Fyavolv

6 ADVERSE REACTIONS The most common adverse reactions with Fyavolv (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 Lupin Pharmaceuticals, Inc. at 1-800-399-2561, or FDA at 1-800-FDA-1088 or www.fda.gov/Medwatch . 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 )] . 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 women in controlled clinical studies of norethindrone acetate and ethinyl estradiol are shown in Table 1. Table 1. Associated Adverse Reactions Reported by ≥5 Percent of Women by Body System* * The total number of women for each body system may be less than the number of women with AEs in that body system because a woman may have had more than one AE per body system BODY SYSTEM/ Adverse Reaction Number (Percent) of Subjects Placebo N = 247 Norethindrone Acetate and Ethinyl Estradiol 0.5/2.5 N = 244 Norethindrone Acetate and Ethinyl Estradiol 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. 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 Undiagnosed abnormal genital bleeding ( 4 , 5.2 ) Breast cancer or a history of breast cancer ( 4 , 5.2 ) 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, angioedema, or hypersensitivity to Fyavolv ( 4 ) Hepatic impairment or disease ( 4 , 5.10 ) Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders ( 4 ) Fyavolv is contraindicated in women with any of the following conditions: Undiagnosed abnormal genital bleeding [see Warnings and Precautions ( 5.2 )] . Breast cancer or a history of breast cancer [see Warnings and Precautions ( 5.2 )] . Estrogen-dependent neoplasia [see Warnings and Precautions ( 5.2 )] . Active DVT, PE or a history of these conditions [see Warnings and Precautions ( 5.1 )] . Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions [see Warnings and Precautions ( 5.1 )] . Known anaphylactic reaction, angioedema, or hypersensitivity to Fyavolv . Hepatic impairment or disease. Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders.

11 DESCRIPTION Fyavolv (norethindrone acetate and ethinyl estradiol tablets USP) is a continuous dosage regimen of a progestin-estrogen combination for oral administration. The following strength of Fyavolv tablets is available: Fyavolv (0.5 mg/0.0025 mg): Each white to off-white, round film-coated tablet, debossed with "F51" on one side and "LU" on the other side contains 0.5 mg norethindrone acetate and 0.0025 mg ethinyl estradiol. Fyavolv (1 mg/0.005 mg): Each blue, round film-coated tablet, debossed with "F52" on one side and "LU" on the other side contains 1 mg norethindrone acetate and 0.005 mg ethinyl estradiol. Each tablet contains the following inactive ingredients: calcium stearate, corn starch, hypromellose, lactose monohydrate, microcrystalline cellulose, polyethylene glycol 400, titanium dioxide and vitamin E. Each tablet of 1 mg/0.005 mg also contains FD&C Blue No. 2 Aluminum Lake. The structural formulas are as follows. Ethinyl Estradiol [19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-] Molecular Weight: 296.40 Molecular Formula: C 20 H 24 O 2 Norethindrone Acetate [19-Norpregn-4-en-20-yn-3-one, 17-(acetyloxy)-, (17α)-] Molecular Weight: 340.46 Molecular Formula: C 22 H 28 O 3 Figure 1 Figure 2

2 DOSAGE AND ADMINISTRATION One tablet orally once daily ( 2.1 , 2.2 ) Use estrogen, alone or in combination with a progestogen, at the lowest effective dose and the shortest duration consistent with treatment goals and risks for the individual woman. Re-evaluate postmenopausal women periodically as clinically appropriate to determine whether treatment is still necessary. 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Take a single Fyavolv tablet, orally once daily. 2.2 Prevention of Postmenopausal Osteoporosis Take a single Fyavolv tablet, orally once daily.

1 INDICATIONS AND USAGE Fyavolv is a combination of an estrogen and 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, first consider the use of non-estrogen medications. Consider estrogen therapy only for women at significant risk of osteoporosis.

10 OVERDOSAGE Overdosage of estrogen plus progestogen 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 Fyavolv therapy with institution of appropriate symptomatic care.

