DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. The tablet dispenser has been designed to make oral contraceptive dosing as easy and as convenient as possible. The tablets are arranged in either three or four rows of seven tablets each, with the days of the week appearing on the tablet dispenser above the first row of tablets.Note: Each tablet dispenser has been preprinted with the days of the week, starting with Sunday, to facilitate Sunday-Start regimen. Six different day label strips have been provided with the Detailed Patient Brief Summary Patient Package Insert in order to accommodate Day-1 Start regimen. If the patient is using the Day-1 Start regimen, she should place the self-adhesive day label strip that corresponds to her starting day over the preprinted days.Important: The patient should be instructed to use an additional method of protection until after the first week of administration in the initial cycle when utilizing the Sunday-Start regimen.The possibility of ovulation and conception prior to initiation of use should be considered.Dosage and Administration for 21-Day Dosage RegimenTo achieve maximum contraceptive effectiveness, MICROGESTIN must be taken exactly as directed and at intervals not exceeding 24 hours. MICROGESTIN provides the patient with convenient tablet schedule of 3 weeks on--1 week off. Two dosage regimens are described, one of which may be more convenient or suitable than the other for an individual patient. For the initial cycle of therapy, the patient begins her tablets according to the Day-1 Start or Sunday-Start regimen. With either regimen, the patient takes one tablet daily for 21 consecutive days followed by one week of no tablets.A. Sunday-Start Regimen: The patient begins taking tablets from the top row on the first Sunday after menstrual flow begins. When menstrual flow begins on Sunday, the first tablet is taken on the same day. The last tablet in the dispenser will then be taken on Saturday, followed by no tablets for week (7 days). For all subsequent cycles, the patient then begins new 21-tablet regimen on the eighth day, Sunday, after taking her last tablet. Following this regimen, of 21 days on--7 days off, the patient will start all subsequent cycles on Sunday.B. Day-1 Regimen: The first day of menstrual flow is Day 1. The patient places the self-adhesive day label strip that corresponds to her starting day over the preprinted days on the tablet dispenser. She starts taking one tablet daily, beginning with the first tablet in the top row. The patient completes her 21-tablet regimen when she has taken the last tablet in the tablet dispenser. She will then take no tablets for week (7 days). For all subsequent cycles, the patient begins new 21-tablet regimen on the eighth day after taking her last tablet, again starting with the first tablet in the top row after placing the appropriate day label strip over the preprinted days on the tablet dispenser. Following this regimen of 21 days on--7 days off, the patient will start all subsequent cycles on the same day of the week as the first course. Likewise, the interval of no tablets will always start on the same day of the week.Tablets should be taken regularly with meal or at bedtime. It should be stressed that efficacy of medication depends on strict adherence to the dosage schedule.Special Notes on AdministrationMenstruation usually begins two or three days, but may begin as late as the fourth or fifth day, after discontinuing medication. If spotting occurs while on the usual regimen of one tablet daily, the patient should continue medication without interruption.If the patient forgets to take one or more tablets, the following is suggested:One tablet is missedtake tablet as soon as remembered take next tablet at the regular timeTwo consecutive tablets are missed (week or week 2)take two tablets as soon as remembered take two tablets the next day use another birth control method for seven days following the missed tabletsTwo consecutive tablets are missed (week 3)Sunday-Start Regimen:take one tablet daily until Sunday discard remaining tablets start new pack of tablets immediately (Sunday) use another birth control method for seven days following the missed tabletsDay-1 Start Regimen:discard remaining tablets start new pack of tablets that same day use another birth control method for seven days following the missed tabletsThree (or more) consecutive tablets are missedSunday-Start Regimen:take one tablet daily until Sunday discard remaining tablets start new pack of tablets immediately (Sunday) use another birth control method for seven days following the missed tabletsDay-1 Start Regimen:discard remaining tablets start new pack of tablets that same day use another birth control method for seven days following the missed tabletsThe possibility of ovulation occurring increases with each successive day that scheduled tablets are missed. While there is little likelihood of ovulation occurring if only one tablet is missed, the possibility of spotting or bleeding is increased. This is particularly likely to occur if two or more consecutive tablets are missed.In the rare case of bleeding which resembles menstruation, the patient should be advised to discontinue medication and then begin taking tablets from new tablet dispenser on the next Sunday or the first day (Day 1), depending on her regimen. Persistent bleeding which is not controlled by this method indicates the need for reexamination of the patient, at which time nonfunctional causes should be considered.Dosage and Administration for 28-Day Dosage RegimenTo achieve maximum contraceptive effectiveness, MICROGESTIN Fe should be taken exactly as directed and at intervals not exceeding 24 hours.MICROGESTIN Fe provides continuous administration regimen consisting of 21 light-colored (white or green) tablets of MICROGESTIN and brown non-hormone containing tablets of ferrous fumarate. The ferrous fumarate tablets are present to facilitate ease of drug administration via 28-day regimen and do not serve any therapeutic purpose. There is no need for the patient to count days between cycles because there are no off-tablet days.A. Sunday-Start Regimen: The patient begins taking the first light-colored tablet from the top row of the dispenser (labeled Sunday) on the first Sunday after menstrual flow begins. When the menstrual flow begins on Sunday, the first light-colored tablet is taken on the same day. The patient takes one light-colored tablet daily for 21 days. The last light-colored tablet in the dispenser will be taken on Saturday. Upon completion