) 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 t 380a 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 adapted from hatcher et al., 1998, ref#1. 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.

hout this labeling, epidemiologic 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 non-users. 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 non-users. the attributable risk does provide information about the actual occurrence of a disease in the population (adapted from refs. 2 and 3 with the authors' permission). for further information, the reader is referred to a text on epidemiologic methods. 1. thromboembolic disorders 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 thromboembolic disease, 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 is not related to length of use and disappears after pill use is stopped. 2 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. 102–104 in general, these studies indicate an approximate two-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 two-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. 9,26 the relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. 9,26 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 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. 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 infarction 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, over the age of 35 and non-smokers over the age of 40 (table iii) 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. 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. 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 non-users, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes. 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 0.035 mg or less of estrogen. e. persistence of risk of vascular disease there are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. in a study in the united states, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40–49 years old 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 more of estrogen. 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 iv). 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. 35 however, current clinical practice involves the use of lower estrogen formulations combined with careful consideration of risk factors. 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, 100,101 the fertility and maternal health drugs advisory committee was asked to review the topic in 1989. the committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are 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. therefore, 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 the lowest possible dose formulation that is effective. table iv : annual number of birth-related or method-related deaths associated with control of fertility per 100,000 non-sterile women, by fertility control method according to age method of control and outcome 15 - 19 20 - 24 25 - 29 30 - 34 35 - 39 40 - 44 no fertility control methods* 7.0 7.4 9.1 14.8 25.7 28.2 oral contraceptives non-smoker** 0.3 0.5 0.9 1.9 13.8 31.6 oral contraceptives smoker** 2.2 3.4 6.6 13.5 51.1 117.2 iud** 0.8 0.8 1.0 1.0 1.4 1.4 condom* 1.1 1.6 0.7 0.2 0.3 0.4 diaphragm/spermicide* 1.9 1.2 1.2 1.3 2.2 2.8 periodic abstinence* 2.5 1.6 1.6 1.7 2.9 3.6 *deaths are birth related **deaths are method related adapted from h.w. ory, ref. #35. 3. carcinoma of the reproductive organs and breasts numerous epidemiologic studies have been performed on the incidence of breast, endometrial, ovarian, and cervical cancer in women using oral contraceptives. while there are conflicting reports, most studies suggest that the use of oral contraceptives is not associated with an overall increase in the risk of developing breast cancer. some studies have reported an increased relative risk of developing breast cancer, particularly at a younger age. this increased relative risk appears to be related to duration of use. 36–43, 79–89 some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intra-epithelial 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. 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 rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage. 50,51 studies from britain have shown an increased risk of developing hepatocellular carcinoma 52–54 in long-term (>8 years) 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 pimtrea™ prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see contraindications ] . pimtrea™ 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 epidemiologic studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. 55–57 studies also do not suggest 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 before continuing oral contraceptive use. if the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the first missed period. oral contraceptive use should be discontinued until pregnancy is ruled out. 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 oral contraceptives containing greater than 75 micrograms of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance. 65 progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents. 17,66 however, in the non-diabetic 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 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 continued 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 quantities 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 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, 69 and there is no difference in the occurrence of hypertension between ever- 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. non-hormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. if pathology has been excluded, time or a change to another formulation may solve the problem. in the event of amenorrhea, pregnancy should be ruled out. some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was pre-existent. 13. ectopic pregnancy ectopic as well as intrauterine pregnancy may occur in contraceptive failures. image-02 image-03

