Fyavolv

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

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.

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.

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.

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.

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/anaph …

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.

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 )] .

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.

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

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.

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].