sed edition. new york, ny: irvington publishers; 1998. % of women experiencing an unintended pregnancy within the first year of use % of women continuing use at one year 3 method (1) typical use 1 (2) perfect use 2 (3) (4) chance 4 85 85 spermicides 5 26 6 40 periodic abstinence 25 63 calendar 9 ovulation method 3 sympto-thermal 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 levonorgestrel implants (norplant ® ) 0.05 0.05 88 female sterilization 0.5 0.5 100 male sterilization 0.15 0.10 100 emergency contraceptive pills: the fda has concluded that certain combined oral contraceptives containing ethinyl estradiol and norgestrel or levonorgestrel are safe and effective for use as postcoital emergency contraception. treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%. 9 lactation amenorrhea method: lam is a highly effective, temporary method of contraception. 10 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. 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. among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. the proportion of women who become 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 proportion who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether. foams, creams, gels, vaginal suppositories, and vaginal film. cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. with spermicidal cream or jelly. without spermicides. the treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. the fda has declared the following dosage regimens of oral contraceptives to be safe and effective for emergency contraception: for tablets containing 50 mcg of ethinyl estradiol and 500 mcg of norgestrel 1 dose is 2 tablets; for tablets containing 20 mcg of ethinyl estradiol and 100 mcg of levonorgestrel 1 dose is 5 tablets; for tablets containing 30 mcg of ethinyl estradiol and 150 mcg of levonorgestrel 1 dose is 4 tablets. 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. in a clinical trial with aviane (levonorgestrel and ethinyl estradiol tablets), 1,477 subjects had 7,720 cycles of use and a total of 5 pregnancies were reported. this represents an overall pregnancy rate of 0.84 per 100 woman-years. this rate includes patients who did not take the drug correctly. one or more pills were missed during 1,479 (18.8%) of the 7,870 cycles; thus all tablets were taken during 6,391 (81.2%) of the 7,870 cycles. of the total 7,870 cycles, a total of 150 cycles were excluded from the calculation of the pearl index due to the use of backup contraception and/or missing 3 or more consecutive pills.

, obesity, diabetes, and surgery or trauma with increased risk of thrombosis (see contraindications ). practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks. the information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher doses of estrogens and progestogens than those in common use today. the effect of long-term use of the oral contraceptives with lower doses of both estrogens and progestogens remains to be determined. throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. case control studies provide a measure of the relative risk of disease, namely, a ratio of the incidence of a disease among oral-contraceptive users to that among nonusers. the relative risk does not provide information on the actual clinical occurrence of a disease. cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral-contraceptive users and nonusers. the attributable risk does provide information about the actual occurrence of a disease in the population. for further information, the reader is referred to a text on epidemiological methods. 1. thromboembolic disorders and other vascular problems a. myocardial infarction an increased risk of myocardial infarction has been attributed to oral-contraceptive use. this risk is primarily in smokers or women with other underlying risk factors for coronary-artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. the relative risk of heart attack for current oral-contraceptive users has been estimated to be two to six. the risk is very low under the age of 30. smoking in combination with oral-contraceptive use has been shown to contribute substantially to the incidence of myocardial infarction in women in their mid-thirties or older with smoking accounting for the majority of excess cases. mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and nonsmokers over the age of 40 ( figure 2 ) among women who use oral contraceptives. figure 2: circulatory disease mortality rates per 100,000 woman years by age, smoking status and oral-contraceptive use (adapted from p.m. layde and v. beral, lancet, 1:541–546, 1981.) oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age, and obesity. in particular, some progestogens are known to decrease 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. venous thrombosis and thromboembolism an increased risk of venous 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. 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 approximate incidence of deep-vein thrombosis and pulmonary embolism in users of low dose (<50 mcg ethinyl estradiol) combination oral contraceptives is up to 4 per 10,000 woman-years compared to 0.5 to 3 per 10,000 woman-years for non-users. however, the incidence is less than that associated with pregnancy (6 per 10,000 woman-years). the excess risk is highest during the first year a woman ever uses a combined oral contraceptive. venous thromboembolism may be fatal. the risk of thromboembolic disease due to oral contraceptives is not related to length of use and gradually disappears after pill use is stopped. a two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives. the relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. if feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four weeks after delivery in women who elect not to breast-feed or after a midtrimester pregnancy termination. c. cerebrovascular diseases oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes. in a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension. the relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension. the attributable risk is also greater in older women. oral contraceptives also increase the risk for stroke in women with other underlying risk factors such as certain inherited or acquired thrombophilias. women with migraine (particularly migraine/headaches with focal neurological symptoms, see contraindications ) who take combination oral contraceptives may be at an increased risk of stroke. d. dose-related risk of vascular disease from oral contraceptives a positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease. a