Kelnor

Kelnor is part of the drug class:

• Progesterone and Estrogen Contraceptives Used in Sequence

Ethinyl estradiol and ethynodiol diacetate is a combination birth control pill that contains female hormones to prevent ovulation (the release of an egg from an ovary). This medication also causes changes in your cervical mucus and uterine lining, making it harder for sperm to reach the uterus and harder for a fertilized egg to attach to the uterus.

Ethinyl estradiol and ethynodiol diacetate is used to prevent pregnancy.

Ethinyl estradiol and ethynodiol diacetate may also be used for purposes not listed in this medication guide.

Do not use birth control pills if you are pregnant or if you have recently had a baby.

You should not take birth control pills if you have any of the following conditions: uncontrolled high blood pressure, heart disease, a blood-clotting disorder, circulation problems, diabetic problems with your eyes or kidneys, unusual vaginal bleeding, liver disease or liver cancer, severe migraine headaches, if you smoke and are over 35, or if you have ever had breast or uterine cancer, jaundice caused by birth control pills, a heart attack, a stroke, or a blood clot.

Taking birth control pills can increase your risk of blood clots, stroke, or heart attack, especially if you have certain other conditions, or if you are overweight.

Smoking can greatly increase your risk of blood clots, stroke, or heart attack. You should not take birth control pills if you smoke and are over 35 years old.

Taking birth control pills can increase your risk of blood clots, stroke, or heart attack. You are even more at risk if you have high blood pressure, diabetes, high cholesterol, or if you are overweight. Your risk of stroke or blood clot is highest during your first year of taking birth control pills. Your risk is also high when you restart birth control pills after not taking them for 4 weeks or longer.

Smoking can greatly increase your risk of blood clots, stroke, or heart attack. Your risk increases the older you are and the more you smoke. You should not take combination birth control pills if you smoke and are over 35 years old.

Do not use if you are pregnant. Stop taking this medicine and tell your doctor if you become pregnant, or if you miss two menstrual periods in a row. If you have recently had a baby, wait at least 4 weeks before taking birth control pills.

You should not take birth control pills if you have:

• untreated or uncontrolled high blood pressure;

• heart disease (coronary artery disease, uncontrolled heart valve disorder, history of heart attack, stroke, or blood clot);

• a blood-clotting disorder or circulation problems;

• problems with your eyes, kidneys or circulation caused by diabetes;

• a history of hormone-related cancer such as breast or uterine cancer;

• unusual vaginal bleeding that has not been checked by a doctor;

• liver disease or liver cancer;

• severe migraine headaches (with aura, numbness, weakness, or vision changes), especially if you are older than 35;

• a history of jaundice caused by pregnancy or birth control pills; or

• if you smoke and are over 35 years old.

To make sure birth control pills are safe for you, tell your doctor if you have:

• high blood pressure, varicose veins;

• high cholesterol or triglycerides;

• a history of depression;

• underactive thyroid, gallbladder disease;

• seizures or epilepsy;

• kidney disease;

• a history of irregular menstrual cycles;

• tuberculosis; or

• a history of fibrocystic breast disease, an abnormal mammogram, or an abnormal pap smear.

The hormones in birth control pills can pass into breast milk and may harm a nursing baby. This medication may also slow breast milk production. Do not use if you are breast-feeding a baby.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• This medicine may raise the chance of blood clots, a stroke, or a heart attack. Talk with the doctor.
• Talk with your doctor if you will need to be still for long periods of time like long trips, bedrest after surgery, or illness. Not moving for long periods may raise your chance of blood clots.
• High blood pressure has happened with drugs like this one. Have your blood pressure checked as you have been told by your doctor.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• If you have high blood sugar (diabetes), you will need to watch your blood sugar closely.
• Be sure to have regular breast exams and gynecology check-ups. Your doctor will tell you how often to have these. You will also need to do breast self-exams as your doctor has told you. Talk with your doctor.
• This medicine may affect certain lab tests. Tell all of your health care providers and lab workers that you take Kelnor.
• Certain drugs, herbal products, or health problems could cause this medicine to not work as well. Be sure your doctor knows about all of your drugs and health problems.
• This medicine does not stop the spread of diseases like HIV or hepatitis that are passed through blood or having sex. Do not have any kind of sex without using a latex or polyurethane condom. Do not share needles or other things like toothbrushes or razors. Talk with your doctor.
• If you have any signs of pregnancy or if you have a positive pregnancy test, call your doctor right away.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

