Norethindrone Acetate and Ethinyl Estradiol

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular Disorders [see Boxed Warning , Warnings and Precautions (5.1) ]. Malignant Neoplasms [ see Boxed Warning , Warnings and Precautions (5.2) ]. Most common adverse reactions (incidence greater than or equal to 5 percent) are headache, abdominal pain, breast pain, and edema (generalized). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Nivagen Pharmaceuticals Toll-free at 1-877-977-0687 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions reported by ≥5 percent of subjects in controlled clinical studies of norethindrone acetate and ethinyl estradiol tablets are shown in Table 1. Table 1. Associated Adverse Reactions Reported by ≥ 5 Percent of Subjects by Body System The total number of subjects for each body system may be less than the number of subjects with AEs in that body system because a subject may have had more than one AE per body system BODY SYSTEM/ Adverse Reaction Number (Percent) of Subjects Placebo N = 247 NDAc-EE 0.5/2.5 NDAc-EE 0.5/2.5 = Norethindrone Acetate - Ethinyl Estradiol 0.5 mg/2.5 mcg NDAc-EE 1/5 = Norethindrone Acetate - Ethinyl Estradiol 1 mg/5 mcg N = 244 NDAc-EE 1/5 N = 258 BODY AS A WHOLE 23 (12.8) 30 (16.9) 30 (15.7) Edema – Generalized 10 (4.0) 12 (4.9) 11 (4.3) Headache 12 (4.9) 14 (5.7) 16 (6.2) DIGESTIVE SYSTEM 8 (4.4) 17 (9.6) 25 (13.1) Abdominal Pain 3 (1.2) 13 (5.3) 14 (6.8) UROGENITAL SYSTEM 20 (11.1) 34 (19.2) 45 (23.6) Breast Pain 9 (3.6) 22 (9.0) 20 (7.8) 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of norethindrone acetate and ethinyl estradiol tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Genitourinary System Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; increase in size of uterine leiomyomata, vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer; uterine cancer; vaginal hemorrhage; ovarian cyst; irregular menstruation; metrorrhagia; menorrhagia; dysmenorrhea; uterine enlargement. Breasts Tenderness, enlargement, breast pain, nipple pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer; breast disorder; breast mass; breast enlargement. Cardiovascular Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; thrombosis; chest pain; myocardial infarction; cerebrovascular accident (stroke); transient ischemic attack; hemiparesis; increase in blood pressure; irregular heart rate; palpitations; dyspnea. Gastrointestinal Nausea, vomiting; cholestatic jaundice; pancreatitis, enlargement of hepatic hemangiomas; bloating, abdominal cramps; abdominal pain; increased incidence of gallbladder disease; cholecystitis; cholelithiasis. Skin Chloasma or melasma that may persist when drug is discontinued; generalized erythema; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; rash, pruritus. Eyes Retinal vascular thrombosis; visual impairment; intolerance to contact lenses. Central Nervous System (CNS) Headache; migraine; dizziness; depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia; paresthesia; insomnia. Miscellaneous Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthralgias; leg cramps; back pain; changes in libido; urticaria, angioedema, anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides; blood glucose abnormal; fatigue; myalgia; hypersensitivity.

4 CONTRAINDICATIONS Norethindrone acetate and ethinyl estradiol tablets are contraindicated in women with any of the following conditions: Undiagnosed abnormal genital bleeding Known, suspected, or history of breast cancer Known or suspected estrogen-dependent neoplasia Active DVT, PE or a history of these conditions Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions Known anaphylactic reaction or angioedema to Norethindrone acetate and Ethinyl estradiol tablets. Known liver impairment or disease Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders Known or suspected pregnancy Undiagnosed abnormal genital bleeding ( 4 ) Known, suspected, or history of breast cancer ( 4 , 5.2 ) Known or suspected estrogen-dependent neoplasia ( 4 , 5.2 ) Active DVT, PE, or history of these conditions ( 4 , 5.1 ) Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions ( 4 , 5.1 ) Known anaphylactic reaction or angioedema to norethindrone acetate and ethinyl estradiol tablets. ( 4 ) Known liver impairment or disease ( 4 , 5.10 ) Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders ( 4 ) Known or suspected pregnancy ( 4 , 8.1 )

11 DESCRIPTION Norethindrone acetate and ethinyl estradiol tablets are a continuous dosage regimen of a progestin-estrogen combination for oral administration. The following two strengths of norethindrone acetate and ethinyl estradiol tablets are available: 0.5 mg/2.5 mcg: Each round light yellow tablet contains 0.5 mg norethindrone acetate and 2.5 mcg ethinyl estradiol; debossed with N1 on one side. 1 mg/5 mcg: Each round white tablet contains 1 mg norethindrone acetate and 5 mcg ethinyl estradiol; debossed with N2 on one side. Each white tablet also contains lactose monohydrate, pregelatinized starch, polyethylene glycol, magnesium stearate, ethyl cellulose, vitamin E, titanium dioxide, hypromelloses, macrogol/PEG, triacetin, polydextrose. Each light yellow tablet also contains lactose monohydrate, pregelatinized starch, polyethylene glycol, magnesium stearate, ethyl cellulose, vitamin E, iron oxide yellow, iron oxide black, talc, polyvinyl alcohol, titanium dioxide, lecithin (soya). The structural formulas are as follows. Norethindrone Acetate [19-Norpregn-4-en-20-yn-3-one, 17-(acetyloxy)-, (17α)-]; Molecular Weight: 340.47 Molecular Formula: C22H28O3 Ethinyl Estradiol [19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-]; Molecular Weight: 296.41 Molecular Formula: C20H24O2 Chemical Structure Chemical Structure