decline in serum high-density lipoproteins (hdl) has been reported with many progestational agents. a decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. because estrogens increase hdl cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogen used in the contraceptive. the amount of both hormones should be considered in the choice of an oral contraceptive. minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. for any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. new acceptors of oral-contraceptive agents should be started on preparations containing the lowest estrogen content which is judged appropriate for the individual 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 five or more years, but this increased risk was not demonstrated in other age groups. in another study in great britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small. however, both studies were performed with oral contraceptive formulations containing 50 mcg or higher of estrogens. chart 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 3 ). these estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. each method of contraception has its specific benefits and risks. the study concluded that with the exception of oral-contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is less than that associated with childbirth. the observation of a possible increase in risk of mortality with age for oral-contraceptive users is based on data gathered in the 1970's — but not reported until 1983. however, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral-contraceptive use to women who do not have the various risk factors listed in this labeling. because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed, the fertility and maternal health drugs advisory committee was asked to review the topic in 1989. the committee concluded that although cardiovascular disease risks may be increased with oral-contraceptive use after age 40 in healthy nonsmoking women (even with the newer low-dose formulations), there are greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception. therefore, the committee recommended that the benefits of oral-contraceptive use by healthy nonsmoking women over 40 may outweigh the possible risks. of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective. table 3: annual number of birth-related or method-related deaths associated with control of fertility per 100,000 nonsterile women, by fertility-control method and 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 nonsmoker ** 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, family planning perspectives, 15 :57-63, 1983. 3. malignant neoplasms breast cancer aviane is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see contraindications (4) ]. 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 ]. cervical cancer some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia or invasive cervical cancer 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 these benign tumors is rare in the united states. indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use. rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage. studies from britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral-contraceptive users. however, these cancers are extremely rare in the u.s. and the attributable risk (the excess incidence) of liver cancers in oral-contraceptive users approaches less than one per million users. 5. risk of liver enzyme elevations with concomitant hepatitis c treatment during clinical trials with the hepatitis c combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, alt elevations greater than 5 times the upper limit of normal (uln), including some cases greater than 20 times the uln, were significantly more frequent in women using ethinyl estradiol-containing medications such as cocs. discontinue aviane prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (see contraindications ). aviane 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 that may lead to partial or complete loss of vision. oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. appropriate diagnostic and therapeutic measures should be undertaken immediately. 7. oral-contraceptive use before or during early pregnancy extensive epidemiological studies have revealed no increased risk of birth defects in infants born to 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 (see contraindications section). 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. 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 combination oral contraceptives may worsen existing gallbladder disease and may accelerate the development of this disease in previously asymptomatic women. 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 nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives. a small proportion of women will have persistent hypertriglyceridemia while on the pill. as discussed earlier (see warnings , 1 a . and 1 d . ; precautions , 3 ), changes in serum triglycerides and lipoprotein levels have been reported in oral-contraceptive users. 10. elevated blood pressure an increase in blood pressure has been reported in women taking oral contraceptives and this increase is more likely in older oral-contraceptive users and with continued use. data from the royal college of general practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing quantities of progestogens. women with a history of hypertension or hypertension-related diseases, or renal disease should be encouraged to use another method of contraception. if women with hypertension elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued (see contraindications section). for most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension among ever- and never-users. 11. headache the onset or exacerbation of migraine or development of headache with a new pattern that is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause (see warnings , 1 c . and contraindications ). 12. bleeding irregularities breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. the type and dose of progestogen may be important. if bleeding persists or recurs, nonhormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. if pathology has been excluded, time or a change to another formulation may solve the problem. in the event of amenorrhea, pregnancy should be ruled out. some women may encounter post-pill amenorrhea or oligomenorrhea (possibly with anovulation), especially when such a condition was preexistent. 13. ectopic pregnancy ectopic as well as intrauterine pregnancy may occur in contraceptive failures.

