14 (female) without spermicide 5 21 cervical cap nulliparous women 9 20 parous women 26 40 vaginal sponge nulliparous women 9 20 parous women 20 40 diaphragm with spermicidal cream or jelly 6 20 spermicides alone (foam, creams, jellies, and vaginal suppositories) 6 26 periodic abstinence (all methods) 1 to 9 * 25 withdrawal 4 19 no contraception (planned pregnancy) 85 85

iliar with the following information relating to these risks. the information contained in this package insert is based principally on studies carried out in patients who used oral contraceptives with higher formulations of 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 disease, namely, a ratio of the incidence of a disease among oral-contraceptive users to that among nonusers. 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 nonusers. 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. 1. thromboembolic disorders and other vascular problems 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. the relative risk of heart attack for current oral-contraceptive users has been estimated to be two to six. the risk is very low 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 the age of 35 and nonsmokers over the age of 40 (table iii) among women who use oral contraceptives. circulatory disease mortality rates per 100,000 woman years by age, smoking status and oral-contraceptive use 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 section 10 in "warnings"). 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 nonusers 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 postoperative 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 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 post-partum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four to six weeks after delivery in women who elect not to breast-feed, or a midtrimester pregnancy termination. 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 nonusers, 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 3 for normotensive users to 14 for users with severe hypertension. the relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers 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. 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 increase in 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 progestogen used in the contraceptive. the amount of both hormones should be considered in the choice of an oral 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 oral-contraceptive agents should be started on preparations containing less than 50 mcg of estrogen. e 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 to 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 higher of estrogens. 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 less than 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 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, 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 nonsmoking 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 nonsmoking 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. table * deaths are birth related ** deaths are method related adapted from h.w. ory, family planning perspectives, 15 :57-63, 1983. 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 and outcome 15 to 19 20 to 24 25 to 29 30 to 34 35 to 39 40 to 44 no fertility-control methods * 7.0 7.4 9.1 14.8 25.7 28.2 oral contraceptives 0.3 0.5 0.9 1.9 13.8 31.6 nonsmoker ** 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 3 malignant neoplasms breast cancer levonorgestrel and ethinyl estradiol tablet is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see contraindications]. epidemiology studies have not found a consistent association between use of combined oral contraceptives (cocs) and breast cancer risk. studies do not show an association between ever (current or past) use of cocs and risk of breast cancer. however, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and also among current users with longer duration of coc use [see adverse reactions]. cervical cancer 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. 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 u.s., and the attributable risk (the excess incidence) of liver cancers in oral-contraceptive users approaches less than one per million users. 5 risk of liver enzyme elevations with concomitant hepatitis c treatment during clinical trials with the hepatitis c combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, alt elevations greater than 5 times the upper limit of normal (uln), including some cases greater than 20 times the uln, were significantly more frequent in women using ethinyl estradiol-containing medications such as cocs. discontinue levonorgestrel and ethinyl estradiol tablets prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (see contraindications ). levonorgestrel and ethinyl estradiol tablets can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen. 6 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. 7 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. studies also do not suggest 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 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 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 if pregnancy is confirmed. 8 gallbladder disease earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens. more recent studies, however, have shown that the relative risk of developing 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 estrogens and progestogens. 9 carbohydrate and lipid metabolic effects oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users. oral contraceptives containing greater than 75 micrograms of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance. progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents. however, in the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. because of these demonstrated effects, prediabetic and diabetic women should be carefully observed 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. 10 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 quantities 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 with hypertension 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. 11 headache the onset or exacerbation of migraine or development of headache with a new pattern that is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause. 12 bleeding irregularities breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. the type and dose of progestogen may be important. 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. image 02

e associated with birth defects, but these studies have not been confirmed. nevertheless, oral contraceptives or any other drugs should not be used during pregnancy unless clearly necessary and prescribed by your doctor. you should check with your doctor about risks to your unborn child of any medication taken during pregnancy. 2. while breast-feeding if you are breast-feeding, consult your doctor before starting oral contraceptives. some of the drug will be passed on to the child in the milk. a few adverse effects on the child have been reported, including yellowing of the skin (jaundice) and breast enlargement. in addition, oral contraceptives may decrease the amount and quality of your milk. if possible, do not use oral contraceptives while breast-feeding. you should use another method of contraception since breast-feeding provides only partial protection from becoming pregnant, and this partial protection decreases significantly as you breast-feed for longer periods of time. you should consider starting oral contraceptives only after you have weaned your child completely. 3. laboratory tests if you are schedule for any laboratory tests, tell your doctor you are taking birth-control pills. certain blood tests may be affected by birth control-pills. 4. drug interactions certain drugs may interact with birth-control pills to make them less effective in preventing pregnancy or cause an increase in breakthrough bleeding. such drugs include rifampin, drugs used for epilepsy such as barbiturates (for example, phenobarbital) and phenytoin (dilantin is one brand of this drug), phenylbutazone (butazolidin is one brand), and possibly certain antibiotics. you may need to use an additional method of contraception during any cycle in which you take drugs that can make oral contraceptives less effective.

