amate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant and products containing st. john's wort. interactions between cocs 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 ethinyl estradiol (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 ee increase auc values for ee by approximately 20 to 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., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase 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. 7.3 interference 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.

ular problems • stop tri-lo-marzia if an arterial thrombotic event or venous thrombotic (vte) event occurs. • stop tri-lo-marzia if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. evaluate for retinal vein thrombosis immediately [see adverse reactions ( 6.2 )]. • if feasible, stop tri-lo-marzia 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 tri-lo-marzia 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 cocs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. 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 tri-lo-marzia in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of 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 tri-lo-marzia if jaundice develops. liver tumors tri-lo-marzia 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 risk of liver cancers in coc users is less than one case per million users. 5.3 high blood pressure tri-lo-marzia 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 tri-lo-marzia 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 with extended duration of use. the incidence of hypertension increases with increasing concentrations of progestin. 5.4 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. 5.5 carbohydrate and lipid metabolic effects carefully monitor prediabetic and diabetic women who take tri-lo-marzia. 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. 5.6 headache if a woman taking tri-lo-marzia develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue tri-lo-marzia if indicated. consider discontinuation of tri-lo-marzia in the case of increased frequency or severity of migraine during coc use (which may be prodromal of a cerebrovascular event). 5.7 bleeding irregularities and amenorrhea unscheduled bleeding and spotting unscheduled (breakthrough or intracyclic) bleeding and spotting sometimes occur in patients on cocs, especially during the first three months of use. if bleeding persists or occurs after previously regular cycles, 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 contraceptive product. in the clinical trial of tri-lo-marzia, the frequency and duration of unscheduled bleeding and/or spotting was assessed in 1,673 women (11,015 evaluable cycles). a total of 3 (0.2%) women discontinued tri-lo-marzia, at least in part, due to bleeding or spotting. based on data from the clinical trials, 7 to 17% of women using tri-lo-marzia experienced unscheduled bleeding per cycle in the first year. the percent of women who experienced unscheduled bleeding tended to decrease over time. amenorrhea and oligomenorrhea women who use tri-lo-marzia may experience amenorrhea. some women may experience amenorrhea or oligomenorrhea after discontinuation of cocs, especially when such a condition was pre-existent. if scheduled (withdrawal) bleeding does not occur, consider the possibility of pregnancy. if the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. if the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. 5.8 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 tri-lo-marzia use if pregnancy is confirmed. administration of cocs to induce withdrawal bleeding should not be used as a test for pregnancy [see use in specific populations ( 8.1 )]. 5.9 depression carefully observe women with a history of depression and discontinue tri-lo-marzia if depression recurs to a serious degree. 5.10 carcinoma of breast and cervix • tri-lo-marzia 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. 5.11 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. 5.12 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 healthcare. 5.13 hereditary angioedema in women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. 5.14 chloasma chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking tri-lo-marzia.