The use of oral contraceptives is associated with increased risk of several serious conditions including venous and arterial thromboembolism, thrombotic and hemorrhagic stroke, myocardial infarction, liver tumors or other liver lesions, and gallbladder disease. The risk of morbidity and mortality increases significantly in the presence of other risk factors such as hypertension, hyperlipidemia, obesity, and diabetes mellitus.

Practitioners prescribing oral contraceptives should be familiar with the following information relating to these and other risks.

The information contained herein is principally based on studies carried out in patients who used oral contraceptives with formulations containing higher amounts of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lesser amounts of both estrogens and progestogens remains to be determined.

Throughout this labeling, epidemiological studies reported are of two types: retrospective case-control studies and prospective cohort studies. Case-control studies provide an estimate of the relative risk of a disease, which is defined as the ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk (or odds ratio) does not provide information about the actual clinical occurrence of a disease. Cohort studies provide a measure of both the relative risk and the attributable risk. The latter is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence or incidence of a disease in the subject population. For further information, the reader is referred to a text on epidemiological methods.

1. Thromboembolic Disorders and Other Vascular Problems

An increased risk of myocardial infarction has been associated with oral contraceptive use.2-21 This increased risk is primarily in smokers or in women with other underlying risk factors for coronary artery disease such as hypertension, obesity, diabetes, and hypercholesterolemia. The relative risk for myocardial infarction in current oral contraceptive users has been estimated to be 2 to 6. The risk is very low under the age of 30. However, there is the possibility of a risk of cardiovascular disease even in very young women who take oral contraceptives.

Smoking in combination with oral contraceptive use has been reported to contribute substantially to the risk of myocardial infarction in women in their mid-thirties or older, with smoking accounting for the majority of excess cases.22 Mortality rates associated with circulatory disease have been shown to increase substantially in smokers, especially in those 35 years of age and older among women who use oral contraceptives (see Figure 1, Table 2).

Figure 1. Circulatory disease mortality rates per 100,000 woman-years by age, smoking status, and oral contraceptive use.14

Oral contraceptives may compound the effects of well-known cardiovascular risk factors such as hypertension, diabetes, hyperlipidemias, hypercholesterolemia, age, cigarette smoking, and obesity. In particular, some progestogens decrease HDL cholesterol23-31 and cause glucose intolerance, while estrogens may create a state of hyperinsulinism.32 Oral contraceptives have been shown to increase blood pressure among some users (see WARNINGS, No. 10). Similar effects on risk factors have been associated with an increased risk of heart disease.

An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established.17, 33-51 Case-control studies have estimated the relative risk to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease.34-37, 45, 46 Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases (subjects with no past history of venous thrombosis or varicose veins) and about 4.5 for new cases requiring hospitalization.42, 47, 48 The risk of venous thromboembolic disease associated with oral contraceptives is not related to duration of use.

A two- to seven-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives.38, 39 The relative risk of venous thrombosis in women who have predisposing conditions is about twice that of women without such medical conditions.43 If feasible, oral contraceptives should be discontinued at least 4 weeks prior to and for 2 weeks after elective surgery of a type associated with an increased risk of thromboembolism, and also 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 4 to 6 weeks after delivery in women who elect not to breastfeed.

Both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes) have been reported to be increased with oral contraceptive use,14, 17, 18, 34, 42, 46, 52-59 although, in general, the risk was greatest among older (over 35 years), hypertensive women who also smoked. Hypertension was reported to be a risk factor for both users and nonusers, for both types of strokes, while smoking increased the risk for hemorrhagic strokes.

In one large study,52 the relative risk for thrombotic stroke was reported as 9.5 times greater in users than in nonusers. It ranged from 3 for normotensive users to 14 for users with severe hypertension.54 The relative risk for hemorrhagic stroke was reported to be 1.2 for nonsmokers who used oral contraceptives, 1.9 to 2.6 for smokers who did not use oral contraceptives, 6.1 to 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users, and 25.7 for users with severe hypertension. The risk is also greater in older women and among smokers.

