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Desogestrel and Ethinyl Estradiol

WARNING

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.

DESCRIPTION

Ortho-Cept 21 and Ortho-Cept 28 tablets provide an oral contraceptive regimen of 21 orange round tablets each containing 0.15 mg desogestrel (13-ethyl-11-methylene-18,19-dinor-17 alpha-pregn-4-en- 20-yn-17-ol) and 0.03 mg ethinyl estradiol (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne-3,17,diol). Inactive ingredients include vitamin E, corn starch, povidone, stearic acid, colloidal silicon dioxide, lactose, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, talc and ferric oxide. Ortho-Cept 28 also contains 7 green tablets containing the following inactive ingredients: lactose, pregelatinized starch, magnesium stearate, FD&C blue no. 1 aluminum lake, ferric oxide, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide and talc.

CLINICAL PHARMACOLOGY

Pharmacodynamics

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

Receptor binding studies, as well as studies in animals and humans, have shown that 3-keto-desogestrel, the biologically active metabolite of desogestrel, combines high progestational activity with minimal intrinsic androgenicity.91,92 Desogestrel, in combination with ethinyl estradiol, does not counteract the estrogen-induced increases in SHBG, resulting in lower serum levels of free testosterone.96,99

Pharmacokinetics

Desogestrel is rapidly and almost completely absorbed and converted into 3-keto-desogestrel, its biologically active metabolite. Following oral administration, the relative bioavailability of desogestrel, as measured by serum levels of 3-keto-desogestrel, is approximately 84%.

In the third cycle of use after a single dose of desogestrel; ethinyl estradiol, maximum concentrations of 3-keto-desogestrel of 2805 ± 1203 pg/ml (mean ± SD) are reached at 1.4 ± 0.8 hours. The area under the curve (AUC0-x is 33858 ± 11043 pg/ml•hr after a single dose. At steady state, attained from at least day 19 onwards, maximum concentrations of 5840 ± 1667 pg/ml are reached at 1.4 ± 0.9 hours. The minimum plasma levels of 3-keto-desogestrel at steady state are 1400 ± 560 pg/ml. The AUC0-24 at steady state is 52299 ± 17878 pg/ml•hr. The mean AUC0-x for 3-keto-desogestrel at single dose is significantly lower than the mean AUC0-24 at steady state. This indicates that the kinetics of 3-keto-desogestrel are non-linear due to an increase in binding of 3-keto-desogestrel to sex hormone-binding globulin in the cycle, attributed to increased sex hormone-binding globulin levels which are induced by the daily administration of ethinyl estradiol. Sex hormone-binding globulin levels increased significantly in the third treatment cycle from day 1 (150 ± 64 nmol/L) to day 21 (230 ± 59 nmol/L).

The elimination half-life for 3-keto-desogestrel is approximately 38 ± 20 hours at steady state. In addition to 3-keto-desogestrel, other phase I metabolites are 3a-OH-desogestrel, 3b-OH-desogestrel, and 3a-OH-5a-H-desogestrel. These other metabolites are not known to have any pharmacologic effects, and are further converted in party by conjugation (phase II metabolism) into polar metabolities, mainly sulfates and glucuronides.

Ethinyl estradiol is rapidly and almost completely absorbed. In the third cycle of use after a single dose of desogestrel; ethinyl estradiol, the relative bioavailability is approximately 83%.

In the third cycle of use after a single dose of desogestrel; ethinyl estradiol, maximum concentrations of ethinyl estradiol of 95 ± 34 pg/ml are reached at 1.5 ± 0.8 hours. The AUC0-x is 1471 ± 268 pg/ml•hr after a single dose. At steady state, attained from at least day 19 onwards, maximum ethinyl estradiol concentrations of 141 ± 48 pg/ml are reached at about 1.4 ± 0.7 hours. The minimum serum levels of ethinyl estradiol at steady state are 24 ± 8.3 pg/ml. The AUC0-24, at steady state is 1117 ± 302 pg/ml•hr. The mean AUC0-x for ethinyl estradiol following a single dose during treatment cycle 3 does not significantly differ from the mean AUC0-24 at steady state. This finding indicates linear kinetics for ethinyl estradiol.

The elimination half-life is 26 ± 6.8 hours at steady state. Ethinyl estradiol is subject to a significant degree of presystemic conjugation (phase II metabolism). Ethinyl estradiol escaping gut wall conjugation undergoes phase I metabolism and hepatic conjugation (phase II metabolism). Major phase I metabolites are 2-OH-ethinyl estradiol and 2-methoxy-ethinyl estradiol. Sulfate and glucuronide conjugates of both ethinyl estradiol and phase I metabolites, which are excreted in bile, can undergo enterohepatic circulation.

CLINICAL STUDIES

Non-Contraceptive Health Benefits

The following non-contraceptive health benefits related to the use of oral contraceptives are supported by epidemiological studies which largely utilized oral contraceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg of mestranol.73-78

Effects on Menses:

  • Increased menstrual cycle regularity.
  • Decreased blood loss and decreased incidence of iron deficiency anemia.
  • Decreased incidence of dysmenorrhea.

Effects Related to Inhibition of Ovulation:

  • Decreased incidence of functional ovarian cysts.
  • Decreased incidence of ectopic pregnancies.