2 DOSAGE AND ADMINISTRATION Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary. One tablet taken orally once daily ( 2.1 , 2.2 ) 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Norethindrone acetate and ethinyl estradiol tablets therapy consists of a single tablet to be taken orally once daily. 2.2 Prevention of Postmenopausal Osteoporosis Norethindrone acetate and ethinyl estradiol tablets therapy consists of a single tablet taken orally once daily.

1 INDICATIONS AND USAGE Norethindrone acetate and Ethinyl estradiol tablets are an estrogen plus progestin indicated in a woman with a uterus for: Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause ( 1.1 ) Prevention of Postmenopausal Osteoporosis ( 1.2 ) 1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause 1.2 Prevention of Postmenopausal Osteoporosis Limitation of Use When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be condisered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered.

10 OVERDOSAGE Overdosage of estrogen plus progestin may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of norethindrone acetate and ethinyl estradiol tablets with institution of appropriate symptomatic care.

7 DRUG INTERACTIONS No drug-drug interaction studies have been conducted for norethindrone acetate and ethinyl estradiol tablets . Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism ( 7.1 ) 7.1 Effect of Other Drugs on Combined Hormonal Products Substances decreasing or increasing the plasma concentration of estrogen: In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John's wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine and rifampin may decrease the plasma concentration of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase the plasma concentration of estrogens and may result in side effects. Co-administration of atorvastatin and certain hormonal products containing ethinyl estradiol increase AUC values for ethinyl estradiol approximately 20 percent. Ascorbic acid and acetaminophen may increase the plasma ethinyl estradiol concentration, possibly by inhibition of conjugation. 7.2 Effect of Combined Hormonal Products on Other Drugs Combination hormonal products containing some synthetic estrogens (for example, ethinyl estradiol) may inhibit the metabolism of other compounds. Combination hormonal products have been shown to significantly decrease the plasma concentration of lamotrigine likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. The pharmacologic effects of ethinyl estradiol are similar to those of endogenous estrogens.Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.Progestin compounds enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes. Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, bone, skeletal tissue and central nervous system. Progestins produce similar endometrial changes to those of the naturally occurring hormone progesterone. 12.2 Pharmacodynamics Currently, there are no pharmacodynamic data known for norethindrone acetate and ethinyl estradiol tablets. 12.3 Pharmacokinetics Absorption Norethindrone acetate (NA) is completely deacetylated to norethindrone after oral administration, and the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate and ethinyl estradiol (EE) are absorbed from norethindrone acetate and ethinyl estradiol tablets, with maximum plasma concentrations of norethindrone and ethinyl estradiol generally occurring 1 to 2 hours postdose. Both are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64 percent for norethindrone and 55 percent for ethinyl estradiol. Bioavailability of norethindrone acetate and ethinyl estradiol tablets is similar to that from solution for norethindrone and slightly less for ethinyl estradiol. Administration of norethindrone acetate and ethinyl estradiol tablets with a high fat meal decreases rate but not extent of ethinyl estradiol absorption. The extent of norethindrone absorption is increased by 27 percent following administration of norethindrone acetate and ethinyl estradiol tablets with food. The full pharmacokinetic profile of norethindrone acetate and ethinyl estradiol tablets was not characterized due to assay sensitivity limitations. However, the multiple-dose pharmacokinetics were studied at a dose of 1 mg NA/10 mcg EE in 18 postmenopausal women. Mean plasma concentrations are shown below (Figure 1) and pharmacokinetic parameters are found in Table 2. Based on a population pharmacokinetic analysis, mean steady-state concentrations of norethindrone for 1 mg NA/5 mcg EE and 1/10 are slightly more than proportional to dose when compared to 0.5 mg NA/2.5 mcg EE tablets. It can be explained by higher SHBG concentrations. Mean steady-state plasma concentrations of ethinyl estradiol for the norethindrone acetate and ethinyl estradiol 0.5/2.5 tablets and norethindrone acetate and ethinyl estradiol 1/5 tablets are proportional to dose, but there is a less than proportional increase in steady-state concentrations for the NA/EE 1/10 tablet. Figure 1. Mean Steady-State (Day 87) Plasma Norethindrone and Ethinyl Estradiol Concentrations Following Continuous Oral Administration of 1 mg NA/10 mcg EE Tablets Table 2: Mean (SD) Single-Dose (Day 1) and Steady-State (Day 87) Pharmacokinetic Parameters C max = Maximum plasma concentration; T max = Time of Cmax; AUC (0-24) = Area under the plasma concentration-time curve over the dosing interval; and CL/F = Apparent oral clearance; t½ = Elimination half-life Following Administration of 1 mg NA/10 mcg EE Tablets C max t max AUC (0-24) CL/F t½ Norethindrone ng/mL hr ng.hr/mL mL/min hr Day 1 6.0 (3.3) 1.8 (0.8) 29.7 (16.5) 588 (416) 10.3 (3.7) Day 87 10.7 (3.6) 1.8 (0.8) 81.8 (36.7) 226 (139) 13.3 (4.5) Ethinyl Estradiol pg/mL hr pg.hr/mL mL/min hr Day 1 33.5 (13.7) 2.2 (1.0) 339 (113) ND ND = Not determined ND Day 87 38.3 (11.9) 1.8 (0.7) 471 (132) 383 (119) 23.9 (7.1) Based on a population pharmacokinetic analysis, average steady-state concentrations (C ss ) of norethindrone acetate and ethinyl estradiol for the norethindrone acetate and ethinyl estradiol 1/5 tablets are estimated to be 2.6 ng/mL and 11.4 pg/mL, respectively. C ss values of norethindrone and ethinyl estradiol for the norethindrone acetate and ethinyl estradiol 0.5/2.5 tablets are estimated to be 1.1 ng/mL and 5.4 ng/mL, respectively. The pharmacokinetics of ethinyl estradiol and norethindrone acetate were not affected by age, (age range 40-62 years), in the postmenopausal population studied. Figure 1 Distribution The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to SHBG and albumin. Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. Plasma protein binding of both steroids is extensive (greater than 95 percent); 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 Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. 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. A small amount of norethindrone acetate is metabolically converted to ethinyl estradiol, such that exposure to ethinyl estradiol following administration of 1 mg of norethindrone acetate is equivalent to oral administration of 2.8 mcg ethinyl estradiol. 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 Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. 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 1 mg NA/10 mcg EE tablets are approximately 13 hours and 24 hours, respectively. Use in Specific Populations No pharmacokinetic studies were conducted in specific populations, including women with renal or hepatic impairment.

