entage of women experiencing an unintended pregnancy during the first year of typical use and the first year of perfect use of contraception and the percentage continuing use at the end of the first year. united states. % of women experiencing an unintended pregnancy within the first year of use % of women continuing use at one year 3 method typical use 1 perfect use 2 (1) (2) (3) (4) chance 4 85 85 spermicides 5 26 6 40 periodic abstinence 25 63 calendar 9 ovulation method 3 symptothermal 6 2 post-ovulation 1 cap 7 parous women 40 26 42 nulliparous women 20 9 56 sponge parous women 40 20 42 nulliparous women 20 9 56 diaphragm 7 20 6 56 withdrawal 19 4 condom 8 female (reality) 21 5 56 male 14 3 61 pill 5 71 progestin only 0.5 combined 0.1 iud progesterone t 2.0 1.5 81 copper t380a 0.8 0.6 78 lng 20 0.1 0.1 81 depo-provera ® 0.3 0.3 70 norplant ® and norplant-2 ® 0.05 0.05 88 female sterilization 0.5 0.5 100 male sterilization 0.15 0.10 100 emergency contraceptives pills: treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75% 9 . lactational amenorrhea method: lam is a highly effective, temporary method of contraception. 10 source: trussell j, the essentials of contraception. in hatcher ra, trussell j, stewart f, cates w, stewart gk, kowel d, guest f, contraceptive technology: seventeenth revised edition. new york ny: irvington publishers, 1998. 1 among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. 2 among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. 3 among couples attempting to avoid pregnancy, the percentage who continue to use a method for 1 year. 4 the percentages becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. among such populations, about 89% become pregnant within one year. this estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether. 5 foams, creams, gels, vaginal suppositories, and vaginal film. 6 cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. 7 with spermicidal cream or jelly. 8 without spermicides. 9 the treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. the food and drug administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: ovral ® (1 dose is 2 white pills), alesse ® (1 dose is 5 pink pills), nordette ® or levlen ® (1 dose is 4 lightorange pills), lo/ovral ® (1 dose is 4 white pills), triphasil ® or tri-levlen ® (1 dose is 4 yellow pills). 10 however, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches 6 months of age. norethindrone acetate and ethinyl estradiol tablets were evaluated for the treatment of acne vulgaris in two randomized, double-blind, placebo-controlled, multicenter, phase 3, six (28-day) cycle studies. a total of 296 patients received norethindrone acetate and ethinyl estradiol tablets and 295 received placebo. mean age at enrollment for both groups was 24 years. at six months each study demonstrated a statistically significant difference between norethindrone acetate and ethinyl estradiol tablets and placebo for mean change from baseline in lesion counts (see table 3 and figure 2). each study also demonstrated overall treatment success in the investigator's global evaluation. patients with severe androgen excess were not studied. table 3. acne vulgaris indication pooled data 376-403 and 376-404 observed means at six months and at baseline* intent to treat population norethindrone acetate and ethinyl estradiol tablets n = 296 placebo n = 295 difference in counts between norethindrone acetate and ethinyl estradiol tablets and placebo at six months (95% ci) † number of lesions counts % reduction counts % reduction inflammatory lesions baseline mean 29 29 six month mean 14 52% 17 41% 33 ±2 non-inflammatory lesions baseline mean 44 43 six month mean 27 38% 32 25% 5 ±3.5 total lesions baseline mean 74 72 six month mean 42 43% 49 32% 7 ±5 *numbers rounded to nearest integer † limits for 95% confidence interval; not adjusted for baseline differences norethindrone acetate and ethinyl estradiol tablet users who started with about 74 acne lesions had about 42 lesions after 6 months of treatment. placebo users who started with about 72 acne lesions had about 49 lesions after the same duration of treatment. image