to day 21) and has green inactive tablets ( day 22 to day 28) day 1 start: take first active tablet without regard to meals on the first day of menses. take subsequent active tablets once daily at the same time each day for a total of 21 days. take one green inactive tablet daily for 7 days and at the same time of day that active tablets were taken. begin each subsequent pack on the same day of the week as the first cycle pack (i.e., on the day after taking the last inactive tablet) sunday start: take first active tablet without regard to meals on the first sunday after the onset of menses. due to the potential risk of becoming pregnant, use additional non-hormonal contraception (such as condoms and spermicide) for the first seven days of the patient’s first cycle pack of tri-lo-marzia. take subsequent active tablets once daily at the same time each day for a total of 21 days. take one green inactive tablet daily for the following 7 days and at the same time of day that active tablets were taken. begin each subsequent pack on the same day of the week as the first cycle pack (i.e., on the sunday after taking the last inactive tablet) and additional non-hormonal contraceptive is not needed. switching to tri-lo-marzia 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 tri-lo-marzia start tri-lo-marzia: transdermal patch on the day when next application would have been scheduled vaginal ring on the day when next insertion would have been scheduled injection on the day when next injection would have been scheduled intrauterine contraceptive on the day of removal if the iud is not removed on first day of the patient’s menstrual cycle, additional non-hormonal contraceptive (such as condoms and spermicide) is needed for the first seven days of the first cycle pack. 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 tri-lo-marzia after abortion or miscarriage first-trimester: • after a first-trimester abortion or miscarriage, tri-lo-marzia may be started immediately. an additional method of contraception is not needed if tri-lo-marzia is started immediately. • if tri-lo-marzia is not started within 5 days after termination of the pregnancy, the patient should use additional non-hormonal contraception (such as condoms and spermicide) for the first seven days of her first cycle pack of tri-lo-marzia. second-trimester: • do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. start tri-lo-marzia, following the instructions in table 1 for day 1 or sunday start, as desired. if using sunday start, use additional non-hormonal contraception (such as condoms and spermicide) for the first seven days of the patient's first cycle pack of tri-lo-marzia. [see contraindications ( 4 ), warnings and precautions ( 5.1 ), and fda-approved patient labeling.] starting tri-lo-marzia after childbirth • do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. start contraceptive therapy with tri-lo-marzia following the instructions in table 1 for women not currently using hormonal contraception. • tri-lo-marzia is not recommended for use in lactating women [see use in specific populations ( 8.3 )]. • if the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of tri-lo-marzia. [see contraindications ( 4 ), warnings and precautions ( 5.1 ), use in specific populations and ( 8.1 and 8.3 ), and fda-approved patient labeling]. wallet pack: set the day • sunday start: each wallet has been preprinted with the days of the week, starting with sunday, to facilitate a sunday-start regimen. • day 1 start: • six different day label strips of the week have been provided with this pack in order to accommodate a day-1 start regimen. • pick the day label strip that starts with the first day of your period. place this day label strip over the area that has the days of the week (starting with sunday) pre-printed on the wallet (refer figure below). • remove pill "1" by pushing down on the pill. the pill will come out through a hole in the back of the strip. • the patient should wait 24 hours to take the next pill. continue to take one pill each day until all the pills have been taken. • when your wallet is empty, you will start a new wallet on the day after pill "28." the first pill in every refill will always be taken on the same day of the week, no matter when the patient's next period starts. wallet 2.3 missed tablets table 2: instructions for missed tri-lo-marzia tablets if one active tablet is missed in weeks 1, 2, or 3 take the tablet as soon as possible. continue taking one tablet a day until the pack is finished. if two active tablets are missed in week 1 or week 2 take the two missed tablets as soon as possible and the next two active tablets the next day. continue taking one tablet a day until the pack is finished. additional non-hormonal contraception (such as condoms and spermicide) should be used as backup if the patient has sex within 7 days after missing tablets. if two active tablets are missed in the third week or three or more active tablets are missed in a row in weeks 1, 2, or 3 day 1 start: throw out the rest of the pack and start a new pack that same day. sunday start: continue taking one tablet a day until sunday, then throw out the rest of the pack and start a new pack that same day. additional non-hormonal contraception (such as condoms and spermicide) should be used as back-up if the patient has sex within 7 days after missing 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 to 4 hours after taking an active tablet, handle this as a missed tablet [see fda-approved patient labeling].

