vaginal sponge nulliparous parous 9 20 20 40 implant 0.05 0.05 injection: depot medroxyprogesterone acetate 0.3 0.3 iud progesterone t copper t 380a lng 20 1.5 0.6 0.1 2 0.8 0.1 condom without spermicides female male 5 3 21 14 cervical cap with spermicidal cream or jelly nulliparous parous 9 26 20 40 periodic abstinence (all methods) 1 to 9 25 withdrawal 4 19 female sterilization 0.5 0.5 male sterilization 0.10 0.15 adapted from ra hatcher et al, reference 7. * the authors' best guess of the percentage of women expected to experience an accidental pregnancy among couples who initiate a method (not necessarily for the first time) and who use it consistently and correctly during the first year if they do not stop for any other reason. ** this term represents “typical” couples who initiate use of a method (not necessarily for the first time), who experience an accidental pregnancy during the first year if they do not stop use for any other reason. *** n/a--data not available.

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 a 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 (adapted from references 8 and 9 with the author's permission). 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 (10-16). 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 (17). 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 ( table ii ) among women who use oral contraceptives. adapted from p.m. layde and v. beral, reference 18. adapted from p.m. layde and v. beral, reference 18. oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity (19). in particular, some progestogens are known to decrease hdl cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism (20-24). 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. table ii 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 (9,10,25-30). 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 (31). the risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped (8). a two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives (15,32). the relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions (15,32). 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 postpartum 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 breastfeed. c. 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 (greater than 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 (33-35). 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 (36). 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 (36). the attributable risk is also greater in older women (9). 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 (37-39). a decline in serum high-density lipoproteins (hdl) has been reported with many progestational agents (20-22). 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 progestin and the nature of the progestin used in the contraceptives. the amount and activity 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 oral contraceptive, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with the needs of the individual patient. new acceptors of oral contraceptive agents should be started on preparations containing the lowest dose of estrogen which produces satisfactory results for the patient. 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 5 or more years, but this increased risk was not demonstrated in other age groups (14). 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). however, both studies were performed with oral contraceptive formulations containing 50 mcg 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 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 (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 (porter jb, hunter j, jick h, et al. oral contraceptives and nonfatal vascular disease. obstet gynecol 1985;66:1-4; and porter jb, hershel j, walker am. mortality among oral contraceptive users. obstet gynecol 1987;70:29-32), 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. 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 non-smoker ** 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 * deaths are birth related. ** deaths are method related. adapted from h.w. ory, reference 41. 3. malignant neoplasms breast cancer loestrin 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 current users with longer duration of coc use (see adverse reactions, postmarketing experience). 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 (51-54). (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 (55). rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage (56,57). studies from britain have shown an increased risk of developing hepatocellular carcinoma (58-60) in long-term (greater than 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 loestrin prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (see contraindications ) . loestrin 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 and during early pregnancy extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy (61-63). studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb reduction defects are concerned (61,62,64,65), 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 (66,67). more recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal (68-70). 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 (23). oral contraceptives containing greater than 75 mcg of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance (71). progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents (23,72). however, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose (73). 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 (74) and this increase is more likely in older oral contraceptive users (75) and with continued use (74). data from the royal college of general practitioners (18) 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 (76) 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 (75), and there is no difference in the occurrence of hypertension among ever and never users (74,76,77). 11. 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. 12. bleeding irregularities breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three 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-pill amenorrhea or oligomenorrhea, especially when such a condition was preexistent.