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. 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 non-smokers over the age of 40 (figure 3) among women who use oral contraceptives. 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 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 should be started no earlier than 4 to 6 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 (>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 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. d. dose-related risk of vascular disease from oral contraceptives a positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease. a decline in serum high-density lipoproteins (hdl) has been reported with many progestational agents. a decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. because estrogens increase hdl cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and 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 40-49 years who had used oral contraceptives for 5 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 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 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 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. 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 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 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. 3. carcinoma of the reproductive organs and breasts epidemiologic studies have been conducted examining the relationship between combination oral contraceptives and breast cancer. norethindrone and ethinyl estradiol tablets were not included in these studies, and the majority of the combination oral contraceptives used by women in these studies have higher doses of estrogen than norethindrone and ethinyl estradiol tablets. these studies suggest that the risk of having breast cancer diagnosed may be slightly increased among current and recent users of combination oral contraceptives; however, these studies do not provide evidence for causation. the observed pattern of increased risk of breast cancer diagnosis may be due to earlier detection of breast cancer in combination oral contraceptive users, the biological effects of combination oral contraceptives, or a combination of reasons. the risk appears to decrease over time after combination oral contraceptive discontinuation, and by 10 years after cessation of combination oral contraceptive use, the additional risk disappears. the risk does not appear to increase with duration of use and no consistent relationships have been found with age at first use or doses studied or type of steroid. most studies show a similar pattern of risk with combination oral contraceptive use regardless of a woman's reproductive history or her family breast cancer history. breast cancers diagnosed in current or previous combination oral contraceptive users tend to be less clinically advanced than in nonusers. women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is a hormonally-sensitive tumor. 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/ 1 00,000 for users, a risk that increases after 4 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 (>8years) oral contraceptive users. however, these cancers are extremely rare in the us, and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users. 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 tilia fe prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (see contraindications ). tilia fe 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. studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb reduction defects are concerned, when taken inadvertently during early pregnancy. 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 mcg 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 non-diabetic 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 1 a. and 1 d. ), 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 concentrations of progestogens. women with a history of hypertension or hypertension-related diseases or renal disease should be encouraged to use another method of contraception. if women elect to use oral contraceptives, they should be monitored closely, and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. for most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension among ever and never users. 1 1. 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. 1 2. 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 prolonged 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 image

initiation of use should be considered. dosage and administration for 28-day dosage regimen to achieve maximum contraceptive effectiveness, tilia fe should be taken exactly as directed and at intervals not exceeding 24 hours. tilia fe provides a continuous administration regimen consisting of 21 active tablets (pale yellow, light yellow and light brown) and seven 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." a. sunday-start regimen: the patient begins taking the first pale yellow tablet from the top row of the dispenser (labeled sunday) on the first sunday after menstrual flow begins. when menstrual flow begins on sunday, the first pale yellow is taken on the same day. the patient takes one active tablet daily for 21 days. the last light brown tablet in the dispenser will be taken on a saturday. upon completion of all 21 active 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 active tablet in the top row. adhering to this regimen of one active tablet daily for 21 days, followed without interruption by one brown tablet daily for 7 days, the patient will start all subsequent cycles on a sunday. b. day-1 start regimen: the first day of menstrual flow is day 1. the patient places the self-adhesive day label sticker that corresponds to her starting day over the preprinted days on the tablet dispenser. she starts taking one active tablet daily, beginning with the first active tablet in the top row. after the last active 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 active tablet, again starting with the first tablet in the top row after placing the appropriate day label sticker over the preprinted days on the tablet dispenser. following this regimen of 21 active 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 at the same time each day and can be taken without regard to meals. 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 active tablets, continue medication without interruption. if the patient forgets to take one or more active 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 active tablets are missed. while there is little likelihood of ovulation occurring if only one "active" tablet is missed, the possibility of spotting or bleeding is increased. this is particularly likely to occur if two or more consecutive "active" 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 active 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 1. 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. 2. 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. acne the timing of initiation of dosing with tilia fe for acne should follow the guidelines for use of tilia fe as an oral contraceptive. consult the dosage and administration section for oral contraceptives .