ontraceptives might be associated with birth defects, but these studies have not been confirmed. nevertheless, oral contraceptives or any other drugs should not be used during pregnancy unless clearly necessary and prescribed by your doctor or health care provider. you should check with your doctor or health care provider about risks to your unborn child of any medication taken during pregnancy. 2. while breast feeding if you are breast feeding, consult your doctor or health care provider before starting oral contraceptives. some of the drug will be passed on to the child in the milk. a few adverse effects on the child have been reported, including yellowing of the skin (jaundice) and breast enlargement. in addition, oral contraceptives may decrease the amount and quality of your milk. if possible, do not use oral contraceptives while breast feeding. you should use another method of contraception since breast feeding provides only partial protection from becoming pregnant and this partial protection decreases significantly as you breast feed for longer periods of time. you should consider starting oral contraceptives only after you have weaned your child completely. 3. laboratory tests if you are scheduled for any laboratory tests, tell your doctor or health care provider you are taking birth control pills. certain blood tests may be affected by birth control pills. 4. drug interactions certain drugs may interact with birth control pills to make them less effective in preventing pregnancy or cause an increase in breakthrough bleeding. such drugs include rifampin, drugs used for epilepsy such as barbiturates (for example, phenobarbital), phenytoin (dilantin ® is one brand of this drug), phenylbutazone (butazolidin ® is one brand), and possibly certain antibiotics. you may need to use additional contraception when you take drugs which can make oral contraceptives less effective. birth control pills may interact with lamotrigine, an anticonvulsant used for epilepsy. this may increase the risk of seizures, so your physician may need to adjust the dose of lamotrigine. some medicines may make birth control pill less effective, including: • barbiturates • bosentan • carbamazepine • felbamate • griseofulvin • oxcarbazepine • phenytoin • rifampin • st. john's wort • topiramate as with all prescription products, you should notify your healthcare provider of any other medicines and herbal products you are taking. you may need to use a barrier contraceptive when you take drugs or products that can make birth control pills less effective. 5. sexually transmitted diseases this product (like all oral contraceptives) is intended to prevent pregnancy. it does not protect against transmission of hiv (aids) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis b, and syphilis. how to take the pill important points to remember before you start taking your pills: 1. be sure to read these directions: before you start taking your pills. anytime you are not sure what to do. 2. the right way to take the pill is to take one pill every day at the same time. if you miss pills you could get pregnant. this includes starting the pack late. the more pills you miss, the more likely you are to get pregnant. 3. many women have spotting or light bleeding, or may feel sick to their stomach during the first 1–3 packs of pills. if you feel sick to your stomach, do not stop taking the pill. the problem will usually go away. if it doesn't go away, check with your doctor or health care provider. 4. missing pills can also cause spotting or light bleeding, even when you make up these missed pills. on the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. 5. if you have vomiting or diarrhea, for any reason, or if you take some medicines, including some antibiotics, your pills may not work as well. use a back-up method (such as condoms, foam, or sponge) until you check with your doctor or health care provider. 6. if you have trouble remembering to take the pill, talk to your doctor or health care provider about how to make pill-taking easier or about using another method of birth control. 7. if you have any questions or are unsure about the information in this leaflet, call your doctor or health care provider. before you start taking your pills 1. decide what time of day you want to take your pill. it is important to take it at about the same time every day. 2. look at your pill pack: it will have 28 pills: this 28-pill pack has 26 "active" [dark blue and green] pills (with hormones) and 2 "inactive" [white] pills (without hormones). 3. also find: 1) where on the pack to start taking the pills, 2) in what order to take the pills (follow the arrows) and 3) the week numbers as shown in the picture below. 4. be sure you have ready at all times: another kind of birth control (such as condoms, foam, or sponge) to use as a back-up in case you miss pills. an extra, full pill pack. when to start the first pack of pills you have a choice of which day to start taking your first pack of pills. decide with your doctor or health care provider which is the best day for you. pick a time of day which will be easy to remember. day 1 start: 1. pick the day label strip that starts with the first day of your period (this is the day you start bleeding or spotting, even if it is almost midnight when the bleeding begins). 2. place this day label strip in the cycle tablet dispenser over the area that has the days of the week (starting with sunday) imprinted in the plastic. note: if the first day of your period is a sunday, you can skip steps #1 and #2. 3. take the first "active" [dark blue] pill of the first pack during the first 24 hours of your period . 4. you will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period. sunday start: 1. take the first "active" [dark blue] pill of the first pack on the sunday after your period starts , even if you are still bleeding. if your period begins on sunday, start the pack that same day. 2. use another method of birth control as a back-up method if you have sex anytime from the sunday you start your first pack until the next sunday (7 days). condoms, foam, or the sponge are good back-up methods of birth control. what to do during the month 1. take one pill at the same time every day until the pack is empty. do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). do not skip pills even if you do not have sex very often. 2. when you finish a pack or switch your brand of pills: 21 pills: wait 7 days to start the next pack. you will probably have your period during that week. be sure that no more than 7 days pass between 21-day packs. 28 pills: start the next pack on the day after your last pill. do not wait any days between packs.

