elbamate, 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. 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% 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 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, and temazepam. 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 (5.12) ] . 7.3 concomitant use with hcv combination therapy – liver enzyme elevation do not co-administer norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets 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.

che: evaluate significant change in headaches and discontinue norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets if indicated. ( 5.7 ) bleeding irregularities and amenorrhea: evaluate irregular bleeding or amenorrhea. ( 5.8 ) 5.1 thrombotic disorders and other vascular problems stop norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets if an arterial thrombotic event or venous thromboembolic (vte) event occurs. stop norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets 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 the following prolonged immobilization. start norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets 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 a cocs and when restarting oral contraception after a break of 4 weeks or longer. the risk of thromboembolic disease due to cocs gradually disappears after coc 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets if jaundice develops. liver tumors norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets are 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 per 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 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see contraindications (4) ] . norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets can be restarted approximately 2 weeks following completion of treatment with the hepatitis c combination drug regimen. 5.4 high blood pressure norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets are 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets 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. 5.5 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets. cocs may decrease glucose tolerance. consider alternative contraception for women with uncontrolled dyslipidemias. 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets if indicated. consider discontinuation of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets in the case of increased frequency or severity of migraine during coc use (which may be prodromal of a cerebrovascular event). 5.8 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 a clinical trial of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets, the frequency and duration of unscheduled bleeding and/or spotting was assessed in 743 women (3,823 28-day cycles). a total of 10 subjects (1.3%) discontinued norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets, at least in part, due to bleeding or spotting. based on data from the clinical trial, [24% to 38%] of women using norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets experienced unscheduled bleeding per cycle in the six months of the trial. the percent of women who experienced unscheduled bleeding tended to decrease over time. amenorrhea and oligomenorrhea women who use norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets may experience absence of withdrawal bleeding, even if they are not pregnant. in the clinical trial with norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets, 31% to 41% of the women using norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets did not have a withdrawal menses in at least one of 6 cycles of use. some women may experience amenorrhea or oligomenorrhea after discontinuation of cocs, especially when such a condition was preexistent. 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. 5.9 coc 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. 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets 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) ] . 5.10 depression carefully observe women with a history of depression and discontinue norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets if depression recurs to a serious degree. 5.11 malignant neoplasms breast cancer norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets are contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [ see contraindications (4) ]. epidemiology studies have not found a consistent association between use of combined oral contraceptives (cocs) and breast cancer risk. studies do not show an association between ever (current or past) use of cocs and risk of breast cancer. however, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of coc use [ see postmarketing experience (6.2) ]. cervical cancer some studies suggest that cocs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. however, there is controversy about the extent to which these findings may be due to differences in sexual behavior and other factors. 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. 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 healthcare. 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 chloasma should avoid exposure to the sun or ultraviolet radiation while taking norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets.

n of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets starting cocs in women not currently using hormonal contraception (day 1 start or sunday start) important: consider the possibility of ovulation and conception prior to initiation of this product. tablet color: norethindrone acetate and ethinyl estradiol tablets active tablets are white (day 1 to day 24). ferrous fumarate tablets inactive tablets are brown (day 25 to day 28). day 1 start: take first white 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 24 days. take one brown inactive tablet daily for 4 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: for each 28-day course, take in the following order: take the white 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 7 days of the patient’s first cycle pack of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets. take subsequent active tablets once daily at the same time each day for a total of 24 days. take one brown tablet (ferrous fumarate) daily for the following 4 days and at the same time of day that active tablets were taken. a scheduled period should occur during the 4 days that the brown tablets are 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets start norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets: 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 starting norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets after abortion or miscarriage first-trimester after a first-trimester abortion or miscarriage, norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets may be started immediately. an additional method of contraception is not needed if norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets are started immediately. if norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets are not started within 5 days after termination of the pregnancy, the patient must use additional non-hormonal contraception (such as condoms and spermicide) for the first 7 days of her first 28-day course of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets. second-trimester do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. start norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets following the instructions in table 1 for sunday start. use additional non-hormonal contraception (such as condoms and spermicide) for the first 7 days of the patient’s first 28-day course of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets [see contraindications (4) and warnings and precautions (5.1) ] . starting norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets after childbirth do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. start contraceptive therapy with norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets following the instructions in table 1 for women not currently using hormonal contraception. if the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets [see contraindications (4) , warnings and precautions (5.1) , use in specific populations (8.1 and 8.2) ] . 2.3 missed tablets table 2: instructions for missed norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets if one active tablet is missed in weeks 1, 2 or 3 take the tablet as soon as possible. take the next pill at the regular time and continue taking one tablet a day until the pack is finished. back-up contraception is not needed. if two consecutive 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) must be used as back-up if the patient has sex within 7 days after missing tablets. if two consecutive active tablets are missed in week 3 or week 4 or three or more consecutive active tablets are missed at any time 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) 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 must be taken. if vomiting or diarrhea occurs within 3 to 4 hours after taking a white tablet, handle this as a missed tablet [see dosage and administration (2.3) ] .