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

of sebum production. while the combination of norethindrone acetate and ethinyl estradiol increases sex hormone binding globulin (shbg) and decreases free testosterone, the relationship between these changes and a decrease in the severity of facial acne in otherwise healthy women with this skin condition has not been established. pharmacokinetics absorption norethindrone acetate appears to be completely and rapidly deacetylated to norethindrone after oral administration, since the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. norethindrone acetate and ethinyl estradiol are rapidly absorbed, with maximum plasma concentrations of norethindrone and ethinyl estradiol occurring 1 to 2 hours post-dose. both are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for norethindrone and 43% for ethinyl estradiol. administration of norethindrone acetate/ethinyl estradiol with a high fat meal decreases rate, but not extent,of ethinyl estradiol absorption. the extent of norethindrone absorption is increased by 27% following administration with food. plasma concentrations of norethindrone and ethinyl estradiol following chronic administration of norethindrone acetate and ethinyl estradiol tablets to 17 women are shown below (figure 1). mean steady-state concentrations of norethindrone for the 1/20, 1/30, and 1/35 tablet strengths increased as ethinyl estradiol dose increased over the 21-day dose regimen, due to dose-dependent effects of ethinyl estradiol on serum shbg concentrations (table 1).mean steady-state plasma concentrations of ethinyl estradiol for the 1/20, 1/30, and 1/35 tablet strengths were proportional to ethinyl estradiol dose (table 1). no age-related differences were seen in plasma concentrations of ethinyl estradiol and norethindrone following administration of norethindrone acetate and ethinyl estradiol tablets to 119 postmenarchal women ages 15 to 48 years. distribution volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 l/kg. plasma protein binding of both steroids is extensive (>95%); norethindrone binds to both albumin and sex hormone binding globulin, whereas ethinyl estradiol binds only to albumin. although ethinyl estradiol does not bind to shbg, it induces shbg synthesis. norethindrone acetate and ethinyl estradiol tablets increase serum shbg concentrations two- to three-fold (table 1). 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. 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. excretion norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites. plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 l/hr/kg). steady-state elimination half-lives of norethindrone and ethinyl estradiol following administration of norethindrone acetate and ethinyl estradiol tablets are approximately 13 hours and 19 hours, respectively. special population race: the effect of race on the disposition of tilia fe has not been evaluated. renal insufficiency the effect of renal disease on the disposition of tilia fe 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 tilia fe 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. image image

omen are shown below (figure 1). mean steady-state concentrations of norethindrone for the 1/20, 1/30, and 1/35 tablet strengths increased as ethinyl estradiol dose increased over the 21-day dose regimen, due to dose-dependent effects of ethinyl estradiol on serum shbg concentrations (table 1).mean steady-state plasma concentrations of ethinyl estradiol for the 1/20, 1/30, and 1/35 tablet strengths were proportional to ethinyl estradiol dose (table 1). no age-related differences were seen in plasma concentrations of ethinyl estradiol and norethindrone following administration of norethindrone acetate and ethinyl estradiol tablets to 119 postmenarchal women ages 15 to 48 years. distribution volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 l/kg. plasma protein binding of both steroids is extensive (>95%); norethindrone binds to both albumin and sex hormone binding globulin, whereas ethinyl estradiol binds only to albumin. although ethinyl estradiol does not bind to shbg, it induces shbg synthesis. norethindrone acetate and ethinyl estradiol tablets increase serum shbg concentrations two- to three-fold (table 1). 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. 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. excretion norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites. plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 l/hr/kg). steady-state elimination half-lives of norethindrone and ethinyl estradiol following administration of norethindrone acetate and ethinyl estradiol tablets are approximately 13 hours and 19 hours, respectively.

carton of 3 compacts ndc 51862-896-03 carton of 6 compacts ndc 51862-896-06 store at 20°c to 25°c (68°f to 77°f). [see usp controlled room temperature]. protect from light. keep this drug and all drugs out of the reach of children. rx only. references available upon request