A positive association has been reported between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease.41, 43, 53, 59-64 A decline in serum high density lipoproteins (HDL) has been reported with many progestogens.23-31 A decline in serum high density lipoproteins has been associated with an increased incidence of ischemic heart disease.65 Because estrogens increase HDL-cholesterol, the net effect of an oral contraceptive depends on the balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogens used in the contraceptives. The amount of both steroids 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 that contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptives should be started on preparations containing the lowest estrogen content that produces satisfactory results in the individual.

There are three studies that have shown persistence of risk of vascular disease for users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persisted for at least 9 years for women 40 to 49 years old who had used oral contraceptives for 5 or more years, but this increased risk was not demonstrated in other age groups.16 Another American study reported former use of oral contraceptives was significantly associated with increased risk of subarachnoid hemorrhage.57 In another study, in Great Britain, the risk of developing nonrheumatic heart disease plus hypertension, subarachnoid hemorrhage, cerebral thrombosis, and transient ischemic attacks persisted for at least 6 years after discontinuation of oral contraceptives, although the excess risk was small.14, 18, 66 It should be noted that these studies were performed with oral contraceptive formulations containing 50 mcg or more of estrogens.

2. Estimates of Mortality From Contraceptive Use

One study67 gathered data from a variety of sources that have estimated the mortality rates 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 or older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth. The observation of a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970's, but not reported until 1983.67 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 that suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed,48, 152 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 nonsmoking 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 that 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 nonsmoking 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.

Adapted from Ory.67

3. Carcinoma of the Breast and Reproductive Organs

Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian, and cervical cancer in women using oral contraceptives. While there are conflicting reports, many studies suggest that the use of oral contraceptives is not associated with an overall increase in the risk of developing breast cancer.17, 40, 68-78 Other studies, however, have reported an increased risk overall,153-155 or in certain subgroups. In these studies, increased risk has been associated with long duration of use, use beginning at a young age, use before the first term pregnancy, use by those who had an early menarche, those who had a positive family history of breast cancer, or in nulliparas.79-102, 151, 156-162 These risks have been surveyed in two books163-164 and in review articles.85, 99, 153, 165-167

Some studies suggested that oral contraceptive use was associated with an increase in the risk of cervical intraepithelial neoplasia, dysplasia, erosion, carcinoma, or microglandular dysplasia in some populations of women.17, 50, 103-115 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, a cause and effect relationship has not been established.

4. Hepatic Neoplasia

Benign hepatic adenomas and other hepatic lesions have been associated with oral contraceptive use,116-121 although the incidence of such benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases per 100,000 for users, a risk that increases after 4 or more years of use.120 Rupture of benign, hepatic adenomas or other lesions may cause death through intra-abdominal hemorrhage. Therefore, such lesions should be considered in women presenting with abdominal pain and tenderness, abdominal mass, or shock. About one quarter of the cases presented because of abdominal masses; up to one half had signs and symptoms of acute intraperitoneal hemorrhage.121 Diagnosis may prove difficult.

Studies from the U.S.,122, 150 Great Britain,123, 124 and Italy125 have shown an increased risk of hepatocellular carcinoma in long-term (> 8 years; relative risk of 7 to 20) oral contraceptive users. However, these cancers are rare in the United States, and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than 1 per 1,000,000 users.

5. Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 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 Kelnor prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (see CONTRAINDICATIONS). Kelnor can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen.

6. Ocular Lesions

There have been reports of retinal thrombosis and other ocular lesions associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained, gradual or sudden, partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or any evidence of retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately.

7. Oral Contraceptive Use Before or During Pregnancy

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy.126, 129 The majority of recent studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb reduction defects are concerned,126-129 when the pill is taken inadvertently during early pregnancy.

The administration of oral contraceptives to induce withdrawal bleeding should not be used as a 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 and further use of oral contraceptives should be withheld until pregnancy has been ruled out. Oral contraceptive use should be discontinued if pregnancy is confirmed.

