felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing st. john's wort. interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with cocs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability. colesevelam : colesevelam, a bile acid sequestrant, given together with a coc, has been shown to significantly decrease the auc of ee. the drug interaction between the contraceptive and colesevelam was decreased when the two drug products were given 4 hours apart. substances increasing the plasma concentrations of cocs: co-administration of atorvastatin or rosuvastatin and certain cocs containing ethinyl estradiol (ee) increase auc values for ee by approximately 20-25%. ascorbic acid and acetaminophen may increase plasma ee concentrations, possibly by inhibition of conjugation. cyp3a4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma hormone concentrations. human immunodeficiency virus (hiv)/ hepatitis c virus (hcv) protease inhibitors and non-nucleoside reverse transcriptase inhibitors: significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of co-administration with hiv protease inhibitors(decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/hcv protease inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]). 7.2 effects of combined oral contraceptives on other drugs cocs containing ee may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. cocs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, temazepam and lamotrigine. significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. this may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because the serum concentration of thyroid-binding globulin increases with use of cocs [see warnings and precautions (5.11 )] . 7.3 concomitant use with hepatitis c vaccine (hcv) combination therapy – liver enzyme elevatio do not co-administer setlakin tm with hcv drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for alt elevations [see warnings and precautions ( 5.3 )] . 7.4 interactions with laboratory tests the use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

p setlakin tm if an arterial thrombotic event or venous thromboembolic (vte) event occurs. stop setlakin tm if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. evaluate for retinal vein thrombosis immediately. if feasible, stop setlakin tm at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of vte as well as during and following prolonged immobilization. start setlakin tm no earlier than 4 weeks after delivery, in women who are not breastfeeding. the risk of postpartum vte decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week. the use of cocs increases the risk of vte. however, pregnancy increases the risk of vte as much or more than the use of cocs. the risk of vte in women using cocs is 3 to 9 cases per 10,000 woman- years. the risk of vte is highest during the first year of use of cocs and when restarting hormonal contraception after a break of 4 weeks or longer. the risk of thromboembolic disease due to cocs gradually disappears after use is discontinued. use of setlakin tm provides women with more hormonal exposure on a yearly basis than conventional monthly cocs containing the same strength synthetic estrogens and progestins (an additional 9 weeks of exposure per year). in the clinical trial, one case of pulmonary embolism was reported. postmarketing adverse reactions of vte have been reported in women who used setlakin tm . use of cocs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. stroke has been reported in women associated with the use of setlakin tm . cocs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes). this risk increases with age, particularly in women over 35 years of age who smoke. use cocs with caution in women with cardiovascular disease risk factors. 5.2 liver disease impaired liver function do not use setlakin tm in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see contraindications ( 4 )] . acute or chronic disturbances of liver function may necessitate the discontinuation of coc use until markers of liver function return to normal and coc causation has been excluded. discontinue setlakin tm if jaundice develops. liver tumors setlakin tm is contraindicated in women with benign and malignant liver tumors [see contraindications ( 4 )] . hepatic adenomas are associated with coc use. an estimate of the attributable risk is 3.3 cases/100,000 coc users. rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage. studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) coc users. however, the attributable risk of liver cancers in coc users is less than one case per million users. 5.3 risk of liver enzyme elevations with concomitant hepatitis c treatment during clinical trials with the hepatitis c combination drug regimen that contains obmitasvir/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 setlakin tm prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see contraindications ( 4 )] . setlakin tm can be restarted approximately 2 weeks following completion of treatment with the hepatitis c combination drug regimen. 5.4 high blood pressure setlakin tm is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see contraindications ( 4 )]. for women with well-controlled hypertension, monitor blood pressure and stop setlakin tm if blood pressure rises significantly. an increase in blood pressure has been reported in women taking cocs, and this increase is more likely in older women and with extended duration of use. the incidence of hypertension increases with increasing concentration of progestin. 