irst 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 sympto-thermal 6 2 post-ovulation 1 withdrawal 19 4 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 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 contraceptive pills: treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%. 9 lactational amenorrhea method: lam is highly effective, temporary method of contraception. 10 source: trussell j, contraceptive efficacy. in hatcher ra, trussell j, stewart f, cates w, stewart gk, kowal 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 one year. 4 the percents 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 fda 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 yellow pills). 10 however, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency of duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches 6 months of age. desogestrel and ethinyl estradiol tablets have not been studied for and is not indicated for use in emergency contraception .

out 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 refs. 2 and 3 with the author's permission). for further information, the reader is referred to a text on epidemiological methods. 1. thromboembolic disorder and other vascular problems a. 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. 2,3,19-24 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. 25 the risk of thromboembolic disease associated with oral contraceptives gradually disappears after combined oral contraceptive (coc) use is stopped. 2 vte risk is highest in the first year of use and when restarting hormonal contraception after a break of four weeks or longer. several epidemiologic studies indicate that third generation oral contraceptives, including those containing desogestrel, are associated with a higher risk of venous thromboembolism than certain second generation oral contraceptives. in general, these studies indicate an approximate 2-fold increased risk, which corresponds to an additional 1-2 cases of venous thromboembolism per 10,000 women-years of use. however, data from additional studies have not shown this 2-fold increase in risk. a two-to four-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives. 9 the relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. 26 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 breastfeed. b. 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. 4-10 the risk is very low in women under the age of 30. smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases. 11 mortality rates associated with circulatory disease have been shown to increase substantially in smokers, especially in those 35 years of age and older and in nonsmokers over the age of 40 among women who use oral contraceptives. (see figure 1.) oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity. 13 in particular, some progestogens are known to decrease hdl cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. 14-18 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. there is some evidence that the risk of myocardial infarction associated with oral contraceptives is lower when the progestogen has minimal androgenic activity than when the activity is greater. receptor binding and animal studies have shown that desogestrel or its active metabolite has minimal androgenic activity (see clinical pharmacology ), although these findings have not been confirmed in adequate and well-controlled clinical trials. 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, and smoking interacted to increase the risk of stroke. 27-29 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. 30 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. 30 the attributable risk is also greater in older women. 3 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. 31-33 a decline in serum high density lipoproteins (hdl) has been reported with many progestational agents. 14-16 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 progestogens used in the contraceptives. 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 40–49 years who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups. 8 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. 34 however, both studies were performed with oral contraceptive formulations containing 50 micrograms or higher of estrogens. 2. estimates of mortality from contraceptive use one study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (table 2). 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 an increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970's. 35 current clinical recommendation involves the use of lower estrogen dose formulations and a careful consideration of risk factors. in 1989, the fertility and maternal health drugs advisory committee was asked to review the use of oral contraceptives in women 40 years of age and over. the committee concluded that although cardiovascular disease risk may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception. the committee recommended that the benefits of low-dose 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 an oral contraceptive which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and individual patient needs. table ii: 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 adapted from h.w. ory, ref. #35. *deaths are birth-related **deaths are