of all 21 light-colored tablets, and without interruption, the patient takes one brown tablet daily for days. Upon completion of this first course of tablets, the patient begins second course of 28-day tablets, without interruption, the next day (Sunday), starting with the Sunday light-colored tablet in the top row. Adhering to this regimen of one light-colored tablet daily for 21 days, followed without interruption by one brown tablet daily for seven days, the patient will start all subsequent cycles on Sunday.B. Day-1 Start Regimen: The first day of menstrual flow is Day 1. The patient places the self-adhesive day label strip that corresponds to her starting day over the preprinted days on the tablet dispenser. She starts taking one light-colored tablet daily, beginning with the first light-colored tablet in the top row. After the last light-colored tablet (at the end of the third row) has been taken, the patient will then take the brown tablets for week (7 days). For all subsequent cycles, the patient begins new 28 tablet regimen on the eighth day after taking her last light-colored tablet, again starting with the first tablet in the top row after placing the appropriate day label strip over the preprinted days on the tablet dispenser. Following this regimen of 21 light-colored tablets and brown tablets, the patient will start all subsequent cycles on the same day of the week as the first course.Tablets should be taken regularly with meal or at bedtime. It should be stressed that efficacy of medication depends on strict adherence to the dosage schedule.Special Notes on AdministrationMenstruation usually begins two or three days, but may begin as late as the fourth or fifth day, after the brown tablets have been started. In any event, the next course of tablets should be started without interruption. If spotting occurs while the patient is taking light-colored tablets, continue medication without interruption.If the patient forgets to take one or more light-colored tablets, the following is suggested:One tablet is missedtake tablet as soon as remembered take next tablet at the regular timeTwo consecutive tablets are missed (week or week 2)take two tablets as soon as remembered take two tablets the next day use another birth control method for seven days following the missed tabletsTwo consecutive tablets are missed (week 3)Sunday-Start Regimen:take one tablet daily until Sunday discard remaining tablets start new pack of tablets immediately (Sunday) use another birth control method for seven days following the missed tabletsDay-1 Start Regimen:discard remaining tablets start new pack of tablets that same day use another birth control method for seven days following the missed tabletsThree (or more) consecutive tablets are missedSunday-Start Regimen:take one tablet daily until Sunday discard remaining tablets start new pack of tablets immediately (Sunday) use another birth control method for seven days following the missed tabletsDay-1 Start Regimen:discard remaining tablets start new pack of tablets that same day use another birth control method for seven days following the missed tablets The possibility of ovulation occurring increases with each successive day that scheduled light-colored tablets are missed. While there is little likelihood of ovulation occurring if only one light-colored tablet is missed, the possibility of spotting or bleeding is increased. This is particularly likely to occur if two or more consecutive light-colored tablets are missed.If the patient forgets to take any of the seven brown tablets in week four, those brown tablets that were missed are discarded and one brown tablet is taken each day until the pack is empty. back-up birth control method is not required during this time. new pack of tablets should be started no later than the eighth day after the last light-colored tablet was taken.In the rare case of bleeding which resembles menstruation, the patient should be advised to discontinue medication and then begin taking tablets from new tablet dispenser on the next Sunday or the first day (Day-1), depending on her regimen. Persistent bleeding which is not controlled by this method indicates the need for reexamination of the patient, at which time nonfunctional causes should be considered.Use of Oral Contraceptives in the Event of Missed Menstrual Period1. If the patient has not adhered to the prescribed dosage regimen, the possibility of pregnancy should be considered after the first missed period and oral contraceptives should be withheld until pregnancy has been ruled out.2. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen.After several months on treatment, bleeding may be reduced to point of virtual absence. This reduced flow may occur as result of medication, in which event it is not indicative of pregnancy.. take tablet as soon as remembered take next tablet at the regular time. take two tablets as soon as remembered take two tablets the next day use another birth control method for seven days following the missed tablets. take one tablet daily until Sunday discard remaining tablets start new pack of tablets immediately (Sunday) use another birth control method for seven days following the missed tablets. discard remaining tablets start new pack of tablets that same day use another birth control method for seven days following the missed tablets. take one tablet daily until Sunday discard remaining tablets start new pack of tablets immediately (Sunday) use another birth control method for seven days following the missed tablets. discard remaining tablets start new pack of tablets that same day use another birth control method for seven days following the missed tablets. take tablet as soon as remembered take next tablet at the regular time. take two tablets as soon as remembered take two tablets the next day use another birth control method for seven days following the missed tablets. take one tablet daily until Sunday discard remaining tablets start new pack of tablets immediately (Sunday) use another birth control method for seven days following the missed tablets. discard remaining tablets start new pack of tablets that same day use another birth control method for seven days following the missed tablets. take one tablet daily until Sunday discard remaining tablets start new pack of tablets immediately (Sunday) use another birth control method for seven days following the missed tablets. discard remaining tablets start new pack of tablets that same day use another birth control method for seven days following the missed tablets.

PRECAUTIONS SECTION.