tions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. the safety of tri-lo-marzia was evaluated in 1,723 subjects who participated in a randomized, partially blinded, multicenter, active-controlled clinical trial of tri-lo-marzia for contraception. this trial examined healthy, nonpregnant, volunteers aged 18 to 45 (nonsmoker if 35 to 45 years of age), who were sexually active with regular coitus. subjects were followed for up to 13 28-day cycles. common adverse reactions (≥ 2% of subjects) the most common adverse reactions reported by at least 2% of the 1,723 women using the 28-day regimen were the following in order of decreasing incidence: headache/migraine (30.5%), nausea/vomiting (16.3%); breast issues (including tenderness, pain, enlargement, swelling, discharge, discomfort, cyst, and nipple pain) (10.3%), abdominal pain (9.2%), menstrual disorders (including dysmenorrhea, menstrual discomfort, menstrual disorder) (9.2%), mood disorders (including depression, mood altered, mood swings and depressed mood) (7.6%); acne (5.1%), vulvovaginal infection (3.5%), abdominal distension (2.8%), weight increased (2.4%), fatigue (2.1%). adverse reactions leading to study discontinuation in the clinical trial of tri-lo-marzia 4% of subjects discontinued the trial due to an adverse reaction. the most common adverse reactions leading to discontinuation were headache/migraine (1.2%), nausea/vomiting (0.7%), cervical dysplasia (0.7%), abdominal pain (0.4%), ovarian cyst (0.3%), acne (0.2%), flatulence (0.2%) and depression (0.2%). serious adverse reactions carcinoma of the cervix in situ (1 subject) and cervical dysplasia (1 subject). 6.2 postmarketing experience the following additional adverse drug reactions have been reported from worldwide postmarketing experience with norgestimate/ethinyl estradiol. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. infections and infestations urinary tract infection neoplasms benign, malignant and unspecified (including cysts and polyps) breast cancer, benign breast neoplasm, hepatic adenoma, focal nodular hyperplasia, breast cyst immune system disorders hypersensitivity metabolism and nutrition disorders dyslipidemia psychiatric disorders anxiety, insomnia nervous system disorders syncope, convulsion, paresthesia, dizziness eye disorders visual impairment, dry eye, contact lens intolerance ear and labyrinth disorders vertigo cardiac disorders tachycardia, palpitations vascular events deep vein thrombosis, pulmonary embolism, retinal vascular thrombosis, hot flush arterial events arterial thromboembolism, myocardial infarction, cerebrovascular accident respiratory, thoracic and mediastinal disorders dyspnea gastrointestinal disorders pancreatitis, abdominal distension, diarrhea, constipation hepatobiliary disorders hepatitis skin and subcutaneous tissue disorders angioedema, erythema nodosum, hirsutism, night sweats, hyperhidrosis, photosensitivity reaction, urticaria, pruritus, acne musculoskeletal, connective tissue, and bone disorders muscle spasms, pain in extremity, myalgia, back pain reproductive system and breast disorders ovarian cyst, suppressed lactation, vulvovaginal dryness general disorders and administration site conditions chest pain, asthenic conditions.

amate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant and products containing st. john's wort. interactions between cocs 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 ethinyl estradiol (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 ee increase auc values for ee by approximately 20 to 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., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase 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. 7.3 interference 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.

lites are present in breast milk. 8.4 pediatric use safety and efficacy of tri-lo-marzia tablets have been established in women of reproductive age. efficacy is expected to be the same for post-pubertal adolescents under the age of 18 and for users 18 years and older. use of this product before menarche is not indicated. 8.5 geriatric use tri-lo-marzia has not been studied in postmenopausal women and is not indicated in this population. 8.6 hepatic impairment the pharmacokinetics of tri-lo-marzia has 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 tri-lo-marzia has not been studied in women with renal impairment.