of another drug and may not reflect the rates observed in practice. the safety of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets was evaluated in 743 subjects who participated in an open-label, randomized, active-controlled, multicenter clinical trial of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets for contraception. this trial examined healthy, non-pregnant volunteers aged 18 to 45 years, who were sexually active and had a body mass index of ≤ 35 kg/m 2 . subjects were followed for up to six 28-day cycles providing a total of 3,823 treatment-cycles of exposure. common adverse reactions (≥ 2% of all subjects): the most common adverse reactions reported by at least 2% of the 743 women using norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets were the following, in order of decreasing incidence: headache (6.3%), vaginal candidiasis (6.1%), nausea (4.6%), menstrual cramps (4.4%), breast tenderness (3.4%), mood changes (including mood swings (2.2%) and depression (1.1%), bacterial vaginitis (3.1%), acne (2.7%), and weight gain (2.0%). adverse reactions leading to study discontinuation: among the 743 women using norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets, 46 women (6.2%) withdrew because of an adverse event. adverse events occurring in 3 or more subjects leading to discontinuation of treatment were, in decreasing order: abnormal bleeding (0.9%), nausea (0.8%), mood changes (0.8%), menstrual cramps (0.4%), increased blood pressure (0.4%), and irregular bleeding (0.4%). 6.2 post-marketing experience five studies that compared breast cancer risk between ever-users (current or past use) of cocs and never-users of cocs reported no association between ever use of cocs and breast cancer risk, with effect estimates ranging from 0.90 to 1.12 (figure 1). three studies compared breast cancer risk between current or recent coc users (<6 months since last use) and never users of cocs (figure 1). one of these studies reported no association between breast cancer risk and coc use. the other two studies found an increased relative risk of 1.19 to 1.33 with current or recent use. both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of coc use to approximately 1.4 with more than 8 to 10 years of coc use. figure 1 rr = relative risk; or = odds ratio; hr = hazard ratio. “ever coc” are females with current or past coc use; “never coc use” are females that never used cocs. the following adverse reactions have been identified during post approval use of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets. because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure. cardiovascular: chest pain, palpitations, tachycardia, angina pectoris, myocardial infarction. endocrine disorders: hypothyroidism, hyperthyroidism. eye disorders: blurred vision, visual impairment, transient blindness, corneal thinning, change in corneal curvature (steepening). gi disorders: nausea, vomiting, abdominal pain, constipation, pancreatitis. hepatobiliary disorders: cholelithiasis, cholecystitis, hepatic adenoma, hemangioma of liver. immune system disorders: anaphylactic reactions, including urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms. infections: vaginal infection. metabolism and nutrition disorders: change in weight or appetite (increase or decrease). hypoglycemia, diabetes mellitus, anemia. musculoskeletal and connective tissue disorders: myalgia. skin and subcutaneous disorders: alopecia, rash (generalized and allergic), pruritus, skin discoloration, night sweats, swelling face or lips, hirsutism, skin burning sensation, erythema multiforme, erythema nodosum, hemorrhagic eruption. nervous system disorders: headache, dizziness, migraine, hyperesthesia, paraesthesia, hypoaesthesia, somnolence, loss of consciousness, sensory disturbance. psychiatric disorders: mood swings, depression, insomnia, anxiety, suicidal ideation, panic attack, changes in libido, bipolar disorder, dissociation, homicidal ideation. renal and urinary disorders: pollakiuria, dysuria, cystitis-like syndrome. reproductive system and breast disorders: breast changes (tenderness, pain, enlargement, and secretion), premenstrual syndrome, ovarian cyst, pelvic pain, ovarian cyst ruptured, pelvic fluid collection. vascular disorders: hot flush, thrombosis/embolism (coronary artery, pulmonary, cerebral, deep vein), migraine, transient ischemic attack, ischemic stroke. 1