7 DRUG INTERACTIONS Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration. ( 7.1 ) 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 and progestin 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 and progestins, 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 the estrogen or the progestin or both and may result in adverse reactions. 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. 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 Generally, a serum estrogen concentration does not predict an individual woman's therapeutic response to norethindrone acetate and ethinyl estradiol nor her risk for adverse outcomes. Likewise, exposure comparisons across different estrogen products to infer efficacy or safety for the individual woman may not be valid. 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 tablet 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 tablet was not characterized due to assay sensitivity limitations. However, the multiple-dose pharmacokinetics were studied at a dose of 1 mg norethindrone acetate and 0.01 mg ethinyl estradiol 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 norethindrone acetate and 0.005 mg ethinyl estradiol and 1/10 are slightly more than proportional to dose when compared to 0.5 mg norethindrone acetate and 0.0025 mg ethinyl estradiol 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 norethindrone acetate and ethinyl estradiol 1/10 tablet. Figure 1. Mean Steady-State (Day 87) Plasma Norethindrone and Ethinyl Estradiol Concentrations Following Continuous Oral Administration of 1 mg Norethindrone Acetate and 0.01 mg Ethinyl Estradiol Tablets Table 2. Mean (SD) Single-Dose (Day 1) and Steady-State (Day 87) Pharmacokinetic Parameters† Following Administration of 1 mg Norethindrone Acetate and 0.01 mg Ethinyl Estradiol Tablets † C max = Maximum plasma concentration; t max = time of C max ; AUC (0-24) = Area under the plasma concentration-time curve over the dosing interval; and CL/F = Apparent oral clearance; t ½ = Elimination half-life ‡ ND = Not determined C max t max AUC (0-24) CL/F t ½ 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 pg/mL hr pg·hr/mL mL/min hr Estradiol Day 1 33.5 (13.7) 2.2 (1.0) 339 (113) ND ‡ 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 (Css) of norethindrone and ethinyl estradiol for norethindrone acetate and ethinyl estradiol 1/5 tablets are estimated to be 2.6 ng/mL and 11.4 pg/mL, respectively. Css values of norethindrone and ethinyl estradiol for 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 to 62 years), in the postmenopausal population studied. 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 norethindrone acetate and 0.01 mg ethinyl estradiol tablets are approximately 13 hours and 24 hours, respectively. Figure 3 Figure 4

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 Generally, a serum estrogen concentration does not predict an individual woman's therapeutic response to norethindrone acetate and ethinyl estradiol nor her risk for adverse outcomes. Likewise, exposure comparisons across different estrogen products to infer efficacy or safety for the individual woman may not be valid.

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 tablet 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 tablet was not characterized due to assay sensitivity limitations. However, the multiple-dose pharmacokinetics were studied at a dose of 1 mg norethindrone acetate and 0.01 mg ethinyl estradiol 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 norethindrone acetate and 0.005 mg ethinyl estradiol and 1/10 are slightly more than proportional to dose when compared to 0.5 mg norethindrone acetate and 0.0025 mg ethinyl estradiol 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 norethindrone acetate and ethinyl estradiol 1/10 tablet. Figure 1. Mean Steady-State (Day 87) Plasma Norethindrone and Ethinyl Estradiol Concentrations Following Continuous Oral Administration of 1 mg Norethindrone Acetate and 0.01 mg Ethinyl Estradiol Tablets Table 2. Mean (SD) Single-Dose (Day 1) and Steady-State (Day 87) Pharmacokinetic Parameters† Following Administration of 1 mg Norethindrone Acetate and 0.01 mg Ethinyl Estradiol Tablets † C max = Maximum plasma concentration; t max = time of C max ; AUC (0-24) = Area under the plasma concentration-time curve over the dosing interval; and CL/F = Apparent oral clearance; t ½ = Elimination half-life ‡ ND = Not determined C max t max AUC (0-24) CL/F t ½ 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 pg/mL hr pg·hr/mL mL/min hr Estradiol Day 1 33.5 (13.7) 2.2 (1.0) 339 (113) ND ‡ 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 (Css) of norethindrone and ethinyl estradiol for norethindrone acetate and ethinyl estradiol 1/5 tablets are estimated to be 2.6 ng/mL and 11.4 pg/mL, respectively. Css values of norethindrone and ethinyl estradiol for 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 to 62 years), in the postmenopausal population studied. 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 norethindrone acetate and 0.01 mg ethinyl estradiol tablets are approximately 13 hours and 24 hours, respectively.

20231129

14

3 DOSAGE FORMS AND STRENGTHS Tablet: 0.5 mg norethindrone acetate and 0.0025 mg ethinyl estradiol ( 3 ) Tablet: 1 mg norethindrone acetate and 0.005 mg ethinyl estradiol ( 3 ) The following two strengths of Fyavolv tablets are available: Fyavolv tablets, (0.5 mg/0.0025 mg): Each are white to off-white, round film-coated tablet, debossed with "F51" on one side and "LU" on the other side contains 0.5 mg norethindrone acetate and 0.0025 mg ethinyl estradiol. Fyavolv tablets, (1 mg/0.005 mg): Each are blue, round film-coated tablet, debossed with "F52" on one side and "LU" on the other side contains 1 mg norethindrone acetate and 0.005 mg ethinyl estradiol.