ose is approximately 1.5 to 2 fold for ngmn and approximately 1.5 fold for ee compared with single dose administration, in agreement with that predicted based on linear kinetics of ngmn and ee. the pharmacokinetics of ngmn is dose proportional following ngm doses of 0.18 to 0.25 mg. steady-state conditions for ngmn following each ngm dose and for ee were achieved during the three cycle study. non-linear accumulation (4.5 to 14.5 fold) of ng was observed as a result of high affinity binding to shbg, which limits its biological activity. table 3 summary of ngmn, ng and ee pharmacokinetic parameters. table 3: mean (sd) pharmacokinetic parameters of tri-lo-marzia during a three cycle study nc = not calculated analyte ngmn = norelgestromin, ng = norgestrel, ee = ethinyl estradiol cycle day c max t max (h) auc 0 to 24h t 1/2 (h) ngmn ( c max = peak serum concentration, t max = time to reach peak serum concentration, auc 0to24h = area under serum concentration vs. time curve from 0 to 24 hours, t 1/2 = elimination half-life. to units for ngmn and ng - c max = ng/ml, auc 0to24h = h.ng/ml ) 1 1 0.91 (0.27) 1.8 (1.0) 5.86 (1.54) nc 3 7 1.42 (0.43) 1.8 (0.7) 11.3 (3.2) nc 14 1.57 (0.39) 1.8 (0.7) 13.9 (3.7) nc 21 1.82 (0.54) 1.5 (0.7) 16.1 (4.8) 28.1 (10.6) ng ( to ) 1 1 0.32 (0.14) 2.0 (1.1) 2.44 (2.04) nc 3 7 1.64 (0.89) 1.9 (0.9) 27.9 (18.1) nc 14 2.11 (1.13) 4.0 (6.3) 40.7 (24.8) nc 21 2.79 (1.42) 1.7 (1.2) 49.9 (27.6) 36.4 (10.2) ee ( , units for all analytes; h = hours , units for ee only - c max = pg/ml, auc 0to24h = h.pg/ml ) 1 1 55.6 (18.1) 1.7 (0.5) 421 (118) nc 3 7 91.1 (36.7) 1.3 (0.3) 782 (329) nc 14 96.9 (38.5) 1.3 (0.3) 796 (273) nc 21 95.9 (38.9) 1.3 (0.6) 771 (303) 17.7 (4.4) food effect: the effect of food on the pharmacokinetics of tri-lo-marzia has not been studied. distribution ngmn and ng are highly bound (>97%) to serum proteins. ngmn is bound to albumin and not to shbg, while ng is bound primarily to shbg. ee is extensively bound (>97%) to serum albumin and induces an increase in the serum concentrations of shbg. metabolism ngm is extensively metabolized by first-pass mechanisms in the gastrointestinal tract and/or liver. ngm's primary active metabolite is ngmn. subsequent hepatic metabolism of ngmn occurs and metabolites include ng, which is also active and various hydroxylated and conjugated metabolites. although ngmn and its metabolites inhibit a variety of p450 enzymes in human liver microsomes, under the recommended dosing regimen, the in vivo concentrations of ngmn and its metabolites, even at the peak serum levels, are relatively low compared to the inhibitory constant (k i ). ee is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates. excretion following 3 cycles of administration of tri-lo-marzia, the mean (± sd) elimination half-life values, at steady-state, for ngmn, ng and ee were 28.1 (± 10.6) hours, 36.4 (± 10.2) hours and 17.7 (± 4.4) hours, respectively (table 2). the metabolites of ngmn and ee are eliminated by renal and fecal pathways. use in specific populations effects of body weight, body surface area, and age: the effects of body weight, body surface area, age and race on the pharmacokinetics of ngmn, ng and ee were evaluated in 79 healthy women using pooled data following single dose administration of ngm 0.18 or 0.25 mg / ee 0.025 mg tablets in four pharmacokinetic studies. increasing body weight and body surface area were each associated with decreases in c max and auc 0 to 24h values for ngmn and ee and increases in cl/f (oral clearance) for ee. increasing body weight by 10 kg is predicted to reduce the following parameters: ngmn c max by 9% and auc 0 to 24h by 19%, ng c max by 12% and auc 0 to 24h by 46%, ee c max by 13% and auc 0 to 24h by 12%. these changes were statistically significant. increasing age was associated with slight decreases (6% with increasing age by 5 years) in c max and auc 0 to 24h for ngmn and were statistically significant, but there was no significant effect for ng or ee. only a small to moderate fraction (5 to 40%) of the overall variability in the pharmacokinetics of ngmn and ee following tri-lo-marzia tablets may be explained by any or all of the above demographic parameters.