8. Gallbladder Disease

Earlier studies reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens.40, 42, 53, 70 More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal.130-132 The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower doses of estrogens and progestogens.

9. Carbohydrate and Lipid Metabolic Effects

Oral contraceptives have been shown to cause a decrease in glucose tolerance in a significant percentage of users.32 This effect has been shown to be directly related to estrogen dose.133 Progestogens increase insulin secretion and create insulin resistance, the effect varying with different progestational agents.32, 134 However, in the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives.

Some women may 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.23-31, 135, 136

10. Elevated Blood Pressure

An increase in blood pressure has been reported in women taking oral contraceptives50, 53, 137-139 and this increase is more likely in older oral contraceptive users137 and with extended duration of use.53 Data from the Royal College of General Practitioners138 and subsequent randomized trials have shown that the incidence of hypertension increases with increasing concentrations of progestogens.

Women with a history of hypertension or hypertension-related disease, or renal disease139 should be encouraged to use another method of contraception. If such 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,137 and there is no difference in the occurrence of hypertension among ever- and never-users.140

11. Headache

The onset or exacerbation of migraine or the development of headache of a new pattern that 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 a pathologic basis has been excluded, time alone or a 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 a condition was pre-existent.

1. Hatcher RA, et al. Contraceptive Technology: Seventeenth Revised Edition. New York, NY, 1998. 1a. Physicians' Desk Reference. 47th ed. Oradell, NJ: Medical Economics Co Inc; 1993:2598-2601. 2. Mann JI, et al. Br Med J. 1975;2(May 3):241. 3. Mann JI, et al. Br Med J. 1975;3(Sept 13):631. 4. Mann JI, et al. Br Med J. 1975;2(May 3):245. 5. Mann JI, et al. Br Med J. 1976;2(Aug 21):445. 6. Arthes FG, et al. Chest. 1976;70(Nov):574. 7. Jain AK, Am J Obstet Gynecol. 1976;301(Oct 1):126; and Stud Fam Plann. 1977;8(March):50. 8. Ory HW. JAMA. 1977;237(June 13):2619. 9. Jick H, et al. JAMA. 1978;239(April 3):1403, 1407. 10. Jick H, et al. JAMA. 1978;240(Dec 1):2548. 11. Shapiro S, et al. Lancet. 1979;1(April 7):743. 12. Rosenberg L, et al. Am J Epidemiol. 1980;111(Jan):59. 13. Krueger DE, et al. Am J Epidemiol. 1980;111(June):655. 14. Layde P, et al. Lancet. 1981;1(March 7):541. 15. Adam SA, et al. Br J Obstet Gynaecol. 1981;88(Aug):838. 16. Slone D, et al. N Engl J Med. 1981;305(Aug 20):420. 17. Ramcharan S, et al. The Walnut Creek Contraceptive Drug Study. Vol 3. US Govt Ptg Off; 1981; and J Reprod Med. 1980;25(Dec):346. 18. Layde PM, et al. J R Coll Gen Pract. 1983;33(Feb):75. 19. Rosenberg L, et al. JAMA. 1985;253(May 24/31):2965. 20. Mant D, et al. J Epidemiol Community Health. 