12.1 Mechanism of Action Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. The pharmacologic effects of ethinyl estradiol are similar to those of endogenous estrogens.Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.Progestin compounds enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes. Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, bone, skeletal tissue and central nervous system. Progestins produce similar endometrial changes to those of the naturally occurring hormone progesterone.

12.2 Pharmacodynamics Currently, there are no pharmacodynamic data known for norethindrone acetate and ethinyl estradiol tablets.

12.3 Pharmacokinetics Absorption Norethindrone acetate (NA) is completely deacetylated to norethindrone after oral administration, and the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate and ethinyl estradiol (EE) are absorbed from norethindrone acetate and ethinyl estradiol tablets, with maximum plasma concentrations of norethindrone and ethinyl estradiol generally occurring 1 to 2 hours postdose. Both are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64 percent for norethindrone and 55 percent for ethinyl estradiol. Bioavailability of norethindrone acetate and ethinyl estradiol tablets is similar to that from solution for norethindrone and slightly less for ethinyl estradiol. Administration of norethindrone acetate and ethinyl estradiol tablets with a high fat meal decreases rate but not extent of ethinyl estradiol absorption. The extent of norethindrone absorption is increased by 27 percent following administration of norethindrone acetate and ethinyl estradiol tablets with food. The full pharmacokinetic profile of norethindrone acetate and ethinyl estradiol tablets was not characterized due to assay sensitivity limitations. However, the multiple-dose pharmacokinetics were studied at a dose of 1 mg NA/10 mcg EE in 18 postmenopausal women. Mean plasma concentrations are shown below (Figure 1) and pharmacokinetic parameters are found in Table 2. Based on a population pharmacokinetic analysis, mean steady-state concentrations of norethindrone for 1 mg NA/5 mcg EE and 1/10 are slightly more than proportional to dose when compared to 0.5 mg NA/2.5 mcg EE tablets. It can be explained by higher SHBG concentrations. Mean steady-state plasma concentrations of ethinyl estradiol for the norethindrone acetate and ethinyl estradiol 0.5/2.5 tablets and norethindrone acetate and ethinyl estradiol 1/5 tablets are proportional to dose, but there is a less than proportional increase in steady-state concentrations for the NA/EE 1/10 tablet. Figure 1. Mean Steady-State (Day 87) Plasma Norethindrone and Ethinyl Estradiol Concentrations Following Continuous Oral Administration of 1 mg NA/10 mcg EE Tablets Table 2: Mean (SD) Single-Dose (Day 1) and Steady-State (Day 87) Pharmacokinetic Parameters C max = Maximum plasma concentration; T max = Time of Cmax; AUC (0-24) = Area under the plasma concentration-time curve over the dosing interval; and CL/F = Apparent oral clearance; t½ = Elimination half-life Following Administration of 1 mg NA/10 mcg EE Tablets C max t max AUC (0-24) CL/F t½ Norethindrone ng/mL hr ng.hr/mL mL/min hr Day 1 6.0 (3.3) 1.8 (0.8) 29.7 (16.5) 588 (416) 10.3 (3.7) Day 87 10.7 (3.6) 1.8 (0.8) 81.8 (36.7) 226 (139) 13.3 (4.5) Ethinyl Estradiol pg/mL hr pg.hr/mL mL/min hr Day 1 33.5 (13.7) 2.2 (1.0) 339 (113) ND ND = Not determined ND Day 87 38.3 (11.9) 1.8 (0.7) 471 (132) 383 (119) 23.9 (7.1) Based on a population pharmacokinetic analysis, average steady-state concentrations (C ss ) of norethindrone acetate and ethinyl estradiol for the norethindrone acetate and ethinyl estradiol 1/5 tablets are estimated to be 2.6 ng/mL and 11.4 pg/mL, respectively. C ss values of norethindrone and ethinyl estradiol for the norethindrone acetate and ethinyl estradiol 0.5/2.5 tablets are estimated to be 1.1 ng/mL and 5.4 ng/mL, respectively. The pharmacokinetics of ethinyl estradiol and norethindrone acetate were not affected by age, (age range 40-62 years), in the postmenopausal population studied. Figure 1 Distribution The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to SHBG and albumin. Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. Plasma protein binding of both steroids is extensive (greater than 95 percent); 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 Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. 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. A small amount of norethindrone acetate is metabolically converted to ethinyl estradiol, such that exposure to ethinyl estradiol following administration of 1 mg of norethindrone acetate is equivalent to oral administration of 2.8 mcg ethinyl estradiol. 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 Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. 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 1 mg NA/10 mcg EE tablets are approximately 13 hours and 24 hours, respectively. Use in Specific Populations No pharmacokinetic studies were conducted in specific populations, including women with renal or hepatic impairment.