PRECAUTIONS. 1. Patients 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 hyperlipidemia 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. Effects of Other Drugs on Oral Contraceptives (78)Rifampin: Metabolism of both norethindrone and ethinyl estradiol is increased by rifampin. reduction in contraceptive effectiveness and increased incidence of breakthrough bleeding and menstrual irregularities have been associated with concomitant use of rifampin.Anticonvulsants: Anticonvulsants such as phenobarbital, phenytoin, and carbamazepine, have been shown to increase the metabolism of ethinyl estradiol and/or norethindrone, which could result in reduction in contraceptive effectiveness.Troglitazone: Administration of troglitazone with an oral contraceptive containing ethinyl estradiol and norethindrone reduced the plasma concentrations of both by approximately 30%, which could result in reduction in contraceptive effectiveness.Antibiotics: Pregnancy while taking oral contraceptives has been reported when the oral contraceptives were administered with antimicrobials such as ampicillin, tetracycline, and griseofulvin. However, clinical pharmacokinetic studies have not demonstrated any consistent effect of antibiotics (other than rifampin) on plasma concentrations of synthetic steroids.Atorvastatin: Coadministration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol by approximately 30% and 20%, respectively.Concomitant Use with HCV Combination Therapy= Liver Enzyme Elevation: Do not co-administer MICROGESTIN and MICROGESTIN Fe with HCV 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)Other: Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. reduction in contraceptive effectiveness and increased incidence of breakthrough bleeding has been suggested with phenylbutazone.Effects of Oral Contraceptives on Other DrugsOral contraceptive combinations containing ethinyl estradiol may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporine, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives. In addition, oral contraceptives may induce the conjugation of other compounds. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine, and clofibric acid have been noted when these drugs were administered with oral contraceptives.. 9. Interactions With Laboratory Tests. Certain endocrine and liver function tests and blood components may be affected by oral contraceptives:a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.b. 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.c. Other binding proteins may be elevated in serum.d. 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.e. Triglycerides may be increased.f. Glucose tolerance may be decreased.g. 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 section.. 11. Pregnancy. See CONTRAINDICATIONS and WARNINGS sections.. 12. Nursing Mothers. Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers, and few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child.. 13. Pediatric Use. Safety and efficacy of MICROGESTIN 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.

REFERENCES SECTION.

REFERENCES. 1. Back DJ, Breckenridge AM, Crawford FE, McIver M, Orme MLE, Rowe PH and Smith E: Kinetics of norethindrone in women II. Single-dose kinetics. Clin Pharmacol Ther 1978; 24:448-453. 2. Humpel M, Nieuweboer B, Wendt and Speck U: Investigations of pharmacokinetics of ethinyloestradiol to specific consideration of possible first-pass effect in women. Contraception 1979;19:421-432. 3. Back DJ, Breckenridge AM, Crawford FE, MacIver M, Orme MLE, Rowe PH and Watts MJ. An investigation of the pharmacokinetics of ethynylestradiol in women using radioimmunoassay. Contraception 1979; 20:263-273. 4. Hammond GL, Lahteenmaki PLA, Lahteenmaki and Luukkainen T. Distribution and percentages of non-protein bound contraceptive steroids in human serum. Steriod Biochem 1982;17:375-380. 5. Fotherby K. Pharmacokinetics and metabolism of progestins in humans, in Pharmacology of the contraceptive steroids, Goldzieher JW, Fotherby (eds), Raven Press, Ltd., New York, 1994; 99-126. 6. Goldzieher JW. Pharmacokinetics and metabolism of ethynyl estrogens, in Pharmacology of the contraceptive steroids, Goldzieher JW, Fotherby (eds), Raven Press Ltd., New York, 1994; 127-151. 7. Hatcher RA, et al. 1998. Contraceptive Technology, Seventeenth Edition. New York: Irvington Publishers. 8. Stadel, B.V.: Oral contraceptives and cardiovascular disease. (Pt. 1). New England Journal of Medicine, 305:612-618, 1981. 9. Stadel, B.V.: Oral contraceptives and cardiovascular disease. (Pt. 2). New England Journal of Medicine, 305:672-677, 1981. 10. Adam, S.A., and M. Thorogood: Oral contraception and myocardial infarction revisited: The effects of new preparations and prescribing patterns. Brit. J. Obstet. and Gynec., 88:838-845, 1981. 11. Mann, J.I., and W.H. Inman: Oral contraceptives and death from myocardial infarction. Brit. Med. J., 2(5965): 245-248, 1975. 12. Mann, J.I., M.P. Vessey, M. Thorogood, and R. Doll: Myocardial infarction in young women with special reference to oral contraceptive practice. Brit. Med. J., 2(5956):241-245, 1975. 13. Royal College of General Practitioners Oral Contraception Study: Further analyses of mortality in oral contraceptive users. Lancet, 1:541-546, 1981. 14. Slone, D., S. Shapiro, D.W. Kaufman, L. Rosenberg, O.S. Miettinen, and P.D. Stolley: Risk of myocardial infarction in relation to current and discontinued use of oral contraceptives. N.E.J.M., 305:420-424, 1981. 15. Vessey, M.P.: Female hormones and vascular disease: An epidemiological overview. Brit. J. Fam.Plann., 6:1-12, 1980. 16. Russell-Briefel, R.G., T.M. Ezzati, R. Fulwood, J.A. Perlman, and R.S. Murphy: Cardiovascular risk status and oral contraceptive use, United States, 1976-80. Preventive Medicine, 15:352-362, 1986. 