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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 III). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke, and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth. The observation of 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 risks may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception. Text Continues Below
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 III: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY CONTROL METHOD ACCORDING TO 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/ 1.9 1. 2 1.2 1. 3 2.2 2.8 spermicide*
Periodic 2.5 1. 6 1.6 1. 7 2.9 3.6 abstinence*
** 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. The risk of having breast cancer diagnosed may be slightly increased among current and recent users of COCs. However, this excess risk appears to decrease over time after COC discontinuation and by 10 years after cessation the increased risk disappears. Some studies report an increased risk with duration of use while other studies do not and no consistent relationships have been found with dose or type of steroid. Some studies have found a small increase in risk for women who first use COCs before age 20. Most studies show a similar pattern of risk with COC use regardless of a woman's reproductive history or her family breast cancer history.
Breast cancers diagnosed in current or previous OC users tend to be less clinically advanced than in nonusers. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usually a hormonally-sensitive tumor. 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.
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 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 contra-ceptives of higher dose. 49 Rupture of benign, hepatic adenomas may cause death through intra-abdominal hemorrhage. 50,51 Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) oral contraceptive users. However, these cancers are extremely rare in the U. S. and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users. 5. 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. 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 concerned, 55,56,58,59 when taken inadvertently during early pregnancy. The administration of oral contraceptives to induce withdrawal bleeding should not be used as 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. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be con-sidered at the time of the first missed period. Oral contraceptive use should be discontinued if pregnancy is confirmed. 7. GALLBLADDER DISEASE Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contra-ceptives 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. 8. 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 Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents. 17,66 However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. 67 Because of these demonstrated effects, prediabetic and diabetic women in particular should be carefully monitored while taking oral contraceptives. A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1a and 1d), changes in serum triglycerides and lipoprotein levels have been reported in oral
contraceptive users. 9. ELEVATED BLOOD PRESSURE
Women with significant hypertension should not be started on hormonal contraception. 92 An increase in blood pressure has been reported in women taking oral contraceptives 68 and this increase is more likely in older oral contraceptive users 69 and with extended duration of use. 61 Data from the Royal College of General Practitioners 12 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 70 should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension between former and never users. 68-71 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, 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 preexistent. 12. ECTOPIC PREGNANCY Ectopic as well as intrauterine pregnancy may occur in contraceptive failures. PRECAUTIONS 1. GENERAL Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
2. PHYSICAL EXAMINATION AND FOLLOW UP
It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral
contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical
cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleed-ing, 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. 3. LIPID DISORDERS Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contra-ceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more
difficult. 4. LIVER FUNCTION If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function. 5. FLUID RETENTION
Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. 6. EMOTIONAL DISORDERS
Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.
7. CONTACT LENSES
Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.
8. DRUG INTERACTIONS Changes in contraceptive effectiveness associated with co-administration of other products: Contraceptive effectiveness may be reduced when hormonal contraceptives are co-administered with antibiotics, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. This could result in unintended pregnancy or breakthrough bleeding. Examples include rifampin, barbiturates, phenylbutazone, phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate, and griseofulvin. Several cases of contraceptive failure and breakthrough bleeding have been reported in the literature with concomitant administration of antibiotics such as ampicillin and tetracyclines. However, clinical pharmacology studies investigating drug interaction between combined oral contraceptives and these antibiotics have reported inconsistent results. Several of the anti-HIV protease inhibitors have been studied with co-administration of oral combination hormonal contraceptives; significant changes (increase and decrease) in the plasma levels of the estrogen and progestin have been noted in some cases. The safety and efficacy of oral contraceptive products may be affected with co-administration of anti-HIV protease inhibitors. Healthcare providers should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information. Herbal products containing St. John's Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding. Increase in plasma levels associated with co-administered drugs:
Co-administration of atorvastatin and certain oral contraceptives containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP 3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels. Changes in plasma levels of co-administered drugs:
Combination hormonal contraceptives containing some synthetic estrogens (e. g., ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporin, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine and clofibric acid, due to induction of conjugation, have been noted when these drugs were administered with oral contraceptives. Healthcare providers are advised to also refer to prescribing information of co-administered drugs for recommendations regarding management of concomitant therapy. 9. INTERACTIONS WITH LABORATORY TESTS
Certain endocrine and liver function tests and blood components may be affected by oral contraceptives: a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced
platelet aggregability. b. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased,
reflecting the elevated TBG, free T4 concentration is unaltered. c. Other binding proteins may be elevated in serum. d. Sex-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged. e. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected. 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. 10. CARCINOGENESIS
See WARNINGS Section. 11. PREGNANCY Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS Sections. 12. 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, com-bination 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 combination oral contraceptives but to use other forms of contraception until she has completely weaned her child. 13. PEDIATRIC USE Safety and efficacy of ORTHO-NOVUM Tablets and MODICON Tablets has been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated. 14. GERIATRIC USE This product has not been studied in women over 65 years of age and is not indicated in this population.
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