20231124

5

3 DOSAGE FORMS AND STRENGTHS The following two strengths of norethindrone acetate and ethinyl estradiol tablets are available: 0.5 mg/2.5 mcg: Each round light yellow tablet contains 0.5 mg norethindrone acetate and 2.5 mcg ethinyl estradiol; debossed with N1 on one side. 1 mg/5 mcg: Each round white tablet contains 1 mg norethindrone acetate and 5 mcg ethinyl estradiol; debossed with N2 on one side. Round light yellow tablet contains 0.5 mg norethindrone acetate and 2.5 mcg ethinyl estradiol ( 3 ) Round white tablet contains 1 mg norethindrone acetate and 5 mcg ethinyl estradiol ( 3 )

Norethindrone Acetate and Ethinyl Estradiol Norethindrone Acetate and Ethinyl Estradiol Norethindrone Acetate NORETHINDRONE Ethinyl Estradiol Ethinyl Estradiol Lactose monohydrate STARCH, CORN POLYETHYLENE GLYCOL 300 Magnesium Stearate HYDROXYETHYL CELLULOSE (140 MPA.S AT 5%) .ALPHA.-TOCOPHEROL Titanium Dioxide Hypromellose, Unspecified Triacetin Polydextrose N2 Norethindrone Acetate and Ethinyl Estradiol Norethindrone Acetate and Ethinyl Estradiol Norethindrone Acetate NORETHINDRONE Ethinyl Estradiol Ethinyl Estradiol Lactose monohydrate STARCH, CORN POLYETHYLENE GLYCOL 300 Magnesium Stearate HYDROXYETHYL CELLULOSE (140 MPA.S AT 5%) .ALPHA.-TOCOPHEROL FERRIC OXIDE YELLOW FERROSOFERRIC OXIDE Talc Polyvinyl Alcohol, Unspecified Titanium Dioxide LECITHIN, SOYBEAN Light N1

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

ANDA203435

Norethindrone Acetate and Ethinyl Estradiol

Norethindrone Acetate and Ethinyl Estradiol

75834-130

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - 1 mg/5 mcg Tablet Blister Pack Carton 3 Blister Cards of 28 Tablets each. NDC 75834-130-29 Norethindrone Acetate and Ethinyl Estradiol Tablets, USP 1 mg/5 mcg Each light yellow tablet contains norethindrone acetate 1 mg and ethinyl estradiol 5 mcg. Each tablet dispenser contains 28 white tablets 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 NIVAGEN PHARMACEUTICALS PRINCIPAL DISPLAY PANEL - 1 mg/5 mcg Tablet Blister Pack Carton

Warnings and Precautions, Malignant Neoplasms (5.2) 11/2017

Distributed by: Nivagen Pharmaceuticals, Inc. Sacramento, CA 95827, USA Toll Free 1-877-977-0687 Manufactured by: Novast Laboratories Ltd. Nantong, China 226009 Iss. 08/2022 Rev D I0058

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) 17.1 Abnormal Vaginal Bleeding Inform postmenopausal women of the importance of reporting abnormal vaginal bleeding to their healthcare provider as soon as possible [ see Warnings and Precautions (5.2) ]. 17.2 Possible Serious Adverse Reactions with Estrogen Plus Progestin Therapy Inform postmenopausal women of possible serious adverse reactions of estrogen plus progestin therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions (5.1 , 5.2 , 5.3) ]. 17.3 Possible Less Serious but Common Adverse Reactions with Estrogen Plus Progestin Therapy Inform postmenopausal women of possible less serious but common adverse reactions of estrogen plus progestin therapy such as headache, breast pain and tenderness, nausea and vomiting.

