After taking all of the pills at the end of row 3, go back to row and complete the active pills. Once all of the active pills have been taken, proceed to row and take the reminder pills to complete the pack.. When you start taking the pill for the first time, use an additional method of protection until you have taken your first pills.. Your tablet dispenser consists of three parts, the foil pouch, wallet, and blister pack containing 28 individually sealed pills. Note that the pills are arranged in four numbered rows of pills each with the days of the week printed above them. The 21 colored pills are active birth control pills. The white pills are inactive; their purpose is to help make your pill-taking schedule simple and easy to remember.. You must take your pills in order, one pill each day at intervals of 24 hours. Always start with the colored pills in row 1. To remove pill, push down on the pill with your thumb and forefinger so that the pill releases through the back of the dispenser. See diagram below: Note: Rows 1, and are active pills and row contains the reminder pills.. After you have taken all 21 pills, take one white pill daily for days: During this time your period should begin.. After you have taken all of the pills, start new pack of pills even if your period is not yet over.. Follow the sticker with the days of the week (placed above the pills).. Always go from left to right.. Always finish your pills.. history of heart attack or stroke. Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes. history of blood clots in the deep veins of your legs. An inherited problem that makes your blood clot more than normal. Chest pain (angina pectoris). Known or suspected breast cancer or cancer of the lining of the uterus, cervix or vagina Unexplained vaginal bleeding (until diagnosis is reached by your healthcare professional). Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or during previous use of the pill. Liver tumor (benign or cancerous). Take any Hepatitis drug combination containing ombitasvir/paritaprevir/ ritonavir, with or without dasabuvir. This may increase levels of the liver enzyme alanine aminotransferase (ALT) in the blood.. Known or suspected pregnancy. Valvular heart disease with complications. Severe hypertension. Diabetes with vascular involvement. Headaches with focal neurological symptoms. If you plan to have surgery with prolonged bed rest. Hypersensitivity to any component of this product.. Breast nodules, fibrocystic disease of the breast, an abnormal breast x-ray or mammogram. Diabetes. Elevated cholesterol or triglycerides. High blood pressure. Migraine or other headaches or epilepsy. Mental depression. Gallbladder, liver, heart or kidney disease. History of scanty or irregular menstrual periods. First start taking birth control pills. Restart the same or different birth control pills after not using them for month or more Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating possible clot in the lung). Pain in the calf (indicating possible clot in the leg). Crushing chest pain or heaviness in the chest (indicating possible heart attack). Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating possible stroke). Sudden partial or complete loss of vision (indicating possible clot in the eye). Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your healthcare professional to show you how to examine your breasts). Severe pain or tenderness in the stomach area (indicating possibly ruptured liver tumor). Difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood (possibly indicating severe depression). Jaundice or yellowing of the skin or eyeballs, accompanied frequently by fever, fatigue, loss of appetite, dark colored urine, or light colored bowel movements (indicating possible liver problems). certain seizure medicines (carbamazepine, felbamate, oxcarbazepine, phenytoin, rufinamide, and topiramate). aprepitant. barbiturates. bosentan. colesevelam. griseofulvin. certain combinations of HIV medicines (nelfinavir, ritonavir, ritonavir-boosted protease inhibitors). certain non nucleoside reverse transcriptase inhibitors (nevirapine). rifampin and rifabutin. St. Johns wort. acetaminophen. ascorbic acid. medicines that affect how your liver breaks down other medicines (itraconazole, ketoconazole, voriconazole, and fluconazole). certain HIV medicines (atazanavir, indinavir). atorvastatin. rosuvastatin. etravirine. BE SURE TO READ THESE DIRECTIONS:Before you start taking your pills.Anytime you are not sure what to do.. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME.If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant.. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesnt go away, check with your healthcare professional.. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills.On the days you take pills to make up for missed pills, you could also feel little sick to your stomach.. IF YOU HAVE VOMITING OR DIARRHEA, or IF YOU TAKE SOME MEDICINES, your pills may not work as well. Use back-up method (such as condom or spermicide) until you check with your healthcare professional.. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your healthcare professional about how to make pill-taking easier or about using another method of birth control.. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your healthcare professional.. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day.. LOOK AT YOUR PILL PACK TO SEE IF IT HAS 21 OR 28 PILLS. The 21-pill pack has 21 active pills (with hormones) to take for weeks. This is followed by week without pills. The 28-pill pack has 21 active pills (with hormones) to take for weeks. This is followed by week of white reminder pills (without hormones). Nortrel 1/35 (norethindrone and ethinyl estradiol tablets): There are 21 yellow active pills. Nortrel 0.5/35 (norethindrone and ethinyl estradiol tablets): There are 21 light yellow active pills.. ALSO FIND: 1) where on the pack to start taking pills, 2) in what order to take the pills. CHECK ADDITIONAL INSTRUCTIONS FOR USING THIS PACKAGE IN THE BRIEF SUMMARY PATIENT PACKAGE INSERT.. BE SURE YOU HAVE READY AT ALL TIMES: ANOTHER KIND OF BIRTH CONTROL (such as condom or spermicide) to use as back-up method in case you miss pills. AN EXTRA, FULL PILL PACK.. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY.Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). Do not skip pills even if you do not have sex very often.. WHEN YOU FINISH PACK OR SWITCH YOUR BRAND OF PILLS:21 pills: Wait days to start the next pack. You will probably have your period during that week. Be sure that no more than days pass between 21-day packs.28 pills: Start the next pack on the day after your last white reminder pill. Do not wait any days between packs.. Take it as soon as you remember. Take the next pill at your regular time. This means you may take pills in day. You do not need to use back-up birth control method if you have sex.. Take pills on the day you remember and pills the next day. Then take pill day until you finish the pack. You COULD BECOME PREGNANT if you have sex in the days after you miss pills. You MUST use another birth control method (such as condom or spermicide) as back-up method for those days.. Take it as soon as you remember. Take the next pill at your regular time. This means you may take pills in day. You do not need to use back-up birth control method if you have sex.. Take pills on the day you remember and pills the next day. Then take pill day until you finish the pack. You COULD BECOME PREGNANT if you have sex in the days after you miss pills. You MUST use another birth control method (such as condom or spermicide) as back-up method for those days.. menstrual cycles may become more regular. blood flow during menstruation may be lighter and less iron may be lost. Therefore, anemia due to iron deficiency is less likely to occur.. pain or other symptoms during menstruation may be encountered less frequently. ectopic (tubal) pregnancy may occur less frequently. noncancerous cysts or lumps in the breast may occur less frequently. acute pelvic inflammatory disease may occur less frequently. oral contraceptive use may provide some protection against developing two forms of cancer: cancer of the ovaries and cancer of the lining of the uterus.. 21 day blister image. 28 day blister image.