e first sunday after the onset of menstruation. if menstruation begins on a sunday, the first tablet (orange) is taken that day. one orange tablet should be taken daily for 21 consecutive days, followed by one light-green inert tablet daily for 7 consecutive days. withdrawal bleeding should usually occur within 3 days following discontinuation of orange tablets and may not have finished before the next pack is started. during the first cycle, contraceptive reliance should not be placed on aviane-28 until an orange tablet has been taken daily for 7 consecutive days, and a nonhormonal back-up method of birth control should be used during those 7 days. day 1 start: during the first cycle of medication, the patient is instructed to begin taking aviane-28 during the first 24 hours of her period (day one of her menstrual cycle). one orange tablet should be taken daily for 21 consecutive days, followed by one light-green inert tablet daily for 7 consecutive days. withdrawal bleeding should usually occur within 3 days following discontinuation of orange tablets and may not have finished before the next pack is started. if medication is begun on day one of the menstrual cycle, no back-up contraception is necessary. if aviane-28 tablets are started later than day one of the first menstrual cycle or postpartum, contraceptive reliance should not be placed on aviane-28 tablets until after the first 7 consecutive days of administration, and a nonhormonal back-up method of birth control should be used during those 7 days. after the first cycle of use the patient begins her next and all subsequent courses of tablets on the day after taking her last light-green tablet. she should follow the same dosing schedule: 21 days on orange tablets followed by 7 days on light-green tablets. if in any cycle the patient starts tablets later than the proper day, she should protect herself against pregnancy by using a nonhormonal back-up method of birth control until she has taken an orange tablet daily for 7 consecutive days. switching from another hormonal method of contraception when the patient is switching from a 21-day regimen of tablets, she should wait 7 days after her last tablet before she starts aviane. she will probably experience withdrawal bleeding during that week. she should be sure that no more than 7 days pass after her previous 21-day regimen. when the patient is switching from a 28-day regimen of tablets, she should start her first pack of aviane on the day after her last tablet. she should not wait any days between packs. the patient may switch any day from a progestin-only pill and should begin aviane the next day. if switching from an implant or injection, the patient should start aviane on the day of implant removal or, if using an injection, the day the next injection would be due. in switching from a progestin-only pill, injection, or implant, the patient should be advised to use a nonhormonal back-up method of birth control for the first 7 days of tablet-taking. if spotting or breakthrough bleeding occurs if spotting or breakthrough bleeding occur, the patient is instructed to continue on the same regimen. this type of bleeding is usually transient and without significance; however, if the bleeding is persistent or prolonged, the patient is advised to consult her physician. risk of pregnancy if tablets are missed while there is little likelihood of ovulation occurring if only one or two orange tablets are missed, the possibility of ovulation increases with each successive day that scheduled orange tablets are missed. although the occurrence of pregnancy is unlikely if aviane is taken according to directions, if withdrawal bleeding does not occur, the possibility of pregnancy must be considered. if the patient has not adhered to the prescribed schedule (missed one or more tablets or started taking them on a day later than she should have), the probability of pregnancy should be considered at the time of the first missed period and appropriate diagnostic measures taken. if the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out. the risk of pregnancy increases with each active (orange) tablet missed. for additional patient instructions regarding missed tablets, see the what to do if you miss pills section in the detailed patient labeling below. use after pregnancy, abortion or miscarriage aviane may be initiated no earlier than day 28 postpartum in the nonlactating mother or after a second trimester abortion due to the increased risk for thromboembolism (see contraindications , warnings , and precautions concerning thromboembolic disease). the patient should be advised to use a non-hormonal back-up method for the first 7 days of tablet taking. aviane may be initiated immediately after a first trimester abortion or miscarriage. if the patient starts aviane immediately, back-up contraception is not needed.