Fyavolv Norethindrone Acetate and Ethinyl Estradiol ETHINYL ESTRADIOL ETHINYL ESTRADIOL NORETHINDRONE ACETATE NORETHINDRONE CALCIUM STEARATE CELLULOSE, MICROCRYSTALLINE HYPROMELLOSES LACTOSE MONOHYDRATE POLYETHYLENE GLYCOL 400 STARCH, CORN TITANIUM DIOXIDE TOCOPHEROL white to off-white round LU;F51 Fyavolv Norethindrone Acetate and Ethinyl Estradiol ETHINYL ESTRADIOL ETHINYL ESTRADIOL NORETHINDRONE ACETATE NORETHINDRONE CALCIUM STEARATE CELLULOSE, MICROCRYSTALLINE FD&C BLUE NO. 2 HYPROMELLOSES LACTOSE MONOHYDRATE POLYETHYLENE GLYCOL 400 STARCH, CORN TITANIUM DIOXIDE TOCOPHEROL Blue round LU;F52

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.

ANDA204213

Fyavolv

Norethindrone Acetate and Ethinyl Estradiol

68180-828

HUMAN PRESCRIPTION DRUG

ORAL

5.17 Laboratory Tests Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of postmenopausal women with moderate to severe vasomotor symptoms.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Fyavolv™ (norethindrone and ethinyl estradiol tablets USP) 0.5 mg/0.0025 mg Rx Only Wallet and Pouch Label: 28 Tablets - NDC 68180-827-11 Carton Label: 3 Wallets of 28 Tablets Each - NDC 68180-827-13 Fyavolv™ (norethindrone and ethinyl estradiol tablets USP) 0.5 mg/0.0025 mg Rx Only NDC 68180-827-09 Bottle Label: 90 Tablets Fyavolv™ (norethindrone and ethinyl estradiol tablets USP) 1 mg/0.005 mg Rx Only Wallet and Pouch Label: 28 Tablets - NDC 68180-828-11 Carton Label: 3 Wallets of 28 Tablets Each - NDC 68180-828-13 Fyavolv™ (norethindrone and ethinyl estradiol tablets USP) 1 mg/0.005 mg Rx Only NDC 68180-828-09 Bottle Label: 90 Tablets Fyavolv™ (norethindrone and ethinyl estradiol tablets USP) 0.5 mg/0.0025 mg Rx Only Blister and Pouch Label: 28 Tablets - NDC 68180-827-71 Carton Label: 3 Blister of 28 Tablets Each - NDC 68180-827-73 Fyavolv™ (norethindrone and ethinyl estradiol tablets USP) 1 mg/0.005 mg Rx Only Blister and Pouch Label: 28 Tablets - NDC 68180-828-71 Carton Label: 3 Blister of 28 Tablets Each - NDC 68180-828-73 Fyavolv (norethindrone and ethinyl estradiol tablets USP) 0.5 mg/0.0025 mg Rx Only NDC 68180-827-13 Wallet Label: 28 Tablets Fyavolv (norethindrone and ethinyl estradiol tablets USP) 0.5 mg/0.0025 mg Rx Only NDC 68180-827-13 Pouch Label: 1 Wallet of 28 Tablets Fyavolv (norethindrone and ethinyl estradiol tablets USP) 0.5 mg/0.0025 mg Rx Only NDC 68180-827-13 Carton Label: 3 Wallets of 28 Tablets Each Bottle label Fyavolv (norethindrone and ethinyl estradiol tablets USP) 1 mg/0.005 mg Rx Only NDC 68180-828-13 Wallet Label: 28 Tablets Fyavolv (norethindrone and ethinyl estradiol tablets USP) 1 mg/0.005 mg Rx Only NDC 68180-828-13 Pouch Label: 1 Wallet of 28 Tablets Fyavolv (norethindrone and ethinyl estradiol tablets USP) 1 mg/0.005 mg Rx Only NDC 68180-828-13 Carton Label: 3 Wallets of 28 Tablets Each Bottle label Blister Label: 28 Tablets - NDC 68180-827-71 Pouch Label: 28 Tablets - NDC 68180-827-71 Carton Label: 3 Blister of 28 Tablets Each - NDC 68180-827-73 Blister Label: 28 Tablets - NDC 68180-828-71 Pouch Label: 28 Tablets - NDC 68180-828-71 Carton Label: 3 Blister of 28 Tablets Each - NDC 68180-828-73