ADVERSE REACTIONS SECTION.

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 0.90-1.12 (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 UseRR 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 embolismArterial thromboembolismPulmonary embolismMyocardial infarctionCerebral hemorrhageCerebral thrombosisHypertensionGallbladder diseaseHepatic adenomas or benign liver tumorsThere is evidence of an association between the following conditions and the use of oral contraceptives: Mesenteric thrombosis Retinal thrombosisThe following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related:NauseaVomitingGastrointestinal symptoms (such as abdominal cramps and bloating)Breakthrough bleedingSpottingChange in menstrual flowAmenorrheaTemporary infertility after discontinuation of treatmentEdemaMelasma which may persistBreast changes: tenderness, enlargement, secretionChange in weight (increase or decrease)Change in cervical erosion and secretionDiminution in lactation when given immediately postpartumCholestatic jaundiceMigraineAllergic reaction, including rash, urticaria, angioedemaMental depressionReduced tolerance to carbohydratesVaginal candidiasisChange in corneal curvature (steepening)Intolerance to contact lensesThe following adverse reactions have been reported in users of oral contraceptives and causal association has been neither confirmed nor refuted:Pre-menstrual syndromeCataractsChanges in appetiteCystitis-like syndromeHeadacheNervousnessDizzinessHirsutismLoss of scalp hairErythema multiformeErythema nodosumHemorrhagic eruptionVaginitisPorphyriaImpaired renal functionHemolytic uremic syndromeAcneChanges in libidoColitisBudd-Chiari SyndromeThe following adverse reactions were also reported in clinical trials or during post-marketing experience: Gastrointestinal Disorders: diarrhea, pancreatitis; Musculoskeletal and Connective Tissue Disorders: muscle spasms, back pain; Reproductive System and Breast Disorders vulvovaginal pruritus, pelvic pain, dysmenorrhea, vulvovaginal dryness; Psychiatric Disorders: anxiety, mood swings, mood altered; Skin and Subcutaneous Tissue Disorders: pruritus, photosensitivity reaction; General Disorders and Administration Site Conditions: edema peripheral, fatigue, irritability, asthenia, malaise; Neoplasms Benign, Malignant, and Unspecified (Including Cysts and Polyps): breast cancer, breast mass, breast neoplasm, cervix carcinoma; Immune System Disorders: anaphylactic/anaphylactoid reaction; Hepatobiliary Disorders: hepatitis, cholelithiasis.. 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. Mesenteric thrombosis Retinal thrombosis. 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, angioedema. Mental depression. Reduced tolerance to carbohydrates. Vaginal candidiasis. Change in corneal curvature (steepening). Intolerance to contact lenses. 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. Figure 2.

BOXED WARNING SECTION.

WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH SMOKING. Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, combination oral contraceptives, including Nortrel(R) 0.5/35 and 1/35, should not be used by women who are over 35 years of age and smoke.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

10. Carcinogenesis. See WARNINGS.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Combined Oral ContraceptivesCombined oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).

CONTRAINDICATIONS SECTION.

CONTRAINDICTIONS. Nortrel 0.5/35 and 1/35 is contraindicated in females who are known to have or develop the following conditions:Thrombophlebitis or thromboembolic disordersA past history of deep vein thrombophlebitis or thromboembolic disordersKnown thrombophilic conditionsCerebral vascular or coronary artery disease (current or history)Valvular heart disease with complicationsPersistent blood pressure values of 160 mm Hg systolic or 100 mg Hg diastolic96 Diabetes with vascular involvementHeadaches with focal neurological symptomsMajor surgery with prolonged immobilizationCurrent diagnosis of, or history of, breast cancer, which may be hormone-sensitive Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasiaUndiagnosed abnormal genital bleedingCholestatic jaundice of pregnancy or jaundice with prior pill useAcute or chronic hepatocellular disease with abnormal liver functionHepatic adenomas or carcinomasKnown or suspected pregnancyHypersensitivity to any component of this productAre receiving Hepatitis 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 Treatment).. Thrombophlebitis or thromboembolic disorders. 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 mg Hg diastolic96 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 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 Treatment).