lation and conception prior to initiation of use should be considered. dosage and administration for 21-day dosage regimen to achieve maximum contraceptive effectiveness, loestrin 21 must be taken exactly as directed and at intervals not exceeding 24 hours. loestrin 21 provides the patient with a convenient tablet schedule of “3 weeks on --1 week off”. two dosage regimens are described, one of which may be more convenient or suitable than the other for an individual patient. for the initial cycle of therapy, the patient begins her tablets according to the day-1 start or sunday-start regimen. with either regimen, the patient takes one tablet daily for 21 consecutive days followed by one week of no tablets. sunday-start regimen: the patient begins taking tablets from the top row on the first sunday after menstrual flow begins. when menstrual flow begins on sunday, the first tablet is taken on the same day. the last tablet in the dispenser will then be taken on a saturday, followed by no tablets for a week (7 days). for all subsequent cycles, the patient then begins a new 21-tablet regimen on the eighth day, sunday, after taking her last tablet. following this regimen, of 21 days on--7 days off, the patient will start all subsequent cycles on a sunday. day-1 regimen: the first day of menstrual flow is day 1. the patient places the self-adhesive days of the week sticker that corresponds to her starting day over the preprinted days on the blister card. she starts taking one tablet daily, beginning with the first tablet in the top row. the patient completes her 21-tablet regimen when she has taken the last tablet in the tablet dispenser. she will then take no tablets for a week (7 days). for all subsequent cycles, the patient begins a new 21-tablet regimen on the eighth day after taking her last tablet, again starting with the first tablet in the top row after placing the appropriate days of the week sticker over the preprinted days on the blister card. following this regimen of 21 days on--7 days off, the patient will start all subsequent cycles on the same day of the week as the first course. likewise, the interval of no tablets will always start on the same day of the week. tablets should be taken regularly with a meal or at bedtime. it should be stressed that efficacy of medication depends on strict adherence to the dosage schedule. special notes on administration menstruation usually begins two or three days, but may begin as late as the fourth or fifth day, after discontinuing medication. if spotting occurs while on the usual regimen of one tablet daily, the patient should continue medication without interruption. if the patient forgets to take one or more tablets, the following is suggested: one tablet is missed take tablet as soon as remembered take next tablet at the regular time two consecutive tablets are missed (week 1 or week 2) take two tablets as soon as remembered take two tablets the next day use another birth control method for seven days following the missed tablets two consecutive tablets are missed (week 3) sunday-start regimen: take one tablet daily until sunday discard remaining tablets start new pack of tablets immediately (sunday) use another birth control method for seven days following the missed tablets day-1 start regimen: discard remaining tablets start new pack of tablets that same day use another birth control method for seven days following the missed tablets three (or more) consecutive tablets are missed sunday-start regimen: take one tablet daily until sunday discard remaining tablets start new pack of tablets immediately (sunday) use another birth control method for seven days following the missed tablets day-1 start regimen: discard remaining tablets start new pack of tablets that same day use another birth control method for seven days following the missed tablets the possibility of ovulation occurring increases with each successive day that scheduled tablets are missed. while there is little likelihood of ovulation occurring if only one tablet is missed, the possibility of spotting or bleeding is increased. this is particularly likely to occur if two or more consecutive tablets are missed. in the rare case of bleeding which resembles menstruation, the patient should be advised to discontinue medication and then begin taking tablets from a new tablet dispenser on the next sunday or the first day (day 1), depending on her regimen. persistent bleeding which is not controlled by this method indicates the need for reexamination of the patient, at which time nonfunctional causes should be considered. dosage and administration for 28-day dosage regimen to achieve maximum contraceptive effectiveness, loestrin fe should be taken exactly as directed and at intervals not exceeding 24 hours. loestrin fe provides a continuous administration regimen consisting of 21 light yellow or pink tablets of loestrin and 7 brown non-hormone containing tablets of ferrous fumarate. the ferrous fumarate tablets are present to facilitate ease of drug administration via a 28-day regimen and do not serve any therapeutic purpose. there is no need for the patient to count days between cycles because there are no “off-tablet days.” sunday-start regimen: the patient begins taking the first light yellow or pink tablet from the top row of the dispenser (labeled sunday) on the first sunday after menstrual flow begins. when the menstrual flow begins on sunday, the first light yellow or pink tablet is taken on the same day. the patient takes one light yellow or pink tablet daily for 21 days. the last light yellow or pink tablet in the dispenser will be taken on a saturday. upon completion of all 21 light yellow or pink tablets, and without interruption, the patient takes one brown tablet daily for 7 days. upon completion of this first course of tablets, the patient begins a second course of 28-day tablets, without interruption, the next day (sunday), starting with the sunday light yellow or pink tablet in the top row. adhering to this regimen of one light yellow or pink tablet daily for 21 days, followed without interruption by one brown tablet daily for seven days, the patient will start all subsequent cycles on a sunday. day-1 regimen: the first day of menstrual flow is day 1. the patient places the self-adhesive days of the week sticker that corresponds to her starting day over the preprinted days on the blister card. she starts taking one light yellow or pink tablet daily, beginning with the first light yellow or pink tablet in the top