17. Goldbaum, G.M., J.S. Kendrick, G.C. Hogelin, and E.M. Gentry: The relative impact of smoking and oral contraceptive use on women in the United States. J.A.M.A., 258:1339-1342, 1987. 18. Layde, P.M., and V. Beral: Further analyses of mortality in oral contraceptive users: Royal College General Practitioners Oral Contraception Study. (Table 5) Lancet, 1:541-546, 1981. 19. Knopp, R.H.: Arteriosclerosis risk: The roles of oral contraceptives and postmenopausal estrogens. J. ofReprod. Med., 31(9)(Supplement): 913-921, 1986. 20. Krauss, R.M., S. Roy, D.R. Mishell, J. Casagrande, and M.C. Pike: Effects of two low-dose oral contraceptives on serum lipids and lipoproteins: Differential changes in high-density lipoproteins subclasses. Am. J. Obstet. Gyn., 145:446-452, 1983. 21. Wahl, P., C. Walden, R. Knopp, J. Hoover, R. Wallace, G. Heiss, and B. Rifkind: Effect of estrogen/progestin potency on lipid/lipoprotein cholesterol. N.E.J.M., 308:862-867, 1983. 22. Wynn, V., and R. Niththyananthan: The effect of progestin in combined oral contraceptives on serum lipids with special reference to high-density lipoproteins. Am. J. Obstet. and Gyn., 142:766-771, 1982. 23. Wynn, V., and I. Godsland: Effects of oral contraceptives on carbohydrate metabolism. J. Reprod.Medicine, 31 (9)(Supplement): 892-897, 1986. 24. LaRosa, J.C.: Atherosclerotic risk factors in cardiovascular disease. J. Reprod. Med., 31(9)(Supplement): 906-912, 1986. 25. Inman, W.H., and M.P. Vessey: Investigations of death from pulmonary, coronary, and cerebral thrombosis and embolism in women of child-bearing age. Brit. Med. J., 2(5599): 193-199, 1968. 26. Maguire, M.G., J. Tonascia, P.E. Sartwell, P.D. Stolley, and M.S. Tockman: Increased risk of thrombosis due to oral contraceptives: further report. Am. J. Epidemiology, 110(2): 188-195, 1979. 27. Pettiti, D.B., J. Wingerd, F. Pellegrin, and S. Ramacharan: Risk of vascular disease in women: Smoking, oral contraceptives, noncontraceptive estrogens, and other factors. J.A.M.A., 242:1150-1154, 1979. 28. Vessey, M.P., and R. Doll: Investigation of relation between use of oral contraceptives and thromboembolic disease. Brit. Med. J., 2(5599): 199-205, 1968. 29. Vessey, M.P., and R. Doll: Investigation of relation between use of oral contraceptives and thromboembolic disease: further report. Brit. Med. J., 2(5658): 651-657, 1969. 30. Porter, J.B., J.R. Hunter, D.A. Danielson, H. Jick, and A. Stergachis: Oral contraceptives and non-fatal vascular disease: Recent experience. Obstet. and Gyn., 59(3):299-302, 1982. 31. Vessey, M., R. Doll, R. Peto, B. Johnson, and P. Wiggins: long-term follow-up study of women using different methods of contraception: An interim report. J. Biosocial. Sci., 8:375-427, 1976. 32. Royal College of General Practitioners: Oral contraceptives, venous thrombosis, and varicose veins. J.of Royal College of General Practitioners, 28:393-399, 1978. 33. Collaborative Group for the study of stroke in young women: Oral contraception and increased risk of cerebral ischemia or thrombosis. N.E.J.M., 288:871-878, 1973. 34. Petitti, D.B., and J. Wingerd: Use of oral contraceptives, cigarette smoking, and risk of subarachnoid hemorrhage. Lancet, 2:234-236, 1978. 35. Inman, W.H.: Oral contraceptives and fatal subarachnoid hemorrhage. Brit. Med. J., 2(6203): 1468-70, 1979. 36. Collaborative Group for the study of stroke in young women: Oral contraceptives and stroke in young women: Associated risk factors. J.A.M.A., 231:718-722, 1975. 37. Inman, W.H., M.P. Vessey, B. Westerholm, and A. Engelund: Thromboembolic disease and the steroidal content of oral contraceptives. report to the Committee on Safety of Drugs. Brit. Med. J., 2:203-209, 1970. 38. Meade, T.W., G. Greenberg, and S.G. Thompson: Progestogens and cardiovascular reactions associated with oral contraceptives and comparison of the safety of 50- and 35-mcg oestrogen preparations. Brit.Med. J., 280(6224): 1157-1161, 1980. 39. Kay, C.R.: Progestogens and arterial disease: Evidence from the Royal College of General Practitioners study. Amer. J. Obstet. Gyn., 142:762-765, 1982. 40. Royal College of General Practitioners: Incidence of arterial disease among oral contraceptive users. J.Coll. Gen. Pract., 33:75-82, 1983. 41. Ory, H.W: Mortality associated with fertility and fertility control:1983. Family Planning Perspectives, 15:50-56, 1983. 42. 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. N.E.J.M., 315: 405-411, 1986. 43. Pike, M.C., B.E. Henderson, M.D. Krailo, A. Duke, and S. Roy: Breast cancer in young women and use of oral contraceptives: Possible modifying effect of formulation and age at use. Lancet, 2:926-929, 1983. 44. Paul, C., D.G. Skegg, G.F.S. Spears, and J.M. Kaldor: Oral contraceptives and breast cancer: national study. Brit. Med. J., 293:723-725, 1986. 45. Miller, D.R., L. Rosenberg, D.W. Kaufman, D. Schottenfeld, P.D. Stolley, and S. Shapiro: Breast cancer risk in relation to early oral contraceptive use. Obstet. Gynec., 68:863-868, 1986. 46. Olson, H., K.L. Olson, T.R. Moller, J. Ranstam, P. Holm: Oral contraceptive use and breast cancer in young women in Sweden (letter). Lancet, 2:748-749, 1985. 47. McPherson, K., M. Vessey, A. Neil, R. Doll, L. Jones, and M. Roberts: Early contraceptive use and breast cancer: Results of another case-control study. Brit. J. Cancer, 56: 653-660, 1987. 48. Huggins, G.R., and P.F. Zucker: Oral contraceptives and neoplasia: 1987 update. Fertil. Steril., 47:733-761, 1987. 49. McPherson, K., and J.O. Drife: The pill and breast cancer: Why the uncertainty Brit. Med. J., 293:709-710, 1986. 50. Shapiro, S.: Oral contraceptives: Time to take stock. N.E.J.M., 315:450-451, 1987. 