1987;41(Sept):215. 21. Croft P, et al. Br Med J. 1989;298(Jan 21):165. 22. Goldbaum GM, et al. JAMA. 1987;258(Sept 11):1339. 23. Bradley DD, et al. N Engl J Med. 1978;299(July 6):17. 24. Tikkanen MJ. J Reprod Med. 1986;31(Sept suppl):898. 25. Lipson A, et al. Contraception. 1986;34(Aug):121. 26. Burkman RT, et al. Obstet Gynecol. 1988; 71(Jan):33. 27. Knopp RH, J Reprod Med. 1986;31(Sept suppl):913. 28. Krauss RM, et al. Am J Obstet Gynecol. 1983;145(Feb 15):446. 29. Wahl P, et al. N Engl J Med. 1983;308(April 14):862. 30. Wynn V, et al. Am J Obstet Gynecol. 1982;142(March 15):766. 31. LaRosa JC. J Reprod Med. 1986;31(Sept suppl):906. 32. Wynn V, et al. J Reprod Med. 1986;31(Sept suppl):892. 33. Royal College of General Practitioners. J R Coll Gen Pract. 1967;13(May):267. 34. Inman WHW, et al. Br Med J. 1968;2(April 27):193. 35. Vessey MP, et al. Br Med J. 1968;2(April 27):199. 36. Vessey MP, et al. Br Med J. 1969;2(June 14):651. 37. Sartwell PE, et al. Am J Epidemiol. 1969;90(Nov):365. 38. Vessey MP, et al. Br Med J. 1970;3(July 18):123. 39. Greene GR, et al. Am J Public Health. 1972;62(May):680. 40. Boston Collaborative Drug Surveillance Programme. Lancet. 1973;1(June 23):1399. 41. Stolley PD, et al. Am J Epidemiol. 1975;102(Sept):197. 42. Vessey MP, et al. J Biosoc Sci. 1976;8(Oct):373. 43. Kay CR, J R Coll Gen Pract. 1978;28(July):393. 44. Petitti DB, et al. Am J Epidemiol. 1978;108(Dec):480. 45. Maguire MG, et al. Am J Epidemiol. 1979;110(Aug):188. 46. Petitti DB, et al. JAMA. 1979;242(Sept 14):1150. 47. Porter JB, et al. Obstet Gynecol. 1982;59(March):299. 48. Porter JB, et al. Obstet Gynecol. 1985;66(July):1. 49. Vessey MP, et al. Br Med J. 1986;292(Feb 22):526. 50. Hoover R, et al. Am J Public Health. 1978;68(April):335. 51. Vessey MP. Br J Fam Plann. 1980;6(Oct suppl):1. 52. Collaborative Group for the Study of Stroke in Young Women. N Engl J Med. 1973;288(April 26):871. 53. Royal College of General Practitioners. Oral Contraceptives and Health. New York, NY: Pitman Publ Corp; May 1974. 54. Collaborative Group for the Study of Stroke in Young Women. JAMA. 1975;231(Feb 17):718. 55. Beral V. Lancet. 1976;2(Nov 13):1047. 56. Vessey MP, et al. Lancet. 1977;2(Oct 8):731; and 1981;1(March 7):549. 57. Petitti DB, et al. Lancet. 1978;2(July 29):234. 58. Inman WHW. Br Med J. 1979;2(Dec 8):1468. 59. Vessey MP, et al. Br Med J. 1984;289(Sept 1):530. 60. Inman WHW, et al. Br Med J. 1970;2(April 25):203. 61. Meade TW, et al. Br Med J. 1980;280(May 10):1157. 62. Böttiger LE, et al. Lancet. 1980;1(May 24):1097. 63. Kay CR, Am J Obstet Gynecol. 1982;142(March 15):762. 64. Vessey MP, et al. Br Med J. 1986;292(Feb 22):526. 65. Gordon T, et al. Am J Med. 1977;62(May):707. 66. Beral V, et al. Lancet. 1977;2(Oct 8):727. 67. Ory H. Fam Plann Perspect. 1983;15(March-April):57. 68. Arthes FG, et al. Cancer. 1971;28(Dec):1391. 69. Vessey MP, et al. Br Med J. 1972;3(Sept 23):719. 70. Boston Collaborative Drug Surveillance Program. N Engl J Med. 1974;290(Jan 3):15. 71. Vessey MP, et al. Lancet. 1975;1(April 26):941. 72. Casagrande J, et al. J Natl Cancer Inst. 1976;56(April):839. 73. Kelsey JL, et al. Am J Epidemiol. 