the increased risk of thromboembolic disease associated with the postpartum period must be considered (see contraindications and warnings concerning thromboembolic disease. see also precautions for " nursing mothers "). if the patient starts on pimtrea™ postpartum, and has not yet had a period, she should be instructed to use another method of contraception until a dark blue tablet has been taken daily for 7 days. sunday start when initiating a sunday start regimen, another method of contraception should be used until after the first 7 consecutive days of administration. using a sunday start, tablets are taken daily without interruption as follows: the first dark blue tablet should be taken on the first sunday after menstruation begins (if menstruation begins on sunday, the first dark blue tablet is taken on that day). one dark blue tablet is taken daily for 21 days, followed by 1 white (inert) tablet daily for 2 days and 1 green (active) tablet daily for 5 days. for all subsequent cycles, the patient then begins a new 28-tablet regimen on the next day (sunday) after taking the last green tablet. [if switching from a sunday start oral contraceptive, the first pimtrea™ (desogestrel/ethinyl estradiol and ethinyl estradiol) tablet should be taken on the second sunday after the last tablet of a 21 day regimen or should be taken on the first sunday after the last inactive tablet of a 28 day regimen.] if a patient misses 1 dark blue tablet, she should take the missed tablet as soon as she remembers. if the patient misses 2 consecutive dark blue tablets in week 1 or week 2, the patient should take 2 tablets the day she remembers and 2 tablets the next day; thereafter, the patient should resume taking 1 tablet daily until she finishes the cycle pack. the patient should be instructed to use a back-up method of birth control if she has intercourse in the 7 days after missing pills. if the patient misses 2 consecutive dark blue tablets in the third week or misses 3 or more dark blue tablets in a row at any time during the cycle, the patient should keep taking 1 dark blue tablet daily until the next sunday. on sunday the patient should throw out the rest of that cycle pack and start a new cycle pack that same day. the patient should be instructed to use a back-up method of birth control if she has intercourse in the 7 days after missing pills. day 1 start counting the first day of menstruation as "day 1", tablets are taken without interruption as follows: one dark blue tablet daily for 21 days, one white (inert) tablet daily for 2 days followed by 1 green (ethinyl estradiol) tablet daily for 5 days. for all subsequent cycles, the patient then begins a new 28-tablet regimen on the next day after taking the last green tablet. [if switching directly from another oral contraceptive, the first dark blue tablet should be taken on the first day of menstruation which begins after the last active tablet of the previous product.] if a patient misses 1 dark blue tablet, she should take the missed tablet as soon as she remembers. if the patient misses 2 consecutive dark blue tablets in week 1 or week 2, the patient should take 2 tablets the day she remembers and 2 tablets the next day; thereafter, the patient should resume taking 1 tablet daily until she finishes the cycle pack. the patient should be instructed to use a back-up method of birth control if she has intercourse in the 7 days after missing pills. if the patient misses 2 consecutive dark blue tablets in the third week or if the patient misses 3 or more dark blue tablets in a row at any time during the cycle, the patient should throw out the rest of that cycle pack and start a new cycle pack that same day. the patient should be instructed to use a back-up method of birth control if she has intercourse in the 7 days after missing pills. all oral contraceptives 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, non-functional 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 both pregnancy and pathology have been excluded, time or a change to another preparation 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 until pregnancy is ruled out. 2. if the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing oral contraceptive use.