ee cycle study. non-linear accumulation (4.5 to 14.5 fold) of ng was observed as a result of high affinity binding to shbg, which limits its biological activity. table 3 summary of ngmn, ng and ee pharmacokinetic parameters. table 3: mean (sd) pharmacokinetic parameters of tri-lo-marzia during a three cycle study nc = not calculated analyte ngmn = norelgestromin, ng = norgestrel, ee = ethinyl estradiol cycle day c max t max (h) auc 0 to 24h t 1/2 (h) ngmn ( c max = peak serum concentration, t max = time to reach peak serum concentration, auc 0to24h = area under serum concentration vs. time curve from 0 to 24 hours, t 1/2 = elimination half-life. to units for ngmn and ng - c max = ng/ml, auc 0to24h = h.ng/ml ) 1 1 0.91 (0.27) 1.8 (1.0) 5.86 (1.54) nc 3 7 1.42 (0.43) 1.8 (0.7) 11.3 (3.2) nc 14 1.57 (0.39) 1.8 (0.7) 13.9 (3.7) nc 21 1.82 (0.54) 1.5 (0.7) 16.1 (4.8) 28.1 (10.6) ng ( to ) 1 1 0.32 (0.14) 2.0 (1.1) 2.44 (2.04) nc 3 7 1.64 (0.89) 1.9 (0.9) 27.9 (18.1) nc 14 2.11 (1.13) 4.0 (6.3) 40.7 (24.8) nc 21 2.79 (1.42) 1.7 (1.2) 49.9 (27.6) 36.4 (10.2) ee ( , units for all analytes; h = hours , units for ee only - c max = pg/ml, auc 0to24h = h.pg/ml ) 1 1 55.6 (18.1) 1.7 (0.5) 421 (118) nc 3 7 91.1 (36.7) 1.3 (0.3) 782 (329) nc 14 96.9 (38.5) 1.3 (0.3) 796 (273) nc 21 95.9 (38.9) 1.3 (0.6) 771 (303) 17.7 (4.4) food effect: the effect of food on the pharmacokinetics of tri-lo-marzia has not been studied. distribution ngmn and ng are highly bound (>97%) to serum proteins. ngmn is bound to albumin and not to shbg, while ng is bound primarily to shbg. ee is extensively bound (>97%) to serum albumin and induces an increase in the serum concentrations of shbg. metabolism ngm is extensively metabolized by first-pass mechanisms in the gastrointestinal tract and/or liver. ngm's primary active metabolite is ngmn. subsequent hepatic metabolism of ngmn occurs and metabolites include ng, which is also active and various hydroxylated and conjugated metabolites. although ngmn and its metabolites inhibit a variety of p450 enzymes in human liver microsomes, under the recommended dosing regimen, the in vivo concentrations of ngmn and its metabolites, even at the peak serum levels, are relatively low compared to the inhibitory constant (k i ). ee is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates. excretion following 3 cycles of administration of tri-lo-marzia, the mean (± sd) elimination half-life values, at steady-state, for ngmn, ng and ee were 28.1 (± 10.6) hours, 36.4 (± 10.2) hours and 17.7 (± 4.4) hours, respectively (table 2). the metabolites of ngmn and ee are eliminated by renal and fecal pathways. use in specific populations effects of body weight, body surface area, and age: the effects of body weight, body surface area, age and race on the pharmacokinetics of ngmn, ng and ee were evaluated in 79 healthy women using pooled data following single dose administration of ngm 0.18 or 0.25 mg / ee 0.025 mg tablets in four pharmacokinetic studies. increasing body weight and body surface area were each associated with decreases in c max and auc 0 to 24h values for ngmn and ee and increases in cl/f (oral clearance) for ee. increasing body weight by 10 kg is predicted to reduce the following parameters: ngmn c max by 9% and auc 0 to 24h by 19%, ng c max by 12% and auc 0 to 24h by 46%, ee c max by 13% and auc 0 to 24h by 12%. these changes were statistically significant. increasing age was associated with slight decreases (6% with increasing age by 5 years) in c max and auc 0 to 24h for ngmn and were statistically significant, but there was no significant effect for ng or ee. only a small to moderate fraction (5 to 40%) of the overall variability in the pharmacokinetics of ngmn and ee following tri-lo-marzia tablets may be explained by any or all of the above demographic parameters.