5.5 gallbladder disease studies suggest a small increased relative risk of developing gallbladder disease among coc users. use of cocs may worsen existing gallbladder disease. a past history of coc-related cholestasis predicts an increased risk with subsequent coc use. women with a history of pregnancy-related cholestasis may be at an increased risk for coc-related cholestasis. 5.6 carbohydrate and lipid metabolic effects carefully monitor prediabetic and diabetic women who are taking setlakin tm . cocs may decrease glucose tolerance. consider alternative contraception for women with uncontrolled dyslipidemia. a small proportion of women will have adverse lipid changes while on cocs. women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using cocs. 5.7 headache if a woman taking setlakin tm develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue setlakin tm if indicated. consider discontinuation of setlakin tm in the case of increased frequency or severity of migraine during coc use (which may be prodromal of a cerebrovascular event) [see contraindications ( 4 )]. 5.8 bleeding irregularities and amenorrhea bleeding and/or spotting that occurs at any time while taking the first 84 tablets of each extended-cycle regimen is considered "unscheduled" bleeding/spotting. bleeding that occurs during the time a woman takes the seven white inert tablets is considered "scheduled" bleeding. unscheduled and scheduled bleeding and spotting unscheduled (breakthrough) bleeding and spotting sometimes occur in patients on cocs, especially during the first 3 months of use. if unscheduled bleeding persists or occurs after previously regular cycles on levonorgestrel and ethinyl estradiol tablets 0.15 mg and 0.03 mg, check for causes such as pregnancy or malignancy. if pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different coc. before prescribing levonorgestrel and ethinyl estradiol tablets 0.15 mg and 0.03 mg, advise the woman to weigh the convenience of fewer scheduled menses (4 per year instead of 13 per year) against the inconvenience of increased unscheduled bleeding and/or spotting. the clinical trial of the efficacy of levonorgestrel and ethinyl estradiol tablets 0.15 mg and 0.03 mg (91-day cycles) in preventing pregnancy also assessed scheduled and unscheduled bleeding. the participants in the study were composed primarily of women who had used oral contraceptives previously as opposed to new users. women with a history of breakthrough bleeding/spotting 10 consecutive days on oral contraceptives were excluded from the study. more levonorgestrel and ethinyl estradiol tablets 0.15 mg and 0.03 mg subjects, compared to subjects on the comparator 28-day cycle regimen, discontinued prematurely for unacceptable bleeding (7.7% [levonorgestrel and ethinyl estradiol tablets 0.15 mg and 0.03 mg] vs. 1.8% [28-day cycle regimen]). unscheduled bleeding and unscheduled spotting decreased over successive 91-day cycles. table 3 below presents the number of days with unscheduled bleeding and/or spotting for each respective 91-day cycle. table 3:number of unscheduled bleeding and/or spotting days per 91-day cycle cycle ( n ) days of unscheduled bleeding and / or spotting per 84 - day interval median days per subject - month mean q1 median q3 1 (446) 15.1 3.0 12 23.0 3.0 2 (368) 11.6 2.0 6 17.5 1.5 3 (309) 10.6 1.0 6 15.0 1.5 4 (282) 8.8 1.0 4 14.0 1.0 q1=quartile 1: 25% of women had ≤ this number of days of unscheduled bleeding/spotting median: 50% of women had ≤ this number of days of unscheduled bleeding/spotting q3=quartile 3: 75% of women had ≤ this number of days of unscheduled bleeding/spotting table 4 shows the percentages of women with 7 days and 20 days of unscheduled spotting and/or bleeding in the setlakin tm and the 28-day cycle treatment groups. table 4:percentage of subjects with unscheduled bleeding and/or spotting days of unscheduled bleeding and/or spotting percentage of subjects a setlakin t m cycle 1 (n=385) cycle 4 (n=261)  7 days 65% 42%  20 days 35% 15% 28 - day regimen cycles 1-4 (n=194) cycles 10-13 (n=158)  7 days 38% 39%  20 days 6% 4% a based on spotting and/or bleeding on days 1-84 of a 91 day cycle in the setlakin t m subjects and days 1-21 of a 28 day cycle over 4 cycles in the 28-day dosing regimen. total days of bleeding and/or spotting (scheduled plus unscheduled) were similar over one year of treatment for setlakin tm subjects and subjects on the 28-day cycle regimen. amenorrhea and oligomenorrhea women who are not pregnant and use setlakin tm may experience amenorrhea. based on data from the clinical trial, amenorrhea occurred in approximately 0.8% of women during cycle 1, 1.2% of women during cycle 2, 3.7% of women during cycle 3, and 3.4% of women during cycle 4. because women using setlakin tm will likely have scheduled bleeding only 4 times per year, rule out pregnancy at the time of any missed menstrual period. some women may experience amenorrhea or oligomenorrhea after stopping cocs, especially when such a condition was pre-existent. 