method-related 3. carcinoma of the reproductive organs and breasts numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian, and cervical cancer in women using oral contraceptives. the risk of having breast cancer diagnosed may be slightly increased among current and recent users of combined oral contraceptives (coc). however, this excess risk appears to decrease over time after coc discontinuation and by 10 years after cessation the increased risk disappears. some studies report an increased risk with duration of use while other studies do not and no consistent relationships have been found with dose or type of steroid. some studies have found a small increase in risk for women who first use cocs before age 20. most studies show a similar pattern of risk with coc use regardless of a woman's reproductive history or her family breast cancer history. breast cancers diagnosed in current or previous 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 usually 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. 45-48 however, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. in spite of many studies of the relationship between oral contraceptive use and breast and cervical cancers, a cause-and-effect relationship has not been established. 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 especially with oral contraceptives of higher dose. 49 rupture of benign, hepatic adenomas may cause death through intra-abdominal hemorrhage. 50, 51 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 desogestrel and ethinyl estradiol tablets prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see contraindications ] . desogestrel and ethinyl estradiol tablets can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen. 6. ocular lesions there have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. appropriate diagnostic and therapeutic measures should be undertaken immediately. 7. oral contraceptive use before or during early pregnancy extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. 56-57 the majority of recent studies also do not indicate a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned 55,56,58,59 when oral contraceptives are 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. 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. 60,61 more recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal. 62-64 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 a decrease in glucose tolerance in a significant percentage of users. 17 this effect has been shown to be directly related to estrogen dose. 65 in general, progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents. 17,66 in the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. 67 because of these demonstrated effects, prediabetic and diabetic women should be carefully monitored 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 women with significant hypertension should not be started on hormonal contraception. 98 an increase in blood pressure has been reported in women taking oral contraceptives 68 and this increase is more likely in older oral contraceptive users 69 and with extended duration of use. 61 data from the royal college of general practitioners 12 and subsequent randomized trials have shown that the incidence of hypertension increases with increasing progestational activity and concentrations of progestogens. women with a history of hypertension or hypertension-related diseases, or renal disease 70 should be encouraged to use another method of contraception. if these women elect to use oral contraceptives, they should be monitored closely and if a clinically significant persistent elevation of blood pressure (bp) occurs ( ≥160 mm hg systolic or ≥100 mm hg diastolic) and cannot be adequately controlled, oral contraceptives should be discontinued. in general, women who develop hypertension during hormonal contraceptive therapy should be switched to a non-hormonal contraceptive. if other contraceptive methods are not suitable, hormonal contraceptive therapy may continue combined with antihypertensive therapy. regular monitoring of bp throughout hormonal contraceptive therapy is recommended. 102 for most women, elevated blood pressure will return to normal after stopping oral contraceptives, 69 and there is no difference in the occurrence of hypertension among former and never users. 68,70,71 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. nonhormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. if pathology has been excluded, time or a change to another formulation may solve the problem. in the event of amenorrhea, pregnancy should be ruled out. some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was pre-existent. 13. ectopic pregnancy ectopic as well as intrauterine pregnancy may occur in contraceptive failures. imgae-02