51. Ory, H., Z. Naib, S.B. Conger, R.A. Hatcher, and C.W. Tyler: Contraceptive choice and prevalence of cervical dysplasia and carcinoma in situ. Am. J. Obstet. Gynec., 124:573-577, 1976. 52. Vessey, M.P., M. Lawless, K. McPherson, D. Yeates: Neoplasia of the cervix uteri and contraception: possible adverse effect of the pill. Lancet, 2:930, 1983. 53. Brinton, L.A., G.R. Huggins, H.F. Lehman, K. Malli, D.A. Savitz, E. Trapido, J. Rosenthal, and R. Hoover: Long-term use of oral contraceptives and risk of invasive cervical cancer. Int. J. Cancer, 38:339-344, 1986. 54. WHO Collaborative Study of Neoplasia and Steroid Contraceptives: Invasive cervical cancer and combined oral contraceptives. Brit. Med. J., 290:961-965, 1985. 55. Rooks, J.B., H.W. Ory, K.G. Ishak, L.T. Strauss, J.R. Greenspan, A.P. Hill, and C.W. Tyler: Epidemiology of hepatocellular adenoma: The role of oral contraceptive use. J.A.M.A., 242:644-648, 1979. 56. Bein, N.N., and H.S. Goldsmith: Recurrent massive hemorrhage from benign hepatic tumors secondary to oral contraceptives. Brit. J. Surg., 64:433-435, 1977. 57. Klatskin, G.: Hepatic tumors: Possible relationship to use of oral contraceptives. Gastroenterology, 73:386-394, 1977. 58. Henderson, B.E., S. Preston-Martin, H.A. Edmondson, R.L. Peters, and M.C. Pike: Hepatocellular carcinoma and oral contraceptives. Brit. J. Cancer, 48:437-440, 1983. 59. Neuberger, J., D. Forman, R. Doll, and R. Williams: Oral contraceptives and hepatocellular carcinoma. Brit. Med. J., 292:1355-1357, 1986. 60. Forman, D., T.J. Vincent, and R. Doll: Cancer of the liver and oral contraceptives. Brit. Med. J., 292: 1357-1361, 1986. 61. Harlap, S., and J. Eldor: Births following oral contraceptive failures. Obstet. Gynec., 55:447-452, 1980. 62. Savolainen, E., E. Saksela, and L. Saxen: Teratogenic hazards of oral contraceptives analyzed in national malformation register. Amer. J. Obstet. Gynec., 140:521-524, 1981. 63. Janerich, D.T., J.M. Piper, and D.M. Glebatis: Oral contraceptives and birth defects. Am. J.Epidemiology, 112:73-79, 1980. 64. Ferencz, C., G.M. Matanoski, P.D. Wilson, J.D. Rubin, C.A. Neill, and R. Gutberlet: Maternal hormone therapy and congenital heart disease. Teratology, 21:225-239, 1980. 65. Rothman, K.J., D.C. Fyler, A. Goldbatt, and M.B. Kreidberg: Exogenous hormones and other drug exposures of children with congenital heart disease. Am. J. Epidemiology, 109:433-439, 1979. 66. Boston Collaborative Drug Surveillance Program: Oral contraceptives and venous thromboembolic disease, surgically confirmed gallbladder disease, and breast tumors. Lancet, 1:1399-1404, 1973. 67. Royal College of General Practitioners: Oral Contraceptives and Health. New York, Pittman, 1974, 100p. 68. Layde, P.M., M.P. Vessey, and D. Yeates: Risk of gallbladder disease: cohort study of young women attending family planning clinics. J. of Epidemiol. and Comm. Health, 36: 274-278, 1982. 69. Rome Group for the Epidemiology and Prevention of Cholelithiasis (GREPCO): Prevalence of gallstone disease in an Italian adult female population. Am. J. Epidemiol., 119:796-805, 1984. 70. Strom, B.L., R.T. Tamragouri, M.L. Morse, E.L. Lazar, S.L. West, P. D. Stolley, and J.K. Jones: Oral contraceptives and other risk factors for gallbladder disease. Clin. Pharmacol. Ther., 39:335-341, 1986. 71. Wynn, V., P.W. Adams, I.F. Godsland, J. Melrose, R. Niththyananthan, N.W. Oakley, and A. Seedj: Comparison of effects of different combined oral-contraceptive formulations on carbohydrate and lipid metabolism. Lancet, 1:1045-1049, 1979. 72. Wynn, V.: Effect of progesterone and progestins on carbohydrate metabolism. In Progesterone and Progestin. Edited by C.W. Bardin, E. Milgrom, P. Mauvis-Jarvis. New York, Raven Press, pp. 395-410, 1983. 73. Perlman, J.A., R. G. Roussell-Briefel, T.M. Ezzati, and G. Lieberknecht: Oral glucose tolerance and the potency of oral contraceptive progestogens. J. Chronic Dis., 38:857-864, 1985. 74. Royal College of General Practitioners Oral Contraception Study: Effect on hypertension and benign breast disease of progestogen component in combined oral contraceptives. Lancet, 1:624, 1977. 75. Fisch, I.R., and J. Frank: Oral contraceptives and blood pressure. J.A.M.A., 237:2499-2503, 1977. 76. Laragh, A.J.: Oral contraceptive induced hypertension: Nine years later. Amer. J. Obstet. Gynecol., 126:141-147, 1976. 77. Ramcharan, S., E. Peritz, F.A. Pellegrin, and W.T. Williams: Incidence of hypertension in the Walnut Creek Contraceptive Drug Study cohort. In Pharmacology of Steroid Contraceptive Drugs. Edited by S. Garattini and H.W. Berendes. New York, Raven Press, pp. 277-288, 1977. (Monographs of the Mario Negri Institute for Pharmacological Research, Milan.) 78. Back DJ, Orme MLE. Drug interactions, in Pharmacology of the contraceptive steroids. Goldzieher JW, Fotherby (eds), Raven Press, Ltd., New York, 1994, 407-425. 79. 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. J.A.M.A., 249:1596-1599, 1983. 80. 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. J.A.M.A., 257:796-800, 1987. 81. Ory, H.W.: Functional ovarian cysts and oral contraceptives: Negative association confirmed surgically. J.A.M.A., 228:68-69, 1974. 82. Ory, H.W., P. Cole, B. Macmahon, and R. Hoover: Oral contraceptives and reduced risk of benign breast disease. N.E.J.M., 294:41-422, 1976. 83. Ory, H.W.: The noncontraceptive health benefits from oral contraceptive use. Fam. Plann. Perspectives, 14:182-184, 1982. 84. Ory, H.W., J.D. Forrest, and R. Lincoln: Making Choices: Evaluating the health risks and benefits of birth control methods. New York, The Alan Guttmacher Institute, p.1, 1983. 85. Miller, D.R., L. Rosenberg, D.W. Kaufman, P. Stolley, M.E. Warshauer, and S. Shapiro: Breast cancer before age 45 and oral contraceptive use: new findings. Am. J. Epidemiol., 129:269-280, 1989. 