openFDA text is shown for search and cross-checking; DailyMed SPL is canonical.
Warnings sections page 1 of 1 · 3 matching rows.
warnings
WARNINGS Cigarette smoking increases the risk of serious cardiovascular side effects from combination 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 combination hormonal contraceptives, including NuvaRing ® , should be strongly advised not to smoke. NuvaRing ® and other contraceptives that contain both an estrogen and a progestin are called combination hormonal contraceptives. There is no epidemiologic data available to determine whether safety and efficacy with the vaginal route of administration of combination hormonal contraceptives would be different than the oral route. The use of oral contraceptives is associated with increased risks of several serious conditions including venous and arterial thrombotic and thromboembolic events (such as myocardial infarction, thromboembolism, and stroke), hepatic neoplasia, gallbladder disease, and hypertension, 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 certain inherited thrombophilias, hypertension, hyperlipidemias, obesity, and diabetes. The information contained in this package insert is principally based on studies carried out in women 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 oral contraceptives with lower doses of both estrogens and progestogens remains to be determined. Throughout this labeling, epidemiologic 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 non-users. 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 non-users. The attributable risk does provide information about the actual occurrence of a disease in the population. For further information, the reader is referred to a text on epidemiologic methods. 1. THROMBOEMBOLIC DISORDERS AND OTHER VASCULAR PROBLEMS a. 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 three for the first episode of superficial venous thrombosis, four to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to six for women with predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower, about three for new cases and about 4.5 for new cases requiring hospitalization. The risk of thromboembolic disease associated with oral contraceptives is not related to length of use and disappears after pill use is stopped. Several epidemiology studies indicate that third generation oral contraceptives, including those containing desogestrel (etonogestrel, the progestin in NuvaRing ® , is the biologically active metabolite of desogestrel), are associated with a higher risk of venous thromboembolism than certain second generation oral contraceptives. In general, these studies indicate an approximate two-fold increased risk, which corresponds to an additional one to two cases of venous thromboembolism per 10,000 women-years of use. However, data from additional studies have not shown this two-fold increase in risk. It is unknown if NuvaRing ® has a different risk of venous thromboembolism than second generation oral contraceptives. A two- to four-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. If feasible, combination hormonal contraceptives, including NuvaRing ® , 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, combination hormonal contraceptives, such as NuvaRing ® , should be started no earlier than four to six weeks after delivery in women who elect not to breast-feed. The clinician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, pulmonary embolism, cerebrovascular disorders, and retinal thrombosis). Should any of these occur or be suspected, NuvaRing ® should be discontinued immediately. b. 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 combination oral contraceptive users has been estimated to be two to six. 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 infarction in women in their mid-thirties or older with smoking accounting for the majority of excess cases. 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 IV ). TABLE IV: CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN-YEARS BY AGE, SMOKING STATUS, AND COMBINATION ORAL CONTRACEPTIVE USE. AGE EVER-USERS NON-SMOKERS EVER-USERS SMOKERS CONTROLS NON-SMOKERS CONTROLS SMOKERS (Adapted from P.M. Layde and V. Beral, Lancet, 1981;1:541–546.) 15–24 0.0 10.5 0.0 0.0 25–34 4.4 14.2 2.7 4.2 35–44 21.5 63.4 6.4 15.2 45+ 52.4 206.7 11.4 27.9 Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age, and obesity. In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. Oral contraceptives have been shown to increase blood pressure among users (see WARNINGS ). Similar effects on risk factors have been associated with an increased risk of heart disease. NuvaRing ® must be used with caution in women with cardiovascular disease risk factors. c. 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 non-users, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes. In a large study, the relative risk of thrombotic strokes has been shown to range from three for normotensive users to 14 for users with severe hypertension. 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. The attributable risk is also greater in older women. Oral contraceptives also increase the risk for stroke in women with other underlying risk factors such as certain inherited or acquired thrombophilias, hyperlipidemias, and obesity. Women with migraine (particularly migraine with aura) who take combination oral contraceptives may be at an increased risk of stroke. 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. A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents. 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 activity and amount of both hormones should be considered in the choice of a hormonal 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 hormonal contraceptive agents should be started on a product containing the lowest hormone content that provides satisfactory results in the individual. e. Persistence of risk of vascular disease There are two studies that 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 nine 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. In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least six years after discontinuation of oral contraceptives, although excess risk was very small. However, both studies were performed with oral contraceptive formulations containing 50 micrograms or more of estrogen. It is unknown whether NuvaRing ® is distinct from combination oral contraceptives with regard to the occurrence of venous or arterial thrombosis. 2. ESTIMATES OF MORTALITY FROM CONTRACEPTIVE USE One study gathered data from a variety of sources that have estimated the mortality rate associated with different methods of contraception at different ages (Table V). 