row. after the last light yellow or pink tablet (at the end of the third row) has been taken, the patient will then take the brown tablets for a week (7 days). for all subsequent cycles, the patient begins a new 28 tablet regimen on the eighth day after taking her last light yellow or pink tablet, again starting with the first tablet in the top row after placing the appropriate days of the week sticker over the preprinted days on the blister card. following this regimen of 21 light yellow or pink tablets and 7 brown tablets, the patient will start all subsequent cycles on the same day of the week as the first course. tablets should be taken regularly with a meal or at bedtime. it should be stressed that efficacy of medication depends on strict adherence to the dosage schedule. special notes on administration menstruation usually begins two or three days, but may begin as late as the fourth or fifth day, after the brown tablets have been started. in any event, the next course of tablets should be started without interruption. if spotting occurs while the patient is taking light yellow or pink tablets, continue medication without interruption. if the patient forgets to take one or more light yellow or pink tablets, the following is suggested: one tablet is missed take tablet as soon as remembered take next tablet at the regular time two consecutive tablets are missed (week 1 or week 2) take two tablets as soon as remembered take two tablets the next day use another birth control method for seven days following the missed tablets two consecutive tablets are missed (week 3) sunday-start regimen: take one tablet daily until sunday discard remaining tablets start new pack of tablets immediately (sunday) use another birth control method for seven days following the missed tablets day-1 start regimen: discard remaining tablets start new pack of tablets that same day use another birth control method for seven days following the missed tablets three (or more) consecutive tablets are missed sunday-start regimen: take one tablet daily until sunday discard remaining tablets start new pack of tablets immediately (sunday) use another birth control method for seven days following the missed tablets day-1 start regimen: discard remaining tablets start new pack of tablets that same day use another birth control method for seven days following the missed tablets the possibility of ovulation occurring increases with each successive day that scheduled light yellow or pink tablets are missed. while there is little likelihood of ovulation occurring if only one light yellow or pink tablet is missed, the possibility of spotting or bleeding is increased. this is particularly likely to occur if two or more consecutive light yellow or pink tablets are missed. if the patient forgets to take any of the seven brown tablets in week four, those brown tablets that were missed are discarded and one brown tablet is taken each day until the pack is empty. a back-up birth control method is not required during this time. a new pack of tablets should be started no later than the eighth day after the last light yellow or pink tablet was taken. in the rare case of bleeding which resembles menstruation, the patient should be advised to discontinue medication and then begin taking tablets from a new tablet dispenser on the next sunday or the first day (day-1), depending on her regimen. persistent bleeding which is not controlled by this method indicates the need for reexamination of the patient, at which time nonfunctional causes should be considered. use of oral contraceptives in the event of a missed menstrual period if the patient has not adhered to the prescribed dosage regimen, the possibility of pregnancy should be considered after the first missed period and oral contraceptives should be withheld until pregnancy has been ruled out. if the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen. after several months on treatment, bleeding may be reduced to a point of virtual absence. this reduced flow may occur as a result of medication, in which event it is not indicative of pregnancy.

k of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of coc use to approximately 1.4 with more than 8-10 years of coc use. figure 1: relevant studies of risk of breast cancer with combined oral contraceptives rr = relative risk; or = odds ratio; hr = hazard ratio. “ever coc” are females with current or past coc use; “never coc use” are females that never used cocs. 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: pre-menstrual syndrome cataracts 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 figure 1

for ethinyl estradiol (1-3). distribution volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 l/kg (1-3). plasma protein binding of both steroids is extensive (greater than 95%); norethindrone binds to both albumin and sex hormone binding globulin, whereas ethinyl estradiol binds only to albumin (4). metabolism norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. the majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites (5). a small amount of norethindrone acetate is metabolically converted to ethinyl estradiol. ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. the primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the cyp3a4 isoform of cytochrome p450. part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. ethinyl estradiol may undergo enterohepatic circulation (6). excretion norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites (5,6). plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 l/hr/kg) (1-3). special population race: the effect of race on the disposition of loestrin has not been evaluated. renal insufficiency the effect of renal disease on the disposition of loestrin has not been evaluated. in premenopausal women with chronic renal failure undergoing peritoneal dialysis who received multiple doses of an oral contraceptive containing ethinyl estradiol and norethindrone, plasma ethinyl estradiol concentrations were higher and norethindrone concentrations were unchanged compared to concentrations in premenopausal women with normal renal function. hepatic insufficiency the effect of hepatic disease on the disposition of loestrin has not been evaluated. however, ethinyl estradiol and norethindrone may be poorly metabolized in patients with impaired liver function. drug-drug interactions numerous drug-drug interactions have been reported for oral contraceptives. a summary of these is found under precautions, drug interactions .

