warnings
WARNINGS Cigarette smoking increases the risk of serious cardiovascular side effects from contraceptives containing estrogen. 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 LUNELLE™ Monthly Contraceptive Injection should be 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, obesity, and diabetes. Practitioners prescribing LUNELLE™ Monthly Contraceptive Injection should be familiar with the following information relating to these risks. 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 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 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. 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. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over 35 years of age and older and non-smokers over 40 years of age who use oral contraceptives (see Table 3). Tablet 3. Circulatory Disease Mortality Rates per 100,000 Women years by Age, Smoking Status and Oral Contraceptive Use Age (y) Ever-Users Non-smokers Ever-Users Smokers Controls Non-smokers Controls Smokers 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 Adapted from Layde PM. Beral V., 1981. 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 high density lipoproteins (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, No. 9). Similar effects on risk factors have been associated with an increased risk of heart disease. LUNELLE™ Monthly Contraceptive Injection must be used with caution in women with cardiovascular disease risk factors. Thromboembolism An increased risk of thromboembolic and thrombotic diseases associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared with 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. 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. The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped. 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, oral contraceptives should be discontinued at least 4 weeks prior to and for 2 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 and other combined hormonal contraceptives such as LUNELLE™ Monthly Contraceptive Injection, should be started no earlier than 4 weeks after delivery. 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, LUNELLE™ Monthly Contraceptive Injection should not be readministered. Cerebrovascular Disease 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 stroke. The relative risk of thrombotic strokes has been shown to range from 3 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. Dose-related Risk of Vascular Disease 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 HDL has been reported with many progestational agents. A decline in serum HDL 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 type of progestogens used in the contraceptives. The activity and amount of both hormones should be considered in the choice of a hormonal contraceptive. 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 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 6 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. 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 (see Table 4). 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 years and older who smoke, and oral contraceptive users 40 years 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 until 1983. 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 because of some limited new data that suggest 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 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 that 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 age 40 may outweigh the possible risks. Women of all ages who take oral contraceptives should take a product which contains the lowest amount of estrogen and progestogen that is effective. Table 4. 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 Range of Age (years) Method of Control and Outcome 15 - 19 20 - 24 25 - 29 30 - 34 35 - 39 40 - 44 No fertility control * 7.0 7.4 9.1 14.8 25.7 28.2 Oral Hormonal contraceptives ** (non-smoker) 0.3 0.5 0.9 1.9 13.8 31.6 Oral hormonal 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 Adapted from Ory WH. 1983 * Deaths are birth-related ** Deaths are method-related 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. Although the risk of breast cancer may be slightly increased among current and recent users of combined oral contraceptives, this excess risk decreases over time after product discontinuation, and by 10 years after cessation the increased risk disappears. In addition, breast cancers diagnosed in current or ever-oral contraceptive users tend to be less invasive than in non-users. The risk of breast cancer 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 sub-group for whom risk has been found to be significantly elevated is women who first used combined oral contraceptives before age 20, but because breast cancer is so rare at these young ages, the number of cases attributable to this early combined oral contraceptive use is extremely small. Women who currently have or have had breast cancer should not use combined hormonal contraceptives because breast cancer is a hormonally sensitive tumor. Long-term case-controlled surveillance of users of depot medroxyprogesterone acetate (DMPA) found slight or no increased overall risk of breast cancer. A pooled analysis from two case-control studies, the World Health Organization (WHO) Study and the New Zealand Study, reported the relative risk of breast cancer for women who had ever used DMPA as 1.1. Overall, there was no increase in risk with increasing duration of use of DMPA. The relative risk of breast cancer for women of all ages who had initiated use of DMPA within the previous 5 years was estimated to be 2.0. The WHO Study, a component of the pooled analysis described above, showed an increased relative risk of 2.19 of breast cancer associated with use of DMPA in women whose first exposure to drug was within the previous 4 years and who were under 35 years of age. However, the overall relative risk for ever-users of DMPA was only 1.2. 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. A statistically insignificant increase in relative risk estimates of invasive squamous-cell cervical cancer has been associated with the use of DMPA in women who were first exposed before the age of 35 years. The overall, non-significant relative rate of invasive squamous-cell cervical cancer in women who ever used DMPA was estimated to be 1.11. No trends in risk with duration of use or times since initial or most recent exposure were observed. 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. No long-term studies have been conducted with LUNELLE™ Monthly Contraceptive Injection to evaluate risk for carcinoma of the reproductive organs. 