5.9 coc 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. studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb-reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. discontinue setlakin tm use if pregnancy is confirmed. administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy [see use in specific populations ( 8.1 )] . 5.10 depression depression associated with the use of setlakin tm has been reported. carefully observe women with a history of depression and discontinue setlakin tm if severe depression recurs. 5.11 carcinoma of the breast and cervix setlakin tm is contraindicated in women who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see contraindications ( 4 )]. there is substantial evidence that cocs do not increase the incidence of breast cancer. although some past studies have suggested that cocs might increase the incidence of breast cancer, more recent studies have not confirmed such findings. some studies suggest that coc use has been associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. however, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. 5.12 effect on binding globulins the estrogen component of cocs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin and cortisol-binding globulin. the dose of replacement thyroid hormone or cortisol therapy may need to be increased. 5.13 monitoring a woman who is taking cocs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated health care. 5.14 hereditary angioedema in women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. 5.15 chloasma chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. women with a tendency to develop chloasma should avoid prolonged exposure to the sun or ultraviolet radiation while taking setlakin tm .

l contraception ( sunday start ) important : consider the possibility of ovulation and conception prior to initiation of this product. tablet color : setlakin t m active tablets are pink (day 1 to day 84). setlakin t m inactive tablets are white (day 85 to day 91). sunday start : for each 91 - day course , take in the following order : take the first pink tablet (0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol) on the first sunday after the onset of menstruation. if menstruation begins on a sunday, take the tablet on that day. due to the potential risk of becoming pregnant , use additional non - hormonal contraception ( such as condoms or spermicide ) for the first 7 days of treatment . take subsequent pink tablets once daily at the same time each day for a total of 84 days. take one white tablet (inert) daily for the following 7 days and at the same time of day that active tablets were taken. a scheduled period should occur during the 7 days that the white tablets are taken. begin the next and all subsequent 91-day courses of setlakin t m without interruption on the same day of the week (i.e., sunday) on which the patient began her first dose. follow the same schedule as the initial 91-day course: a pink tablet once a day for 84 days, and a white tablet once a day for 7 days. if the patient does not immediately start her next pill pack, instruct her to protect herself from pregnancy by using a non-hormonal back-up method of contraception until she has taken a pink tablet daily for 7 consecutive days. switching to setlakin t m from another oral contraceptive start on the same day that a new pack of the previous oral contraceptive would have started. switching from another contraceptive method to setlakin t m start setlakin t m : transdermal patch on the day when the next application would have been scheduled. vaginal ring on the day when the next insertion would have been scheduled. injection on the day when the next injection would have been scheduled. intrauterine contraceptive ( iud ) on the day of removal. if the iud is not removed on first day of the patient’s menstrual cycle, additional non- hormonal contraception (such as condoms or spermicide) is needed for the first seven days of the first 91-day course. implant on the day of removal. complete instructions to facilitate patient counseling on proper tablet usage are located in the fda - approved patient labeling . starting setlakin tm after abortion or miscarriage first-trimester ● after a first-trimester abortion or miscarriage, setlakin tm may be started immediately. an additional method of contraception is not needed if setlakin tm is started immediately. ● if setlakin tm is not started within 5 days after termination of the pregnancy, the patient should use additional non-hormonal contraception (such as condoms or spermicide) for the first seven days of her first 91-day course of setlakin tm . second-trimester ● do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. start setlakin tm following the instructions in table 1 for sunday start. use additional non-hormonal contraception (such as condoms or spermicide) for the first seven days of the patient's first 91-day course of setlakin tm [see contraindications ( 4 ), warnings and precautions ( 5.1 ), and fda-approved patient labeling ]. starting setlakin tm after childbirth ● do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. start contraceptive therapy with setlakin tm following the instructions in table 1 for women not currently using hormonal contraception. ● setlakin tm is not recommended for use in lactating women [see use in specific populations ( 8.3 ) and fda-approved patient labeling ] . ● if the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of setlakin tm [see contraindications ( 4 ), warnings and precautions ( 5.1 ), use in specific populations ( 8.1 and 8.3 ), and fda-approved patient labeling ]. tablet dispenser instructions: ● the tablet dispenser consists of 3 blister strips that hold 91 individually sealed pills (a 13-week, or 91-day, cycle). the 91 pills consist of 84 pink pills (active pills with hormones) and 7 white pills (inactive pills without hormone). ● blister strip 1 (weeks 1 to 4) and blister strip 2 (weeks 5 to 8) each contain 28 pink pills (4 rows of 7 pills). see figure a. ● blister strip 3 (weeks 9 to 13) contains 35 pills consisting of 28 pink pills (4 rows of 7 pills) and 7 white pills (1 row of 7 pills). see figure b. advise the patient to remove the first pill in the upper left corner by pushing down on the pill. the pill will come out through a hole in the back of the tablet dispenser. advise the patient to wait 24 hours to take the next pill, and continue to take one pill each day until all the pills have been taken. advise the patient, after taking the last white pill, to start taking the first pink pill from a new tablet dispenser the very next day, regardless of when their period started. 2.3 missed tablets table 2:instructions for missed setlakin t m tablets if one active tablet (pink) is missed in days 1 through 84 take the tablet as soon as possible. take the next tablet at the regular time and continue taking one tablet a day until the 91-day course is finished. if two consecutive active tablets (pink) are missed in days 1 through 84 take 2 tablets on the day remembered and 2 tablets the next day. then continue taking one tablet a day until the 91-day course is finished. additional non - hormonal contraception ( such as condoms or spermicide ) should be used as back - up if the patient has sex within 7 days after missing 2 tablets . if three or more consecutive active tablets (pink) are missed in days 1 through 84 do not take the missed tablets. continue taking one tablet a day until the 91-day course is finished. additional non - hormonal contraception ( such as condoms or spermicide ) must be used as back - up if the patient has sex within 7 days after missing 3 tablets . 2.4 advice in case of gastrointestinal disturbances in case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. if vomiting or diarrhea occurs within 3-4 hours after taking a pink tablet, handle this as a missed tablet [see fda-approved patient labeling ] . image-01 image-02

cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. the clinical trial that evaluated the safety and efficacy of levonorgestrel and ethinyl estradiol tablets 0.15 mg and 0.03 mg was a 12-month, randomized, multicenter, open-label study, which enrolled women aged 18-40, of whom 456 took at least one dose of levonorgestrel and ethinyl estradiol tablets 0.15 mg and 0.03 mg (345.14 woman-years of exposure) [see clinical studies ( 14 )] . adverse reactions leading to study discontinuation : 14.9% of the women discontinued from the clinical trial due to an adverse reaction; the most common adverse reactions ( 1% of women) leading to discontinuation in the levonorgestrel and ethinyl estradiol tablets 0.15 mg and 0.03 mg group were menorrhagia (5.7%), mood swings (1.9%), weight/appetite increase (1.5%), and acne (1.3%). common adverse reactions ( 2% of women) : headache (20.6%), menorrhagia (11.6%), nausea (7.5%), dysmenorrhea (5.7%), acne (4.6%), migraine (4.4%), breast tenderness (3.5%), weight increased (3.1%), and depression (2.1%). serious adverse reactions: pulmonary embolus, cholecystitis. 6.2 postmarketing experience the following adverse reactions have been identified during post-approval use of setlakin tm . because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. gastrointestinal disorders : abdominal distension, vomiting general disorders and administration site conditions : chest pain, fatigue, malaise, edema peripheral, pain immune system disorder: h ypersensitivity reactions, including itching, rash, and angioedema investigations: blood pressure increased musculoskeletal and connective tissue disorders : muscle spasms, pain in extremity nervous system disorders : dizziness, loss of consciousness psychiatric disorders : insomnia reproductive and breast disorders : dysmenorrhea skin and subcutaneous tissue disorders : alopecia vascular disorders : thrombosis, pulmonary embolism, pulmonary thrombosis

felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing st. john's wort. interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with cocs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability. colesevelam : colesevelam, a bile acid sequestrant, given together with a coc, has been shown to significantly decrease the auc of ee. the drug interaction between the contraceptive and colesevelam was decreased when the two drug products were given 4 hours apart. substances increasing the plasma concentrations of cocs: co-administration of atorvastatin or rosuvastatin and certain cocs containing ethinyl estradiol (ee) increase auc values for ee by approximately 20-25%. ascorbic acid and acetaminophen may increase plasma ee concentrations, possibly by inhibition of conjugation. cyp3a4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma hormone concentrations. human immunodeficiency virus (hiv)/ hepatitis c virus (hcv) protease inhibitors and non-nucleoside reverse transcriptase inhibitors: significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of co-administration with hiv protease inhibitors(decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/hcv protease inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]). 