51285-125-70) . loestrin 1.5/30 (21 tablets) (norethindrone acetate 1.5 mg and ethinyl estradiol 30 mcg tablets usp) are packaged in cartons of five blister cards. each card contains 21 pink, round, flat-faced, beveled-edge, unscored tablets debossed with stylized b on one side and 978 on the other side. (ndc 51285-127-97) . loestrin fe 1.5/30 (28 tablets) (norethindrone acetate 1.5 mg and ethinyl estradiol 30 mcg tablets usp and ferrous fumarate tablets) are packaged in cartons of five blister cards. each card contains 21 pink, round, flat-faced, beveled-edge, unscored tablets debossed with stylized b on one side and 978 on the other side and 7 brown, round, flat-faced, beveled-edge, unscored tablets debossed with stylized b on one side and 247 on the other side. each brown tablet contains 75 mg ferrous fumarate. the ferrous fumarate tablets are present to facilitate ease of drug administration via a 28 day regimen, are non-hormonal, and do not serve any therapeutic purpose. (ndc 51285-128-70) . store at 20° to 25°c (68° to 77°f) [see usp controlled room temperature].

will be as effective as possible. however, this leaflet is not a replacement for a careful discussion between you and your healthcare provider. you should discuss the information provided in this leaflet with him or her, both when you first start taking the pill and during your revisits. you should also follow your healthcare provider's advice with regard to regular check-ups while you are on the pill. effectiveness of oral contraceptives oral contraceptives or “birth control pills” or “the pill” are used to prevent pregnancy and are more effective than other non-surgical methods of birth control. when they are taken correctly, the chance of becoming pregnant is less than 1% (1 pregnancy per 100 women per year of use) when used perfectly, without missing any pills. typical failure rates are actually 3% per year. the chance of becoming pregnant increases with each missed pill during a menstrual cycle. in comparison, typical failure rates for other methods of birth control during the first year of use are as follows: implant: <1% injection: <1% iud: <1 to 2% diaphragm with spermicides: 20% spermicides alone: 26% vaginal sponge: 20 to 40% female sterilization: <1% male sterilization: <1% cervical cap: 20 to 40% condom alone (male): 14% condom alone (female): 21% periodic abstinence: 25% withdrawal: 19% no method: 85% who should not take oral contraceptives 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. some women should not use the pill. for example, you should not take the pill if you are pregnant or think you may be pregnant. you should also not use the pill if you have any of the following conditions: a history of heart attack or stroke blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes a history of blood clots in the deep veins of your legs chest pain (angina pectoris) known or suspected breast cancer or cancer of the lining of the uterus, cervix or vagina unexplained vaginal bleeding (until a diagnosis is reached by your doctor) yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or during previous use of the pill liver tumor (benign or cancerous) take any hepatitis c drug combination containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. this may increase levels of the liver enzyme “alanine aminotransferase” (alt) in the blood. known or suspected pregnancy tell your healthcare provider if you have ever had any of these conditions. your healthcare provider can recommend a safer method of birth control. other considerations before taking oral contraceptives tell your healthcare provider if you have: breast nodules, fibrocystic disease of the breast, an abnormal breast x-ray or mammogram diabetes elevated cholesterol or triglycerides high blood pressure migraine or other headaches or epilepsy mental depression gallbladder, heart, or kidney disease history of scanty or irregular menstrual periods women with any of these conditions should be checked often by their healthcare provider if they choose to use oral contraceptives. also, be sure to inform your doctor or healthcare provider if you smoke or are on any medications. risks of taking oral contraceptives risk of developing blood clots blood clots and blockage of blood vessels are the most serious side effects of taking oral contraceptives; in particular, a clot in the legs can cause thrombophlebitis, and a clot that travels to the lungs can cause a sudden blocking of the vessel carrying blood to the lungs. rarely, clots occur in the blood vessels of the eye and may cause blindness, double vision, or impaired vision. if you take oral contraceptives and need elective surgery, need to stay in bed for a prolonged illness, or have recently delivered a baby, you may be at risk of developing blood clots. you should consult your doctor about stopping oral contraceptives three to four weeks before surgery and not taking oral contraceptives for two weeks after surgery or during bed rest. you should also not take oral contraceptives soon after delivery of a baby. it is advisable to wait for at least four weeks after delivery if you are not breastfeeding. if you are breastfeeding, you should wait until you have weaned your child before using the pill. (see also the section on breastfeeding in general precautions .) heart attacks and strokes oral