1978;107(March):236. 74. Kay CR. Br Med J. 1981;282(June 27):2089. 75. Vessey MP, et al. Br Med J. 1981;282(June 27):2093. 76. The Cancer and Steroid Hormone Study of the Center for Disease Control and the National Institute of Child Health and Human Development. Oral contraceptive use and the risk of breast cancer. N Engl J Med. 1986;315(Aug 14):405. 77. Paul C, et al. Br Med J. 1986; 293(Sept 20):723. 78. Miller DR, et al. Obstet Gynecol. 1986;68(Dec):863. 79. Pike MC, et al. Lancet. 1983;2(Oct 22):926. 80. McPherson K, et al. Br J Cancer. 1987;56(Nov):653. 81. Hoover R, et al. N Engl J Med. 1976;295(Aug 19):401. 82. Lees AW, et al. Int J Cancer. 1978;22(Dec):700. 83. Brinton LA, et al. J Natl Cancer Inst. 1979;62(Jan):37. 84. Black MM, Pathol Res Pract. 1980;166:491; and Cancer. 1980;46(Dec):2747; and Cancer. 1983;51(June):2147. 85. Thomas DB. JNCI. 1993;85(March 3):359. 86. Brinton LA, et al. Int J Epidemiol. 1982;11(Dec):316. 87. Harris NV, et al. Am J Epidemiol. 1982;116(Oct):643. 88. Jick H, et al. Am J Epidemiol. 1980;112(Nov):577. 89. McPherson K, et al. Lancet. 1983;2(Dec 17):1414. 90. Hoover R, et al. J Natl Cancer Inst. 1981;67(Oct):815. 91. Jick H, et al. Am J Epidemiol. 1980;112(Nov):586. 92. Meirik O, et al. Lancet. 1986;2(Sept 20):650. 93. Fasal E, et al. J Natl Cancer Inst. 1975;55(Oct):767. 94. Paffenbarger RS, et al. Cancer. 1977;39(April suppl):1887. 95. Stadel BV, et al. Contraception. 1988;38(Sept):287. 96. Miller DR, et al. Am J Epidemiol. 1989;129(Feb):269. 97. Kay CR, et al. Br J Cancer. 1988;58(Nov):675. 98. Miller DR, et al. Obstet Gynecol. 1986;68(Dec):863. 99. Hulka BS, et al. Cancer. 1994;74(August 1 suppl):1111. 100. Chilvers C, et al. Lancet. 1989;1(May 6):973. 101. Huggins GR, et al. Fertil Steril. 1987;47(May):733. 102. Pike MC, et al. Br J Cancer. 1981;43(Jan):72. 103. Ory H, et al. Am J Obstet Gynecol. 1976;124(March 15):573. 104. Stern E, et al. Science. 1977;196(June 24):1460. 105. Peritz E, et al. Am J Epidemiol. 1977;106(Dec):462. 106. Ory HW, et al. In: Garattini S, Berendes H, eds. Pharmacology of Steroid Contraceptive Drugs. New York, NY: Raven Press; 1977;211-224. 107. Meisels A, et al. Cancer. 1977;40(Dec):3076. 108. Goldacre MJ, et al. Br Med J. 1978;1(March 25):748. 109. Swan SH, et al. Am J Obstet Gynecol. 1981;139(Jan 1):52. 110. Vessey MP, et al. Lancet. 1983;2(Oct 22):930. 111. Dallenbach-Hellweg G. Pathol Res Pract. 1984;179:38. 112. Thomas DB, et al. Br Med J. 1985;290(March 30):961. 113. Brinton LA, et al. Int J Cancer. 1986;38 (Sept):339. 114. Ebeling K, et al. Int J Cancer. 1987;39(April):427. 115. Beral V, et al. Lancet. 1988;2(Dec 10):1331. 116. Baum JK, et al. Lancet. 1973;2(Oct 27):926. 117. Edmondson HA, et al. N Engl J Med. 1976;294(Feb 26):470. 118. Bein NN, et al. Br J Surg. 1977;64(June):433. 119. Klatskin G. Gastroenterology. 1977;73(Aug):386. 120. Rooks JB, et al. JAMA. 1979;242(Aug 17):644. 121. Sturtevant FM. In: Moghissi K, ed. Controversies in Contraception. Baltimore, MD: Williams & Wilkins; 1979:93-150. 122. Henderson BE, et al. Br J Cancer. 1983;48(July):437. 123. Neuberger J, et al. Br Med J. 1986;292(May 24):1355. 