elbamate, 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. 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% 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 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, and temazepam. 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 (5.12) ] . 7.3 concomitant use with hcv combination therapy – liver enzyme elevation do not co-administer norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets 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.

es and limb-reduction defects) following exposure to chcs before conception or during early pregnancy. 8.2 lactation risk summary contraceptive hormones and/or metabolites are present in human milk. chcs can reduce milk production in breastfeeding females. this reduction can occur at any time but is less likely to occur once breastfeeding is well-established. when possible, advise the nursing female to use other methods of contraception until she discontinues breastfeeding [see dosage and administration (2.2) ] . the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets and any potential adverse effects on the breastfed child from norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets or from the underlying maternal condition. 8.4 pediatric use safety and efficacy of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets have been established in women of reproductive age. efficacy is expected to be the same in postpubertal adolescents under the age of 18 years as for users 18 years and older. use of this product before menarche is not indicated. 8.5 geriatric use norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets have not been studied in postmenopausal women and are not indicated in this population. 8.6 hepatic impairment the pharmacokinetics of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets has not been studied in women with renal impairment. 8.8 body mass index the safety and efficacy of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets in women with a body mass index (bmi) > 35 kg/m 2 has not been evaluated [see clinical studies (14) ] .

nyl estradiol pharmacokinetics following single- and multiple-dose administrations of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets in 17 healthy female volunteers are provided in figures 2 and 3, and table 3. following multiple-dose administration of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets, mean maximum concentrations of norethindrone and ethinyl estradiol were increased by 95% and 27%, respectively, as compared to single-dose administration. mean norethindrone and ethinyl estradiol exposures (auc values) were increased by 164% and 51% respectively, as compared to single-dose administration of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets. steady-state with respect to norethindrone was reached by day 17 and steady-state with respect to ethinyl estradiol was reached by day 13. mean shbg concentrations were increased by 150% from baseline (57.5 nmol/l) to 144 nmol/l at steady-state. figure 2. mean plasma norethindrone concentration-time profiles following single- and multiple-dose oral administration of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets to healthy female volunteers under fasting condition (n = 17) figure 3. mean plasma ethinyl estradiol concentration-time profiles following single- and multiple-dose oral administration of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets to healthy female volunteers under fasting condition (n = 17) table 3. summary of norethindrone (ne) and ethinyl estradiol (ee) pharmacokinetics following single- and multiple-dose oral administration of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets to healthy female volunteers under fasting condition (n = 17) regimen analyte arithmetic mean a (% cv) by pharmacokinetic parameter c max (pg/ml) t max (hr) auc (0−24) (pg/ml•h) c min (pg/ml) t ½ (hr) c avg (pg/ml) day 1 (single dose) ne 8420 (31) 1.0 (0.7 to 4.0) 33390 (40) -- -- -- ee 64.5 (27) 1.3 (0.7 to 4.0) 465.4 (26) -- -- -- shbg -- -- -- 57.5 (37) b -- -- day 24 (multiple dose) ne 16400 (26) 1.3 (0.7 to 4.0) 88160 (30) 880 (51) 8.4 3670 (30) ee 81.9 (24) 1.7 (1.0 to 2.0) 701.3 (28) 11.4 (43) 14.5 29.2 (28) shbg -- -- -- 144 (24) -- -- c max = maximum plasma concentration t max = time of c max c min = minimum plasma concentration at steady-state auc (0−24) = area under plasma concentration versus time curve from 0 to 24 hours t ½ = apparent first-order terminal elimination half-life c avg = average plasma concentration = auc (0–24)/24 % cv = coefficient of variation (%) shbg = sex hormone binding globulin (nmol/l) a the harmonic mean (0.693/mean apparent elimination rate constant) is reported for t ½ , and the median (range) is reported for t max . b the shbg concentration reported here is the pre-dose concentration. food effect a single-dose administration of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets with food decreased the maximum concentration of norethindrone by 11% and increased the extent of absorption by 27% and decreased the maximum concentration of ethinyl estradiol by 30% but not the extent of absorption. distribution volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 l/kg. plasma protein binding of both steroids is extensive (>95%); norethindrone binds to both albumin and shbg, whereas ethinyl estradiol binds only to albumin. although ethinyl estradiol does not bind to shbg, it induces shbg synthesis. metabolism norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. the majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites. ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. the primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the cyp3a4 isoform of cytochrome p450. part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. ethinyl estradiol may undergo enterohepatic circulation. excretion norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites. plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 l/hr/kg). steady-state elimination half-lives of norethindrone and ethinyl estradiol following administration of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets are approximately 8 hours and 14 hours, respectively. fig-1 fig-2