contraceptives may increase the tendency to develop strokes (stoppage or rupture of blood vessels in the brain) and angina pectoris and heart attacks (blockage of blood vessels in the heart). any of these conditions can cause death or disability. smoking greatly increases the possibility of suffering heart attacks and strokes. furthermore, smoking and the use of oral contraceptives greatly increase the chances of developing and dying of heart disease. gallbladder disease oral contraceptive users probably have a greater risk than nonusers of having gallbladder disease, although this risk may be related to pills containing high doses of estrogens. liver tumors in rare cases, oral contraceptives can cause benign but dangerous liver tumors. these benign liver tumors can rupture and cause fatal internal bleeding. in addition, a possible but not definite association has been found with the pill and liver cancers in two studies, in which a few women who developed these very rare cancers were found to have used oral contraceptives for long periods. however, liver cancers are extremely rare. the chance of developing liver cancer from using the pill is thus even rarer. risk of cancer it is not known if hormonal birth control pills cause breast cancer. some studies, but not all, suggest that there could be a slight increase in the risk of breast cancer among current users with longer duration of use. if you have breast cancer now, or have had it in the past, do not use hormonal birth control because some breast cancers are sensitive to hormones. some studies have found an increase in the incidence of cancer of the cervix in women who use oral contraceptives. however, this finding may be related to factors other than the use of oral contraceptives. estimated risk of death from a birth control method or pregnancy all methods of birth control and pregnancy are associated with a risk of developing certain diseases which may lead to disability or death. an estimate of the number of deaths associated with different methods of birth control and pregnancy has been calculated and is shown in the following table. 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 non-smoker ** 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 * deaths are birth related. ** deaths are method related. in the above table, the risk of death from any birth control method is less than the risk of childbirth, except for oral contraceptive users over the age of 35 who smoke and pill users over the age of 40 even if they do not smoke. it can be seen in the table that for women aged 15 to 39, the risk of death was highest with pregnancy (7 to 26 deaths per 100,000 women, depending on age). among pill users who do not smoke, the risk of death was always lower than that associated with pregnancy for any age group, although over the age of 40, the risk increases to 32 deaths per 100,000 women, compared to 28 associated with pregnancy at that age. however, for pill users who smoke and are over the age of 35, the estimated number of deaths exceeds those for other methods of birth control. if a woman is over the age of 40 and smokes, her estimated risk of death is four times higher (117/100,000 women) than the estimated risk associated with pregnancy (28/100,000 women) in that age group. the suggestion that women over 40 who don't smoke should not take oral contraceptives is based on information from older higher dose pills and on less selective use of pills than is practiced today. an advisory committee of the fda discussed this issue in 1989 and recommended that the benefits of oral contraceptive use by healthy, non-smoking women over 40 years of age may outweigh the possible risks. however, all women, especially older women, are cautioned to use the lowest dose pill that is effective. warning signals if any of these adverse effects occur while you are taking oral contraceptives, call your doctor immediately: sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible clot in the lung) pain in the calf (indicating a possible clot in the leg) crushing chest pain or heaviness in the chest (indicating a possible heart attack) sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating a possible stroke) sudden partial or complete loss of vision (indicating a possible clot in the eye) breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your doctor or healthcare provider to show you how to examine your breasts) severe pain or tenderness in the stomach area (indicating a possibly ruptured liver tumor) difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood (possibly indicating severe depression) jaundice or a yellowing of the skin or eyeballs, accompanied frequently by fever, fatigue, loss of appetite, dark colored urine, or light colored bowel movements (indicating possible liver problems) side effects of oral contraceptives vaginal bleeding irregular vaginal bleeding or spotting may occur while you are taking the pills. irregular bleeding may vary from slight staining between menstrual periods to breakthrough bleeding which is a flow much like a regular period. irregular bleeding occurs most often during the first few months of oral contraceptive use, but may also occur after you have been taking the pill for some time. such bleeding may be temporary and usually does not indicate serious problems. it is important to continue