Effects From Long-term Use:

  • Decreased incidence of fibroadenomas and fibrocystic disease of the breast.
  • Decreased incidence of acute pelvic inflammatory disease.
  • Decreased incidence of endometrial cancer.
  • Decreased incidence of ovarian cancer.


INDICATIONS

Desogestrel; ethinyl estradiol is indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.

Oral contraceptives are highly effective. TABLE 1 lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, depends upon the reliability with which they are used. Correct and consistent use of these methods can result in lower failure rates.

TABLE 1 Lowest Expected and Typical Failure Rates During the First Year of Continuous Use of a Method % of Women Experiencing an Accidental Pregnancy in the First Year of Continuous Use
Method Lowest Expected* Typical†
 (No Contraceptive) (85) (85)
 Oral Contraceptives   3

    combined

0.1 N/A‡

    progestin only

0.5 N/A‡
 Diaphragm with spermicidal cream or jelly 6 18
 Spermicides alone (foams, creams, gels, jellies, vaginal
 suppositories, and vaginal film)		 6 21
 Vaginal Sponge    

    nulliparous

9 18

    parous

20 36
 Implant 0.09 0.09
 Injection: depot medroxyprogesterone acetate 0.3 0.3
 IUD    

    progesterone

1.5 2.0

    copper T 380A

0.6 0.8
 Condom without spermicides    

    female

5 21

    male

3 12
 Cervical Cap with spermicidal cream or jelly    

    nulliparous

9 18

    parous

26 36
 Periodic abstinence    

    (all methods)

1-9 20
 Female sterilization 0.4 0.4
 Male sterilization 0.10 0.15
Adapted from RA Hatcher et al., TABLE 5-2, (1994) ref. #1.  
* The authors' best guess of the percentage of women expected to experience an accidental pregnancy among couples who initiate a method (not necessarily for the first time) and who use it consistently and correctly during the first year if they do not stop for any other reason.
† This term represents “typical” couples who initiate use of a method (not necessarily for the first time), who experience an accidental pregnancy during the first year if they do not stop use for any other reason.
‡ N/A¾Data not available.


In a clinical trial with desogestrel; ethinyl estradiol, 1195 subjects completed 11,656 cycles and a total of 10 pregnancies were reported. This represents an overall user-efficacy (typical user-efficacy) pregnancy rate of 1.12 per 100 women-years. This rate includes patients who did not take the drug correctly.

DOSAGE AND ADMINISTRATION

To achieve maximum contraceptive effectiveness, desogestrel; ethinyl estradiol must be taken exactly as directed and at intervals not exceeding 24 hours. Desogestrel; ethinyl estradiol is available in the Dialpak tablet dispenser which is preset for a Sunday Start. Day 1 start is also provided.

21-Day Regimen (Day 1 Start)

The dosage of desogestrel; ethinyl estradiol 21 for the initial cycle of therapy is one tablet administered daily from the 1st day through the 21st day of the menstrual cycle, counting the first day of menstrual flow as "Day 1." For subsequent cycles, no tablets are taken for 7 days, then a new course is started of one tablet a day for 21 days. The dosage regimen then continues with 7 days of no medication, followed by 21 days of medication, instituting a three-weeks-on, one-week-off dosage regimen.

The use of desogestrel; ethinyl estradiol 21 for contraception may be initiated 4 weeks postpartum in women who elect not to breast feed. When the tablets are administered during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered. (See CONTRA

INDICATIONS

and WARNINGS, Thromboembolic Disorders and Other Vascular Problems concerning thromboembolic disease. See also PRECAUTIONS, Nursing Mothers.) If the patient starts on desogestrel; ethinyl estradiol postpartum, and has not yet had a period, she should be instructed to use another method of contraception until an orange tablet has been taken daily for 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered. If the patient misses one (1) active tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she remembers. If the patient misses two (2) active tablets in Week 1 or Week 2, the patient should take two (2) tablets the day she remembers and two (2) tablets the next day; and then continue taking one (1) tablet a day until she finishes the pack. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills. If the patient misses two (2) active tablets in the third week or misses three (3) or more active tablets in a row, the patient should throw out the rest of the pack and start a new pack that same day. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills.

21-Day Regimen (Sunday Start)

When taking desogestrel; ethinyl estradiol 21, the first orange tablet should be taken on the first Sunday after menstruation begins. If period begins on Sunday, the first orange tablet is taken on that day. If switching directly from another oral contraceptive, the first orange tablet should be taken on the first Sunday after the last ACTIVE tablet of the previous product. One orange tablet is taken daily for 21 days. For subsequent cycles, no tablets are taken for seven days, then a new course is started of one tablet a day for 21 days instituting a 3-weeks-on, one-week-off dosage regimen. When initiating a Sunday start regimen, another method of contraception should be used until after the first 7 consecutive days of administration.