administration of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets, mean maximum concentrations of norethindrone and ethinyl estradiol were increased by 95% and 27%, respectively, as compared to single-dose administration. mean norethindrone and ethinyl estradiol exposures (auc values) were increased by 164% and 51% respectively, as compared to single-dose administration of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets. steady-state with respect to norethindrone was reached by day 17 and steady-state with respect to ethinyl estradiol was reached by day 13. mean shbg concentrations were increased by 150% from baseline (57.5 nmol/l) to 144 nmol/l at steady-state. figure 2. mean plasma norethindrone concentration-time profiles following single- and multiple-dose oral administration of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets to healthy female volunteers under fasting condition (n = 17) figure 3. mean plasma ethinyl estradiol concentration-time profiles following single- and multiple-dose oral administration of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets to healthy female volunteers under fasting condition (n = 17) table 3. summary of norethindrone (ne) and ethinyl estradiol (ee) pharmacokinetics following single- and multiple-dose oral administration of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets to healthy female volunteers under fasting condition (n = 17) regimen analyte arithmetic mean a (% cv) by pharmacokinetic parameter c max (pg/ml) t max (hr) auc (0−24) (pg/ml•h) c min (pg/ml) t ½ (hr) c avg (pg/ml) day 1 (single dose) ne 8420 (31) 1.0 (0.7 to 4.0) 33390 (40) -- -- -- ee 64.5 (27) 1.3 (0.7 to 4.0) 465.4 (26) -- -- -- shbg -- -- -- 57.5 (37) b -- -- day 24 (multiple dose) ne 16400 (26) 1.3 (0.7 to 4.0) 88160 (30) 880 (51) 8.4 3670 (30) ee 81.9 (24) 1.7 (1.0 to 2.0) 701.3 (28) 11.4 (43) 14.5 29.2 (28) shbg -- -- -- 144 (24) -- -- c max = maximum plasma concentration t max = time of c max c min = minimum plasma concentration at steady-state auc (0−24) = area under plasma concentration versus time curve from 0 to 24 hours t ½ = apparent first-order terminal elimination half-life c avg = average plasma concentration = auc (0–24)/24 % cv = coefficient of variation (%) shbg = sex hormone binding globulin (nmol/l) a the harmonic mean (0.693/mean apparent elimination rate constant) is reported for t ½ , and the median (range) is reported for t max . b the shbg concentration reported here is the pre-dose concentration. food effect a single-dose administration of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets with food decreased the maximum concentration of norethindrone by 11% and increased the extent of absorption by 27% and decreased the maximum concentration of ethinyl estradiol by 30% but not the extent of absorption. distribution volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 l/kg. plasma protein binding of both steroids is extensive (>95%); norethindrone binds to both albumin and shbg, whereas ethinyl estradiol binds only to albumin. although ethinyl estradiol does not bind to shbg, it induces shbg synthesis. metabolism norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. the majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites. ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. the primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the cyp3a4 isoform of cytochrome p450. part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. ethinyl estradiol may undergo enterohepatic circulation. excretion norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites. plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 l/hr/kg). steady-state elimination half-lives of norethindrone and ethinyl estradiol following administration of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets are approximately 8 hours and 14 hours, respectively. fig-1 fig-2