taking your pills on schedule. if the bleeding occurs in more than one cycle or lasts for more than a few days, talk to your doctor or healthcare provider. contact lenses if you wear contact lenses and notice a change in vision or an inability to wear your lenses, contact your doctor or healthcare provider. fluid retention oral contraceptives may cause edema (fluid retention) with swelling of the fingers or ankles and may raise your blood pressure. if you experience fluid retention, contact your doctor or healthcare provider. melasma a spotty darkening of the skin is possible, particularly of the face. other side effects other side effects may include change in appetite, headache, nervousness, depression, dizziness, loss of scalp hair, rash, and vaginal infections. if any of these side effects bother you, call your doctor or healthcare provider. general precautions missed periods and use of oral contraceptives before or during early pregnancy there may be times when you may not menstruate regularly after you have completed taking a cycle of pills. if you have taken your pills regularly and miss one menstrual period, continue taking your pills for the next cycle but be sure to inform your healthcare provider before doing so. if you have not taken the pills daily as instructed and missed a menstrual period, or if you missed two consecutive menstrual periods, you may be pregnant. check with your healthcare provider immediately to determine whether you are pregnant. do not continue to take oral contraceptives until you are sure you are not pregnant, but continue to use another method of contraception. there is no conclusive evidence that oral contraceptive use is associated with an increase in birth defects, when taken inadvertently during early pregnancy. previously, a few studies had reported that oral contraceptives might be 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. while breastfeeding if you are breastfeeding, 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 breastfeeding. you should use another method of contraception since breastfeeding provides only partial protection from becoming pregnant, and this partial protection decreases significantly as you breastfeed for longer periods of time. you should consider starting oral contraceptives only after you have weaned your child completely. laboratory tests if you are scheduled for any laboratory tests, tell your doctor you are taking birth control pills. certain blood tests may be affected by birth control pills. 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), carbamazepine, and phenytoin (dilantin ® is one brand of this drug); troglitazone; phenylbutazone; and possibly certain antibiotics. you may need to use additional contraception when you take drugs which can make oral contraceptives less effective. birth control pills interact with certain drugs. these drugs include acetaminophen, clofibric acid, cyclosporine, morphine, prednisolone, salicylic acid, temazepam, and theophylline. you should tell your doctor if you are taking any of these medications. this product (like all oral contraceptives) is intended to prevent pregnancy. it does not protect against transmission of hiv (aids) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis b, and syphilis. instructions to patient tablet dispenser the loestrin tablet dispenser has been designed to make oral contraceptive dosing as easy and as convenient as possible. the tablets are arranged in either three or four rows of seven tablets each, with the days of the week appearing above the first row of tablets. if your tablet dispenser contains: you are taking: 21 light yellow tablets loestrin 21 1/20 21 pink tablets loestrin 21 1.5/30 21 light yellow tablets and 7 brown tablets loestrin fe 1/20 21 pink tablets and 7 brown tablets loestrin fe 1.5/30 each light yellow tablet contains 1 mg norethindrone acetate and 20 mcg ethinyl estradiol. each pink tablet contains 1.5 mg norethindrone acetate and 30 mcg ethinyl estradiol. each brown tablet contains 75 mg ferrous fumarate, and is intended to help you remember to take the tablets correctly. these brown tablets are not intended to have any health benefit. directions to remove a tablet, press down on it with your thumb or finger. the tablet will drop through the back of the tablet dispenser. do not press with your thumbnail, fingernail, or any other sharp object. how to take the pill important points to remember before you start taking your pills: be sure to read these directions: before you start taking your pills. anytime you are not sure what to do. the right way to take the pill is to take one pill every day at the same time. if you miss pills you could get pregnant. this includes starting the pack late. the more pills you miss, the more likely you are to get pregnant. many women have spotting or light bleeding, or may feel sick to their stomach during the first 1 to 3 packs of pills. if you do have spotting or light bleeding or feel sick to your stomach, do not stop taking the pill. the problem will usually go away. if it doesn't go away, check with your doctor or clinic. missing pills can also cause spotting or light bleeding, even when you make up these missed pills. on the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. if you have vomiting or diarrhea, for any reason, or if you take some medicines, including