14 CLINICAL STUDIES 14.1 Effects on Vasomotor Symptoms A 12-week placebo-controlled, multicenter, randomized clinical trial was conducted in 266 symptomatic women who had at least 56 moderate to severe hot flushes during the week prior to randomization. On average, patients had 12 hot flushes per day upon study entry. A total of 66 women were randomized to receive norethindrone acetate and ethinyl estradiol 1/5 and 66 women were randomized to the placebo group. Norethindrone acetate and ethinyl estradiol 1/5 was shown to be statistically better than placebo at weeks 4, and 12 for relief of the frequency of moderate to severe vasomotor symptoms (see Table 3 ). In Table 4, norethindrone acetate and ethinyl estradiol 1/5 was shown to be statistically better than placebo at weeks 4 and 12 for relief of the severity of moderate to severe vasomotor symptoms. Table 3: Mean Change from Baseline in the Number of Moderate to Severe Vasomotor Symptoms per Week-ITT Population, LOCF Visit Placebo (N=66) Norethindrone Acetate and Ethinyl Estradiol 0.5/2.5 (N=67) Norethindrone Acetate and Ethinyl Estradiol 1/5 (N=66) ITT = intent to treat; LOCF = last observation carried forward; CI = confidence interval 2 randomized subjects (1 in Placebo and 1 in norethindrone acetate and ethinyl estradiol) did not return diaries. Baseline The baseline number of moderate to severe vasomotor symptoms (MSVS) is the weekly average number of MSVS during the two week prerandomization observation period. Mean (SD) 76.5 (21.4) 77.6 (26.5) 70.0 (16.6) Week 4 Mean (SD) 39.4 (27.6) 30.2 (26.1) 20.4 (22.7) Mean Change from Baseline (SD) -37.0 (26.6) -47.4 Denotes statistical significance at the 0.05 level (26.1) -49.6 (22.1) p-Value vs. Placebo (95% CI) ANCOVA - Analysis of Covariance model where the observation variable is change from baseline; independent variables include treatment, center and baseline as covariate. The 95% CI -Mann-Whitney confidence interval for the difference between means (not stratified by center). 0.041 ( -20.0, -1.0) <0.001 ( -22.0, -6.0) Week 12 Mean (SD) 31.1 (27.0) 13.8 (20.4) 11.3 (18.9) Mean Change from Baseline (SD) -45.3 (30.2) -63.8 (27.5) -58.7 (23.1) p-Value vs. Placebo (95% CI) <0.001 ( -27.0, -7.0) <0.001 ( -25.0, -5.0) Table 4: Mean Change from Baseline in the Daily Severity Score of Moderate to Severe Vasomotor Symptoms per Week - ITT Population, LOCF Visit Placebo (N=66) Norethindrone Acetate and Ethinyl Estradiol 0.5/2.5 (N=67) Norethindrone Acetate and Ethinyl Estradiol 1/5 (N=66) ITT = intent to treat; LOCF = last observation carried forward; CI = confidence interval 2 randomized subjects (1 in Placebo and 1 in norethindrone acetate and ethinyl estradiol) did not return diaries. Baseline The baseline severity of moderate to severe vasomotor symptoms (MSVS) is the daily severity score of MSVS during the two week pre-randomization observation period. Mean (SD) 2.49 (0.26) 2.48 (0.22) 2.47 (0.23) Week 4 Mean (SD) 2.13 (0.74) 1.88 (0.89) 1.45 (1.03) Mean Change from Baseline (SD) -0.36 (0.68) -0.59 (0.83) -1.02 Denotes statistical significance at the 0.05 level (1.06) p-Value vs. Placebo (95% CI) ANCOVA - Analysis of Covariance model where the observation variable is change from baseline; independent variables include treatment, center and baseline as covariate. The 95% CI - Mann-Whitney confidence interval for the difference between means (not stratified by center). - 0.130 ( -0.3, 0.0) <0.001 ( -0.9, -0.2) Week 5 Mean (SD) 2.06 (0.79) 1.68 (0.99) 1.23 (1.03) Mean Change from Baseline (SD) -0.44 (0.74) -0.80 (0.94) -1.24 (1.07) p-Value vs. Placebo (95% CI) - 0.041 ( -0.4, -0.0) <0.001 ( -1.2, -0.3) Week 12 Mean (SD) 1.82 (1.03) 1.22 (1.11) 1.02 (1.16) Mean Change from Baseline (SD) -0.67 (1.02) -1.26 (1.08) -1.45 (1.19) p-Value vs. Placebo (95% CI) - 0.002 ( -0.9, -0.2) <0.001 ( -1.4, -0.3) 14.2 Effects on the Endometrium A 2-year, placebo-controlled, multicenter, randomized clinical trial was conducted to determine the safety and efficacy of norethindrone acetate and ethinyl estradiol on maintaining bone mineral density, protecting the endometrium, and to determine effects on lipids. A total of 1265 women were enrolled and randomized to either placebo, 0.2 mg NA/1 mcg EE, norethindrone acetate and ethinyl estradiol 0.5/2.5, norethindrone acetate and ethinyl estradiol 1/5 and 1 mg NA/10 mcg EE or matching unopposed EE doses (1, 2.5, 5, or 10 mcg) for a total of 9 treatment groups. All participants received 1000 mg of calcium supplementation daily. Of the 1265 women randomized to the various treatment arms of this study, 137 were randomized to placebo, 146 to norethindrone acetate and ethinyl estradiol 1/5, 136 to norethindrone acetate and ethinyl estradiol 0.5/2.5 and 141 to EE 5 mcg and 137 to EE 2.5 mcg. Of these, 134 placebo, 143 norethindrone acetate and ethinyl estradiol 1/5, 136 norethindrone acetate and ethinyl estradiol 0.5/2.5,139 EE 5 mcg and 137 EE 2.5 mcg had a baseline endometrial result. Baseline biopsies were classified as normal (in approximately 95% of subjects), or insufficient tissue (in approximately 5% of subjects). Follow-up biopsies were obtained in approximately 70-80% of patients in each arm after 12 and 24 months of therapy. Results for norethindrone acetate and ethinyl estradiol 1/5 and appropriate comparators are shown in Table 5. Table 5: Endometrial Biopsy Results After 12 and 24 Months of Treatment (CHART Study, 376 -359) Endometrial Status Placebo Norethindrone Acetate and Ethinyl Estradiol EE Alone 0.5/2.5 1/5 2.5 mcg 5 mcg Number of Patients Biopsied at Baseline N= 134 N=136 N= 143 N=137 N=139 MONTH 12 (% Patients) Patients Biopsied (%) 113 (84) 103 (74) 110 (77) 100 (73) 114 (82) Insufficient Tissue 30 34 45 20 20 Atrophic Tissue 60 41 41 15 2 Proliferative Tissue 23 28 24 65 91 Endometrial Hyperplasia All patients with endometrial hyperplasia were carried forward for all time points 0 0 0 0 1 MONTH 24 (% Patients) Patients Biopsied (%) 94 (70) 99 (73) 102 (71) 89 (65) 107 (77) Insufficient Tissue 35 42 37 23 17 Atrophic Tissue 38 30 33 6 2 Proliferative Tissue 20 27 32 60 86 Endometrial Hyperplasia 1 0 0 0 2 14.3 Effects on Uterine Bleeding or Spotting The cumulative incidence of amenorrhea, defined as no bleeding or spotting obtained from subject recall, was evaluated over 12 months for norethindrone acetate and ethinyl estradiol (NA/EE) 1/5 and placebo arms. Results are shown in Figure 2. Figure 2. Patients With Cumulative Amenorrhea Over Time: Intent-to-Treat Population, Last Observation Carried Forward Figure 2 14.4 Effect on Bone Mineral Density In the 2 year study, trabecular bone mineral density (BMD) was assessed at lumbar spine using