The use of desogestrel; ethinyl estradiol 21 for contraception may be initiated 4 weeks postpartum in women who elect not to breast feed. When the tablets are administered during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered. (See CONTRA

INDICATIONS

and WARNINGS, Thromboembolic Disorders and Other Vascular Problems concerning thromboembolic disease. See also PRECAUTIONS, Nursing Mothers.) If the patient starts on desogestrel; ethinyl estradiol postpartum, and has not yet had a period, she should be instructed to use another method of contraception until an orange tablet has been taken daily for 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered. If the patient misses one (1) active tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she remembers. If the patient misses two (2) active tablets in Week 1 or Week 2, the patient should take two (2) tablets the day she remembers and two (2) tablets the next day; and then continue taking one (1) tablet a day until she finishes the pack. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills. If the patient misses two (2) active tablets in the third week or misses three (3) or more tablets in a row, the patient should continue taking one tablet every day until Sunday. On Sunday the patient should throw out the rest of the pack and start a new pack that same day. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills.

28-Day Regimen (Day 1 Start)

The dosage of desogestrel; ethinyl estradiol 28 for the initial cycle of therapy is one tablet administered daily from the 1st day through 21st day of the menstrual cycle, counting the first day of menstrual wflow as “Day 1”. Tablets are taken without interruption as follows: One orange tablet daily for 21 days, then one green tablet daily for 7 days. After 28 tablets have been taken, a new course is started and an orange tablet is taken the next day.

The use of desogestrel; ethinyl estradiol 28 for contraception may be initiated 4 weeks postpartum in women who elect not to breast feed. When the tablets are administered during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered. (See CONTRA

INDICATIONS

and WARNINGS, Thromboembolic Disorders and Other Vascular Problems concerning thromboembolic disease. See also PRECAUTIONS, Nursing Mothers.) If the patient starts on desogestrel; ethinyl estradiol postpartum, and has not yet had a period, she should be instructed to use another method of contraception until an orange tablet has been taken daily for 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered. If the patient misses one (1) active tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she remembers. If the patient misses two (2) active tablets in Week 1 or Week 2, the patient should take two (2) tablets the day she remembers and two (2) tablets the next day; and then continue taking one (1) tablet a day until she finishes the pack. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills. If the patient misses two (2) active tablets in the third week or misses three (3) or more active tablets in a row, the patient should throw out the rest of the pack and start a new pack that same day. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills.

28-Day Regimen (Sunday Start)

When taking desogestrel; ethinyl estradiol 28, the first orange tablet should be taken on the first Sunday after menstruation begins. If period begins on Sunday, the first orange tablet is taken on that day. If switching directly from another oral contraceptive, the first orange tablet should be taken on the first Sunday after the last ACTIVE tablet of the previous product. Tablets are taken without interruption as follows: One orange tablet daily for 21 days, then one green tablet daily for 7 days. After 28 tablets have been taken, a new course is started and an orange tablet is taken the next day (Sunday). When initiating a Sunday start regimen, another method of contraception should be used until after the first 7 consecutive days of administration.

The use of desogestrel; ethinyl estradiol 28 for contraception may be initiated 4 weeks postpartum. When the tablets are administered during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered. (See CONTRA

INDICATIONS

and WARNINGS, Thromboembolic Disorders and Other Vascular Problems concerning thromboembolic disease. See also PRECAUTIONS, Nursing Mothers.) If the patient starts on desogestrel; ethinyl estradiol postpartum, and has not yet had a period, she should be instructed to use another method of contraception until an orange tablet has been taken daily for 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered. If the patient misses one (1) active tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she remembers. If the patient misses two (2) active tablets in Week 1 or Week 2, the patient should take two (2) tablets the day she remembers and two (2) tablets the next day; and then continue taking one (1) tablet a day until she finishes the pack. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills. If the patient misses two (2) active tablets in the third week or misses three (3) or more tablets in a row, the patient should continue taking one tablet every day until Sunday. On Sunday the patient should throw out the rest of the pack and start a new pack that same day. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills.

All Oral Contraceptives

Breakthrough bleeding, spotting, and amenorrhea are frequent reasons for patients discontinuing oral contraceptives. In breakthrough bleeding, as in all cases of irregular bleeding from the vagina, nonfunctional causes should be borne in mind. In undiagnosed persistent or recurrent abnormal bleeding from the vagina, adequate diagnostic measures are indicated to rule out pregnancy or malignancy. If pathology has been excluded, time or a change to another formulation may solve the problem. Changing to an oral contraceptive with a higher estrogen content, while potentially useful in minimizing menstrual irregularity, should be done only if necessary since this may increase the risk of thromboembolic disease.

Use of oral contraceptives in the event of a missed menstrual period:

1. 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 oral contraceptive use should be discontinued until pregnancy is ruled out.

2. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing oral contraceptive use.

HOW SUPPLIED

Ortho-Cept 21 Tablets: Are available in a Dialpak Tablet Dispenser containing 21 orange tablets (0.15 mg desogestrel and 0.03 mg ethinyl estradiol) which are unscored with “Ortho” on one side and “D 150” on the opposite side.

Ortho-Cept 28 Tablets: Are available in a Dialpak Tablet Dispenser containing 28 tablets, as follows: 21 orange tablets as described under Ortho-Cept 21, and 7 green tablets containing inert ingredients.

Storage: Store below 86° F (30° C).

REFERENCES

1. Hatcher RA, et al. 1994. Contraceptive Technology. Sixteenth Edition. New York: Irvington Publishers.

2. Stadel BV. Oral contraceptives and cardiovascular disease. (Pt.1). N Engl J Med 1981; 305:612-618.

3. Stadel BV. Oral contraceptives and cardiovascular disease. (Pt. 2). N Engl J Med 1981; 305:672-677.

4. Adam SA, Thorogood M. Oral contraception and myocardial infarction revisited: the effects of new preparations and prescribing patterns. Br J Obstet and Gynecol 1981; 88:838-845.