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. To achieve maximum contraceptive effectiveness, Nortrel (norethindrone and ethinyl estradiol tablets) must be taken exactly as directed and at intervals not exceeding 24 hours. Nortrel (norethindrone and ethinyl estradiol tablets) is available in the Blister Pack Tablet Dispenser which is preset for Sunday Start. Day Start is also available.. 21-Day Regimen (Sunday Start):. When taking Nortrel 1/35 (norethindrone and ethinyl estradiol tablets) (21) Day Regimen, the first active tablet should be taken on the first Sunday after menstruation begins. If the period begins on Sunday, the first active tablet should be taken that day. Take one active tablet daily for 21 days. For subsequent cycles, no tablets are taken for days, then tablet is taken the next day (Sunday). For the first cycle of Sunday Start regimen, another method of contraception, such as condom or spermicide, should be used until after the first consecutive days of administration.If the patient misses one (1) active tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she remembers. If the patient misses two (2) active tablets in Week or Week 2, the patient should take two (2) tablets the day she remembers and two (2) tablets the next day; and then continue taking one (1) tablet day until she finishes the pack. The patient should be instructed to use back-up method of birth control, such as condom or spermicide, if she has sex in the seven (7) days after missing pills. If the patient misses two (2) active tablets in the third week or misses three (3) or more active tablets in row, the patient should continue taking one tablet every day until Sunday. On Sunday the patient should throw out the rest of the pack and start new pack that same day. The patient should be instructed to use back-up method of birth control if she has sex in the seven (7) days after missing pills.Complete instructions to facilitate patient counseling on proper pill usage may be found in the Detailed Patient Labeling (How to Take the Pill section).. 21-Day Regimen (Day Start):. The dosage of Nortrel 1/35 (norethindrone and ethinyl estradiol tablets) (21) Day Regimen, for the initial cycle of therapy is one 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. For subsequent cycles, no tablets are taken for days, then new course is started of one tablet day for 21 days. The dosage regimen then continues with days of no medication, followed by 21 days of medication, instituting three-weeks-on, one-week-off dosage regimen.If the patient misses one (1) active tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she remembers. If the patient misses two (2) active tablets in Week or Week 2, the patient should take two (2) tablets the day she remembers and two (2) tablets the next day; and then continue taking one (1) tablet day until she finishes the pack. The patient should be instructed to use back-up method of birth control, such as condom or spermicide, if she has sex in the seven (7) days after missing pills. If the patient misses two (2) active tablets in the third week or misses three (3) or more active tablets in row, the patient should throw out the rest of the pack and start new pack that same day. The patient should be instructed to use back-up method of birth control if she has sex in the seven (7) days after missing pills.Complete instructions to facilitate patient counseling on proper pill usage may be found in the Detailed Patient Labeling (How to Take the Pill section).. 28-Day Regimen (Sunday Start):. When taking Nortrel 1/35 and 0.5/35 (norethindrone and ethinyl estradiol tablets) (28) Day Regimen, the first active tablet should be taken on the first Sunday after menstruation begins. If the period begins on Sunday, the first active tablet should be taken that day. Take one active tablet daily for 21 days followed by one white reminder tablet daily for days. After 28 tablets have been taken, new course is started the next day (Sunday). For the first cycle of Sunday Start regimen, another method of contraception such as condom or spermicide should be used until after the first consecutive days of administration.If the patient misses one (1) active tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she remembers. If the patient misses two (2) active tablets in Week or Week 2, the patient should take two (2) tablets the day she remembers and two (2) tablets the next day; and then continue taking one (1) tablet day until she finishes the pack. The patient should be instructed to use back-up method of birth control such as condom or spermicide if she has sex in the seven (7) days after missing pills. If the patient misses two (2) active tablets in the third week or misses three (3) or more active tablets in row, the patient should continue taking one tablet every day until Sunday. On Sunday the patient should throw out the rest of the pack and start new pack that same day. The patient should be instructed to use back-up method of birth control if she has sex in the seven (7) days after missing pills.Complete instructions to facilitate patient counseling on proper pill usage may be found in the Detailed Patient Labeling (How to Take the Pill section).. 28-Day Regimen (Day Start):. The dosage of Nortrel 1/35 and 0.5/35 (norethindrone and ethinyl estradiol tablets) (28) Day Regimen, for the initial cycle of therapy is one active tablet administered daily from the 1st through the 21st day of the menstrual cycle, counting the first day of menstrual flow as Day 1 followed by one white reminder tablet daily for days. Tablets are taken without interruption for 28 days. After 28 tablets have been taken, new course is started the next day.If the patient misses one (1) active tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she remembers. If the patient misses two (2) active tablets in Week or Week 2, the patient should take two (2) tablets the day she remembers and two (2) tablets the next day; and then continue taking one (1) tablet day until she finishes the pack. The patient should be instructed to use back-up method of birth control such as condom or spermicide if she has sex in the seven (7) days after missing pills. If the patient misses two (2) active tablets in the third week or misses three (3) or more active tablets in row, the patient should throw out the rest of the pack and start new pack that same day. The patient should be instructed to use back-up method of birth control if she has sex in the seven (7) days after missing pills.Complete instructions to facilitate patient counseling on proper pill usage may be found in the Detailed Patient Labeling (How to Take the Pill section).The use of Nortrel 1/35 and 0.5/35 (norethindrone and ethinyl estradiol tablets) for contraception may be initiated 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.) The possibility of ovulation and conception prior to initiation of medication should be considered.(See Discussion of Dose-Related Risk of Vascular Disease from Oral Contraceptives.).