quantitative computed tomography. A total of 419 postmenopausal primarily Caucasian women, aged 40 to 64 years, with intact uteri and non-osteoporotic bone mineral densities were randomized (1:1:1) to norethindrone acetate and ethinyl estradiol 1/5, norethindrone acetate and ethinyl estradiol 0.5/2.5 or placebo. Approximately 75 percent of the subjects in each group completed the two-year study. All patients received 1000 mg calcium in divided doses. Vitamin D was not supplemented. As shown in Figure 3, women treated with norethindrone acetate and ethinyl estradiol 1/5 had an average increase of 3.1percent in lumbar spine BMD from baseline to Month 24. Women treated with placebo had average decreases of –6.3 percent in spinal BMD from baseline to Month 24. The differences in the changes from baseline to Month 24 in the norethindrone acetate and ethinyl estradiol 1/5 group compared with the placebo group were statistically significant. Figure 3: Mean Percent Change (+ SE) From Baseline in Volumetric Bone Mineral Density* at Lumbar Spine Measured by Quantitative Computed Tomography after 12 and 24 Months of Treatment (Intent-to-Treat Population) *It should be noted that when measured by QCT, BMD gains and losses are greater than when measured by dual X-ray absorptiometry (DXA). Therefore, the differences in the changes in BMD between the placebo and active drug treated groups will be larger when measured by QCT compared with DXA. Changes in BMD measured by DXA should not be compared with changes in BMD measured by QCT. Figure 3 14.5 Women's Health Initiative Studies The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE plus MPA or CE-alone on menopausal symptoms. WHI Estrogen Plus Progestin Substudy The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the "global index". The absolute excess risk of events included in the "global index" was 19 per 10,000 women-years. For those outcomes included in the WHI "global index" that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other), are presented in Table 6. These results reflect centrally adjudicated data after an average follow-up of 5.6 years. Table 6. Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 years Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi , Results are based on centrally adjudicated data. Event Relative Risk CE/MPA vs placebo (95 pecent nCI Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. ) CE/MPA n = 8506 Placebo n = 8102 Absolute Risk per 10,000 Women -years CHD events 1.23 (0.99 -1.53) 41 34 Non-fatal MI 1.28 (1.00 -1.63) 31 25 CHD death 1.10 (0.70 -1.75) 8 8 All strokes 1.31 (1.03 -1.68) 33 25 Ischemic stroke 1.44 (1.09 - 1.90) 26 18 Deep vein thrombosis Not included in "global index". 1.95 (1.43 -2.67) 26 13 Pulmonary embolism 2.13 (1.45 -3.11) 18 8 Invasive breast cancer Includes metastatic and non -metastatic breast cancer with the exception of in situ cancer. 1.24 (1.01 -1.54) 41 33 Colorectal cancer 0.61 (0.42 -0.87) 10 16 Endometrial cancer 0.81 (0.48 -1.36) 6 7 Cervical cancer 1.44 (0.47 -4.42) 2 1 Hip fracture 0.67 (0.47 -0.96) 11 16 Vertebral fractures 0.65 (0.46 -0.92) 11 17 Lower arm/wrist fractures 0.71 (0.59 -0.85) 44 62 Total fractures 0.76 (0.69 -0.83) 152 199 Overall Mortality , All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 1.00 (0.83 -1.19) 52 52 Global Index A subset of the events was combined in a "global index" defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other uses. 1.13 (1.02 -1.25) 184 165 Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age, a non-significant trend toward reduced risk for overall mortality [hazard ratio (HR) 0.69 (95 percent CI, 0.44-1.07)]. WHI Estrogen-Alone Substudy The WHI estrogen-alone substudy was also stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints. Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow-up of 7.1 years, are presented in Table 7. Table 7. Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI Adapted from numerous WHI publications. WHI publications can be viewed at www.nblbi.nih.gov/whi. Event Relative Risk CE vs placebo (95 percent nCI Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. ) CE n = 5,310 Placebo n = 5,429 Absolute Risk per 10,000 Women -years CHD events Results are based on centrally adjudicated data for an average follow -up of 7.1 years. 0.95 (0.78 -1.16) 54 57 Non - fatal MI 0.91 (0.73 - 1.14) 40 43 CHD death 1.01 (0.71 - 1.43) 16 16 All strokes 1.33 (1.05 -1.68) 45 33 Ischemic stroke 1.55 (1.19 - 2.01) 38 25 Deep vein thrombosis , Not included in "global index". 1.47 (1.06 -2.06) 23 15 Pulmonary embolism 1.37 (0.90 -2.07) 14 10 Invasive breast cancer 0.80 (0.62 -1.04) 28 34 Colorectal cancer Results are based on an average follow -up of 6.8 years. 1.08 (0.75 -1.55) 17 16 Hip fracture 0.65 (0.45 -0.94) 12 19 Vertebral fractures , 0.64 (0.44 -0.93) 11 18 Lower arm/wrist fractures , 0.58 (0.47 -0.72) 35 59 Total fractures , 0.71 (0.64 -0.80) 144 197 Deaths due to other causes , All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 1.08 (0.88 -1.32) 53 50 Overall Mortality , 1.04 (0.88 -1.22) 79 75 Global Index A subset of the events was combined in a "global index" defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes. 1.02 (0.92 -1.13) 206 201 For those outcomes included in the WHI "global index" that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone were 12 more strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures. 9 The absolute excess risk of events included in the "global index" was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years (see Table 7 ). Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone therapy increased the risk of ischemic stroke, and this excess was present in all subgroups of women examined 10 (see Table 7 ). Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy stratified by age, showed in women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [HR 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)]. 14.6 Women's Health Initiative Memory Study The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age, 35 percent were 70 to 74 years of age, and 18 percent were 75 years of age and older) to evaluate the effects of CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger post-menopausal women [see Warnings and Precautions (5.3) , and Use in Specific Populations (8.5) ]. The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo. After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included AD, VaD and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.3) , and Use in Specific Populations (8.5) ]. When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.3) , and Use in Specific Populations (8.5) ].