RECENT MAJOR CHANGES Boxed Warning 5/2023 Warnings and Precautions, Malignant Neoplasms ( 5.2 ) 11/2023

17 PATIENT COUNSELING INFORMATION Advise women to read the FDA-approved patient labeling (Patient Information) Vaginal Bleeding Inform postmenopausal women to report any vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions ( 5.2 )] . Possible Serious Adverse Reactions with Estrogen Plus Progestogen Therapy Inform postmenopausal women of possible serious adverse reactions of estrogen plus progestogen therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 )] . Possible Common Adverse Reactions with Estrogen Plus Progestogen Therapy Inform postmenopausal women of possible less serious but common adverse reactions of estrogen plus progestogen therapy such as headache, breast pain and tenderness, nausea and vomiting. Distributed by: Lupin Pharmaceuticals, Inc. Baltimore, Maryland 21202 United States Manufactured by: Lupin Limited Pithampur (M.P.) - 454 775 India Revised: December 2023

14 CLINICAL STUDIES 14.1 Effects on Vasomotor Symptoms in Postmenopausal Women 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, women 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 è Denotes statistical significance at the 0.05 level [1] The baseline number of moderate to severe vasomotor symptoms (MSVS) is the weekly average number of MSVS during the two week pre-randomization observation period. [2] ANCOVA -Analysis of Covariance model where the observation variable is change from baseline; independent variables include treatment, center and baseline as covariate. The 95 percent CI -Mann-Whitney confidence interval for the difference between means (not stratified by center). ITT = intent to treat; LOCF = last observation carried forward; CI = confidence interval 2 randomized women (1 in Placebo and 1 in norethindrone acetate and ethinyl estradiol) did not return diaries. Visit Placebo (N = 66) Norethindrone Acetate and Ethinyl Estradiol 0.5/2.5 (N = 67) Norethindrone Acetate and Ethinyl Estradiol 1/5 (N = 66) Baseline [1] Mean (SD) 76.5 (21.4) 77.6 (26.5) 70.0 (16.6) Week 4 Mean (SD) Mean Change from Baseline (SD) p-Value vs. Placebo (95 percent CI) [2] 39.4 (27.6) -37.0 (26.6) 30.2 (26.1) -47.4 è (26.1) 0.041 (-20.0, -1.0) 20.4 (22.7) -49.6 è (22.1) <0.001 (-22.0,-6.0) Week 12 Mean (SD) Mean Change from Baseline (SD) 31.1 (27.0) -45.3 (30.2) 13.8 (20.4) -63.8 è (27.5) 11.3 (18.9) -58.7 è (23.1) p-Value vs. Placebo (95 percent CI) [2] <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 ¥ Denotes statistical significance at the 0.05 level [1] 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. [2] ANCOVA -Analysis of Covariance model where the observation variable is change from baseline; independent variables include treatment, center and baseline as covariate. The 95 percent CI -Mann-Whitney confidence interval for the difference between means (not stratified by center). ITT = intent to treat; LOCF = last observation carried forward; CI = confidence interval 2 randomized women (1 in Placebo and 1 in norethindrone acetate and ethinyl estradiol) did not return diaries. Visit Placebo (N = 66) Norethindrone Acetate and Ethinyl Estradiol 0.5/2.5 (N = 67) Norethindrone Acetate and Ethinyl Estradiol 1/5 (N = 66) Baseline [1] Mean (SD) 2.49 (0.26) 2.48 (0.22) 2.47 (0.23) Week 4 Mean (SD) Mean Change from Baseline (SD) p-Value vs. Placebo (95 percent CI) [2] 2.13 (0.74) -0.36 (0.68) - 1.88 (0.89) -0.59 (0.83) 0.130 (-0.3, 0.0) 1.45 (1.03) -1.02 ¥ (1.06) <0.001 (-0.9, -0.2) Week 5 Mean (SD) Mean Change from Baseline (SD) p-Value vs. Placebo (95 percent CI) [2] 2.06 (0.79) -0.44 (0.74) 1.68 (0.99) -0.80 ¥ (0.94) 0.041 (-0.4, -0.0) 1.23 (1.03) -1.24 ¥ (1.07) <0.001 (-1.2, -0.3) Week 12 Mean (SD) Mean Change from Baseline (SD) p-Value vs. Placebo (95 percent CI) [2] 1.82 (1.03) -0.67 (1.02) - 1.22 (1.11) -1.26 ¥ (1.08) 0.002 (-0.9, -0.2) 1.02 (1.16) -1.45 ¥ (1.19) <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 1,265 women were enrolled and randomized to either placebo, 0.2 mg norethindrone acetate/1 mcg ethinyl estradiol (NA/EE 0.2/1), 0.5 mg norethindrone acetate/2.5 mcg ethinyl estradiol (NA/EE 0.5/2.5), norethindrone acetate and ethinyl estradiol 1/5 and 1 mg norethindrone acetate/10 mcg ethinyl estradiol (NA/EE 1/10) 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 1,265 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/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/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 percent of subjects), or insufficient tissue (in approximately 5 percent of subjects). Follow-up biopsies were obtained in approximately 70 to 80 percent 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 to 359) *All patients with endometrial hyperplasia were carried forward for all time points. 