DailyMed Label: Nexesta Fe

DailyMed Label: Nexesta Fe

2021

DailyMed Prescription

Nexesta Fe

norethindrone and ethinyl estradiol and ferrous fumarate

Aurobindo Pharma Limited

NDC: 65862-926

NDC: 65862-926

NDC: 65862-926

NDC: 65862-926

Nexesta Fe is a combinational contraceptive containing the progestational compound norethindrone and the estrogenic compound ethinyl estradiol. The packaging includes 21 white to off-white tablets composed of norethindrone and ethinyl estradiol followed by 7 brown ferrous fumarate (placebo) tablets. The chemical name for norethindrone is 17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one and for ethinyl estradiol the chemical name is 19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol. The structural formulas are: The active white to off-white Nexesta Fe (norethindrone and ethinyl estradiol tablets USP (chewable) 0.4 mg/0.035 mg and ferrous fumarate tablets (chewable)) tablets contain 0.4 mg norethindrone USP and 0.035 mg ethinyl estradiol USP and the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, dibasic calcium phosphate, dihydrate, lactose monohydrate, magnesium stearate, nat spearmint, povidone, sodium starch glycolate, and sucralose. The brown tablets contain croscarmellose sodium, ferrous fumarate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, nat spearmint, povidone, and sucralose. The ferrous fumarate tablets do not serve any therapeutic purpose. USP dissolution test is pending. Chemical Structure

Nexesta Fe is indicated for use by females of reproductive potential to prevent pregnancy. Nexesta Fe is a progestin/estrogen COC indicated for use by females of reproductive potential to prevent pregnancy. ( 1 )

Take one tablet by mouth at the same time every day. Tablets may be chewed or swallowed. ( 2.1 ) Take tablets in the order directed on the blister pack. ( 2.1 ) Nexesta Fe is dispensed in a blister pack [see How Supplied/Storage and Handling (16) ] . Nexesta Fe may be started using either a Day 1 start or a Sunday start (see Table 1). For the first cycle of a Sunday Start regimen, an additional method of contraception should be used until after the first 7 consecutive days of administration. Nexesta Fe (white to off-white active tablets and brown placebo tablets) may be swallowed whole or chewed and swallowed. If the tablet is chewed, the patient should drink a full glass (8 ounces) of liquid immediately after swallowing. Table 1:                Instructions for Administration of Nexesta Fe Starting CHCs 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: • Nexesta Fe active tablets are white to off-white (Day 1 to Day 21). • Nexesta Fe placebo tablets are brown (Day 22 to Day 28). Day 1 Start: • Take first white to off-white active tablet on the first day of menses. • Take subsequent white to off-white active tablets once daily at the same time each day for a total of 21 days. • Take one brown placebo 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 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 Nexesta Fe. • Take subsequent white to off-white active tablets once daily at the same time each day for a total of 21 days. • Take one brown placebo 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 Nexesta Fe from another hormonal contraceptive Start on the same day that a new pack of the previous hormonal contraceptive would have started. Switching from another contraceptive method to Nexesta Fe Start Nexesta Fe: • 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 Nexesta Fe after Abortion or Miscarriage First-trimester After a first-trimester abortion or miscarriage, Nexesta Fe may be started immediately. An additional method of contraception is not needed if Nexesta Fe is started within 5 days after termination of the pregnancy. If Nexesta Fe 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 Nexesta Fe. Second-trimester Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start Nexesta Fe, 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 Nexesta Fe. [See Contraindications (4) , Warnings and Precautions (5.1) , and FDA-Approved Patient Labeling .] Starting Nexesta Fe after Childbirth Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with Nexesta Fe 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 Nexesta Fe. [See Contraindications (4) , Warnings and Precautions (5.1) ,  Use in Specific Populations (8.1 and 8.3) , and FDA-Approved Patient Labeling ]. Table 2: Instructions for Missed Nexesta Fe Tablets If one white to off-white 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 white to off-white 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 back-up if the patient has sex within 7 days after missing tablets. If two white to off-white active tablets are missed in Week 3 or three or more white to off-white 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. 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 ] .