86. Kay, C.R., and P.C. Hannaford: Breast cancer and the pill: further report from the Royal College of General Practitioners Oral Contraception Study. Br. J. Cancer, 58:675-680, 1988. 87. Stadel, B.V., S. Lai, J.J. Schlesselman, and P. Murray: Oral contraceptives and premenopausal breast cancer in nulliparous women. Contraception, 38:287-299, 1988. 88. UK National Case--Control Study Group: Oral contraceptive use and breast cancer risk in young women. Lancet, 973-982, 1989. 89. Romieu, I., W.C. Willett, G.A. Colditz, M.J. Stampfer, B. Rosner, C.H. Hennekens, and F.E. Speizer: Prospective study of oral contraceptive use and risk of breast cancer in women. J. Natl. Cancer Inst., 81:1313-1321, 1989.Distributed by: Mayne Pharma Greenville, NC 27834MICROGESTIN(R) is registered trademark of Mayne Pharma LLC.Revised: June 2020MIC-001The patient labeling for oral contraceptive drug products is set forth below:.

SPL PATIENT PACKAGE INSERT SECTION.

BRIEF SUMMARY PATIENT PACKAGE INSERT. MICROGESTIN(R)(Norethindrone Acetate and Ethinyl Estradiol Tablets, USP)MICROGESTIN(R) 1/20 (Each white tablet contains mg norethindrone acetate and 20 mcg ethinyl estradiol.) MICROGESTIN(R) 1.5/30 (Each green tablet contains 1.5 mg norethindrone acetate and 30 mcg ethinyl estradiol.)MICROGESTIN(R) Fe (Norethindrone Acetate and Ethinyl Estradiol Tablets, USP and Ferrous Fumarate Tablets) Ferrous fumarate tablets are not USP for dissolution and assay.MICROGESTIN(R) Fe 1/20 (Each white tablet contains mg norethindrone acetate and 20 mcg ethinyl estradiol. Each brown tablet contains 75 mg ferrous fumarate.)MICROGESTIN(R) Fe 1.5/30 (Each green tablet contains 1.5 mg norethindrone acetate and 30 mcg ethinyl estradiol. Each brown tablet contains 75 mg ferrous fumarate.)This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted diseases.Oral contraceptives, also known as birth control pills or the pill, are taken to prevent pregnancy and, when taken correctly, have failure rate of about 1% per year when used without missing any pills. The typical failure rate of large numbers of pill users is less than 3% 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 life-threatening or may cause temporary or permanent disability. The risks associated with taking oral contraceptives increase significantly if you:1. Smoke2. Have high blood pressure, diabetes, high cholesterol3. 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.You should not take the pill if you suspect you are pregnant or have unexplained vaginal bleeding.Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke.Most side effects of the pill are not serious. The most common side effects are nausea, vomiting, bleeding between menstrual periods, weight gain, breast tenderness, and difficulty wearing contact lenses. These side effects, especially nausea, vomiting, and breakthrough bleeding 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:1. 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.2. Liver tumors, which may rupture and cause severe bleeding. possible but not definite association has been found with the pill and liver cancer. However, liver cancers are extremely rare. The chance of developing liver cancer from using the pill is thus even rarer.3. 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 doctor or healthcare provider if you notice any unusual physical disturbances while taking the pill. In addition, drugs such as rifampin, as well as some anticonvulsants and some antibiotics, may decrease oral contraceptive effectiveness.Most of the studies to date on breast cancer and pill use have found no increase in the risk of developing breast cancer, although some studies have reported an increased risk of developing breast cancer in certain groups of women. However, some studies have found an increase in the risk of developing cancer of the cervix in women taking the pill, but this finding may be related to differences in sexual behavior or other factors not related to use of the pill. Therefore, there is insufficient evidence to rule out the possibility that the pill may cause cancer of the breast or cervix.Taking the 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 provider. Your healthcare provider will take medical and family history and examine you before prescribing oral contraceptives. The physical examination may be delayed to another time if you request it and your healthcare provider believes that it is good medical practice to postpone it. You should be reexamined at least once year while taking oral contraceptives. The detailed patient information leaflet gives you further information which you should read and discuss with your healthcare provider.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 and syphilis.INSTRUCTIONS TO PATIENTTABLET DISPENSERThe MICROGESTIN tablet dispenser has been designed to make oral contraceptive dosing as easy and as convenient as possible. The tablets are arranged in either three or four rows of seven tablets each with the days of the week appearing above the first row of tablets.If your TABLET DISPENSER contains:You are taking:21 white tabletsMICROGESTIN 1/2021 green tabletsMICROGESTIN 1.5/3021 white tablets and brown tabletsMICROGESTIN Fe 1/2021 green tablets and brown tabletsMICROGESTIN Fe 1.5/30Each white tablet contains mg norethindrone acetate and 20 mcg ethinyl estradiol.Each green tablet contains 1.5 mg norethindrone acetate and 30 mcg ethinyl estradiol.Each brown tablet contains 75 mg ferrous fumarate, and is intended to help you remember to take the tablets correctly. These brown tablets are not intended to have any health benefit.DIRECTIONSTo remove tablet, press down on it with your thumb or finger. The tablet will drop through the back of the tablet dispenser. Do not press with your thumbnail, fingernail, or any other sharp object.HOW TO TAKE THE PILLIMPORTANT POINTS TO REMEMBERBEFORE YOU START TAKING YOUR PILLS:1. BE SURE TO READ THESE DIRECTIONS:Before you start taking your pills.Anytime you are not sure what to do.2. 