e studies compared breast cancer risk between current or recent coc users (<6 months since last use) and never users of cocs ( figure 3 ). one of these studies reported no association between breast cancer risk and coc use. the other two studies found an increased relative risk of 1.19 - 1.33 with current or recent use. both of these studies found an increased risk 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 3: 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. the following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug related (alphabetically listed): acne amenorrhea anaphylactic/anaphylactoid reactions, including urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms breast changes: tenderness, pain, enlargement, secretion budd-chiari syndrome cervical erosion and secretion, change in cholestatic jaundice chorea, exacerbation of colitis contact lenses, intolerance to corneal curvature (steepening), change in dizziness edema/fluid retention erythema multiforme erythema nodosum gastrointestinal symptoms (such as abdominal pain, cramps, and bloating) hirsutism infertility after discontinuation of treatment, temporary lactation, diminution in, when given immediately postpartum libido, change in melasma/chloasma which may persist menstrual flow, change in mood changes, including depression nausea nervousness pancreatitis porphyria, exacerbation of rash (allergic) scalp hair, loss of serum folate levels, decrease in spotting systemic lupus erythematosus, exacerbation of unscheduled bleeding vaginitis, including candidiasis varicose veins, aggravation of vomiting weight or appetite (increase or decrease), change in the following adverse reactions have been reported in users of oral contraceptives: cataracts cystitis-like syndrome dysmenorrhea hemolytic uremic syndrome hemorrhagic eruption optic neuritis, which may lead to partial or complete loss of vision premenstrual syndrome renal function, impaired to report suspected adverse events, contact teva at 1-888-838-2872 or fda at 1-800-fda-1088 or http://www.fda.gov/medwatch for voluntary reporting of adverse reactions. 1

gestrel are 2.8 ± 0.9 ng/ml (mean ± sd) at 1.6 ± 0.9 hours. at steady state, attained from day 19 onwards, maximum levonorgestrel concentrations of 6.0 ± 2.7 ng/ml are reached at 1.5 ± 0.5 hours after the daily dose. the minimum serum levels of levonorgestrel at steady state are 1.9 ± 1.0 ng/ml. observed levonorgestrel concentrations increased from day 1 (single dose) to days 6 and 21 (multiple doses) by 34% and 96%, respectively ( figure 1 ). unbound levonorgestrel concentrations increased from day 1 to days 6 and 21 by 25% and 83%, respectively. the kinetics of total levonorgestrel are non-linear due to an increase in binding of levonorgestrel to sex hormone binding globulin (shbg), which is attributed to increased shbg levels that are induced by the daily administration of ethinyl estradiol. following a single dose, maximum serum concentrations of ethinyl estradiol of 62 ± 21 pg/ml are reached at 1.5 ± 0.5 hours. at steady state, attained from at least day 6 onwards, maximum concentrations of ethinyl estradiol were 77 ± 30 pg/ml and were reached at 1.3 ± 0.7 hours after the daily dose. the minimum serum levels of ethinyl estradiol at steady state are 10.5 ± 5.1 pg/ml. ethinyl estradiol concentrations did not increase