Nexesta Fe (norethindrone and ethinyl estradiol tablets USP (chewable) and ferrous fumarate tablets (chewable)) is available in blister packs. Each blister pack contains 28 tablets in the following order: 21 round, flat faced, beveled edge, white to off-white (active) tablets debossed with ‘S’ on one side and ‘47’ on other side and each containing 0.4 mg norethindrone USP and 0.035 mg ethinyl estradiol USP. 7 round, mottled, flat-faced, beveled-edge, brown (non-hormonal placebo) tablets debossed with ‘S’ on one side and ‘57’ on other side each containing 75 mg ferrous fumarate USP. The ferrous fumarate tablets do not serve any therapeutic purpose. Nexesta Fe consists of 28 tablets in the following order ( 3 ): 21 white to off-white tablets (active), each containing 0.4 mg norethindrone USP and   0.035 mg ethinyl estradiol USP 7 brown tablets (non-hormonal placebo), each containing 75 mg ferrous fumarate USP. The ferrous fumarate tablets do not serve any therapeutic purpose.

Nexesta Fe is contraindicated in females who are known to have or develop the following conditions:  • A high risk of arterial or venous thrombotic diseases. Examples include women who are known to:       o Smoke, if over age 35 [see  Boxed Warning and Warnings and Precautions (5.1) ]       o Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions (5.1) ]       o Have inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1) ]       o Have cerebrovascular disease [see Warnings and Precautions (5.1) ]       o Have coronary artery disease [see Warnings and Precautions (5.1) ]       o Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions (5.1) ]       o Have uncontrolled hypertension [see Warnings and Precautions (5.4) ]       o Have diabetes mellitus with vascular disease [see Warnings and Precautions (5.6) ]       o Have headaches with focal neurological symptoms or have migraine headaches with aura [see Warnings and Precautions (5.7) ]           • Women over age 35 with any migraine headaches [see Warnings and Precautions (5.7) ]  •  Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions (5.2) ]  •  Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.8) ]  •  Pregnancy, because there is no reason to use COCs during pregnancy [see  Warnings and Precautions (5.9) and Use in Specific Populations (8.1) ]  •  Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [see Warnings and Precautions (5.11) ].  •  Hypersensitivity to any of the components.  •  Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations [see Warnings and Precautions (5.3) ] A high risk of arterial or venous thrombotic diseases ( 4 ) Liver tumors or liver disease ( 4 ) Undiagnosed abnormal uterine bleeding ( 4 ) Pregnancy ( 4 ) Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive ( 4 ) Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir ( 4 )

Thrombotic Disorders and Other Vascular Problems: Stop Nexesta Fe if a thrombotic event occurs. Stop at least 4 weeks before through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in women who are not breastfeeding ( 5.1 ) Liver disease : Discontinue Nexesta Fe if jaundice occurs ( 5.2 ) High blood pressure: If used in women with well-controlled hypertension, monitor blood pressure and stop Nexesta Fe if blood pressure rises significantly. ( 5.4 ) Carbohydrate and lipid metabolic effects : Monitor prediabetic and diabetic women taking Nexesta Fe. Consider an alternative contraceptive method for women with uncontrolled dyslipidemia ( 5.6 ) Headache: Evaluate significant change in headaches and discontinue Nexesta Fe if indicated ( 5.7 ) Bleeding Irregularities and Amenorrhea : Evaluate irregular bleeding or amenorrhea ( 5.8 ) • Stop Nexesta Fe if an arterial thrombotic event or venous thromboembolic (VTE) event occurs. • Stop Nexesta Fe if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately . • If feasible, stop Nexesta Fe 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 Nexesta Fe 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 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).  The 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. Impaired Liver Function Do not use Nexesta Fe 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 Nexesta Fe if jaundice develops. Liver Tumors Nexesta Fe 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. 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 Nexesta Fe prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4) ]. Nexesta Fe can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen. Nexesta Fe 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 Nexesta Fe 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. 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. Carefully monitor prediabetic and diabetic women who take Nexesta Fe. 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. If a woman taking Nexesta Fe develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Nexesta Fe if indicated. Consider discontinuation of Nexesta Fe in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event). 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. Amenorrhea and Oligomenorrhea Women who use Nexesta Fe may experience amenorrhea. 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. 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 Nexesta Fe 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) ]. Carefully observe women with a history of depression and discontinue Nexesta Fe if depression recurs to a serious degree. Breast Cancer Nexesta Fe is 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) ]. Cervical Cancer A causal relationship between the use of CHCs and the development of cervical cancer and intraepithelial neoplasia has not been clearly established. In observational studies, 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. The estrogen component of COCs may raise the serum concentrations of thyroxine-binding globulin, sec hormone-binding globulin, and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased. 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. In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. 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 Nexesta Fe.