5. Mann JI, Inman WH. Oral contraceptives and death from myocardial infarction. Br Med J 1975; 2(5965):245-248.

6. Mann JI, Vessey MP, Thorogood M, Doll R. Myocardial infarction in young women with special reference to oral contraceptive practice. Br Med J 1975 2(5956):241-245.

7. Royal College of General Practitioners' Oral Contraception Study: Further analyses of mortality in oral contraceptive users. Lancet 1981;1:541-546.

8. Slone D, Shapiro S, Kaufman DW, Rosenberg L, Miettinen OS, Stolley PD. Risk of myocardial infarction in relation to current and discontinued use of oral contraceptives. N Engl J Med 1981; 305:420-424.

9. Vessey MP. Female hormones and vascular disease-an epidemiological overview. Br J Fam Plann 1980; 6:1-12.

10. Russell-Briefel RG, Ezzati TM, Fulwood R, Perlman JA, Murphy RS. Cardiovascular risk status and oral contraceptive use, United States, 1976-80. Prevent Med 1986; 15:352-362.

11. Goldbaum GM, Kendrick JS, Hogelin GC, Gentry EM. The relative impact of smoking and oral contraceptive use on women in the United States. JAMA 1987; 258:1339-1342.

12. Layde PM, Beral V. Further analyses of mortality in oral contraceptive users: Royal College of General Practitioners' Oral Contraception Study. (TABLE 5) Lancet 1981; 1:541-546.

13. Knopp RH. Arteriosclerosis risk: the roles of oral contraceptives and postmenopausal estrogens. J Reprod Med 1986; 31(9) (Supplement):913-921.

14. Krauss RM, Roy S, Mishell DR, Casagrande J, Pike MC. Effects of two low-dose oral contraceptives on serum lipids and lipoproteins: Differential changes in high-density lipoproteins subclasses. Am J Obstet 1983; 145:446-452.

15. Wahl P, Walden C, Knopp R, Hoover J, Wallace R, Heiss G, Rifkind B. Effect of estrogen/progestin potency on lipid/lipoprotein cholesterol, N Engl J Med 1983; 308:862-867.

16. Wynn V, Niththyananthan R. The effect of progestin in combined oral contraceptives on serum lipids with special reference to high-density lipoproteins. Am J Obstet Gynecol 1982; 142:766-771.

17. Wynn V, Godsland I. Effects of oral contraceptives and carbohydrate metabolism. J Reprod Med 1986; 31(9) (Supplement):892-897.

18. LaRosa JC. Atherosclerotic risk factors in cardiovascular disease. J Reprod Med 1986; 31 (9) (Supplement):906-912.

19. Inman WH, Vessey MP. Investigation of death from pulmonary, coronary, and cerebral thrombosis and embolism in women of child-bearing age. Br Med J 1968; 2 (5599):193-199.

20. Maguire MG, Tonascia J, Sartwell PE, Stolley PD, Tockman MS. Increased risk of thrombosis due to oral contraceptives: a further report. Am J Epidemiol 1979; 110(2): 188-195.

21. Petitti DB, Wingerd J, Pellegrin F, Ramacharan S. Risk of vascular disease in women: smoking, oral contraceptives, noncontraceptive estrogens, and other factors. JAMA 1979; 242:1150-1154.

22. Vessey MP, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. Br Med J 1968; 2 (5599):199-205.

23. Vessey MP, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. A further report, Br Med J 1969; 2 (5658):651-657.

24. Porter JB, Hunter JR, Danielson DA, Jick H, Stergachis A. Oral contraceptives and non-fatal vascular disease-recent experience. Obstet Gynecol 1982; 59 (3):299-302.

25. Vessey M, Doll R, Peto R, Johnson B, Wiggins P. A long-term follow-up study of women using different methods of contraception: an interim report. J Biosocial Sci 1976; 8:375-427.

26. Royal College of General Practitioners: Oral contraceptives, venous thrombosis, and varicose veins. J Royal Coll Gen Pract 1978; 28:393-399.

27. Collaborative Group for the Study of Stroke in Young Women: Oral contraception and increased risk of cerebral ischemia or thrombosis. N Engl J Med 1973; 288:871-878.

28. Petitti DB, Wingerd J. Use of oral contraceptives, cigarette smoking, and risk of subarachnoid hemorrhage. Lancet 1978; 2:234-236.

29. Inman WH. Oral contraceptives and fatal subarachnoid hemorrhage. Br Med J 1979; 2 (6203):1468-70.

30. Collaborative Group for the study of Stroke in Young Women: Oral contraceptives and stroke in young women: associated risk factors. JAMA 1975; 231:718-722.

31. Inman WH, Vessey MP, Westerholm B, Engelund A. Thromboembolic disease and the steroidal content of oral contraceptives. A report to the Committee on Safety of Drugs. Br Med J 1970; 2:203-209.

32. Meade TW, Greenberg G, Thompson SG. Progestogens and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 35-mcg oestrogen preparations. Br Med J 1980; 280 (6224):1157-1161.