7.2 effects of combined oral contraceptives on other drugs cocs containing ee may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. cocs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, temazepam and lamotrigine. significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. this may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because the serum concentration of thyroid-binding globulin increases with use of cocs [see warnings and precautions (5.11 )] . 7.3 concomitant use with hepatitis c vaccine (hcv) combination therapy – liver enzyme elevatio do not co-administer setlakin tm with hcv drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for alt elevations [see warnings and precautions ( 5.3 )] . 7.4 interactions with laboratory tests the use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

s of oral contraceptive steroids and/or metabolites are present in breast milk. 8.4 pediatric use safety and efficacy of setlakin tm have been established in women of reproductive age. efficacy is expected to be the same for postpubertal adolescents under the age of 18 as for users 18 years and older. use of setlakin tm before menarche is not indicated. 8.5 geriatric use setlakin tm has not been studied in postmenopausal women and is not indicated in this population. 8.6 hepatic impairment the pharmacokinetics of setlakin tm have not been studied in subjects with hepatic impairment. however, steroid hormones may be poorly metabolized in patients with hepatic impairment. acute or chronic disturbances of liver function may necessitate the discontinuation of coc use until markers of liver function return to normal and coc causation has been excluded [see contraindications ( 4 ) and warnings and precautions ( 5.2 )]. 8.7 renal impairment the pharmacokinetics of setlakin tm have not been studied in women with renal impairment.

gestrel and ee reached steady-state within 7 days. the mean plasma pharmacokinetic parameters for setlakin tm under fasting conditions in normal healthy women following once-daily administration of one levonorgestrel/ee combination tablet for 10 days are summarized in table 5. table 5:mean ±sd pharmacokinetic parameters under fasting conditions in healthy women following 10 days administration of one tablet of levonorgestrel and ethinyl estradiol tablets 0.15 mg and 0.03 mg (n=44) analyte auc0 - 24 cmax cmin cavga tmax levonorgestrel 54.6±16.5 ng*hr/ml 5.0±1.5 ng/ml 1.6±0.5 ng/ml 2.3±0.7 ng/ml 1.4±0.7 hours ethinyl estradiol 935.5±346.9 pg*hr/ml 106.1±41.2 pg/ml 18.5±9.4 pg/ml 38.9±14.4 pg/ml 1.6±0.6 hours a cavg =auc0-24/24 food effect the effect of food on the rate and the extent of levonorgestrel and ee absorption following oral administration of setlakin tm has not been evaluated. distribution the apparent volume of distribution of levonorgestrel and ee are reported to be approximately 1.8 l/kg and 4.3 l/kg, respectively. levonorgestrel is about 97.5 - 99% protein-bound, principally to sex hormone binding globulin (shbg) and, to a lesser extent, serum albumin. ee is about 95 - 97% bound to serum albumin. ee does not bind to shbg, but induces shbg synthesis, which leads to decreased levonorgestrel clearance. following repeated daily dosing of levonorgestrel/ee oral contraceptives, levonorgestrel plasma concentrations accumulate more than predicted based on single-dose pharmacokinetics, due in part, to increased shbg levels that are induced by ee, and a possible reduction in hepatic metabolic capacity. metabolism following absorption, levonorgestrel is conjugated at the 17 -oh position to form sulfate and to a lesser extent, glucuronide conjugates in plasma. significant amounts of conjugated and unconjugated 3 ,5 -tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3 ,5 -tetrahydrolevonorgestrel and 16 -hydroxylevonorgestrel. levonorgestrel and its phase i metabolites are excreted primarily as glucuronide conjugates. 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. first-pass metabolism of ee involves formation of ee-3-sulfate in the gut wall, followed by 2-hydroxylation of a portion of the remaining untransformed ee by hepatic cytochrome p-450 3a4 (cyp3a4). levels of cyp3a4 vary widely among individuals and can explain the variation in rates of ee hydroxylation. hydroxylation at the 4-, 6-, and 16- positions may also occur, although to a much lesser extent than 2-hydroxylation. the various hydroxylated metabolites are subject to further methylation and/or conjugation. excretion about 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. the terminal elimination half-life for levonorgestrel after a single dose of setlakin tm was about 30 hours. ee is excreted in the urine and feces as glucuronide and sulfate conjugates, and it undergoes enterohepatic recirculation. the terminal elimination half-life of ee after a single dose of setlakin tm was found to be about 15 hours.