DRUG INTERACTIONS SECTION.

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 ContraceptivesSubstances decreasing the plasma concentrations of COCs and potentially diminishing the efficacy of COCsDrugs 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. Johns 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 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 COCsCo-administration of atorvastatin or rosuvastatin and certain COCs containing EE increase AUC values for EE by approximately 20-25%. 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 virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitorsSignificant 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 ElevationDo not co-administer Nortrel 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 Treatment).Colesevelam: Colesevelam, bile acid sequestrant, given together with combination oral hormonal contraceptive, has been shown to significantly decrease the AUC of EE. drug interaction between the contraceptive and colesevelam was decreased when the two drug products were given hours apart.Effects of Combined Hormonal Contraceptives on Other DrugsCOCs 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.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Nortrel(R) 1/35 (norethindrone and ethinyl estradiol tablets USP), mg/0.035 mg 21 Day Regimen blister cards contain 21 yellow, round flat-faced, beveled-edge, unscored tablets, debossed with stylized on one side and 949 on the other side. Each tablet contains mg of norethindrone and 0.035 mg of ethinyl estradiol.Cartons of Blister Cards (NDC 0555-9009-42)Nortrel(R) 1/35 (norethindrone and ethinyl estradiol tablets USP), mg/0.035 mg 28 Day Regimen blister cards contain 21 yellow, round, flat-faced, beveled-edge, unscored tablets, debossed with stylized on one side and 949 on the other side and white, round, flat-faced, beveled-edge, unscored, inert tablets, debossed with stylized on one side and 944 on the other side.Cartons of Blister Cards (NDC 0555-9010-58)Nortrel(R) 0.5/35 (norethindrone and ethinyl estradiol tablets USP), 0.5 mg/0.035 mg 28 Day Regimen blister cards contain 21 light yellow, round, flat-faced, beveled-edge, unscored tablets, debossed with stylized on one side and 941 on the other side and white, round, flat-faced, beveled-edge, unscored, inert tablets, debossed with stylized on one side and 944 on the other side.Cartons of Blister Cards (NDC 0555-9008-67)Store at 20 to 25C (68 to 77F) [See USP Controlled Room Temperature].KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Nortrel 1/35 and Nortrel 0.5/35 Tablets are indicated for the prevention of pregnancy in women who elect to use this product as method of contraception.Oral contraceptives are highly effective. Table 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(R) System 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 Year1 Method (1) Typical Use2 (2)Perfect Use3 (3)(4)Chance4 8585Spermicides5 26640Periodic abstinence 2563 Calendar Ovulation Method Sympto-Thermal6 Post-Ovulation1Cap7 Parous Women 402642 Nulliparous Women 20956Sponge Parous Women 402042 Nulliparous Women 20956Diaphragm7 20656Withdrawal194Condom8 Female (Reality(R)) 21556 Male 14361Pill 571 Progestin Only 0.5 Combined 0.1IUD Progesterone 2.01.581 Copper T380A 0.80.678 LNg 20 0.10.181Depo-Provera(R) 0.30.370Norplant(R) and Norplant-2(R) 0.050.0588Female Sterilization 0.50.5100Male Sterilization 0.150.10100Adapted from Hatcher et al., 1998 Ref. 1.Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.9 Lactational Amenorrhea Method: LAM is highly effective, temporary method of contraception.10 Source: Trussell J, Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, CatesW, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998.1. Among couples attempting to avoid pregnancy, the percentage who continue to use method for one year.2. Among typical couples who initiate use of 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.3. Among couples who initiate use of 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.4. 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.5. Foams, creams, gels, vaginal suppositories, and vaginal film.6. Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases.7. With spermicidal cream or jelly.8. Without spermicides9. The treatment schedule is one dose within 72 hours after unprotected intercourse, and 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(R) (1 dose is white pills), Alesse(R) (1 dose is pink pills),Nordette(R) or Levlen(R) (1 dose is light-orange pills), Lo/Ovral(R) (1 dose is white pills), Triphasil(R) or Tri- Levlen(R) (1 dose is yellow pills).10. 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.Nortrel 0.5/35 and 1/35 have not been studied for and are not indicated for use in emergency contraception.