years in 3,565 treatment cycles during which no back-up contraception was used. the pearl index for norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets was 1.82 (95% confidence interval 0.59 to 4.25).

erature]. protect from light. keep this drug and all drugs out of the reach of children.

struct the patient to stop further use [see warnings and precautions (5.9) ] . take one tablet daily by mouth at the same time every day. instruct patients what to do in the event pills are missed [see dosage and administration (2.2) ] . use a back-up or alternative method of contraception when enzyme inducers are used with norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets [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 (8.2) ] . women who start cocs postpartum, and who has not yet had a period, must use an additional method of contraception until she has 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 (5.8) ] . distributed by: amneal pharmaceuticals llc bridgewater, nj 08807 rev. 05-2022-03

rethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets work for contraception? your chance of getting pregnant depends on how well you follow the directions for taking your birth control pills. the better you follow the directions, the less chance you have of getting pregnant. based on the results from the clinical study, about 1 to 4 out of 100 women may get pregnant during the first year they use norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets. the following 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets? do not take norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets 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 had breast cancer or any cancer that is sensitive to female hormones take any hepatitis c drug combination containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. this may increase levels of the liver enzyme “alanine aminotransferase” (alt) in the blood. if any of these conditions happen while you are taking norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets, stop taking norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets right away and talk to your healthcare provider. use non-hormonal contraception (such as condoms and spermicide) when you stop taking norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets. what should i tell my healthcare provider before taking norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets? 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. norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets may decrease the amount of breast milk you make. a small amount of the hormones in norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets 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. norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets may affect the way other medicines work, and other medicines may affect how well norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets work. 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets? read the instructions for use at the end of this patient information. what are the possible serious side effects of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets? like pregnancy, norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets 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 a sudden, severe headache unlike your usual headaches sudden severe shortness of breath weakness or numbness in your arm or leg sudden change in vision or blindness chest pain 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 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets. use sunscreen if you have to be in the sunlight. what are the most common side effects of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets? headache vaginal infections nausea menstrual cramps breast tenderness mood changes acne weight gain these are not all the possible side effects of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets. for more information, ask your healthcare provider or pharmacist. you may report side effects to the fda at 1-800-fda-1088. what else should i know about taking norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets? if you are scheduled for any lab tests, tell your healthcare provider you are taking norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets. certain blood tests may be affected by norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets. norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets do not protect against hiv infection (aids) and other sexually transmitted infections. how should i store norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets? store norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets at room temperature between 68° to 77°f (20° to 25°c). store away from light. keep norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets and all medicines out of the reach of children. general information about the safe and effective use of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets. medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. do not use norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets for a condition for which it was not prescribed. do not give norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets to other people. this patient information summarizes the most important information about norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets. you can ask your pharmacist or healthcare provider for information about norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets that is written for health professionals. for more information, call amneal pharmaceuticals at 1-877-835-5472. does hormonal birth control cause cancer? it is not known if hormonal birth control pills cause breast cancer. some studies, but not all, suggest that there could be a slight increase in the risk of breast cancer among current users with longer duration of use. if you have breast cancer now, or have had it in the past, do not use hormonal birth control 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets? 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets, 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets? active ingredients: white pills: norethindrone acetate, usp and ethinyl estradiol, usp inactive ingredients: brown pills: ferrous fumarate distributed by: amneal pharmaceuticals llc bridgewater, nj 08807 rev. 11-2021-02 chart