Estradiol and Norethindrone Acetate

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

1 INDICATIONS AND USAGE Estradiol and norethindrone acetate tablets are an estrogen and progestin combination indicated in a woman with a uterus for: Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause ( 1.1 ) Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause ( 1.2 ) Limitations of Use: When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause, first consider the use of topical vaginal products. Prevention of Postmenopausal Osteoporosis ( 1.3 ) Limitations 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. Estradiol and norethindrone acetate tablets are indicated for: 1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause 1.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause Limitation of Use When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause, first consider the use of topical vaginal products. 1.3 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 Take a single estradiol and norethindrone acetate 1 mg/0.5 mg or 0.5 mg/0.1 mg tablet orally once daily for the Treatment of Moderate to severe Vasomotor Symptoms due to Menopause and for the Prevention of Postmenopausal Osteoporosis ( 2.1 , 2.3 ) Estradiol and norethindrone acetate 1 mg/0.5 mg tablets are taken orally once daily for the Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause ( 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. Reevaluate 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 estradiol and norethindrone acetate tablet orally once daily for the treatment of moderate to severe vasomotor symptoms due to menopause. Estradiol and norethindrone acetate tablets 1 mg/0.5 mg Estradiol and norethindrone acetate tablets 0.5 mg/0.1 mg 2.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause Take a single estradiol and norethindrone acetate tablet orally once daily for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. Estradiol and norethindrone acetate tablets 1 mg/0.5 mg 2.3 Prevention of Postmenopausal Osteoporosis Take a single estradiol and norethindrone acetate tablet orally once daily for the prevention of postmenopausal osteoporosis. Estradiol and norethindrone acetate tablets 1 mg/0.5 mg Estradiol and norethindrone acetate tablets 0.5 mg/0.1 mg

3 DOSAGE FORMS AND STRENGTHS Estradiol and norethindrone acetate 1 mg/0.5 mg tablet ( 3 ) Estradiol and norethindrone acetate 0.5 mg/0.1 mg tablet ( 3 ) Estradiol and norethindrone acetate tablets, USP are available in two strengths: Each tablet of estradiol and norethindrone acetate 1 mg/ 0.5 mg contains 1 mg of estradiol and 0.5 mg of norethindrone acetate. The tablets are yellow, round, bi-convex tablets debossed "J2" on one side. Each tablet of estradiol and norethindrone acetate 0.5 mg/ 0.1 mg contains 0.5 mg of estradiol and 0.1 mg of norethindrone acetate. The tablets are pale yellow, round, bi-convex tablets debossed "J1" on one side.

4 CONTRAINDICATIONS Undiagnosed abnormal genital bleeding ( 4 ) 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 estradiol and norethindrone acetate tablets ( 4 ) Hepatic impairment or disease ( 4 , 5.10 ) Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders ( 4 ) Estradiol and norethindrone acetate tablets are contraindicated in women with any of the following conditions: • Undiagnosed abnormal genital bleeding [ see Warnings and Precautions ( 5.2 ) ] • Breast cancer or history of breast cancer [ see Warnings and Precautions ( 5.2 ) ] • Estrogen-dependent neoplasia [ see Warnings and Precautions ( 5.2 ) ] • Active DVT, PE, or 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 estradiol and norethindrone acetate tablets • Hepatic impairment or disease • Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders

6 ADVERSE REACTIONS The most common adverse reactions (incidence ≥ 5 percent) with Estradiol and Norethindrone acetate tablets are: back pain, headache, pain in the extremity, nausea, diarrhea, gastroenteritis, insomnia, emotional lability, upper respiratory tract infection, sinusitis, nasopharyngitis, weight increase, breast pain, post-menopausal bleeding, uterine fibroid vaginal hemorrhage, ovarian cyst, endometrial thickening, viral infection, moniliasis genital, and accidental injury. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact 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 with estradiol and norethindrone acetate tablets 1 mg/0.5 mg by investigators during clinical trials regardless of causality assessment are shown in Table 1. Table 1: All Treatment-Emergent Adverse Reactions Regardless of Relationship Reported at a Frequency of ≥ 5 Percent with Estradiol and Norethindrone Acetate Tablets 1 mg/0.5 mg Endometrial Hyperplasia Study (12-Months) Vasomotor Symptoms Study (3-Months) Osteoporosis Study (2-Years) Estradiol and Norethindrone Acetate Tablets 1 mg/0.5 mg (n=295) 1 mg E 2 (n=296) Estradiol and Norethindrone Acetate Tablets 1 mg/0.5 mg (n=29) Placebo (n=34) Estradiol and Norethindrone Acetate Tablets 1 mg/0.5 mg (n=47) Placebo (n=48) Body as a Whole Back Pain 6% 5% 3% 3% 6% 4% Headache 16% 16% 17% 18% 11% 6% Digestive System Nausea 3% 5% 10% 0% 11% 0% Gastroenteritis 2% 2% 0% 0% 6% 4% Nervous System Insomnia 6% 4% 3% 3% 0% 8% Emotional Lability 1% 1% 0% 0% 6% 0% Respiratory System Upper Respiratory Tract Infection 18% 15% 10% 6% 15% 19% Sinusitis 7% 11% 7% 0% 15% 10% Metabolic and Nutritional Weight Increase 0% 0% 0% 0% 9% 6% Urogenital System Breast Pain 24% 10% 21% 0% 17% 8% Post-Menopausal Bleeding 5% 15% 10% 3% 11% 0% Uterine Fibroid 5% 4% 0% 0% 4% 8% Ovarian Cyst 3% 2% 7% 0% 0% 8% Resistance Mechanism Infection Viral 4% 6% 0% 3% 6% 6% Moniliasis Genital 4% 7% 0% 0% 6% 0% Secondary Terms Injury Accidental 4% 3% 3% 0% 17% including one upper extremity fracture in each group 4% Other Events 2% 3% 3% 0% 6% 4% Adverse reactions reported with estradiol and norethindrone acetate tablets 0.5 mg/0.1 mg by investigators during clinical trials regardless of causality assessment are shown in Table 2. Table 2: All Treatment-Emergent Adverse Reactions Regardless of Relationship Reported at a Frequency of ≥ 5 Percent with Estradiol and Norethindrone Acetate Tablets 0.5 mg/0.1 mg Estradiol and Norethindrone Acetate Tablets 0.5 mg/0.1 mg (n=194) Placebo (n=200) Body as a Whole Back Pain 10% 4% Headache 22% 19% Pain in extremity 5% 4% Digestive System Nausea 5% 4% Diarrhea 6% 6% Respiratory System Nasopharyngitis 21% 18% Urogenital System Endometrial thickening 10% 4% Vaginal hemorrhage 26% 12% 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of estradiol and norethindrone acetate 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; dysmenorrhea, increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; pre-menstrual-like syndrome; cy …

7 DRUG INTERACTIONS Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration. ( 7 ) Co-administration of estradiol with norethindrone acetate did not elicit any apparent influence on the pharmacokinetics of norethindrone acetate. Similarly, no relevant interaction of norethindrone acetate on the pharmacokinetics of estradiol was found within the NETA dose range investigated in a single dose study. Estradiol 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 reduce plasma concentrations 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 plasma concentrations of estrogens and result in adverse reactions. Norethindrone Acetate Drugs or herbal products that induce or inhibit cytochrome P-450 enzymes, including CYP3A4, may decrease or increase the serum concentrations of norethindrone.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Estradiol and norethindrone acetate tablets are not indicated for use in pregnancy. There are no data with the use of estradiol and norethindrone acetate tablets in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalities and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogen and progestins) 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 breast-feeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well established. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for estradiol and norethindrone acetate tablets and any potential adverse effects on the breastfed child from estradiol and norethindrone acetate tablets or from the underlying maternal condition. 8.4 Pediatric Use Estradiol and norethindrone acetate tablets are 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 estradiol and norethindrone acetate tablets to determine whether those over 65 years of age differ from younger subjects in their response to estradiol and norethindrone acetate 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. It is unknown whether this finding applies to younger postmenopausal women [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 breast-feeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well established. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for estradiol and norethindrone acetate tablets and any potential adverse effects on the breastfed child from estradiol and norethindrone acetate tablets or from the underlying maternal condition.