from days 1 to 6, but did increase by 19% from days 1 to 21 ( figure 1 ). figure 1: mean (se) levonorgestrel and ethinyl estradiol serum concentrations in 22 subjects receiving 100 mcg levonorgestrel and 20 mcg ethinyl estradiol table 1 provides a summary of levonorgestrel and ethinyl estradiol pharmacokinetic parameters. table 1: mean (sd) pharmacokinetic parameters of aviane over a 21-day dosing period levonorgestrel c max t max auc cl/f vλz/f shbg day ng/ml h ng•h/ml ml/h/kg l/kg nmol/l 1 2.75 (0.88) 1.6 (0.9) 35.2 (12.8) 53.7 (20.8) 2.66 (1.09) 57 (18) 6 4.52 (1.79) 1.5 (0.7) 46.0 (18.8) 40.8 (14.5) 2.05 (0.86) 81 (25) 21 6.00 (2.65) 1.5 (0.5) 68.3 (32.5) 28.4 (10.3) 1.43 (0.62) 93 (40) unbound levonorgestrel pg/ml h pg•h/ml l/h/kg l/kg fu% 1 51.2 (12.9) 1.6 (0.9) 654 (201) 2.79 (0.97) 135.9 (41.8) 1.92 (0.30) 6 77.9 (22.0) 1.5 (0.7) 794 (240) 2.24 (0.59) 112.4 (40.5) 1.80 (0.24) 21 103.6 (36.9) 1.5 (0.5) 1177 (452) 1.57 (0.49) 78.6 (29.7) 1.78 (0.19) ethinyl estradiol pg/ml h pg•h/ml ml/h/kg l/kg 1 62.0 (20.5) 1.5 (0.5) 653 (227) 567 (204) 14.3 (3.7) 6 76.7 (29.9) 1.3 (0.7) 604 (231) 610 (196) 15.5 (4.0) 21 82.3 (33.2) 1.4 (0.6) 776 (308) 486 (179) 12.4 (4.1) figure 1 distribution levonorgestrel in serum is primarily bound to shbg. ethinyl estradiol is about 97% bound to plasma albumin. ethinyl estradiol does not bind to shbg, but induces shbg synthesis. metabolism levonorgestrel: the most important metabolic pathway occurs in the reduction of the Δ4-3-oxo group and hydroxylation at positions 2α, 1β, and 16β, followed by conjugation. most of the metabolites that circulate in the blood are sulfates of 3α,5β-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. some of the parent levonorgestrel also circulates as 17β-sulfate. metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users. ethinyl estradiol: cytochrome p450 enzymes (cyp3a4) in the liver are responsible for the 2-hydroxylation that is the major oxidative reaction. the 2-hydroxy metabolite is further transformed by methylation and glucuronidation prior to urinary and fecal excretion. levels of cytochrome p450 (cyp3a) vary widely among individuals and can explain the variation in rates of ethinyl estradiol 2-hydroxylation. ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates, and undergoes enterohepatic circulation. excretion the elimination half-life for levonorgestrel is approximately 36 ± 13 hours at steady state. levonorgestrel and its metabolites are primarily excreted in the urine (40% to 68%) and about 16% to 48% are excreted in feces. the elimination half-life of ethinyl estradiol is 18 ± 4.7 hours at steady state. special populations race based on the pharmacokinetic study with aviane, there are no apparent differences in pharmacokinetic parameters among women of different races. hepatic insufficiency no formal studies have evaluated the effect of hepatic disease on the disposition of aviane. however, steroid hormones may be poorly metabolized in patients with impaired liver function. renal insufficiency no formal studies have evaluated the effect of renal disease on the disposition of aviane. drug-drug interactions see precautions section - drug interactions