e usp controlled room temperature]. • protect from light.

issed [see dosage and administration ( 2.2 )]. • use a back-up or alternative method of contraception when enzyme inducers are used with tri-lo-marzia [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 cocs postpartum; and who have not yet had a period, should use an additional method of contraception until they have taken a white tablet for 7 consecutive days [see dosage and administration ( 2.2 )]. • amenorrhea may occur. consider pregnancy in the event of amenorrhea at the time of the first missed period. rule out pregnancy in the event of amenorrhea in two or more consecutive cycles [see warnings and precautions ( 5.7 )]. distributed by: lupin pharmaceuticals, inc. baltimore, maryland 21202 united states manufactured by: lupin limited pithampur (m.p.) - 454 775 india relabeled by: proficient rx lp thousand oaks, ca 91320 october 2015 id#: 243295

chart shows the chance of getting pregnant for women who use different methods of birth control. each box on the chart contains a list of birth control methods that are similar in effectiveness. the most effective methods are at the top of the chart. the box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant. who should not take tri-lo-marzia? do not take tri-lo-marzia if you: • smoke and are over 35 years of age • had blood clots in your arms, legs, lungs, or eyes • had a problem with your blood that makes it clot more than normal • have certain heart valve problems or irregular heart beat that increases your risk of having blood clots • had a stroke • had a heart attack • have high blood pressure that cannot be controlled by medicine • have diabetes with kidney, eye, nerve, or blood vessel damage • have certain kinds of severe migraine headaches with aura, numbness, weakness or changes in vision, or any migraine headaches if you are over 35 years of age • have liver problems, including liver tumors • have any unexplained vaginal bleeding • are pregnant • had breast cancer or any cancer that is sensitive to female hormones if any of these conditions happen while you are taking tri-lo-marzia, stop taking tri-lo-marzia right away and talk to your healthcare provider. use non-hormonal contraception when you stop taking tri-lo-marzia. what should i tell my healthcare provider before taking tri-lo-marzia? tell your healthcare provider if you: • are pregnant or think you may be pregnant • are depressed now or have been depressed in the past • had yellowing of your skin or eyes (jaundice) caused by pregnancy (cholestasis of pregnancy) • are breastfeeding or plan to breastfeed. tri-lo-marzia may decrease the amount of breast milk you make. a small amount of the hormones in tri-lo-marzia may pass into your breast milk. talk to your healthcare provider about the best birth control method for you while breastfeeding. tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. tri-lo-marzia may affect the way other medicines work, and other medicines may affect how well tri-lo-marzia works. know the medicines you take. keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. how should i take tri-lo-marzia? read the instructions for use at the end of this patient information. what are the possible serious side effects of tri-lo-marzia? • like pregnancy, tri-lo-marzia may cause serious side effects, including blood clots in your lungs, heart attack, or a stroke that may lead to death. some other examples of serious blood clots include blood clots in the legs or eyes. serious blood clots can happen especially if you smoke, are obese, or are older than 35 years of age. serious blood clots are more likely to happen when you: • first start taking birth control pills • restart the same or different birth control pills after not using them for a month or more call your healthcare provider or go to a hospital emergency room right away if you have: • leg pain that will not go away • sudden severe shortness of breath • sudden change in vision or blindness • chest pain • a sudden, severe headache unlike your usual headaches • weakness or numbness in your arm or leg • trouble speaking other serious side effects include: • liver problems, including: • rare liver tumors • jaundice (cholestasis), especially if you previously had cholestasis of pregnancy. call your healthcare provider if you have yellowing of your skin or eyes. • high blood pressure . you should see your healthcare provider for a yearly check of your blood pressure. • gallbladder problems • changes in the sugar and fat (cholesterol and triglycerides) levels in your blood • new