s, and then 7 orange inert tablets for twenty-eight (28) consecutive days, beginning on day one (1) of her menstrual cycle. (the first day of menstruation is day one.) withdrawal bleeding usually occurs within 3 days following the last pink tablet. (if levonorgestrel and ethinyl estradiol tablets are first taken later than the first day of the first menstrual cycle of medication or postpartum, contraceptive reliance should not be placed on levonorgestrel and ethinyl estradiol tablets until after the first 7 consecutive days of administration. the possibility of ovulation and conception prior to initiation of medication should be considered.) when switching from another oral contraceptive, levonorgestrel and ethinyl estradiol tablets should be started on the first day of bleeding following the last active tablet taken of the previous oral contraceptive. the patient begins her next and all subsequent 28-day courses of levonorgestrel and ethinyl estradiol tablets on the same day of the week that she began her first course, following the same schedule. she begins taking her light blue tablets on the next day after ingestion of the last orange tablet, regardless of whether or not a menstrual period has occurred or is still in progress. any time a subsequent cycle of levonorgestrel and ethinyl estradiol tablets is started later than the next day, the patient should be protected by another means of contraception until she has taken a tablet daily for seven consecutive days. if spotting or breakthrough bleeding occurs, the patient is instructed to continue on the same regimen. this type of bleeding is usually transient and without significance; however, if the bleeding is persistent or prolonged, the patient is advised to consult her physician. although the occurrence of pregnancy is highly unlikely if levonorgestrel and ethinyl estradiol tablets are taken according to directions, if withdrawal bleeding does not occur, the possibility of pregnancy must be considered. if the patient has not adhered to the prescribed schedule (missed one or more tablets or started taking them on a day later than she should have), the probability of pregnancy should be considered at the time of the first missed period and appropriate diagnostic measures taken before the medication is resumed. if the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen. the risk of pregnancy increases with each active (light blue, white to off white, or pink) tablet missed. for additional patient instructions regarding missed pills, see the "what to do if you miss pills" section in the detailed patient labeling below. if breakthrough bleeding occurs following missed active tablets, it will usually be transient and of no consequence. if the patient misses one or more orange tablets, she is still protected against pregnancy provided she begins taking light blue tablets on the again on the proper day. in the nonlactating mother, levonorgestrel and ethinyl estradiol tablets may be initiated postpartum, for contraception. when the tablets are administered in the postpartum period, the increased risk of thromboembolic disease associated with the postparturn period must be considered (see "contraindications," "warnings," and "precautions" concerning thromboembolic disease). it is to be noted that early resumption of ovulation may occur if parlodel ® (bromocriptine mesylate) has been used for the prevention of lactation.

ver used cocs. an increased risk of the following serious adverse reactions has been associated with the use of oral- contraceptives (see "warnings" section): thrombophlebitis. arterial thromboembolism. pulmonary embolism. myocardial infarction. cerebral hemorrhage. cerebral thrombosis. hypertension. gallbladder disease. hepatic adenomas or benign liver tumors. there is evidence of an association between the following conditions and the use of oral contraceptives, although additional confirmatory studies are needed: mesenteric thrombosis. retinal thrombosis. the following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug related: nausea. vomiting. gastrointestinal symptoms (such as abdominal cramps and bloating). breakthrough bleeding. spotting. change in menstrual flow. amenorrhea. temporary infertility after discontinuation of treatment. edema. melasma which may persist. breast changes: tenderness, enlargement, secretion. change in weight (increase or decrease). change in cervical erosion and secretion. diminution in lactation when given immediately postpartum. cholestatic jaundice. migraine. rash (allergic). mental depression. reduced tolerance to carbohydrates. vaginal candidiasis. change in corneal curvature (steepening). intolerance to contact lenses. the following adverse reactions have been reported in users of oral contraceptives, and the association has been neither confirmed nor refuted: congenital anomalies. premenstrual syndrome. cataracts. optic neuritis. changes in appetite. cystitis-like syndrome. headache. nervousness. dizziness. hirsutism. loss of scalp hair. erythema multiforme. erythema nodosum. hemorrhagic eruption. vaginitis. porphyria. impaired renal function. hemolytic uremic syndrome. budd-chiari syndrome. acne. changes in libido. colitis. sickle-cell disease. cerebral-vascular disease with mitral valve prolapse. lupus-like syndromes. figure 1: relevant studies of risk of breast cancer with combined oral contraceptive use

her side. references available upon request. the brands listed are trademarks of their respective owners and are not trademarks of lupin pharmaceuticals, inc. the makers of these brands are not affiliated with and do not endorse lupin pharmaceuticals, inc. or its products. distributed by: lupin pharmaceuticals, inc. baltimore, maryland 21202 united states manufactured by: lupin limited pithampur (m.p.) – 454 775 india revised: june 2022