15 REFERENCES Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA. 2007;297:1465-1477. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med. 2006;166:357-365. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004;292:1573-1580. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med. 2006;166:772-780. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003;289:3234-3253. Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women With Hysterectomy. JAMA. 2006;295:1647-1657. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures. JAMA. 2003;290:1739-1748. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:2947-2958. Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in Postmenopausal Women With Hysterectomy: Results From the Women's Health Initiative Randomized Trial. J Bone Miner Res. 2006;21:817-828. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women's Health Initiative. Circulation. 2006;113:2425-2434.

8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing norethindrone acetate and ethinyl estradiol tablets to determine whether those over 65 years of age differ from younger subjects in their response to norethindrone acetate and ethinyl estradiol tablets. The Women's Health Initiative Studies In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies (14.5) ]. In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [ see Clinical Studies (14.5) ] . The Women's Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen-alone when compared to placebo [see Warnings and Precautions (5.3) , and Clinical Studies (14.6) ]. Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [ see Warnings and Precautions (5.3) , and Clinical Studies (14.6) ].

8.3 Nursing Mothers Norethindrone acetate and ethinyl estradiol tablets should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogen and progestin have been identified in the breast milk of women receiving estrogen plus progestin therapy. Caution should be exercised when norethindrone acetate and ethinyl estradiol tablets are administered to a nursing woman.