some antibiotics, your birth control pills may not work as well. use a back-up birth control method (such as condoms or foam) until you check with your doctor or clinic. if you have trouble remembering to take the pill, talk to your doctor or clinic about how to make pill-taking easier or about using another method of birth control. if you have any questions or are unsure about the information in this leaflet, call your doctor or clinic. before you start taking your pills decide what time of day you want to take your pill. it is important to take it at about the same time every day. look at your pill pack to see if it has 21 or 28 pills: the 21-day pill pack has 21 “active” light yellow or pink pills (with hormones) to take for 3 weeks, followed by 1 week without pills. the 28-day pill pack has 21 “active” light yellow or pink pills (with hormones) to take for 3 weeks, followed by 1 week of reminder brown pills (without hormones). also find: 1) where on the pack to start taking pills, 2) in what order to take the pills. 3) the week numbers as shown in the following pictures: loestrin 21 1/20 will contain: all light yellow pills loestrin 21 1.5/30 will contain: all pink pills loestrin fe 1/20 will contain: 21 light yellow pills for weeks 1, 2, and 3 . week 4 will contain brown pills only . loestrin fe 1.5/30 will contain: 21 pink pills for weeks 1, 2, and 3 . week 4 will contain brown pills only . 4. be sure you have ready at all times: another kind of birth control (such as condoms or foam) to use as a back-up in case you miss pills. an extra, full pill pack. when to start the first pack of pills you have a choice of which day to start taking your first pack of pills. decide with your doctor or clinic which is the best day for you. pick a time of day which will be easy to remember. day-1 start: pick the day label strip that starts with the first day of your period. (this is the day you start bleeding or spotting, even if it is almost midnight when the bleeding begins.) place the day label strip on the tablet dispenser over the area that has the days of the week (starting with sunday) printed on the plastic. take the first “active” light yellow or pink pill of the first pack during the first 24 hours of your period. you will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period. sunday-start: take the first “active” light yellow or pink pill of the first pack on the sunday after your period starts , even if you are still bleeding. if your period begins on sunday, start the pack that same day. use another method of birth control as a back-up method if you have sex anytime from the sunday you start your first pack until the next sunday (7 days). condoms or foam are good back-up methods of birth control. what to do during the month take one pill at the same time every day until the pack is empty. do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). do not skip pills even if you do not have sex very often. when you finish a pack or switch your brand of pills: 21 pills: wait 7 days to start the next pack. you will probably have your period during that week. be sure that no more than 7 days pass between 21-day packs. 28 pills: start the next pack on the day after your last “reminder” pill. do not wait any days between packs. what to do if you miss pills if you miss 1 light yellow or pink “active” pill: take it as soon as you remember. take the next pill at your regular time. this means you may take 2 pills in 1 day. you do not need to use a back-up birth control method if you have sex. if you miss 2 light yellow or pink “active” pills in a row in week 1 or week 2 of your pack: take 2 pills on the day you remember and 2 pills the next day. then take 1 pill a day until you finish the pack. you could get pregnant if you have sex in the 7 days after you miss pills. you must use another birth control method (such as condoms or foam) as a back-up method of birth control until you have taken a light yellow or pink “active” pill every day for 7 days. if you miss 2 light yellow or pink “active” pills in a row in the 3rd week: if you are a day 1 starter throw out the rest of the pill pack and start a new pack that same day. if you are a sunday starter keep taking 1 pill every day until sunday. on sunday, throw out the rest of the pack and start a new pack of pills that same day. you may not have your period this month, but this is expected. however, if you miss your period 2 months in a row, call your doctor or clinic because you might be pregnant. you could get pregnant if you have sex in the 7 days after you miss pills. you must use another birth control method (such as condoms or foam) as a back-up method of birth control until you have taken a light yellow or pink “active” pill every day for 7 days. if you miss 3 or more light yellow or pink “active” pills in a row (during the first 3 weeks): if you are a day-1 starter: throw out the rest of the pill pack and start a new pack that same day. if you are a sunday starter: keep taking 1 pill every day until sunday. on sunday, throw out the rest of the pack and start a new pack of pills that same day. you may not have your period this month, but this is expected. however, if you miss your period 2 months in a row, call your doctor or clinic because you might be pregnant. you could get pregnant if you have sex in the 7 days after