124. Forman D, et al. Br Med J. 1986;292(May 24):1357. 125. La Vecchia C, et al. Br J Cancer. 1989;59(March):460. 126. Savolainen E, et al. Am J Obstet Gynecol. 1981;140(July 1):521. 127. Ferencz C, et al. Teratology. 1980;21(April):225. 128. Rothman KJ, et al. Am J Epidemiol. 1979;109(April):433. 129. Harlap S, et al. Obstet Gynecol. 1980;55(April):447. 130. Layde PM, et al. J Epidemiol Community Health. 1982;36(Dec):274. 131. Rome Group for the Epidemiology and Prevention of Cholelithiasis (GREPCO). Am J Epidemiol. 1984;119(May):796. 132. Strom BL, et al. Clin Pharmacol Ther. 1986;39(March):335. 133. Wynn V. In: Bardin CE, et al. eds. Progesterone and Progestins. New York, NY: Raven Press;1983:395-410. 134. Perlman JA, et al. J Chron Dis. 1985;38(Oct)857. 135. Powell MG, et al. Obstet Gynecol. 1984;63(June):764. 136. Wynn V, et al. Lancet. 1966;2(Oct 1):720. 137. Fisch IR, et al. JAMA. 1977;237(June 6):2499. 138. Kay CR. Lancet. 1977;1(March 19):624. 139. Laragh JH. Am J Obstet Gynecol. 1976;126(Sept 1):141. 140. Ramcharan S. In: Garattini S, Berendes HW, eds. Pharmacology of Steroid Contraceptive Drugs. New York, NY: Raven Press; 1977:277-288. 141. Laumas KR, et al. Am J Obstet Gynecol. 1967;98(June 1):411. 142. Saxena BN, et al. Contraception. 1977;16(Dec):605. 143. Nilsson S. et al. Contraception. 1978;17(Feb):131. 144. Washington AE, et al. JAMA. 1985;253(April 19):2246. 145. Louv WC, et al. Am J Obstet Gynecol. 1989;160(Feb):396. 146. Francis WG, et al. Can Med Assoc J. 1965;92(Jan 23):191. 147. Verhulst HL, et al. J Clin Pharmacol. 1967;7(Jan-Feb):9. 148. Ory HW. Fam Plann Perspect. 1982;14(July-Aug):182. 149. Ory HW, et al. Making Choices: Evaluating the Health Risks and Benefits of Birth Control Methods. New York, NY: The Alan Guttmacher Institute; 1983. 150. Palmer JR, et al. Am J Epidemiol. 1989;130(Nov):878. 151. Romieu I, et al. J Natl Cancer Inst. 1989;81(Sept):1313. 152. Porter JB, et al. Obstet Gynecol. 1987;70(July):29. 153. Olsson H, et al. Cancer Detect Prev. 1991;15:265. 154. Delgado-Rodriguez M, et al. Rev Epidém Santé Publ. 1991;39:165. 155. Clavel F, et al. Int J Epidemiol. 1991;20(March):32. 156. Brinton LA, et al. JNCI. 1995;87(June 7):827. 157. Thomas DB, et al. Br J Cancer. 1992;65(January):108. 158. Thomas DB, et al. Cancer Causes Cont. 1991;2(Nov):389. 159. Weinstein AL, et al. Epidemiology. 1991;2(Sept):353. 160. Ranstam J, et al. Anticancer Res. 1991;11(Nov-Dec):2043. 161. Ursin G, et al. Epidemiology. 1992;3(Sept):414. 162. White E, et al. JNCI. 1994;86(April 6):505. 163. Mann R, et al. Oral Contraceptives and Breast Cancer. Park Ridge, NJ: The Parthenon Publishing Group Inc.; 1990. 164. Institute of Medicine. Committee on the Relationship Between Oral Contraceptives and Breast Cancer. Oral Contraceptives and Breast Cancer. Washington, DC: National Academy Press; 1991. 165. Harlap S. J Reprod Med. 1991;36(May):374. 166. Rushton L, et al. Br J Obstet Gynaecol. 1992;99(March):239. 167. Colditz G. Cancer. 1993;71(Feb 15 suppl):1480.

TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Rev. C 7/2017

Applies to ethinyl estradiol / ethynodiol: oral tablet