INFORMATION FOR PATIENTS SECTION.

INFORMATION FOR THE PATIENT. See Patient Labeling printed below.

LABORATORY TESTS SECTION.

9. Interactions with Laboratory Tests. Certain endocrine and liver function tests and blood components may be affected by oral contraceptives:Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG, free T4 concentration is unaltered.Other binding proteins may be elevated in serum.Sex-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged.Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected.Glucose tolerance may be decreased.Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if woman becomes pregnant shortly after discontinuing oral contraceptives.. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG, free T4 concentration is unaltered.. Other binding proteins may be elevated in serum.. Sex-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged.. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected.. Glucose tolerance may be decreased.. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if woman becomes pregnant shortly after discontinuing oral contraceptives.

NURSING MOTHERS SECTION.

12. Nursing Mothers. Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, combined 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 combined oral contraceptives but to use other forms of contraception until she has completely weaned her child.

OVERDOSAGE SECTION.

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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Package/Label Display Panel, Part of 2. image.

PEDIATRIC USE SECTION.

13. Pediatric Use. Safety and efficacy of Nortrel 0.5/35 and 1/35 have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.14. Geriatric UseThis product has not been studied in women over 65 years of age and is not indicated in this population.

PRECAUTIONS SECTION.

PRECAUTIONS. 1. GeneralPatients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.. 2. Physical Examination and Follow-Up. It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with strong family history of breast cancer or who have breast nodules should be monitored with particular care.. 3. Lipid Disorders. Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult.. 4. Liver Function. If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function.. 5. Fluid Retention. Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention.. 6. Emotional Disorders. Women with history of depression should be carefully observed and the drug discontinued if depression recurs to serious degree.. 7. Contact Lenses. Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.. 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 ContraceptivesSubstances decreasing the plasma concentrations of COCs and potentially diminishing the efficacy of COCsDrugs 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. Johns 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 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 COCsCo-administration of atorvastatin or rosuvastatin and certain COCs containing EE increase AUC values for EE by approximately 20-25%. 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 virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitorsSignificant 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 ElevationDo not co-administer Nortrel 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 Treatment).Colesevelam: Colesevelam, bile acid sequestrant, given together with combination oral hormonal contraceptive, has been shown to significantly decrease the AUC of EE. drug interaction between the contraceptive and colesevelam was decreased when the two drug products were given hours apart.Effects of Combined Hormonal Contraceptives on Other DrugsCOCs 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.. 9. Interactions with Laboratory Tests. Certain endocrine and liver function tests and blood components may be affected by oral contraceptives:Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG, free T4 concentration is unaltered.Other binding proteins may be elevated in serum.Sex-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged.Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected.Glucose tolerance may be decreased.Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if woman becomes pregnant shortly after discontinuing oral contraceptives.. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG, free T4 concentration is unaltered.. Other binding proteins may be elevated in serum.. Sex-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged.. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected.. Glucose tolerance may be decreased.. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if woman becomes pregnant shortly after discontinuing oral contraceptives.. 10. Carcinogenesis. See WARNINGS.. 11. Pregnancy. Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS.. 12. Nursing Mothers. Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, combined 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 combined oral contraceptives but to use other forms of contraception until she has completely weaned her child.. 13. Pediatric Use. Safety and efficacy of Nortrel 0.5/35 and 1/35 have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.14. Geriatric UseThis product has not been studied in women over 65 years of age and is not indicated in this population.