The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling:

Consult the labeling of concurrently used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding. Counsel patients to use a back-up method or alternative method of contraception when enzyme inducers are used with COCs ( 7.1 ) Substances decreasing the plasma concentrations of COCs and potentially diminishing the efficacy of COCs : Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of COCs and potentially diminish the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John’s wort. Interactions between hormonal contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability. Colesevelam: Colesevelam, a bile acid sequestrant, given together with a COC, has been shown to significantly decrease the AUC of EE. The drug interaction between the contraceptive and colesevelam was decreased when the two drug products were given 4 hours apart. Substances increasing the plasma concentrations of COCs: Co-administration of atorvastatin or rosuvastatin and certain COCs containing 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, fluconazole, grapefruit juice, or ketoconazole may increase plasma hormone concentrations. Human immunodeficiency virus (HIV)/Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]). COCs containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. COCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, temazepam and lamotrigine. Significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because the serum concentration of thyroid-binding globulin increases with use of COCs [see Warnings and Precautions (5.12) ]. Do not co-administer Nexesta Fe with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions (5.3) ]. The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

Nursing mothers: Advise use of another contraceptive method. Nexesta Fe can decrease milk production. ( 8.3 ) There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy. Do not use COCs to induce withdrawal bleeding as a test for pregnancy. Do not use COCs during pregnancy to treat threatened or habitual abortion. Advise the nursing mother to use other forms of contraception, when possible, until she has weaned her child. COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk. Safety and efficacy of Nexesta Fe have been established in women of reproductive age. Efficacy is expected to be the same in post-pubertal adolescents under the age of 18 years as for users 18 years and older. Use of this product before menarche is not indicated. Nexesta Fe has not been studied in postmenopausal women and is not indicated in this population. The pharmacokinetics of Nexesta Fe has not been studied in women 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) ]. The pharmacokinetics of Nexesta Fe has not been studied in women with renal impairment.

Nexesta Fe (norethindrone and ethinyl estradiol tablets USP (chewable) 0.4 mg/0.035 mg and ferrous fumarate tablets (chewable)) is available in blister packs: The Blister Packs are packed in Pouches (NDC 65862-926-87) and the pouches are packaged in cartons Carton of 1 Pouch                  NDC 65862-926-87 Carton of 3 Pouches               NDC 65862-926-88 Carton of 5 Pouches              NDC 65862-926-58 Carton of 72 Pouches            NDC 65862-926-97 Each blister pack contains 28 tablets in the following order: 21 round, flat faced, beveled edge, white to off-white (active) tablets debossed with ‘S’ on one side and ‘47’ on other side and each containing 0.4 mg norethindrone USP and 0.035 mg ethinyl estradiol USP. 7 round, mottled, flat-faced, beveled-edge, brown (non-hormonal placebo) tablets debossed with ‘S’ on one side and ‘57’ on other side each containing 75 mg ferrous fumarate USP. Store at 20º to 25°C (68° to 77º F) [see USP Controlled Room Temperature]. Protect from light. Keep out of the reach of children.

COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation. No specific pharmacodynamic studies were conducted with Nexesta Fe. Absorption Ethinyl estradiol and norethindrone are rapidly absorbed with maximum plasma concentrations occurring within 2 hours after Nexesta Fe administration (see Table 1). Norethindrone appears to be completely absorbed following oral administration; however, it is subject to first-pass metabolism resulting in an absolute bioavailability of approximately 65 percent. Large intersubject variability is reflected in a 3- to 5-fold variation in norethindrone bioavailability. Ethinyl estradiol bioavailability is approximately 43 percent due to small-intestinal and hepatic first-pass metabolism. Table 3. Mean±SD Pharmacokinetic Parameters Following Single Dose Administration of Nexesta Fe in Healthy Female Subjects Under Fasting Conditions. a n = 26 b n = 25 C max = maximum plasma concentration; t max = time to reach C max ; AUC = area under the curve; t 1/2 = elimination half-life. Norethindrone/Ethinyl Estradiol t max (h) C max (pg/mL) AUC 0-∞ (pg•h/mL) t 1/2 (h) Norethindrone 0.4 mg 1.24 ± 0.40 a 4210.6 ± 1628.8 a 18034.9 ± 7852.9 b 8.6 ± 3.7 b Ethinyl Estradiol 0.035 mg 1.44 ± 0.33 b 131.4 ± 34.2 b 1065.8 ± 276.2 b 17.1 ± 4.4 b Food Effect : Single-dose administration of Nexesta Fe tablets with food decreased the maximum norethindrone and ethinyl estradiol concentration by 53 percent and 47 percent, respectively; the extent of norethindrone and ethinyl estradiol absorption (AUC values) was not affected by food administration. Distribution Norethindrone is 36 percent bound to sex hormone-binding globulin (SHBG) and 61 percent bound to albumin. Ethinyl estradiol is not bound to SHBG but is highly (98.5 percent) bound to albumin. Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. Metabolism Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation; less than 5 percent of a norethindrone dose is excreted unchanged; greater than 50 percent and 20 to 40 percent of a dose is excreted in urine and feces, respectively. 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, which is formed by the CYP3A4 isoform of cytochrome P450. Excretion Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg). Ethinyl estradiol and norethindrone are excreted in both urine and feces, primarily as metabolites. Ethinyl estradiol is excreted in urine and feces as glucuronides and sulfates, and about 28 to 43 percent undergoes enterohepatic circulation. The mean terminal elimination half-lives of norethindrone and ethinyl estradiol following single dose administration of Nexesta Fe are approximately 9 hours and 17 hours, respectively.

[See  Warnings and Precautions (5.11) and Use in Specific Populations (8.1) .]

The data presented in Section 14 are from a clinical trial conducted with norethindrone 0.4 mg/ethinyl estradiol 0.035 mg tablets. Nexesta Fe is bioequivalent to these norethindrone acetate/ethinyl estradiol tablets. In a multicenter open-label clinical trial, 1,970 women, 98% of whom were 16 to 39 years of age, were studied for up to 31 cycles (28 days per cycle) to assess the efficacy of norethindrone/ethinyl estradiol tablets, completing the equivalent of 20,230 cycles of exposure. The racial demographic of all enrolled women was: Caucasian (56%), African-American (14%), and Other (30%) (Hispanic, Native American, etc.). Of treated women, 10% were lost to follow-up, 11% discontinued related to cycle control and 7% discontinued due to other adverse events. The pregnancy rate (Pearl Index [PI]) in all 1,970 women was 1.48 pregnancies per 100 women-years of use (95% confidence interval 0.94 to 2.22), based on 23 pregnancies that occurred after the onset of treatment of norethindrone /ethinyl estradiol tablets.

