Drug Information for WATSON PHARMARevised: June 2005IN-5260/SPHYSICIAN LABELING Brevicon (Norethindrone and Ethinyl Estradiol Tablets USP, 0.5 mg/0.035 mg) Norinyl 1+35 (Norethindrone and Ethinyl Estradiol Tablets USP, 1 mg/0.035 mg) Norinyl 1+50 (Norethindrone and Mestranol Tablets USP, 1 mg/0.05 mg) Rx Only (Watson Pharma, Inc.): WARNINGS

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  • Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke.

    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, hypercholesterolemia, obesity and diabetes.2-5

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

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

    Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease. Relative risk, the ratio of the incidence of a disease among oral contraceptive users to that among non-users, cannot be assessed directly from case control studies, but the odds ratio obtained is a measure of relative risk. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide not only a measure of relative risk but a measure of attributable risk, which is the difference in the incidence of disease between the oral contraceptive users and non-users. The attributable risk does provide information about the actual occurrence of a disease in the population (adapted from ref. 12 and 13 with the author's permission). For further information, the reader is referred to a text on epidemiological methods.

  • a. 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.2-5, 13 The relative risk of heart attack for current oral contraceptive users has been estimated to be 2 to 6.2,14-19 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 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.20

    Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and non-smokers over the age of 40 among women who use oral contraceptives (see TABLE II).16

    TABLE II: CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN YEARS BY AGE, SMOKING STATUS AND ORAL CONTRACEPTIVE USE
    Adapted from P.M. Layde and V. Beral, Table V 16

    Oral contraceptives may compound the effects of well-known risk factors such as hypertension, diabetes, hyperlipidemias, hypercholesterolemia, age and obesity.3, 13, 21 In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism.21-25 Oral contraceptives have been shown to increase blood pressure among users (see WARNINGS, section 9). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

  • b. Thromboembolism

  • An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to non-users to be 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.12, 13, 26-31 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.32 The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped.12

    A 2- to 6-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions.83 If feasible, oral contraceptives should be discontinued at least 4 weeks prior to and for 2 weeks after elective surgery and during and following prolonged immobilization. Since the immediate postpartum period also is 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 breast feed.33

  • c. Cerebrovascular diseases

  • An increase in both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes) has been shown in users of oral contraceptives. 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 non-users for both types of strokes while smoking interacted to increase the risk for hemorrhagic strokes.34

    In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive uses to 14 for users with severe hypertension.35 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.35 The attributable risk also is greater in women in their mid-thirties or older and among smokers.13

  • d. Dose-related risk of vascular disease from oral contraceptives

  • A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease.36-38 A decline in serum high density lipoproteins (HDL) has been reported with many progestational agents.22-24 A decline in serum high density lipoproteins has been associated with an increased incidence of ischemic heart disease.39 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.37

    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 the lowest estrogen content that produces satisfactory results for the individual.

    Products containing 50 mcg estrogen should be used only when medically indicated.

  • e. Persistence of risk of vascular disease

  • There are three studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives.17, 34, 40 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 who had used oral contraceptives for 5 or more years, but this increased risk was not demonstrated in other age groups.17 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.40 There is a significantly increased relative risk of subarachnoid hemorrhage after termination of use of oral contraceptives.34 However, these studies were performed with oral contraceptive formulations containing 50 mcg or higher of estrogen.

  • 2. ESTIMATES OF MORTALITY FROM CONTRACEPTIVE USE

  • One study gathered data from a variety of sources which have estimated the mortality rates associated with different methods of contraception at different ages (see Table III).41 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 a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970s - but not reported in the U.S. until 1983.16, 41 However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral contraceptive use to women who do not have the various risk factors listed in this labeling.

    Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed,78, 79 the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989. The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception.

    Therefore, the Committee recommended that the benefits of oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective.80

    TABLE III: ESTIMATED 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 outcome15-1920-2425-2930-3435-3940-44
    Estimates adapted from H.W. Ory, Table 341
    No fertility control methods *7.07.49.114.825.728.2
    Oral contraceptives non-smoker **0.30.50.91.913.831.6
    Oral contraceptives smoker **2.23.46.613.551.1117.2
    IUD **0.80.81.01.01.41.4
    Condom *1.11.60.70.20.30.4
    Diaphragm/Spermicide*1.91.21.21.32.22.8
    Periodic abstinence *2.51.61.61.72.93.6
    * Deaths are birth-related
    ** Deaths are method-related
  • 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. The overwhelming evidence in the literature suggests that use of oral contraceptives is not associated with an increase in the risk of developing breast cancer, regardless of the age and parity of first use or with most of the marketed brands and doses.42-44 The Cancer and Steroid Hormone (CASH) study also showed no latent effect on the risk of breast cancer for at least a decade following long-term use.43 A few studies have shown a slightly increased relative risk of developing breast cancer,44-47 although the methodology of these studies, which included differences in examination of users and non-users and differences in age at start of use, has been questioned.47-49 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.81, 82

    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.50-53 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 or 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 per 100,000 for users, a risk that increases after 4 or more years of use.54 Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.55-56

    Studies in the United States and Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral contraceptive users.57-59 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.60-62 Studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb reduction defects are concerned, when taken inadvertently during early pregnancy.60, 61, 63, 64

    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 2 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 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 contraceptives and estrogens.65-66 More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal.67 The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.68

  • 8. CARBOHYDRATE AND LIPID METABOLIC EFFECTS

  • Oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users.25 Oral contraceptives containing greater than 75 mcg of estrogen cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance.70 Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents.25, 71 However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose.69 Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives.

    Some women may develop persistent hypertriglyceridemia while on the pill.72 As discussed earlier (see WARNINGS, sections 1a. and 1d.), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.23

  • 9. ELEVATED BLOOD PRESSURE

  • 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 continued use.73, 84 Data from the Royal College of General Practitioners 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 diseases or renal disease 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 among ever- and never-users.73-75

  • 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 3 months of use. Non-hormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out.

    Some women may encounter post-bill amenorrhea or oligomenorrhea, especially when such a condition was pre-existent.

  • Drug Information Provided by National Library of Medicine (NLM).
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