PREGNANCY SECTION.

11. Pregnancy. Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS.

SPL UNCLASSIFIED SECTION.

WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH SMOKING. Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, combination oral contraceptives, including Nortrel(R) 0.5/35 and 1/35, should not be used by women who are over 35 years of age and smoke.

WARNINGS SECTION.

WARNINGS. Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, combination oral contraceptives, including Nortrel 0.5/35 and 1/35, should not be used by women who are over 35 years of age and smoke.The use of oral contraceptives is associated with increased risks 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 measure of the relative risk of disease, namely, ratio of the incidence of disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of disease. Cohort studies provide 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 disease in the population (adapted from refs. and with the authors permission). For further information, the reader is referred to 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.4-10 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.11 Mortality rates associated with circulatory disease have been shown to increase substantially in smokers, especially in those 35 years of age and older and in nonsmokers over the age of 40 among women who use oral contraceptives (see Figure 1).Figure 1: Circulatory Disease Mortality Rates per 100,000 Woman-Years by Age, Smoking Status and Oral Contraceptive Use(Adapted from P.M. Layde and V. Beral, ref. 12.)Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity.13 In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create state of hyperinsulinism.14-18 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 risk of users compared to nonusers to be for the first episode of superficial venous thrombosis, to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to for women with predisposing conditions for venous thromboembolic disease.2,3,19-24 Cohort studies have shown the relative risk to be somewhat lower, about for new cases and about 4.5 for new cases requiring hospitalization.25 The risk of thromboembolic disease associated with oral contraceptives gradually disappears after combined oral contraceptive (COC) use is stopped.2 VTE risk is highest in the first year of use and when restarting hormonal contraception after break of four weeks or longer.A two- to four-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives.9 The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions.26 If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four weeks after delivery in women who elect not to breast feed.. c. Cerebrovascular Diseases. Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be risk factor for both users and nonusers, for both types of strokes, and smoking interacted to increase the risk of stroke.27-29 In large study, the relative risk of thrombotic strokes has been shown to range from for normotensive users to 14 for users with severe hypertension.30 The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension.30 The attributable risk is also greater in older women.3 d. Dose-Related Risk of Vascular Disease from Oral Contraceptives. positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease.31-33 decline in serum high density lipoproteins (HDL) has been reported with many progestational agents.14-16 decline in serum high density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on balance achieved between doses of estrogen and progestogen and the activity of the progestogen used in the contraceptives. The activity and amount of both hormones should be considered in the choice of an oral contraceptive.Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest estrogen content which is judged appropriate for the individual patient.. e. Persistence of Risk of Vascular Disease. There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least years for women 40-49 years who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups.8 In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least years after discontinuation of oral contraceptives, although excess risk was very small.34 However, both studies were performed with oral contraceptive formulations containing 50 micrograms or higher of estrogens.. 2. Estimates of Mortality from Contraceptive Use. One study gathered data from variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table 2). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke, and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth. The observation of an increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970s.35 Current clinical recommendation involves the use of lower estrogen dose formulations and careful consideration of risk factors. In 1989, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the use of oral contraceptives in women 40 years of age and over. The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception. The Committee recommended that the benefits of low-dose oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks.Of course, older women, as all women who take oral contraceptives, should take an oral contraceptive which contains the least amount of estrogen and progestogen that is compatible with low failure rate and individual patient needs.TABLE 2: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY CONTROL METHOD ACCORDING TO AGE Method of control and outcome 15-19 20-24 25-29 30-34 35-39 40-44No fertility control methods1 7.07.4 9.1 14.8 25.7 28.2Oral contraceptives non-smoker2 0.3 0.5 0.9 1.9 13.8 31.6Oral contraceptives smoker2 2.2 3.4 6.6 13.5 51.1 117.2IUD2 0.8 0.8 1.0 1.0 1.4 1.4Condom1 1.1 1.6 0.7 0.2 0.3 0.4Diaphragm/spermicide1 1.9 1.2 1.2 1.3 2.2 2.8Periodic abstinence1 2.5 1.6 1.6 1.7 2.9 3.6Adapted from H.W. Ory, ref. 35.1. Deaths are birth-related2. Deaths are method-related. 