33. Kay CR. Progestogens and arterial disease-evidence from the Royal College of General Practitioners' Study. Am J Obstet Gynecol 1982; 142:762-765.

34. Royal College of General Practitioners: Incidence of arterial disease among oral contraceptive users. J Royal Coll Gen Pract 1983; 33:75-82.

35. Ory HW. Mortality associated with fertility and fertility control: 1983. Family Planning Perspectives 1983; 15:50-56.

36. 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 Engl J Med 1986; 315:405-411.

37. Pike MC, Henderson BE, Krailo MD, Duke A, Roy S. Breast cancer risk in young women and use of oral contraceptives: possible modifying effect of formulation and age at use. Lancet 1983; 2:926-929.

38. Paul C, Skegg DG, Spears GFS, Kaldor JM. Oral contraceptives and breast cancer: A national study. Br Med J 1986; 293:723-725.

39. Miller DR, Rosenberg L, Kaufman DW, Schottenfeld D, Stolley PD, Shapiro S. Breast cancer risk in relation to early oral contraceptive use. Obstet Gynecol 1986; 68:863-868.

40. Olson H, Olson KL, Moller TR, Ranstam J, Holm P. Oral contraceptive use and breast cancer in young women in Sweden (letter). Lancet 1985; 2:748-749.

41. McPherson K, Vessey M, Neil A, Doll R, Jones L, Roberts M. Early contraceptive use and breast cancer: Results of another case-control study. Br J Cancer 1987; 56:653-660.

42. Huggins GR, Zucker PF. Oral contraceptives and neoplasia: 1987 update. Fertil Steril 1987; 47:733-761.

43. McPherson K, Drife JO. The pill and breast cancer: why the uncertainty? Br Med J 1986; 293:709-710.

44. Shapiro S. Oral contraceptives¾time to take stock. N Engl J Med 1987; 315:450-451.

45. Ory H, Naib Z, Conger SB, Hatcher RA, Tyler CW. Contraceptive choice and prevalence of cervical dysplasia and carcinoma in situ. Am J Obstet Gynecol 1976; 124:573-577.

46. Vessey MP, Lawless M, McPherson K, Yeates D. Neoplasia of the cervix uteri and contraception: a possible adverse effect of the pill. Lancet 1983; 2:930.

47. Brinton LA, Huggins GR, Lehman HF, Malli K, Savitz DA, Trapido E, Rosenthal J, Hoover R. Long term use of oral contraceptives and risk of invasive cervical cancer. Int J Cancer 1986; 38:339-344.

48. WHO Collaborative Study of Neoplasia and Steroid Contraceptives: Invasive cervical cancer and combined oral contraceptives. Br Med J 1985; 290:961-965.

49. Rooks JB, Ory HW, Ishak KG, Strauss LT, Greenspan JR, Hill AP, Tyler CW. Epidemiology of hepatocellular adenoma: the role of oral contraceptive use. JAMA 1979; 242:644-648.

50. Bein NN, Goldsmith HS. Recurrent massive hemorrhage from benign hepatic tumors secondary to oral contraceptives. Br J Surg 1977; 64:433-435.

51. Klatskin G. Hepatic tumors: possible relationship to use of oral contraceptives. Gastroenterology 1977; 73:386-394.

52. Henderson BE, Preston-Martin S, Edmondson HA, Peters RL, Pike MC. Hepatocellular carcinoma and oral contraceptives. Br J Cancer 1983; 48:437-440.

53. Neuberger J, Forman D, Doll R, Williams R. Oral contraceptives and hepatocellular carcinoma. Br Med J 1986; 292:1355-1357.

54. Forman D, Vincent TJ, Doll R. Cancer of the liver and oral contraceptives. Br Med J 1986; 292:1357-1361.

55. Harlap S, Eldor J. Births following oral contraceptive failures. Obstet Gynecol 1980; 55:447-452.

56. Savolainen E, Saksela E, Saxen L. Teratogenic hazards of oral contraceptives analyzed in a national malformation register. Am J Obstet Gynecol 1981; 140:521-524.

57. Janerich DT, Piper JM, Glebatis DM. Oral contraceptives and birth defects. Am J Epidemiol 1980; 112:73-79.

58. Ferencz C, Matanoski GM, Wilson PD, Rubin JD, Neill CA, Gutberlet R. Maternal hormone therapy and congenital heart disease. Teratology 1980; 21:225-239.

59. Rothman KJ, Fyler DC, Goldbatt A, Kreidberg MB. Exogenous hormones and other drug exposures of children with congenital heart disease. Am J Epidemiol 1979; 109:433-439.

60. Boston Collaborative Drug Surveillance Program: Oral contraceptives and venous thromboembolic disease, surgically confirmed gallbladder disease, and breast tumors. Lancet 1973; 1:1399-1404.

61. Royal College of General Practitioners: Oral contraceptives and health. New York, Pittman, 1974.

62. Layde PM, Vessey MP, Yeates D. Risk of gall bladder disease: a cohort study of young women attending family planning clinics. J Epidemiol Community Health 1982; 36:274-278.

63. Rome Group for the Epidemiology and Prevention of Cholelithiasis (GREPCO): Prevalence of gallstone disease in an Italian adult female population. Am J Epidemiol 1984; 119:796-805.