or worsening headaches including migraine headaches • irregular or unusual vaginal bleeding and spotting between your menstrual periods, especially during the first 3 months of taking tri-lo-marzia. • depression • possible cancer in your breast and cervix • swelling of your skin especially around your mouth, eyes, and in your throat (angioedema). call your healthcare provider if you have a swollen face, lips, mouth tongue or throat, which may lead to difficulty swallowing or breathing. your chance of having angioedema is higher is you have a history of angioedema. • dark patches of skin around your forehead, nose, cheeks and around your mouth, especially during pregnancy (chloasma). women who tend to get chloasma should avoid spending a long time in sunlight, tanning booths, and under sun lamps while taking tri-lo-marzia. use sunscreen if you have to be in the sunlight. what are the most common side effects of tri-lo-marzia? • headache (including migraine) • nausea and vomiting • breast problems • tenderness, pain and discomfort • enlargement and swelling • discharge • nipple pain • stomach pain • pain with your periods (menstrual cycle) • mood changes, including depression • acne • vaginal infections • bloating • weight gain • fatigue these are not all the possible side effects of tri-lo-marzia. for more information, ask your healthcare provider or pharmacist. you may report side effects to the fda at 1-800-fda-1088. you may also report side effects to lupin pharmaceuticals, inc. at 1-800-399-2561 or you can visit the lupin website at www.lupinpharmaceuticals.com. what else should i know about taking tri-lo-marzia? • if you are scheduled for any lab tests, tell your healthcare provider you are taking tri-lo-marzia. certain blood tests may be affected by tri-lo-marzia. • tri-lo-marzia does not protect against hiv infection (aids) and other sexually transmitted infections. how should i store tri-lo-marzia? • store tri-lo-marzia at room temperature between 68° to 77°f (20° to 25°c). • keep tri-lo-marzia and all medicines out of the reach of children. • store away from light. general information about the safe and effective use of tri-lo-marzia. medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. do not use tri-lo-marzia for a condition for which it was not prescribed. do not give tri-lo-marzia to other people, even if they have the same symptoms that you have. this patient information summarizes the most important information about tri-lo-marzia. you can ask your pharmacist or healthcare provider for information about tri-lo-marzia that is written for health professionals. for more information, call lupin pharmaceuticals, inc. at 1-800-399-2561 or you can visit the lupin website at www.lupinpharmaceuticals.com. do birth control pills cause cancer? birth control pills do not seem to cause breast cancer. however, if you have breast cancer now, or have had it in the past, do not use birth control pills because some breast cancers are sensitive to hormones. women who use birth control pills may have a slightly higher chance of getting cervical cancer. however, this may be due to other reasons such as having more sexual partners. what if i want to become pregnant? you may stop taking the pill whenever you wish. consider a visit with your healthcare provider for a pre-pregnancy checkup before you stop taking the pill. what should i know about my period when taking tri-lo-marzia? your periods may be lighter and shorter than usual. some women may miss a period. irregular vaginal bleeding or spotting may happen while you are taking tri-lo-marzia, especially during the first few months of use. this usually is not a serious problem. it is important to continue taking your pills on a regular schedule to prevent a pregnancy. what are the ingredients in tri-lo-marzia? active ingredients: each white to off white, light blue, and blue pill contains norgestimate and ethinyl estradiol. inactive ingredients: white to off white pills: anhydrous lactose, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone and titanium dioxide. light blue pills: anhydrous lactose, croscarmellose sodium, fd&c blue no. 2 aluminium lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone and titanium dioxide. blue pills: anhydrous lactose, croscarmellose sodium, fd&c blue no. 2 aluminium lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone and titanium dioxide. green pills: croscarmellose sodium, fd&c blue no. 2 aluminium lake, hypromellose, iron oxide yellow, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol and titanium dioxide. image med guide