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 (Percent Patients) Patients Biopsied (percent) 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* 0 0 0 0 1 MONTH 24 (Percent Patients) Patients Biopsied (percent) 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 in Postmenopausal Women The cumulative incidence of amenorrhea, defined as no bleeding or spotting obtained from participant recall, was evaluated over 12 months for norethindrone acetate and ethinyl estradiol 1/5 and placebo arms. Results are shown in Figure 2 . Figure 2. Participants with Cumulative Amenorrhea Over Time: Intent-to-Treat Population, Last Observation Carried Forward 14.4 Effect on Bone Mineral Density in Postmenopausal Women In the 2 year study, trabecular BMD was assessed at lumbar spine using quantitative computed tomography. A total of 419 postmenopausal primarily Caucasian women, 40 to 64 years of age, 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 women in each group completed the two-year study. All women 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 3.1 percent 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 was statistically significant. *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. 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 1,2 1 Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. 2 Results are based on centrally adjudicated data. 3 Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. 4 Not included in "global index". 5 Includes metastic and non-metastic breast cancer with the exception of in situ cancer. 6 All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 7 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. Event Relative Risk CE/MPA vs. Placebo (95 percent nCI 3 ) CE/MPA n = 8,506 Placebo n = 8,102 Absolute Risk per 10,000 Women-Years CHD events 1.23 (0.99 to 1.53) 41 34 Non-fatal MI 1.28 (1.00 to 1.63) 31 25 CHD death 1.10 (0.70 to 1.75) 8 8 All strokes 1.31 (1.03 to 1.68) 33 25 Ischemic stroke Deep vein thrombosis 4 1.44 (1.09 to 1.90) 1.95 (1.43 to 2.67) 26 26 18 13 Pulmonary embolism 2.13 (1.45 to 3.11) 18 8 Invasive breastcancer 5 1.24 (1.01 to 1.54) 41 33 Colorectal cancer Endometrial cancer 4 Cervical cancer 4 0.61 (0.42 to 0.87) 0.81 (0.48 to 1.36) 1.44 (0.47 to 4.42) 10 6 2 16 7 1 Hip fracture Vertebral fractures 4 0.67 (0.47 to 0.96) 0.65 (0.46 to 0.92) 11 11 16 17 Lower arm/wrist fractures 4 0.71 (0.59 to 0.85) 44 62 Total fractures 4 Overall Mortality 3,6 0.76 (0.69 to 0.83) 1.00 (0.83 to 1.19) 152 52 199 52 Global Index 7 1.13 (1.02 to 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 to 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. Œ Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. œ Results are based on centrally adjudicated data for an average follow-up of 7.1 years. Ɖ Not included in "global index". * Results are based on an average follow-up of 6.8 years. † All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. ‡ 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. Event Relative Risk CE vs Placebo (95 percent nCI Œ ) CE N = 5,310 Placebo n = 5,429 Absolute Risk per 10,000 Women-Years CHD events œ 0.95 (0.78 to 1.16) 54 57 Non-fatal MI œ 0.91 (0.73 to 1.14) 40 42 CHD death œ 1.01 (0.71 to 1.43) 16 16 All strokes œ 1.33 (1.05 to 1.68) 45 33 Ischemic stroke œ 1.55 (1.19 to 2.01) 38 25 Deep vein thrombosis œ Ɖ 1.47 (1.06 to 2.06) 23 15 Pulmonary embolism œ 1.37 (0.90 to 2.07) 14 10 Invasive breast 0.80 (0.62 to 1.04) 28 34 cancer œ Colorectal cancer * 1.08 (0.75 to 1.55) 17 16 Hip fracture œ 0.65 (0.45 to 0.94) 12 19 Vertebral fractures œ Ɖ 0.64 (0.44 to 0.93) 11 18 Lower arm/wrist fractures œ Ɖ 0.58 (0.47 to 0.72) 35 59 Total fractures œ Ɖ 0.71 (0.64 to 0.80) 144 197 Deaths due to other causes * † 1.08 (0.88 to 1.32) 53 50 Overall Mortality œ Ɖ 1.04 (0.88 to 1.22) 79 75 Global Index ‡ 1.02 (0.92 to 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 to 1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46 to 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 to 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 postmenopausal 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 and older (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 to 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 to 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 )] . Figure 5 Figure 6