64. Strom BL, Tamragouri RT, Morse ML, Lazar EL, West SL, Stolley PD, Jones JK. Oral contraceptives and other risk factors for gall bladder disease. Clin Pharmacol Ther 1986; 39:335-341.

65. Wynn V, Adams PW, Godsland IF, Melrose J, Niththyananthan R, Oakley NW, Seedj A. Comparison of effects of different combined oral contraceptive formulations on carbohydrate and lipid metabolism. Lancet 1979; 1:1045-1049.

66. Wynn V. Effect of progesterone and progestins on carbohydrate metabolism. In Progesterone and Progestin. Edited by Bardin CW, Milgrom E, Mauvis-Jarvis P. New York, Raven Press, 1983 pp. 395-410.

67. Perlman JA, Roussell-Briefel RG, Ezzati TM, Lieberknecht G. Oral glucose tolerance and the potency of oral contraceptive progestogens. J Chronic Dis 1985; 38:857-864.

68. Royal College of General Practitioners' Oral Contraception Study: Effect on hypertension and benign breast disease of progestogen component in combined oral contraceptives. Lancet 1977; 1:624.

69. Fisch IR, Frank J. Oral contraceptives and blood pressure. JAMA 1977; 237:2499-2503.

70. Laragh AJ. Oral contraceptive induced hypertension - nine years later. Am J Obstet Gynecol 1976; 126:141-147.

71. Ramcharan S, Peritz E, Pellegrin FA, Williams WT. Incidence of hypertension in the Walnut Creek Contraceptive Drug Study cohort. In Pharmacology of Steroid Contraceptive Drugs. Garattini S, Berendes HW. Eds. New York, Raven Press, 1977 pp. 277-288. (Monographs of the Mario Negri Institute for Pharmacological Research, Milan).

72. Stockley I. Interactions with oral contraceptives. J Pharm 1976; 216:140-143.

73. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral contraceptive use and the risk of ovarian cancer. JAMA 1983; 249:1596-1599.

74. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Combination oral contraceptive use and the risk of endometrial cancer. JAMA 1987; 257:796-800.

75. Ory HW. Functional ovarian cysts and oral contraceptives: negative association confirmed surgically. JAMA 1974; 228:68-69.

76. Ory HW, Cole P, Macmahon B, Hoover R. Oral contraceptives and reduced risk of benign breast disease. N Engl J Med 1976; 294:419-422.

77. Ory HW. The noncontraceptive health benefits from oral contraceptive use. Fam Plann Perspect 1982; 14:182-184.

78. Ory HW, Forrest JD, Lincoln R. Making Choices: Evaluating the health risks and benefits of birth control methods. New York, The Alan Guttmacher Institute, 1983; p.1.

79. Schlesselman J, Stadel BV, Murray P, Lai S. Breast Cancer in relation to early use of oral contraceptives. JAMA 1988; 259:1828-1833.

80. Hennekens CH, Speizer FE, Lipnick RJ, Rosner B, Bain C, Belanger C, Stampfer MJ, Willett W, Peto R. A case-controlled study of oral contraceptive use and breast cancer. JNCI 1984; 72:39-42.

81. LaVecchia C, Decarli A, Fasoli M, Franceschi S, Gentile A, Negri E, Parazzini F, Tognoni G. Oral contraceptives and cancers of the breast and of the female genital tract. Interim results from a case-control study. Br J Cancer 1986; 54:311-317.

82. Meirik O, Lund E, Adami H, Bergstrom R, Christoffersen T, Bergsjo P. Oral contraceptive use in breast cancer in young women. A Joint National Case-control study in Sweden and Norway. Lancet 1986; 11:650-654.

83. Kay CR, Hannaford PC. Breast cancer and the pill-A further report from the Royal College of General Practitioners' oral contraception study. Br J Cancer 1988; 58:675-680.

84. Stadel BV, Lai S, Schlesselman JJ, Murray P. Oral contraceptives and premenopausal breast cancer in nulliparous women. Contraception 1988; 38:287-299.

85. Miller DR, Rosenberg L, Kaufman DW, Stolley P, uer ME, Shapiro S. Breast cancer before age 45 and oral contraceptive use: New Findings. Am J Epidemiol 1989; 129:269-280.

86. The UK National Case-Control Study Group, Oral contraceptive use and breast cancer risk in young women. Lancet 1989; 1:973-982.

87. Schlesselman JJ. Cancer of the breast and reproductive tract in relation to use of oral contraceptives. Contraception 1989; 40:1-38.

88. Vessey MP, McPherson K, Villard-Mackintosh L, Yeates D. Oral contraceptives and breast cancer: latest findings in a large cohort study. Br J Cancer 1989; 59:613-617.

89. Jick SS, Walker AM, Stergachis A, Jick H. Oral contraceptives and breast cancer. Br J Cancer 1989; 59:618-621.

90. Godsland, I et al. The effects of different formulations of oral contraceptive agents on lipid and carbohydrate metabolism. N Engl J Med 1990; 323:1375-81.

91. Kloosterboer, HJ et al. Selectivity in progesterone and androgen receptor binding of progestogens used in oral contraception. Contraception, 1988;38:325-32.

92. Van der Vies, J and de Visser, J. Endocrinological studies with desogestrel. Arzneim Forsch/Drug Res, 1983;33(l),2:231-6.