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.3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you do have spotting or light bleeding or 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 doctor or clinic.4. 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.5. IF YOU HAVE VOMITING OR DIARRHEA, for any reason, or IF YOU TAKE SOME MEDICINES, including some antibiotics, your birth control pills may not work as well. Use back-up birth control method (such as condoms or foam) until you check with your doctor or clinic.6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your doctor or clinic about how to make pill-taking easier or about using another method of birth control.7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your doctor or clinic.BEFORE YOU START TAKING YOUR PILLS1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day.2. LOOK AT YOUR PILL PACK TO SEE IF IT HAS 21 OR 28 PILLS:The 21-Day pill pack has 21 active white or green pills (with hormones) to take for weeks, followed by week without pills.The 28-Day pill pack has 21 active white or green pills (with hormones) to take for weeks, followed by week of reminder brown pills (without hormones).3. ALSO FIND:1) where on the pack to start taking pills,2) in what order to take the pills (follow the arrows), and3) the week numbers as shown in the following pictures:MICROGESTIN 1/20 will contain: ALL WHITE PILLS.MICROGESTIN 1.5/30 will contain: ALL GREEN PILLS.MICROGESTIN Fe 1/20 will contain: 21 WHITE PILLS for WEEKS 1, 2, and 3. WEEK will contain BROWN PILLS ONLY. MICROGESTIN Fe 1.5/30 will contain: 21 GREEN PILLS for WEEKS 1, 2, and 3. WEEK will contain BROWN PILLS ONLY. 4. BE SURE YOU HAVE READY AT ALL TIMES:ANOTHER KIND OF BIRTH CONTROL (such as condoms or foam) to use as back-up 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. Decide with your doctor or clinic which is the best day for you. Pick time of day which will be easy to remember.DAY-1 START:1. Pick the day label strip that starts with the first day of your period. (This is the day you start bleeding or spotting, even if it is almost midnight when the bleeding begins.)2. Place this day label strip on the tablet dispenser over the area that has the days of the week (starting with Sunday) printed on the plastic.3. Take the first active white or green pill of the first pack during the first 24 hours of your period.4. You will not need to use back-up method of birth control, since you are starting the pill at the beginning of your period.SUNDAY START:1. Take the first active white or green 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 that same day.2. Use another method of birth control as back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). Condoms or foam are good back-up methods of birth control.WHAT TO DO DURING THE MONTH1. 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.2. 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 reminder pill. Do not wait any days between packs.WHAT TO DO IF YOU MISS PILLSIf you MISS white or green active pill:1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take pills in day.2. You do not need to use back-up birth control method if you have sex.If you MISS white or green active pills in row in WEEK OR WEEK of your pack:1. Take pills on the day you remember and pills the next day.2. Then take pill day until you finish the pack.3. You COULD GET PREGNANT if you have sex in the days after you miss pills. You MUST use another birth control method (such as condoms or foam) as back-up method of birth control until you have taken white or green active pill every day for days.If you MISS white or green active pills in row in THE 3rd WEEK:1. If you are Day-1 Starter:THROW OUT the rest of the pill pack and start new pack that same day.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.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 GET PREGNANT if you have sex in the days after you miss pills. You MUST use another birth control method (such as condoms or foam) as back-up method of birth control until you have taken white or green active pill every day for days.If you MISS OR MORE white or green active pills in row (during the first weeks):1. If you are Day-1 Starter:THROW OUT the rest of the pill pack and start new pack that same day.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.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 GET PREGNANT if you have sex in the days after you miss pills. You MUST use another birth control method (such as condoms or foam) as back-up method of birth control until you have taken white or green active pill every day for days.A REMINDER FOR THOSE ON 28-DAY PACKS:IF YOU FORGET ANY OF THE BROWN 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 WHITE OR GREEN ACTIVE PILL EACH DAY until you can reach your doctor or clinic.Based on his or her assessment of your medical needs, your doctor or healthcare provider has prescribed this drug for you. Do not give this drug to anyone else.Keep this and all drugs out of the reach of children.Rx onlyStore below 30o (86o F). Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke.Distributed by: Mayne Pharma Greenville, NC 27834MICROGESTIN(R) is registered trademark of Mayne Pharma LLC.Revised: June 2020MICBPL-001 Microgestin Birth Control Pack. MICROGESTIN Fe 1/20 will contain: 21 WHITE PILLS for WEEKS 1, 2, and 3. WEEK will contain BROWN PILLS ONLY. MICROGESTIN Fe 1.5/30 will contain: 21 GREEN PILLS for WEEKS 1, 2, and 3. WEEK will contain BROWN PILLS ONLY.