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 age 35 and older who smoke and age 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 1970's, but not reported until 1983. However, current clinical practice involves the use of lower estrogen-dose formulations combined with careful restriction of hormonal 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, 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 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. Therefore, the Committee recommended that the benefits of low-dose hormonal oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks. Older women, as all women who take hormonal contraceptives, should take the lowest possible dose formulation that is effective and meets the individual patient needs. TABLE V: 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 and outcome 15–19 20–24 25–29 30–34 35–39 40–44 (Adapted from H.W. Ory, Family Planning Perspectives 1983;15:50–56.) No fertility control methods Deaths are birth related 7.0 7.4 9.1 14.8 25.7 28.2 Oral contraceptives non-smoker Deaths are method related 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 3. CARCINOMA OF THE REPRODUCTIVE ORGANS AND BREASTS Numerous epidemiologic studies have been performed on the incidence of breast, endometrial, ovarian, and cervical cancer in women using combination oral contraceptives. Although the risk of breast cancer may be slightly increased among current users of oral contraceptives (RR = 1.24), this excess risk decreases over time after oral contraceptive discontinuation and by 10 years after cessation the increased risk disappears. The risk does not increase with duration of use, and no relationships have been found with dose or type of steroid. The patterns of risk are also similar regardless of a woman's reproductive history or her family breast cancer history. The subgroup for whom risk has been found to be significantly elevated is women who first used oral contraceptives before age 20, but because breast cancer is so rare at these young ages, the number of cases attributable to this early oral contraceptive use is extremely small. Breast cancers diagnosed in current or previous oral contraceptive users tend to be less advanced clinically than in never-users. Women who currently have or have had breast cancer should not use hormonal contraceptives because breast cancer is a hormone-sensitive tumor. Some studies suggest that combination 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. 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. It is unknown whether NuvaRing ® is distinct from oral contraceptives with regard to the above statements. 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 four or more years of use. Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage. 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 US and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users. It is unknown whether NuvaRing ® is distinct from oral contraceptives in this regard. 5. OCULAR LESIONS There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. NuvaRing ® 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. HORMONAL CONTRACEPTIVE USE BEFORE OR DURING EARLY PREGNANCY Hormonal contraceptives should not be used during pregnancy. Extensive epidemiologic studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. Combination hormonal contraceptives, such as NuvaRing ® , should not be used to induce withdrawal bleeding as a test for pregnancy. NuvaRing ® should not be used during pregnancy to treat threatened or habitual abortion. It is recommended that for any woman who has not adhered to the prescribed regimen for use of NuvaRing ® and has missed a menstrual period or who has missed two consecutive periods, pregnancy should be ruled out. 7. GALLBLADDER DISEASE Combination hormonal contraceptives, such as NuvaRing ® , may worsen existing gallbladder disease and may accelerate the development of this disease in previously asymptomatic women. Women with a history of combination hormonal contraceptive-related cholestasis are more likely to have the condition recur with subsequent combination hormonal contraceptive use. 8. CARBOHYDRATE AND LIPID METABOLIC EFFECTS Hormonal contraceptives have been shown to cause a decrease in glucose tolerance in some users. However, in the non-diabetic woman, combination hormonal contraceptives appear to have no effect on fasting blood glucose. Prediabetic and diabetic women should be carefully observed while taking combination hormonal contraceptives, such as NuvaRing ® . In a clinical study involving 37 NuvaRing ® -treated subjects, glucose tolerance tests showed no clinically significant changes in serum glucose levels from baseline to cycle six. A small proportion of women will have persistent hypertriglyceridemia while using oral contraceptives. Changes in serum triglycerides and lipoprotein levels have been reported in combination hormonal contraceptive users. 9. ELEVATED BLOOD PRESSURE Women with severe hypertension should not be started on hormonal contraceptives. 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. 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 these women elect to use NuvaRing ® , they should be monitored closely and if significant elevation of blood pressure occurs, NuvaRing ® should be discontinued. For most women, elevated blood pressure will return to normal after stopping hormonal contraceptives, and there is no difference in the occurrence of hypertension between former and never-users. 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 NuvaRing ® and evaluation of the cause. 11. BLEEDING IRREGULARITIES Bleeding Patterns Breakthrough bleeding and spotting are sometimes encountered in women using NuvaRing ® . If abnormal bleeding while using NuvaRing ® persists or is severe, appropriate investigation should be instituted to rule out the possibility of organic pathology or pregnancy, and appropriate treatment should be instituted when necessary. In the event of amenorrhea, pregnancy should be ruled out. Bleeding patterns were evaluated in three large clinical studies. In the US-Canadian study (n=1177), the percentages of subjects with breakthrough bleeding/spotting ranged from 7.2 to 11.7% during cycles 1–13. In the two non-US studies, the percentages of subjects with breakthrough bleeding/spotting ranged from 2.6 to 6.4% (Study 1, n=1145 European and Israeli subjects) and from 2.0 to 8.7% (Study 2, n=512 European and South American subjects). In these three studies, the percentages of women who did not have withdrawal bleeding in a given cycle ranged from 0.3 to 3.8%. Some women may encounter amenorrhea or oligomenorrhea after discontinuing use of NuvaRing ® , especially when such a condition was pre-existent. 12. ECTOPIC PREGNANCY Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.