om day 1 (single dose) to days 6 and 21 (multiple doses) by 34% and 96%, respectively ( figure 1 ). unbound levonorgestrel concentrations increased from day 1 to days 6 and 21 by 25% and 83%, respectively. the kinetics of total levonorgestrel are non-linear due to an increase in binding of levonorgestrel to sex hormone binding globulin (shbg), which is attributed to increased shbg levels that are induced by the daily administration of ethinyl estradiol. following a single dose, maximum serum concentrations of ethinyl estradiol of 62 ± 21 pg/ml are reached at 1.5 ± 0.5 hours. at steady state, attained from at least day 6 onwards, maximum concentrations of ethinyl estradiol were 77 ± 30 pg/ml and were reached at 1.3 ± 0.7 hours after the daily dose. the minimum serum levels of ethinyl estradiol at steady state are 10.5 ± 5.1 pg/ml. ethinyl estradiol concentrations did not increase from days 1 to 6, but did increase by 19% from days 1 to 21 ( figure 1 ). figure 1: mean (se) levonorgestrel and ethinyl estradiol serum concentrations in 22 subjects receiving 100 mcg levonorgestrel and 20 mcg ethinyl estradiol table 1 provides a summary of levonorgestrel and ethinyl estradiol pharmacokinetic parameters. table 1: mean (sd) pharmacokinetic parameters of aviane over a 21-day dosing period levonorgestrel c max t max auc cl/f vλz/f shbg day ng/ml h ng•h/ml ml/h/kg l/kg nmol/l 1 2.75 (0.88) 1.6 (0.9) 35.2 (12.8) 53.7 (20.8) 2.66 (1.09) 57 (18) 6 4.52 (1.79) 1.5 (0.7) 46.0 (18.8) 40.8 (14.5) 2.05 (0.86) 81 (25) 21 6.00 (2.65) 1.5 (0.5) 68.3 (32.5) 28.4 (10.3) 1.43 (0.62) 93 (40) unbound levonorgestrel pg/ml h pg•h/ml l/h/kg l/kg fu% 1 51.2 (12.9) 1.6 (0.9) 654 (201) 2.79 (0.97) 135.9 (41.8) 1.92 (0.30) 6 77.9 (22.0) 1.5 (0.7) 794 (240) 2.24 (0.59) 112.4 (40.5) 1.80 (0.24) 21 103.6 (36.9) 1.5 (0.5) 1177 (452) 1.57 (0.49) 78.6 (29.7) 1.78 (0.19) ethinyl estradiol pg/ml h pg•h/ml ml/h/kg l/kg 1 62.0 (20.5) 1.5 (0.5) 653 (227) 567 (204) 14.3 (3.7) 6 76.7 (29.9) 1.3 (0.7) 604 (231) 610 (196) 15.5 (4.0) 21 82.3 (33.2) 1.4 (0.6) 776 (308) 486 (179) 12.4 (4.1) figure 1 distribution levonorgestrel in serum is primarily bound to shbg. ethinyl estradiol is about 97% bound to plasma albumin. ethinyl estradiol does not bind to shbg, but induces shbg synthesis. metabolism levonorgestrel: the most important metabolic pathway occurs in the reduction of the Δ4-3-oxo group and hydroxylation at positions 2α, 1β, and 16β, followed by conjugation. most of the metabolites that circulate in the blood are sulfates of 3α,5β-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. some of the parent levonorgestrel also circulates as 17β-sulfate. metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users. ethinyl estradiol: cytochrome p450 enzymes (cyp3a4) in the liver are responsible for the 2-hydroxylation that is the major oxidative reaction. the 2-hydroxy metabolite is further transformed by methylation and glucuronidation prior to urinary and fecal excretion. levels of cytochrome p450 (cyp3a) vary widely among individuals and can explain the variation in rates of ethinyl estradiol 2-hydroxylation. ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates, and undergoes enterohepatic circulation. excretion the elimination half-life for levonorgestrel is approximately 36 ± 13 hours at steady state. levonorgestrel and its metabolites are primarily excreted in the urine (40% to 68%) and about 16% to 48% are excreted in feces. the elimination half-life of ethinyl estradiol is 18 ± 4.7 hours at steady state.