days administration of one tablet of levonorgestrel and ethinyl estradiol tablets 0.15 mg and 0.03 mg (n=44) analyte auc0 - 24 cmax cmin cavga tmax levonorgestrel 54.6±16.5 ng*hr/ml 5.0±1.5 ng/ml 1.6±0.5 ng/ml 2.3±0.7 ng/ml 1.4±0.7 hours ethinyl estradiol 935.5±346.9 pg*hr/ml 106.1±41.2 pg/ml 18.5±9.4 pg/ml 38.9±14.4 pg/ml 1.6±0.6 hours a cavg =auc0-24/24 food effect the effect of food on the rate and the extent of levonorgestrel and ee absorption following oral administration of setlakin tm has not been evaluated. distribution the apparent volume of distribution of levonorgestrel and ee are reported to be approximately 1.8 l/kg and 4.3 l/kg, respectively. levonorgestrel is about 97.5 - 99% protein-bound, principally to sex hormone binding globulin (shbg) and, to a lesser extent, serum albumin. ee is about 95 - 97% bound to serum albumin. ee does not bind to shbg, but induces shbg synthesis, which leads to decreased levonorgestrel clearance. following repeated daily dosing of levonorgestrel/ee oral contraceptives, levonorgestrel plasma concentrations accumulate more than predicted based on single-dose pharmacokinetics, due in part, to increased shbg levels that are induced by ee, and a possible reduction in hepatic metabolic capacity. metabolism following absorption, levonorgestrel is conjugated at the 17 -oh position to form sulfate and to a lesser extent, glucuronide conjugates in plasma. significant amounts of conjugated and unconjugated 3 ,5 -tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3 ,5 -tetrahydrolevonorgestrel and 16 -hydroxylevonorgestrel. levonorgestrel and its phase i metabolites are excreted primarily as glucuronide conjugates. 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. first-pass metabolism of ee involves formation of ee-3-sulfate in the gut wall, followed by 2-hydroxylation of a portion of the remaining untransformed ee by hepatic cytochrome p-450 3a4 (cyp3a4). levels of cyp3a4 vary widely among individuals and can explain the variation in rates of ee hydroxylation. hydroxylation at the 4-, 6-, and 16- positions may also occur, although to a much lesser extent than 2-hydroxylation. the various hydroxylated metabolites are subject to further methylation and/or conjugation. excretion about 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. the terminal elimination half-life for levonorgestrel after a single dose of setlakin tm was about 30 hours. ee is excreted in the urine and feces as glucuronide and sulfate conjugates, and it undergoes enterohepatic recirculation. the terminal elimination half-life of ee after a single dose of setlakin tm was found to be about 15 hours.

er the onset of treatment and within 14 days after the last combination pill. cycles in which conception did not occur, but which included the use of back-up contraception, were not included in the calculation of the pi.

e usp controlled room temperature]. references available upon request. keep out of the reach of children rx only

[see dosage and administration ( 2.3 )]. ● use a back-up or alternative method of contraception when enzyme inducers are used with setlakin tm [see drug interactions ( 7.1 )]. ● cocs may reduce breast milk production; this is less likely to occur if breastfeeding is well established [see use in specific populations ( 8.3 )]. ● women who start on cocs postpartum, and who have not yet had a period, should use an additional method of contraception until they have taken a pink tablet for 7 consecutive days [see dosage and administration ( 2.2 )]. ● amenorrhea may occur. because women using setlakin tm will likely have scheduled bleeding only 4 times per year, rule out pregnancy at the time of any missed menstrual period [see warnings and precautions ( 5.8 )] . image-05