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 cases for users, a risk that increases after 4 or more years of use. Rupture of 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 United States 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. LUNELLE™ Monthly Contraceptive Injection 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. HORMONAL CONTRACEPTIVE USE BEFORE OR DURING PREGNANCY The use of hormonal contraceptives during pregnancy is not indicated. Extensive epidemiological 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. Pregnancies occurring in women receiving injectable progestin-only contraceptives are uncommon. Neonates from unexpected pregnancies that occurred 1 to 2 months after injection of DMPA may be at an increased risk of low birth weight, which, in turn, is associated with an increased risk of neonatal death. A significant increase in incidence of polysyndactyly and chromosomal anomalies was observed among infants of users of DMPA, the former being most pronounced in women under 30 years of age. The unrelated nature of these defects, the lack of confirmation from other studies, the distant preconceptual exposure to DMPA, and the chance effects due to multiple statistical comparisons, make a causal association unlikely. Neonates exposed to MPA in utero and followed to adolescence, showed no evidence of any adverse effects on their health including their physical, intellectual, sexual or social development. Several reports suggest an association between intrauterine exposure to progestational drugs in the first trimester of pregnancy and genital abnormalities in male and female fetuses. The risk of hypospadias (five to eight per 1,000 male births in the general population) may be approximately doubled with exposure to these drugs. There are insufficient data to quantify the risk to exposed female fetuses, but because some of these drugs induce mild virilization of the external genitalia of the female fetus and because of the increased association of hypospadias in the male fetus, these drugs should be avoided during pregnancy. Unexpected pregnancies occurring in women receiving LUNELLE™ Monthly Contraceptive Injection are uncommon and have not shown congenital malformations or other adverse events. The administration of combined hormonal contraceptives, such as LUNELLE™ Monthly Contraceptive Injection, to induce withdrawal bleeding should not be used as a test for pregnancy. LUNELLE™ Monthly Contraceptive Injection 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 considered before initiating or continuing LUNELLE™ Monthly Contraceptive Injection. If the patient has exceeded the prescribed injection interval (> 33 days) for LUNELLE™ Monthly Contraceptive Injection, the possibility of pregnancy should be ruled out before another injection is administered. GALLBLADDER DISEASE Combined hormonal contraceptives may worsen existing gallbladder disease and may accelerate the development of this disease in previously asymptomatic women. Women with a history of combined hormonal contraceptive-related cholestasis are more likely to have the condition recur with subsequent combined hormonal contraceptive use. In a study of 782 women taking LUNELLE™ Monthly Contraceptive Injection for up to 15 cycles, cholecystitis and cholelithiasis were the only serious adverse events judged to be possibly related to the study drug. They were reported as an adverse event in five subjects, and three subjects required cholecystectomy. CARBOHYDRATE AND LIPID METABOLIC EFFECTS Combined hormonal or progestin-only contraceptives have been shown to cause glucose intolerance in some users. However, in the non-diabetic woman, combined hormonal contraceptives appear to have no effect on fasting blood glucose. Pre-diabetic and diabetic patients should be carefully observed while receiving therapy with LUNELLE™ Monthly Contraceptive Injection. A small proportion of women may have persistent hypertriglyceridemia while using 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 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. In a US clinical study, no increase in mean blood pressure was observed over 15 months use of LUNELLE™ Monthly Contraceptive Injection. 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 combined hormonal contraceptives such as LUNELLE™ Monthly Contraceptive Injection, they should be monitored closely and if significant elevation of blood pressure occurs, LUNELLE™ Monthly Contraceptive Injection 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 former and never-users. HEADACHE The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent, or severe requires evaluation of the cause before further injections of LUNELLE™ Monthly Contraceptive Injection are given. BLEEDING IRREGULARITIES Most women using LUNELLE™ Monthly Contraceptive Injection (58.6%) experienced alteration of menstrual bleeding patterns, including 4.1% amenorrhea, after one year of use. Altered bleeding patterns include frequent bleeding, irregular bleeding, prolonged bleeding, infrequent bleeding, and amenorrhea. As women continued using LUNELLE™ Monthly Contraceptive Injection, the percent experiencing frequent or prolonged bleeding decreased, while the percent experiencing amenorrhea increased. The percent of women experiencing irregular bleeding remained fairly constant at approximately 30% throughout the first year of use. Regardless of the bleeding pattern, subsequent injections should be given 1 month (28 to 30 days, not to exceed 33 days) after the previous injection, unless discontinuation is medically indicated. If abnormal bleeding associated with LUNELLE™ Monthly Contraceptive Injection persists or is severe, appropriate investigation should be instituted to rule out the possibility of organic pathology, and appropriate treatment should be instituted when necessary. In the event of amenorrhea, pregnancy should be ruled out. BONE MINERAL DENSITY CHANGES Use of injectable progestogen-only methods may be considered among the risk factors for development of osteoporosis. The rate of bone loss is greatest in the early years of use and then subsequently approaches the normal rate of age-related fall. Formal studies on the effect of bone mineral density changes in women receiving LUNELLE™ Monthly Contraceptive Injection have not been conducted. ANAPHYLAXIS AND ANAPHYLACTOID REACTION Anaphylaxis and anaphylactoid reactions have been reported with the components of LUNELLE™ Monthly Contraceptive Injection. Allergic reactions occurring in women using LUNELLE™ Monthly Contraceptive Injection have been mainly dermatologic, not respiratory, in nature. If an anaphylactic reaction occurs, appropriate therapy should be instituted. Serious anaphylactic reactions require emergency medical treatment.