istered daily from the 1st day through the 21st day of the menstrual cycle, counting the first day of menstrual flow as "day 1". tablets are taken without interruption as follows: one orange "active" tablet daily for 21 days, then one white "reminder" tablet daily for 7 days. after 28 tablets have been taken, a new course is started and a orange "active" tablet is taken the next day. the use of desogestrel and ethinyl estradiol tablets for contraception may be initiated 4 weeks postpartum in women who elect not to breastfeed. when the tablets are administered during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered. (see contraindications and warnings concerning thromboembolic disease. see also precautions nursing mothers .) if the patient starts on desogestrel and ethinyl estradiol tablets postpartum, and has not yet had a period, she should be instructed to use another method of contraception until a orange "active" tablet has been taken daily for 7 days. the possibility of ovulation and conception prior to initiation of medication should be considered. if the patient misses one (1) orange "active" tablet in weeks 1, 2, or 3, the orange "active" tablet should be taken as soon as she remembers. if the patient misses two (2) orange "active" tablets in week 1 or week 2, the patient should take two (2) orange "active" tablets the day she remembers and two (2) orange "active" tablets the next day; and then continue taking one (1) orange "active" tablet a day until she finishes the pack. the patient should be instructed to use a back-up method of birth control such as condoms or spermicide if she has sex in the seven (7) days after missing pills. if the patient misses two (2) orange "active" tablets in the third week or misses three (3) or more orange "active" tablets in a row, the patient should throw out the rest of the pack and start a new pack that same day. the patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills. sunday start when taking desogestrel and ethinyl estradiol tablets, the first orange "active" tablet should be taken on the first sunday after menstruation begins. if the period begins on sunday, the first orange "active" tablet is taken on that day. if switching directly from another oral contraceptive, the first orange "active" tablet should be taken on the first sunday after the last active tablet of the previous product. tablets are taken without interruption as follows: one orange "active" tablet daily for 21 days, then one white "reminder" tablet daily for 7 days. after 28 tablets have been taken, a new course is started and a orange "active" tablet is taken the next day (sunday). when initiating a sunday start regimen, another method of contraception should be used until after the first 7 consecutive days of administration. the use of desogestrel and ethinyl estradiol tablets for contraception may be initiated 4 weeks postpartum. when the tablets are administered during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered. (see contraindications and warnings concerning thromboembolic disease. see also precautions nursing mothers .) if the patient starts on desogestrel and ethinyl estradiol tablets postpartum, and has not yet had a period, she should be instructed to use another method of contraception until a orange "active" tablet has been taken daily for 7 days. the possibility of ovulation and conception prior to initiation of medication should be considered. if the patient misses one (1) orange active tablet in weeks 1, 2, or 3, the orange "active" tablet should be taken as soon as she remembers. if the patient misses two (2) orange "active" tablets in week 1 or week 2, the patient should take two (2) orange "active" tablets the day she remembers and two (2) orange "active" tablets the next day; and then continue taking one (1) orange "active" tablet a day until she finishes the pack. the patient should be instructed to use a back-up method of birth control such as a condom or spermicide if she has sex in the seven (7) days after missing pills. if the patient misses two (2) orange "active" tablets in the third week or misses three (3) or more orange "active" tablets in a row, the patient should continue taking one orange "active" tablet every day until sunday. on sunday the patient should throw out the rest of the pack and start a new pack that same day. the patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills. additional instructions for all dosing regimens breakthrough bleeding, spotting, and amenorrhea are frequent reasons for patients discontinuing oral contraceptives. in breakthrough bleeding, as in all cases of irregular bleeding from the vagina, nonfunctional causes should be borne in mind. in undiagnosed persistent or recurrent abnormal bleeding from the vagina, adequate diagnostic measures are indicated to rule out pregnancy or malignancy. if pathology has been excluded, time or a change to another formulation may solve the problem. changing to an oral contraceptive with a higher estrogen content, while potentially useful in minimizing menstrual irregularity, should be done only if necessary since this may increase the risk of thromboembolic disease. use of oral contraceptives in the event of a missed menstrual period: 1. 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 and oral contraceptive use should be discontinued if pregnancy is confirmed. 2. if the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out.

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 ● allergic reaction, including rash, urticaria, angioedema ● 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 a causal 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 ● acne ● changes in libido ● colitis ● budd-chiari syndrome