3. Malignant Neoplasms. Breast CancerNortrel 0.5/35 and 1/35 is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive (see CONTRAINDICATIONS).Epidemiology studies have not found consistent association between use of combined oral contraceptives (COCs) and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use (see Postmarketing Experience).Cervical CancerSome studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women.45-48 However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.In spite of many studies of the relationship between oral contraceptive use and breast and cervical cancers, cause-and-effect relationship has not been established.. 4. Hepatic Neoplasia. Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, risk that increases after four or more years of use especially with oral contraceptives of higher dose.49 Rupture of benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.50, 51 Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral contraceptive users. However, these cancers are extremely rare in the U.S. and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users.. 5. Risk of Liver Enzyme Elevations with Concomitant Hepatitis Treatment. During clinical trials with the Hepatitis combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications such as COCs. Discontinue Nortrel prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (see CONTRAINDICATIONS). Nortrel can be restarted approximately weeks following completion of treatment with the combination drug regimen.. 6. Ocular Lesions. There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately.. 7. Oral Contraceptive Use Before or During Early Pregnancy. Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy.56,57 The majority of recent studies also do not indicate teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, 55,56,58,59 when taken inadvertently during early pregnancy.The administration of oral contraceptives to induce withdrawal bleeding should not be used as test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion.It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period. Oral contraceptive use should be discontinued if pregnancy is confirmed.. 8. Gallbladder Disease. Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens.60,61 More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal.62-64 The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.. 9. Carbohydrate and Lipid Metabolic Effects. Oral contraceptives have been shown to cause decrease in glucose tolerance in significant percentage of users.17 This effect has been shown to be directly related to estrogen dose.65 Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents.17,66 However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose.67 Because of these demonstrated effects, prediabetic and diabetic women in particular should be carefully monitored while taking oral contraceptives.A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1a and 1d), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.. 10. Elevated Blood Pressure. Women with significant hypertension should not be started on hormonal contraception.92 An increase in blood pressure has been reported in women taking oral contraceptives68 and this increase is more likely in older oral contraceptive users69 and with extended duration of use.61 Data from the Royal College of General Practitioners12 and subsequent randomized trials have shown that the incidence of hypertension increases with increasing progestational activity.Women with history of hypertension or hypertension-related diseases, or renal disease70 should be encouraged to use another method of contraception. If these women elect to use oral contraceptives, they should be monitored closely and if clinically significant persistent elevation of blood pressure (BP) occurs (>= 160 mm Hg systolic or >= 100 mm Hg diastolic) and cannot be adequately controlled, oral contraceptives should be discontinued. In general, women who develop hypertension during hormonal contraceptive therapy should be switched to non-hormonal contraceptive. If other contraceptive methods are not suitable, hormonal contraceptive therapy may continue combined with antihypertensive therapy. Regular monitoring of BP throughout hormonal contraceptive therapy is recommended.96 For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension between former and never users.68-71 11. Headache. The onset or exacerbation of migraine or development of headache with new pattern which is recurrent, persistent or severe requires discontinuation of oral contraceptives and evaluation of the cause.. 12. Bleeding Irregularities. Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. Nonhormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out.Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such condition was preexistent.. 13. Ectopic Pregnancy. Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.