WARNINGS SECTION.

WARNINGS. Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.The use of oral contraceptives is associated with increased 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 References 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 infarctionAn 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 (10-16). 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 (17). Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and non-smokers over the age of 40 (Table II) among women who use oral contraceptives.Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity (19). In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create state of hyperinsulinism (20-24). Oral contraceptives have been shown to increase blood pressure among users (see section 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.b. ThromboembolismAn 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 non-users 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 (9, 10, 25-30). Cohort studies have shown the relative risk to be somewhat lower, about for new cases and about 4.5 for new cases requiring hospitalization (31). The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped (8).A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives (15,32). The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions (15,32). 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 to six weeks after delivery in women who elect not to breastfeed.c. Cerebrovascular diseaseOral 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 (greater than 35 years), hypertensive women who also smoke. Hypertension was found to be risk factor for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes (33-35).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 (36). 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 (36). The attributable risk is also greater in older women (9).d. Dose-related risk of vascular disease from oral contraceptives.A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease (37-39). decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents (20-22). 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 progestin and the nature of the progestin used in the contraceptives. The amount and activity 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 oral contraceptive, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest dose of estrogen which produces satisfactory results for the patient.e. Persistence of risk of vascular diseaseThere 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 or more years, but this increased risk was not demonstrated in other age groups (14). 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 (40). However, both studies were performed with oral contraceptive formulations containing 50 mcg or higher of estrogens.. Table II Circulatory Disease Mortality Rates per 100,000 Women years by age, smoking status and oral contraceptive Use. 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 III). 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 possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970s but not reported until 1983 (41). However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral contraceptive use to women who do not have the various risk factors listed in this labeling.Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed (Porter JB, Hunter J, Jick H, et al. Oral contraceptives and nonfatal vascular disease. Obstet Gynecol 1985;66:1-4; and Porter JB, Hershel J, Walker AM. Mortality among oral contraceptive users. Obstet Gynecol 1987;70:29-32), the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989. 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 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.Therefore, the Committee recommended that the benefits of 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 the lowest possible dose formulation that is effective.TABLE III: 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 15-1920-2425-2930-3435-3940-44No fertility control methods 7.07.49.114.825.728.2Oral contraceptives non-smoker 0.30.50.91.913.831.6Oral contraceptives smoker 2.23.46.613.551.1117.2IUD 0.80.81.01.01.41.4Condom 1.11.60.70.20.30.4Diaphragm/spermicide 1.91.21.21.32.22.8Periodic abstinence2.51.61.61.72.93.6Deaths are birth related.Deaths are method related.Adapted from H.W. Ory, Reference 41.. 3. Carcinoma of the Reproductive Organs. Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian, and cervical cancer in women using oral contraceptives. Most of the studies on breast cancer and oral contraceptive use report that the use of oral contraceptives is not associated with an increase in the risk of developing breast cancer (42,44,89). Some studies have reported an increased risk of developing breast cancer in certain subgroups of oral contraceptive users, but the findings reported in these studies are not consistent (43,45-49,85-88).Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women (51-54). 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 (55).Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage (56,57).Studies from Britain have shown an increased risk of developing hepatocellular carcinoma (58-60) in long-term (greater than 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 MICROGESTIN and MICROGESTIN Fe prior to starting therapy with the combination regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4)]. MICROGESTIN and MICROGESTIN Fe 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 and During Early Pregnancy. Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy (61-63). Studies also do not suggest teratogenic effect, particularly insofar as cardiac anomalies and limb reduction defects are concerned (61,62,64,65), 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 before continuing oral contraceptive use. 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 (66,67). More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal (68-70). 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 glucose intolerance in significant percentage of users (23). Oral contraceptives containing greater than 75 mcg of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance (71). Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents (23,72). However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose (73). Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives. 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. An increase in blood pressure has been reported in women taking oral contraceptives (74) and this increase is more likely in older oral contraceptive users (75) and with continued use (74). Data from the Royal College of General Practitioners (18) and subsequent randomized trials have shown that the incidence of hypertension increases with increasing concentrations of progestogens. Women with history of hypertension or hypertension-related diseases or renal disease (76) should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely, and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives (75), and there is no difference in the occurrence of hypertension among ever and never users. (74,76,77) 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. Non-hormonal 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.