desogestrel and ethinyl estradiol tablets, maximum concentrations of 3-keto-desogestrel of 2,805 ± 1,203 pg/ml (mean ± sd) are reached at 1.4 ± 0.8 hours. the area under the curve (auc 0 -∞) is 33,858 ± 11,043 pg/ml*hr after a single dose. at steady state, attained from at least day 19 onwards, maximum concentrations of 5,840 ± 1,667 pg/ml are reached at 1.4 ± 0.9 hours. the minimum plasma levels of 3-keto-desogestrel at steady state are 1,400 ± 560 pg/ml. the auc 0-24 at steady state is 52,299 ± 17,878 pg/ml*hr. the mean auc 0 -∞ for 3-keto-desogestrel at single dose is significantly lower than the mean auc 0-24 at steady state. this indicates that the kinetics of 3-keto-desogestrel are non-linear due to an increase in binding of 3-keto-desogestrel to sex hormone-binding globulin in the cycle, attributed to increased sex hormone-binding globulin levels which are induced by the daily administration of ethinyl estradiol. sex hormone-binding globulin levels increased significantly in the third treatment cycle from day 1 (150 ± 64 nmol/l) to day 21 (230 ± 59 nmol/l). the elimination half-life for 3-keto-desogestrel is approximately 38 ± 20 hours at steady state. in addition to 3-keto-desogestrel, other phase i metabolites are 3α-oh-desogestrel, 3β-oh-desogestrel, and 3α-oh-5α-h-desogestrel. these other metabolites are not known to have any pharmacologic effects, and are further converted in part by conjugation (phase ii metabolism) into polar metabolites, mainly sulfates and glucuronides. ethinyl estradiol is rapidly and almost completely absorbed. in the third cycle of use after a single dose of desogestrel and ethinyl estradiol tablets, the relative bioavailability is approximately 83%. in the third cycle of use after a single dose of desogestrel and ethinyl estradiol tablets, maximum concentrations of ethinyl estradiol of 95 ± 34 pg/ml are reached at 1.5 ± 0.8 hours. the auc 0 -∞ is 1,471 ± 268 pg/ml*hr after a single dose. at steady state, attained from at least day 19 onwards, maximum ethinyl estradiol concentrations of 141 ± 48 pg/ml are reached at about 1.4 ± 0.7 hours. the minimum serum levels of ethinyl estradiol at steady state are 24 ± 8.3 pg/ml. the auc 0-24 at steady state is 1,117 ± 302 pg/ml*hr. the mean auc 0 -∞ for ethinyl estradiol following a single dose during treatment cycle 3 does not significantly differ from the mean auc 0-24 at steady state. this finding indicates linear kinetics for ethinyl estradiol. the elimination half-life is 26 ± 6.8 hours at steady state. ethinyl estradiol is subject to a significant degree of presystemic conjugation (phase ii metabolism). ethinyl estradiol escaping gut wall conjugation undergoes phase i metabolism and hepatic conjugation (phase ii metabolism). major phase i metabolites are 2-oh-ethinyl estradiol and 2-methoxy-ethinyl estradiol. sulfate and glucuronide conjugates of both ethinyl estradiol and phase i metabolites, which are excreted in bile, can undergo enterohepatic circulation.

steady state. this indicates that the kinetics of 3-keto-desogestrel are non-linear due to an increase in binding of 3-keto-desogestrel to sex hormone-binding globulin in the cycle, attributed to increased sex hormone-binding globulin levels which are induced by the daily administration of ethinyl estradiol. sex hormone-binding globulin levels increased significantly in the third treatment cycle from day 1 (150 ± 64 nmol/l) to day 21 (230 ± 59 nmol/l). the elimination half-life for 3-keto-desogestrel is approximately 38 ± 20 hours at steady state. in addition to 3-keto-desogestrel, other phase i metabolites are 3α-oh-desogestrel, 3β-oh-desogestrel, and 3α-oh-5α-h-desogestrel. these other metabolites are not known to have any pharmacologic effects, and are further converted in part by conjugation (phase ii metabolism) into polar metabolites, mainly sulfates and glucuronides. ethinyl estradiol is rapidly and almost completely absorbed. in the third cycle of use after a single dose of desogestrel and ethinyl estradiol tablets, the relative bioavailability is approximately 83%. in the third cycle of use after a single dose of desogestrel and ethinyl estradiol tablets, maximum concentrations of ethinyl estradiol of 95 ± 34 pg/ml are reached at 1.5 ± 0.8 hours. the auc 0 -∞ is 1,471 ± 268 pg/ml*hr after a single dose. at steady state, attained from at least day 19 onwards, maximum ethinyl estradiol concentrations of 141 ± 48 pg/ml are reached at about 1.4 ± 0.7 hours. the minimum serum levels of ethinyl estradiol at steady state are 24 ± 8.3 pg/ml. the auc 0-24 at steady state is 1,117 ± 302 pg/ml*hr. the mean auc 0 -∞ for ethinyl estradiol following a single dose during treatment cycle 3 does not significantly differ from the mean auc 0-24 at steady state. this finding indicates linear kinetics for ethinyl estradiol. the elimination half-life is 26 ± 6.8 hours at steady state. ethinyl estradiol is subject to a significant degree of presystemic conjugation (phase ii metabolism). ethinyl estradiol escaping gut wall conjugation undergoes phase i metabolism and hepatic conjugation (phase ii metabolism). major phase i metabolites are 2-oh-ethinyl estradiol and 2-methoxy-ethinyl estradiol. sulfate and glucuronide conjugates of both ethinyl estradiol and phase i metabolites, which are excreted in bile, can undergo enterohepatic circulation.