ion 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 • acne • changes in libido • colitis • budd-chiari syndrome

inyl estradiol) tablets provide two different regimens of ethinyl estradiol; 0.02 mg in the combination tablet [dark blue] as well as 0.01 mg in the green tablet. ethinyl estradiol is rapidly and almost completely absorbed. after a single dose of desogestrel/ethinyl estradiol combination tablet [dark blue], the relative bioavailability of ethinyl estradiol is approximately 93% while the relative bioavailability of the 0.01 mg tablet [green] is 99%. the effect of food on the bioavailability of pimtrea™ tablets following oral administration has not been evaluated. the pharmacokinetics of etonogestrel and ethinyl estradiol following multiple dose administration of desogestrel/ethinyl estradiol and ethinyl estradiol tablets were determined during the third cycle in 17 subjects. plasma concentrations of etonogestrel and ethinyl estradiol reached steady-state by day 21. the auc (0–24) for etonogestrel at steady-state on day 21 was approximately 2.2 times higher than auc (0–24) on day 1 of the third cycle. the pharmacokinetic parameters of etonogestrel and ethinyl estradiol during the third cycle following multiple dose administration of desogestrel/ethinyl estradiol and ethinyl estradiol tablets are summarized in table i. table i : mean (sd) pharmacokinetic parameters of desogestrel/ethinyl estradiol and ethinyl estradiol tablets over a 28-day dosing period in the third cycle (n=17). etonogestrel day dose* c m a x t m a x t 1 / 2 auc 0 - 2 4 cl/f mg pg/ml h h pg/ml•hr l/h 1 0.15 2503.6 (987.6) 2.4 (1.0) 29.8 (16.3) 17,832 (5674) 5.4 (2.5) 21 0.15 4091.2 (1186.2) 1.6 (0.7) 27.8 (7.2) 39,391 (12,134) 4.4 (1.4) *desogestrel ethinyl estradiol day dose c m a x t m a x t 1 / 2 auc 0 - 2 4 cl/f mg pg/ml h h pg/ml•hr l/h 1 0.02 51.9 (15.4) 2.9 (1.2) 16.5 (4.8) 566 (173) a 25.7 (9.1) 21 0.02 62.2 (25.9) 2.0 (0.8) 23.9 (25.5) 597 (127) a 35.1 (8.2) 24 0.01 24.6 (10.8) 2.4 (1.0) 18.8 (10.3) 246 (65) 43.6 (12.2) 28 0.01 35.3 (27.5) 2.1 (1.3) 18.9 (8.3) 312 (62) 33.2 (6.6) a n=16 c m a x – measured peak concentration t m a x – observed time of peak concentration t 1 / 2 – elimination half-life, calculated by 0.693/k e l i m auc 0 – 2 4 – area under the concentration-time curve calculated by the linear trapezoidal rule (time 0 to 24 hours) cl/f – apparent clearance distribution etonogestrel, the active metabolite of desogestrel, was found to be 99% protein bound, primarily to sex hormone-binding globulin (shbg). ethinyl estradiol is approximately 98.3% bound, mainly to plasma albumin. ethinyl estradiol does not bind to shbg, but induces shbg synthesis. desogestrel, in combination with ethinyl estradiol, does not counteract the estrogen-induced increase in shbg, resulting in lower serum levels of free testosterone. 96–99 metabolism desogestrel: desogestrel is rapidly and completely metabolized by hydroxylation in the intestinal mucosa and on first pass through the liver to etonogestrel. other metabolites (i.e., 3 -oh-desogestrel, 3 -oh-desogestrel, and 3 -oh-5 -h-desogestrel) with no pharmacologic actions also have been identified and these metabolites may undergo glucuronide and sulfate conjugation. ethinyl estradiol: 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. excretion etonogestrel and ethinyl estradiol are excreted in urine, bile, and feces. at steady state, on day 21, the elimination half-life of etonogestrel is 27.8±7.2 hours and the elimination half-life of ethinyl estradiol for the combination tablet is 23.9±25.5 hours. for the 0.01 mg ethinyl estradiol tablet [green], the elimination half-life at steady state, day 28, is 18.9±8.3 hours. special populations race there is no information to determine the effect of race on the pharmacokinetics of pimtrea™ (desogestrel/ethinyl estradiol and ethinyl estradiol) tablets. hepatic insufficiency no formal studies were conducted to evaluate the effect of hepatic disease on the disposition of pimtrea™. renal insufficiency no formal studies were conducted to evaluate the effect of renal disease on the disposition of pimtrea™. drug-drug interactions interactions between desogestrel/ethinyl estradiol and other drugs have been reported in the literature. no formal drug-drug interaction studies were conducted (see precautions section).