Nexesta TM  Fe (neks-ey-stuh Fe) (norethindrone and ethinyl estradiol tablets USP (chewable) and ferrous fumarate tablets (chewable)) What is the most important information I should know about Nexesta Fe? Do not use Nexesta Fe if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects (heart and blood vessel problems) from birth control pills, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke. What is Nexesta Fe? Nexesta Fe is a birth control pill (oral contraceptive) used by women to prevent pregnancy. How does Nexesta Fe 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 of one clinical study of a 28-day regimen of norethindrone 0.4 mg/ethinyl estradiol 0.035 mg tablets, about 1 to 2 out of 100 women may get pregnant during the first year they use Nexesta Fe. 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 Nexesta Fe? Do not take Nexesta Fe 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 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 Nexesta Fe, stop taking Nexesta Fe right away and talk to your healthcare provider. Use non-hormonal contraception when you stop taking Nexesta Fe. What should I tell my healthcare provider before taking Nexesta Fe? 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. Nexesta Fe may decrease the amount of breast milk you make. A small amount of the hormones in Nexesta Fe 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. Nexesta Fe may affect the way other medicines work, and other medicines may affect how well Nexesta Fe 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 do I take Nexesta Fe? Read the Instructions for Use at the end of this Patient Information . What are the possible serious side effects of Nexesta Fe? Like pregnancy, Nexesta Fe 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:  o leg pain that will not go away o a sudden, severe headache unlike your usual headaches   o sudden severe shortness of breath o weakness or numbness in your arm or leg   o sudden change in vision or blindness      o trouble speaking   o chest pain   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 Nexesta Fe. Use sunscreen if you have to be in the sunlight. What are the most common side effects of Nexesta Fe? The most common side effects of Nexesta Fe include: headache (including migraine) nausea and vomiting breast problems tenderness, pain and discomfort enlargement and swelling discharge nipple pain belly pain pain with your periods (menstrual cycle) mood changes, including depression acne vaginal infections bloating weight gain These are not all the possible side effects of Nexesta Fe. 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 Nexesta Fe? If you are scheduled for any lab tests, tell your healthcare provider you are taking Nexesta Fe. Certain blood tests may be affected by Nexesta Fe. Nexesta Fe does not protect against HIV infection (AIDS) and other sexually transmitted infections. How should I store Nexesta Fe? Store Nexesta Fe at room temperature between 68° to 77°F (20° to 25°C). Keep Nexesta Fe and all medicines out of the reach of children. Store away from light. General information about the safe and effective use of Nexesta Fe. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Nexesta Fe for a condition for which it was not prescribed. Do not give Nexesta Fe to other people. This Patient Information summarizes the most important information about Nexesta Fe. You can ask your pharmacist or healthcare provider for information about Nexesta Fe that is written for health professionals . For more information, call Aurobindo Pharma USA, Inc. at 1-866-850-2876 Does hormonal birth control cause cancer? It is not known if hormonal birth control pills causes 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 Nexesta Fe? 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 Nexesta Fe, 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 Nexesta Fe? Active ingredients: White to off-white pills: norethindrone USP  and ethinyl estradiol USP Brown pills: ferrous fumarate USP Inactive ingredients: White to off-white pills: anhydrous lactose, colloidal silicon dioxide, dibasic calcium phosphate, dihydrate, lactose monohydrate, magnesium stearate, nat spearmint, povidone, sodium starch glycolate, and sucralose. Brown pills: croscarmellose sodium, ferrous fumarate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, nat spearmint, povidone, and sucralose. Figure 2

NDC 65862-926-87 Nexesta TM Fe (Norethindrone and Ethinyl Estradiol Tablets USP (Chewable) 0.4 mg/0.035 mg and Ferrous Fumarate Tablets (Chewable)) Each of the 21 WHITE TO OFF-WHITE tablets contains norethindrone USP 0.4 mg and ethinyl estradiol USP 0.035 mg. Each of the 7 BROWN tablets contains ferrous fumarate USP 75 mg. Ferrous Fumarate tablets are not USP for dissolution and assay. This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted diseases. Rx only           Contains 1 Blister of 28 Tablets Each AUROBINDO PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 0.4 mg/0.035 mg 1 Pouch Label