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, 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. 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, and central nervous system.

11 DESCRIPTION Estradiol and norethindrone acetate tablets USP, 1 mg/0.5 mg is a single tablet for oral administration containing 1 mg of estradiol and 0.5 mg of norethindrone acetate and the following excipients: lactose monohydrate, starch (corn), polysorbate 80, copovidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc, macrogol/polyethylglycol 3350, lecithin (soya), D&C Yellow NO.10 Aluminum lake, FD&C Blue NO.2 Aluminum lake and FD&C Red NO.40 Aluminum lake. Estradiol and norethindrone acetate tablets USP, 0.5 mg/0.1 mg is a single tablet for oral administration containing 0.5 mg of estradiol and 0.1 mg of norethindrone acetate and the following excipients: lactose monohydrate, starch (corn), polysorbate 80, copovidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc, macrogol/polyethylglycol 3350, lecithin (soya), D&C Yellow NO.10 Aluminum lake, FD&C Blue NO.2 Aluminum lake and FD&C Yellow NO.6 Aluminum lake. Estradiol is a white or almost white crystalline powder. Its chemical name is estra-1, 3, 5 (10)- triene-3, 17β-diol hemihydrate with the empirical formula of C 18 H 24 O 2 , 1⁄2 H 2 O and a molecular weight of 281.4. The structural formula of E 2 is as follows: Norethindrone acetate (NETA) is a white or yellowish-white crystalline powder. Its chemical name is 17β -acetoxy-19-nor-17α -pregn-4-en-20-yn-3-one with the empirical formula of C 22 H 28 O 3 and molecular weight of 340.5. The structural formula of NETA is as follows: Product meets USP dissolution test 2. Image Image

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 estradiol and norethindrone acetate tablets therapy with institution of appropriate symptomatic care.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Estradiol and Norethindrone Acetate Tablets USP, 1 mg/0.5 mg are yellow round biconvex tablets, debossed "J2" on one side, supplied as 28 active tablets in a blister card and are available in the following configurations: Carton of 1 blister cards NDC 50742-657-28 Carton of 3 blister cards NDC 50742-657-84 Carton of 6 blister cards NDC 50742-657-68 Estradiol and Norethindrone Acetate Tablets USP, 0.5 mg/0.1 mg are pale yellow round biconvex tablets, debossed "J1" on one side, supplied as 28 active tablets in a blister card and are available in the following configurations: Carton of 1 blister cards NDC 50742-658-28 Carton of 3 blister cards NDC 50742-658-84 Carton of 6 blister cards NDC 50742-658-68 16.2 Storage and Handling Store in a dry place protected from light. Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

16.1 How Supplied Estradiol and Norethindrone Acetate Tablets USP, 1 mg/0.5 mg are yellow round biconvex tablets, debossed "J2" on one side, supplied as 28 active tablets in a blister card and are available in the following configurations: Carton of 1 blister cards NDC 50742-657-28 Carton of 3 blister cards NDC 50742-657-84 Carton of 6 blister cards NDC 50742-657-68 Estradiol and Norethindrone Acetate Tablets USP, 0.5 mg/0.1 mg are pale yellow round biconvex tablets, debossed "J1" on one side, supplied as 28 active tablets in a blister card and are available in the following configurations: Carton of 1 blister cards NDC 50742-658-28 Carton of 3 blister cards NDC 50742-658-84 Carton of 6 blister cards NDC 50742-658-68

16.2 Storage and Handling Store in a dry place protected from light. Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].