you miss pills. you must use another birth control method (such as condoms or foam) as a back-up method of birth control until you have taken a light yellow or pink “active” pill every day for 7 days. a reminder for those on 28-day packs if you forget any of the 7 brown “reminder” pills in week 4: throw away the pills you missed. keep taking 1 pill each day until the pack is empty. you do not need a back-up method. finally, if you are still not sure what to do about the pills you have missed: use a back-up method anytime you have sex. keep taking one light yellow or pink “active” pill each day until you can reach your doctor or clinic. pregnancy due to pill failure the incidence of pill failure resulting in pregnancy is approximately 1% (i.e., one pregnancy per 100 women per year) if taken every day as directed, but more typical failure rates are about 3%. if failure does occur, the risk to the fetus is minimal. pregnancy after stopping the pill there may be some delay in becoming pregnant after you stop using oral contraceptives, especially if you had irregular menstrual cycles before you used oral contraceptives. it may be advisable to postpone conception until you begin menstruating regularly once you have stopped taking the pill and desire pregnancy. there does not appear to be any increase in birth defects in newborn babies when pregnancy occurs soon after stopping the pill. overdosage serious ill effects have not been reported following ingestion of large doses of oral contraceptives by young children. overdosage may cause nausea and withdrawal bleeding in females. in case of overdosage, contact your healthcare provider or pharmacist. other information your healthcare provider will take a medical and family history and examine you before prescribing oral contraceptives. the physical examination may be delayed to another time if you request it and your healthcare provider believes that it is a good medical practice to postpone it. you should be reexamined at least once a year. be sure to inform your healthcare provider if there is a family history of any of the conditions listed previously in this leaflet. be sure to keep all appointments with your healthcare provider, because this is a time to determine if there are early signs of side effects of oral contraceptive use. do not use the drug for any condition other than the one for which it was prescribed. this drug has been prescribed specifically for you; do not give it to others who may want birth control pills. health benefits from oral contraceptives in addition to preventing pregnancy, use of oral contraceptives may provide certain benefits. they are: menstrual cycles may become more regular blood flow during menstruation may be lighter and less iron may be lost. therefore, anemia due to iron deficiency is less likely to occur pain or other symptoms during menstruation may be encountered less frequently ectopic (tubal) pregnancy may occur less frequently noncancerous cysts or lumps in the breast may occur less frequently acute pelvic inflammatory disease may occur less frequently oral contraceptive use may provide some protection against developing two forms of cancer: cancer of the ovaries and cancer of the lining of the uterus. if you want more information about birth control pills, ask your doctor or pharmacist. they have a more technical leaflet called the “physician insert”, which you may wish to read. remembering to take tablets according to schedule is stressed because of its importance in providing you the greatest degree of protection. missed menstrual periods for both dosage regimens at times there may be no menstrual period after a cycle of pills. therefore, if you miss one menstrual period but have taken the pills exactly as you were supposed to , continue as usual into the next cycle. if you have not taken the pills correctly and miss a menstrual period, you may be pregnant and should stop taking oral contraceptives until your doctor or healthcare provider determines whether or not you are pregnant. until you can get to your doctor or healthcare provider, use another form of contraception. if two consecutive menstrual periods are missed, you should stop taking pills until it is determined whether or not you are pregnant. although there does not appear to be any increase in birth defects in newborn babies if you become pregnant while using oral contraceptives, you should discuss the situation with your doctor or healthcare provider. periodic examination your doctor or healthcare provider will take a complete medical and family history before prescribing oral contraceptives. at that time and about once a year thereafter, he or she will generally examine your blood pressure, breasts, abdomen, and pelvic organs (including a papanicolaou smear, i.e., test for cancer). keep this and all medications out of the reach of children. rx only store at 20° to 25°c (68° to 77°f) [see usp controlled room temperature]. brands listed are the trademarks of their respective owners. teva women’s health, inc. subsidiary of teva pharmaceuticals usa, inc. north wales, pa 19454 rev. c 7/2022 to report suspected adverse reactions, contact teva at 1-888-838-2872 or fda at 1800-fda-1088 or www.fda.gov/medwatch. loestrin 21 1/20 blister image loestrin 21 1.5/30 blister image loestrin fe 1/20 blister image loestrin fe 1.5/30 blister image