93. Data on file, Organon Inc.

94. Fotherby, K. Oral contraceptives, lipids and cardiovascular diseases. Contraception, 1985; Vol. 31; 4:367-94.

95. Lawrence, DM et al. Reduced sex hormone binding globulin and derived free testosterone levels in women with severe acne. Clinical Endocrinology, 1981; 15:87-91.

96. Cullberg, Gy et al. Effects of a low-dose desogestrel-ethinyl estradiol combination on hirsutism, androgens and sex hormone binding globulin in women with a polycystic ovary syndrome. Acta Obstet Gynecol Scand, 1985;64:195-202.

97. Jung-Hoffmann, C and Kuhl, H. Divergent effects of two low-dose oral contraceptives on sex hormone-binding globulin and free testosterone. AJOG, 1987; 156:199-203.

98. Hammond, Gy et al. Serum steroid binding protein concentrations, distribution of progestogens, and bioavailability of testosterone during treatment with contraceptives containing desogestrel or levonorgestrel. Fertil Steril, 1984;42:44-51.

99. Palatsi, R et al. Serum total and unbound testosterone and sex hormone binding globulin (SHBG) in female acne patients treated with two different oral contraceptives. Acta Derm Venereol, 1984; 64:517-23.

100. Lewis M, Spitzer WO, Heinemann LAJ, MacRae KD, Bruppacher R, Thorogood M on behalf of Transnational Research Group on Oral Contraceptives and Health of Young Women. Third generation oral contraceptives and risk of myocardial infarction: an international case-control study. Br Med J, 1996;312:88-90.


SIDE EFFECTS

An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS).

  • Thrombophlebitis and venous thrombosis with or without embolism.
  • Arterial thromboembolism.
  • Pulmonary embolism.
  • Myocardial infarction.
  • Cerebral hemorrhage.
  • Cerebral thrombosis.
  • Hypertension.
  • Gallbladder disease.
  • Hepatic adenomas or benign liver tumors.

The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related:

  • Nausea.
  • Vomiting.
  • Gastrointestinal symptoms (such as abdominal cramps and bloating).
  • Breakthrough bleeding.
  • Spotting.
  • Change in menstrual flow.
  • Amenorrhea.
  • Temporary infertility after discontinuation of treatment.
  • Edema.
  • Melasma which may persist.
  • Breast changes: tenderness, enlargement, secretion.
  • Change in weight (increase or decrease).
  • Change in cervical erosion and secretion.
  • Diminution in lactation when given immediately postpartum.
  • Cholestatic jaundice.
  • Migraine.
  • Rash (allergic).
  • Mental depression.
  • Reduced tolerance to carbohydrates.
  • Vaginal candidiasis.
  • Change in corneal curvature (steepening).
  • Intolerance to contact lenses.

The following adverse reactions have been reported in users of oral contraceptives and the association has been neither confirmed nor refuted:

  • Pre-menstrual syndrome.
  • Cataracts.
  • Changes in appetite.
  • Cystitis-like syndrome.
  • Headache.
  • Nervousness.
  • Dizziness.
  • Hirsutism.
  • Loss of scalp hair.
  • Erythema multiforme.
  • Erythema nodosum.
  • Hemorrhagic eruption.
  • Vaginitis.
  • Porphyria.
  • Impaired renal function.
  • Hemolytic uremic syndrome.
  • Acne.
  • Changes in libido.
  • Colitis.
  • Budd-Chiari Syndrome.

DRUG INTERACTIONS

Reduced efficacy and increased incidence of breakthrough bleeding and menstrual irregularities have been associated with concomitant use of rifampin. A similar association, though less marked, has been suggested with barbiturates, phenylbutazone, phenytoin sodium, carbamazepine and possibly with griseofulvin, ampicillin and tetracyclines.72


WARNINGS

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 formulations of higher doses of estrogens and progestogens than those in common use today. The effect of long term use of the oral contraceptives with formulations of lower doses of both estrogens and progestogens remains to be determined.

Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population (Adapted from refs. 2 and 3 with the author's permission). For further information, the reader is referred to a text on epidemiological methods.

Thromboembolic Disorders and Other Vascular Problems

Myocardial Infarction

An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six.4-10 The risk is very low in women under the age of 30.

Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases.11 Mortality rates associated with circulatory disease have been shown to increase substantially in smokers, especially in those 35 years of age and older among women who use oral contraceptives.

CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN-YEARS BY AGE, SMOKING STATUS AND ORAL CONTRACEPTIVE USE

Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity.13 In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism.14-18 Oral contraceptives have been shown to increase blood pressure among users (see Elevated Blood Pressure). 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.

Desogestrel has minimal androgenic activity (see CLINICAL PHARMACOLOGY), and there is some evidence that the risk of myocardial infarction associated with oral contraceptives is lower when the progestogen has minimal androgenic activity than when the activity is greater.100

Thromboembolism

An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Data from case-control and cohort studies report that oral contraceptives containing desogestrel (desogestrel; ethinyl estradiol contains desogestrel) are associated with a two-fold increase in the risk of venous thromboembolic disease as compared to other low-dose (containing less than 50 mcg of estrogen) pills containing other progestins. According to these studies, this two-fold risk increases the yearly occurrence of venous thromboembolic disease by about 10-15 cases per 100,000 women.