8.4 Pediatric Use Norethindrone acetate and ethinyl estradiol tablets are not indicated in children. Clinical studies have not been conducted in the pediatric population.

8.1 Pregnancy Norethindrone acetate and ethinyl estradiol tablets should not be used during pregnancy [see Contraindications (4) ]. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.

8 USE IN SPECIFIC POPULATIONS Nursing Mothers: Estrogen administration to nursing women has been shown to decrease the quantity and quality of breast milk ( 8.3 ) Geriatric Use: An increased risk of probable dementia in women over 65 years of age was reported in the Women's Health Initiative Memory ancillary studies of the Women's Health Initiative ( 5.3 , 8.5 ) 8.1 Pregnancy Norethindrone acetate and ethinyl estradiol tablets should not be used during pregnancy [see Contraindications (4) ]. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy. 8.3 Nursing Mothers Norethindrone acetate and ethinyl estradiol tablets should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogen and progestin have been identified in the breast milk of women receiving estrogen plus progestin therapy. Caution should be exercised when norethindrone acetate and ethinyl estradiol tablets are administered to a nursing woman. 8.4 Pediatric Use Norethindrone acetate and ethinyl estradiol tablets are not indicated in children. Clinical studies have not been conducted in the pediatric population. 8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing norethindrone acetate and ethinyl estradiol tablets to determine whether those over 65 years of age differ from younger subjects in their response to norethindrone acetate and ethinyl estradiol tablets. The Women's Health Initiative Studies In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies (14.5) ]. In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [ see Clinical Studies (14.5) ] . The Women's Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen-alone when compared to placebo [see Warnings and Precautions (5.3) , and Clinical Studies (14.6) ]. Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [ see Warnings and Precautions (5.3) , and Clinical Studies (14.6) ]. 8.6 Renal Impairment The effect of renal impairment on the pharmacokinetics of norethindrone acetate and ethinyl estradiol tablets have not been studied. 8.7 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of norethindrone acetate and ethinyl estradiol tablets have not been studied.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Norethindrone acetate and ethinyl estradiol tablets are available in the following strength and package sizes: 1. 75834-129-84 Blister card of 28 round light yellow tablets with 0.5 mg norethindrone acetate and 2.5 mcg ethinyl estradiol 2. 75834-129-29 Carton containing 3 × 28 tablet blister cards each in a plastic compact. Each blister card contains 28 round light yellow tablets with 0.5 mg norethindrone acetate and 2.5 mcg ethinyl estradiol 3. 75834-129-90 Bottle of 90 round light yellow tablets with 0.5 mg norethindrone acetate and 2.5 mcg ethinyl estradiol 4. 75834-130-84 Blister card of 28 round white tablets with 1 mg norethindrone acetate and 5 mcg ethinyl estradiol 5. 75834-130-29 Carton containing 3 × 28 tablet blister cards each in a plastic compact. Each blister card contains 28 round white tablets with 1 mg norethindrone acetate and 5 mcg ethinyl estradiol 6. 75834-130-90 Bottle of 90 round white tablets with 1 mg norethindrone acetate and 5 mcg ethinyl estradiol. 16.2 Storage and Handling Store at 20º-25º C (68º-77º F); excursions permitted to 15 to 30º C (59 to 86º F) [see USP Controlled Room Temperature].

16.2 Storage and Handling Store at 20º-25º C (68º-77º F); excursions permitted to 15 to 30º C (59 to 86º F) [see USP Controlled Room Temperature].

WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER AND PROBABLE DEMENTIA WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER AND PROBABLE DEMENTIA See full prescribing information for complete boxed warning. Estrogen Plus Progestin Therapy Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia ( 5.1 , 5.3 ) The Women's Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of stroke, deep vein thrombosis (DVT), pulmonary embolism (PE), and myocardial infarction (MI) ( 5.1 ) The WHI estrogen plus progestin substudy reported an increased risk of invasive breast cancer ( 5.2 ) The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older ( 5.3 ) Estrogen-Alone Therapy There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens ( 5.2 ) Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia ( 5.1 , 5.3 ) The WHI estrogen-alone substudy reported increased risks of stroke and DVT ( 5.1 ) The WHIMS estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older ( 5.3 ) Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1 , 5.3) , and Clinical Studies (14.5 , 14.6) ] . The Women's Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [ see Warnings and Precautions (5.1) , and Clinical Studies (14.5) ] . The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3) , Use in Specific Populations (8.5) , and Clinical Studies (14.6) ] . Breast Cancer The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.2) , and Clinical Studies (14.5) ] . In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. Estrogen-Alone Therapy Endometrial Cancer There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.2) ] . Cardiovascular Disorders and Probable Dementia Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1 , 5.3) , and Clinical Studies (14.5 , 14.6) ] . The WHI estrogen-alone substudy reported increased risks of stroke and DVT in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral CE (0.625 mg)-alone, relative to placebo [ see Warnings and Precautions (5.1) , and Clinical Studies (14.5) ] . The WHIMS estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3) , Use in Specific Populations (8.5) , and Clinical Studies (14.6) ] . In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.