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 to determine whether those over 65 years of age differ from younger subjects in their response to norethindrone acetate and ethinyl estradiol. 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 )] .

8.2 Lactation Risk Summary Estrogens plus progestogens are present in human milk and can reduce milk production in breastfeeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well-established. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for norethindrone acetate and ethinyl estradiol and any potential adverse effects on the breastfed child from norethindrone acetate and ethinyl estradiol or from the underlying maternal condition.

8.4 Pediatric Use Norethindrone acetate and ethinyl estradiol is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population.

8.1 Pregnancy Risk Summary Norethindrone acetate and ethinyl estradiol is not indicated for use in pregnancy. There are no data with the use of norethindrone acetate and ethinyl estradiol in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined (estrogens and progestins) product before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Norethindrone acetate and ethinyl estradiol is not indicated for use in pregnancy. There are no data with the use of norethindrone acetate and ethinyl estradiol in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined (estrogens and progestins) product before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 8.2 Lactation Risk Summary Estrogens plus progestogens are present in human milk and can reduce milk production in breastfeeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well-established. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for norethindrone acetate and ethinyl estradiol and any potential adverse effects on the breastfed child from norethindrone acetate and ethinyl estradiol or from the underlying maternal condition. 8.4 Pediatric Use Norethindrone acetate and ethinyl estradiol is not indicated for use in pediatric patients. 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 to determine whether those over 65 years of age differ from younger subjects in their response to norethindrone acetate and ethinyl estradiol. 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 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Fyavolv 0.5 mg/0.0025 mg are white to off-white, round film-coated tablets, debossed with "F51" on one side and "LU" on the other side, containing 0.5 mg of norethindrone acetate and 0.0025 mg of ethinyl estradiol. Fyavolv 0.5 mg/0.0025 mg are available in bottle of 90 tablets (NDC 68180-827-09) and in a blister (NDC 68180-827-71) containing 28 tablets enclosed in a pouch, such 3 pouches are packed in a carton (NDC 68180-827-73). Fyavolv 1 mg/0.005 mg are blue, round film-coated tablets, debossed with "F52" on one side and "LU" on the other side, containing 1 mg of norethindrone acetate and 0.005 mg of ethinyl estradiol. Fyavolv 1 mg/0.005 mg are available in bottle of 90 tablets (NDC 68180-828-09) and in a blister (NDC 68180-828-71) containing 28 tablets enclosed in a pouch, such 3 pouches are packed in a carton (NDC 68180-828-73). 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

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

WARNING: CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, BREAST CANCER, and ENDOMETRIAL CANCER WARNING: CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, BREAST CANCER, and ENDOMETRIAL CANCER See full prescribing information for complete boxed warning. Estrogen Plus Progestin Therapy The Women's Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of pulmonary embolism (PE), deep vein thrombosis (DVT), stroke, and myocardial infarction (MI) ( 5.1 ) The WHI estrogen plus progestin substudy reported 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 ) Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia ( 5.1 , 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 ) 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 ) Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia ( 5.1 , 5.3 ) Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia The Women's Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of pulmonary embolism (PE), deep vein thrombosis (DVT), 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 WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and 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 )] . Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions ( 5.1 , 5.3 ), and Clinical Studies ( 14.5 , 14.6 )] . Breast Cancer The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions ( 5.2 ) and Clinical Studies ( 14.5 )] . Once daily oral 0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events, dementia and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestogen products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen plus progestogen therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestogens 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 progestogen to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, 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 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 and 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 )]. Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia [see Warnings and Precautions ( 5.1 , 5.3 ), and Clinical Studies ( 14.5 , 14.6 )]. Only daily oral 0.625 mg CE was studied in the estrogen-alone substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen-alone products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen-alone therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.