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2. 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 (Table IV). 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 observa-tion of an increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970's. Current clinical recommendation involves the use of lower estrogen dose formulations and a care-ful 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 con-cluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women and with the alternative surgical and medi-cal 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. Text Continues Below
TABLE IV: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NON-STERILE WOMEN,
BY FERTILITY CONTROL METHOD ACCORDING TO AGE Method of control 15-19 20-24 25-29 30-34 35-39 40-44 and outcome
No fertility 7.0 7.4 9.1 14.8 25.7 28.2 control methods* Oral contraceptives 0.3 0.5 0.9 1.9 13.8 31.6 non-smoker** Oral contraceptives 2.2 3.4 6.6 13.5 51.1 117.2 smoker** 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. 3. 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 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, particu-larly at a younger age. This increased relative risk has been reported to be related to duration of use. A meta-analysis of 54 studies found a small increase in the frequency of having breast cancer diagnosed for women who were currently using combined oral contraceptives or had used them within the past ten years. This increase in the frequency of breast cancer diagnosis, within ten years of stopping use, was gen-erally accounted for by cancers localized to the breast. There was no increase in the frequency of having breast cancer diagnosed ten or more years after cessation of use. 95 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. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. 4. HEPATIC NEOPLASIA Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/ 100,000 for users, a risk that increases after four or more years of use especially with oral contraceptives of higher dose. 49 Rupture of benign, hepatic adenomas may cause death through intra-abdominal hemorrhage. 50,51 Studies have shown an increased risk of developing hepatocellular carcinoma 52-54,96 in oral contraceptive users. However, these cancers are rare in the U. S. 5. 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. 6. 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. The majority of recent studies also do not indicate a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, when taken inadvertently during early pregnancy. The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for preg-nancy. 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. 7. GALLBLADDER DISEASE Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral con-traceptives and estrogens. More recent studies, however, have shown that the relative risk of develop-ing gallbladder disease among oral contraceptive users may be minimal. The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estro-gens and progestogens. 8. CARBOHYDRATE AND LIPID METABOLIC EFFECTS Oral contraceptives have been shown to cause a decrease in glucose tolerance in a significant percentage of users. This effect has been shown to be directly related to estrogen dose. Progestogens increase in-sulin secretion and create insulin resistance, this effect varying with different progestational agents. However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. Because of these demonstrated effects, prediabetic and diabetic women in particular should be carefully monitored while taking oral contraceptives.
A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1a and 1d), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users. In clinical studies with ORTHO-CYCLEN there were no clinically significant changes in fasting blood glucose levels. No statistically significant changes in mean fasting blood glucose levels were observed over 24 cycles of use. Glucose tolerance tests showed minimal, clinically insignificant changes from baseline to cycles 3, 12, and 24. In clinical studies with ORTHO TRI-CYCLEN there were no clinically significant changes in fasting blood glucose levels. Minimal statistically significant changes were noted in glucose levels over 24 cycles of use. Glucose tolerance tests showed no clinically significant changes from baseline to cycles 3, 12, and 24. 9. ELEVATED BLOOD PRESSURE Women with significant hypertension should not be started on hormonal contraception. An increase in blood pressure has been reported in women taking oral contraceptives and this increase is more likely in older oral contraceptive users and with extended duration of use. Data from the Royal College of General Practitioners 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 disease should be encour-aged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension between former and never users. It should be noted that in two separate large clinical trials (N = 633 and N = 911), no statistically significant changes in mean blood pressure were observed with ORTHO-CYCLEN. 10. 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. 11. BLEEDING IRREGULARITIES Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, espe-cially during the first three months of use. Non-hormonal causes should be considered and adequate diag-nostic
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 preexistent. 12. 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. 1. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cer-vical 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. 2. LIPID DISORDERS Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral con-traceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult. 3. 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. 4. 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. 5. EMOTIONAL DISORDERS Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree. 6. CONTACT LENSES Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist. 7. 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, griseofulvin, topiramate, and possibly with ampicillin and tetracyclines 72 . A possible interaction has been suggested with hormonal contraceptives and the herbal supplement St. John's Wort based on some reports of oral contraceptive users experiencing breakthrough bleeding shortly after starting St. John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John's Wort. Healthcare prescribers are advised to consult the package inserts of medication administered concomitantly with oral contraceptives. 8. 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 meas-ured 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 total cholesterol (Total-C) may be increased, low-density lipoprotein (LDL-C) may be increased or decreased, while LDL-C/ HDL-C ratio may be decreased and triglycerides may be 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. 9. CARCINOGENESIS See WARNINGS Section. 10. PREGNANCY Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS Sections. 11. 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, combination 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 combi-nation oral contraceptives but to use other forms of contraception until she has completely weaned her child. 12. PEDIATRIC USE Safety and efficacy of ORTHO-CYCLEN Tablets and ORTHO TRI-CYCLEN Tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents
under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated. 13. SEXUALLY TRANSMITTED DISEASES Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. Page: << Prev | 1 | 2 | 3 | 4 | 5
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