Earlier case control studies on older formulations have found the relative risk of users compared to nonusers 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.2,3,19-24 Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization.25 The risk of thromboembolic disease associated with oral contraceptives is not related to length of use and disappears after pill use is stopped.2

A two- to four-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives.9 The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions.26 If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four weeks after delivery in women who elect not to breast feed.

Cerebrovascular Diseases

Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, and smoking interacted to increase the risk of stroke.27-29

In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension.30 The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension.30 The attributable risk is also greater in older women.3

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.31-33 A decline in serum high density lipoproteins (HDL) has been reported with many progestational agents.14-16 A 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 a balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogens used in the contraceptives. The amount of both hormones should be considered in the choice of an oral contraceptive.

Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing 0.035 mg or less of estrogen.

Persistence of Risk of Vascular Disease

There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40-49 years old who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups.8 In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small.34 However, both studies were performed with oral contraceptive formulations containing 0.050 mg or higher of estrogens.

Estimates of Mortality From Contraceptive Use

One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (see TABLE 2). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth.

The observation of an increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970's.35 Current clinical recommendation involves the use of lower estrogen dose formulations and a careful consideration of risk factors. In 1989, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the use of oral contraceptives in women 40 years of age and over. The Committee concluded that although cardiovascular disease risk may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception. The Committee recommended that the benefits of low-dose oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks.

Of course, older women, as all women who take oral contraceptives, should take an oral contraceptive which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and individual patient needs.

TABLE 2 Annual Number of Birth-Related or Method-Related Deaths Associated With Control of Fertility Per 100,000 Nonsterile Women, by Fertility Control Method According to Age
Method of control and outcome 15-19 20-24 25-29 30-34 35-39 40-44
 No fertility control methods* 7.0 7.4 9.1 14.8 25.7 28.2
 Oral contraceptives non-smoker† 0.3 0.5 0.9 1.9 13.8 31.6
 Oral contraceptives smoker† 2.2 3.4 6.6 13.5 51.1 117.2
 IUD† 0.8 0.8 1.0 1.0 1.4 1.4
 Condom* 1.1 1.6 0.7 0.2 0.3 0.4
 Diaphragm/spermicide* 1.9 1.2 1.2 1.3 2.2 2.8
 Periodic abstinence* 2.5 1.6 1.6 1.7 2.9 3.6
* Deaths are birth-related.
† Deaths are method-related.
Adapted from H.W. Ory, ref. #35.


Carcinoma of the Reproductive Organs and Breasts

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 most studies suggest that the use of oral contraceptives is not associated with an overall increase in the risk of developing breast cancer. Some studies have reported an increased relative risk of developing breast cancer, particularly at a younger age. This increased relative risk appears to be related to duration of use.36-43,79-89

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.45-48 However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

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, a risk that increases after four or more years of use especially with oral contraceptives of higher dose.49 Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.50,51

Studies from Britain have shown an increased risk of developing hepatocellular carcinoma52-54 in long-term (>8 years) oral contraceptive users. However, these cancers are 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.

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.

Oral Contraceptive Use Before or During Early Pregnancy

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy.56,57 The majority of recent studies also do not indicate a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned55,56,58,59, when oral contraceptives are 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. Oral contraceptive use should be discontinued until pregnancy is ruled out.

Gallbladder Disease

Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens.60,61 More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal.62-64 The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.

Carbohydrate and Lipid Metabolic Effects

Oral contraceptives have been shown to cause a decrease in glucose tolerance in a significant percentage of users.17 This effect has been shown to be directly related to estrogen dose.65 In general, progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents.17,66 In the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose.67 Because of these demonstrated effects, prediabetic and diabetic women should be carefully monitored while taking oral contraceptives.

A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see Myocardial Infarction and Dose-Related Risk of Vascular Disease from Oral Contraceptives), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.

Elevated Blood Pressure

An increase in blood pressure has been reported in women taking oral contraceptives68 and this increase is more likely in older oral contraceptive users69 and with extended duration of use.61 Data from the Royal College of General Practitioners12 and subsequent randomized trials have shown that the incidence of hypertension increases with increasing progestational activity.

Women with a history of hypertension or hypertension-related diseases, or renal disease70 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 contraceptives69, and there is no difference in the occurrence of hypertension among former and never users.68,70,71

Headache

The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent or severe requires discontinuation of oral contraceptives and evaluation of the cause.

Bleeding Irregularities

Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. Nonhormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or 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.

Ectopic Pregnancy

Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.

PRECAUTIONS

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 a strong family history of breast cancer or who have breast nodules should be monitored with particular care.

Lipid Disorders

Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult.

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.

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.

Emotional Disorders

Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.

Contact Lenses

Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.

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 hormone binding globulins are increased and result in elevated levels of total circulating sex steroids however, free or biologically active levels either decrease or remain unchanged.

e. High-density lipoprotein (HDL-C) and triglycerides may be increased, while low-density lipoprotein cholesterol (LDL-C) and total cholesterol (Total-C) may be decreased or unchanged.

f. Glucose tolerance may be decreased.

g. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.

Carcinogenesis

See

WARNINGS

.

Pregnancy Category X

See CONTRAINDICATIONS and

WARNINGS

.

Nursing Mothers

Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child.

Sexually Transmitted Diseases

Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Information for the Patient

See PATIENT PACKAGE INSERT.


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