ol following multiple dose administration of desogestrel/ethinyl estradiol and ethinyl estradiol tablets were determined during the third cycle in 17 subjects. plasma concentrations of etonogestrel and ethinyl estradiol reached steady-state by day 21. the auc (0–24) for etonogestrel at steady-state on day 21 was approximately 2.2 times higher than auc (0–24) on day 1 of the third cycle. the pharmacokinetic parameters of etonogestrel and ethinyl estradiol during the third cycle following multiple dose administration of desogestrel/ethinyl estradiol and ethinyl estradiol tablets are summarized in table i. table i : mean (sd) pharmacokinetic parameters of desogestrel/ethinyl estradiol and ethinyl estradiol tablets over a 28-day dosing period in the third cycle (n=17). etonogestrel day dose* c m a x t m a x t 1 / 2 auc 0 - 2 4 cl/f mg pg/ml h h pg/ml•hr l/h 1 0.15 2503.6 (987.6) 2.4 (1.0) 29.8 (16.3) 17,832 (5674) 5.4 (2.5) 21 0.15 4091.2 (1186.2) 1.6 (0.7) 27.8 (7.2) 39,391 (12,134) 4.4 (1.4) *desogestrel ethinyl estradiol day dose c m a x t m a x t 1 / 2 auc 0 - 2 4 cl/f mg pg/ml h h pg/ml•hr l/h 1 0.02 51.9 (15.4) 2.9 (1.2) 16.5 (4.8) 566 (173) a 25.7 (9.1) 21 0.02 62.2 (25.9) 2.0 (0.8) 23.9 (25.5) 597 (127) a 35.1 (8.2) 24 0.01 24.6 (10.8) 2.4 (1.0) 18.8 (10.3) 246 (65) 43.6 (12.2) 28 0.01 35.3 (27.5) 2.1 (1.3) 18.9 (8.3) 312 (62) 33.2 (6.6) a n=16 c m a x – measured peak concentration t m a x – observed time of peak concentration t 1 / 2 – elimination half-life, calculated by 0.693/k e l i m auc 0 – 2 4 – area under the concentration-time curve calculated by the linear trapezoidal rule (time 0 to 24 hours) cl/f – apparent clearance distribution etonogestrel, the active metabolite of desogestrel, was found to be 99% protein bound, primarily to sex hormone-binding globulin (shbg). ethinyl estradiol is approximately 98.3% bound, mainly to plasma albumin. ethinyl estradiol does not bind to shbg, but induces shbg synthesis. desogestrel, in combination with ethinyl estradiol, does not counteract the estrogen-induced increase in shbg, resulting in lower serum levels of free testosterone. 96–99 metabolism desogestrel: desogestrel is rapidly and completely metabolized by hydroxylation in the intestinal mucosa and on first pass through the liver to etonogestrel. other metabolites (i.e., 3 -oh-desogestrel, 3 -oh-desogestrel, and 3 -oh-5 -h-desogestrel) with no pharmacologic actions also have been identified and these metabolites may undergo glucuronide and sulfate conjugation. ethinyl estradiol: 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. excretion etonogestrel and ethinyl estradiol are excreted in urine, bile, and feces. at steady state, on day 21, the elimination half-life of etonogestrel is 27.8±7.2 hours and the elimination half-life of ethinyl estradiol for the combination tablet is 23.9±25.5 hours. for the 0.01 mg ethinyl estradiol tablet [green], the elimination half-life at steady state, day 28, is 18.9±8.3 hours.