These Highlights Do Not Include All The Information Needed To Use Estradiol/norethindrone Acetate Tablets Safely And Effectively. See Full Prescribing Information For Estradiol/norethindrone Acetate Tablets.

Read this Patient Information before you start using Estradiol/Norethindrone Acetate Tablets and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment.

What is Estradiol/Norethindrone Acetate Tablets?

Estradiol/Norethindrone Acetate Tablets are a prescription medicine that contains two kinds of hormones, an estrogen and a progestogen.

What is Estradiol/Norethindrone Acetate Tablets used for?

Estradiol/Norethindrone Acetate Tablets are used after menopause to:

• Reduce moderate to severe hot flushes

Estrogens are hormones made by a woman's ovaries. The ovaries normally stop making estrogens when a woman is between 45 and 55 yrs old. This drop in body estrogen levels causes the "change of life" or menopause, the end of monthly menstrual periods. Sometimes both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes "surgical menopause."

When estrogen levels begin dropping, some women get very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden, intense feelings of heat and sweating ("hot flashes" or "hot flushes"). In some women, the symptoms are mild, and they will not need to use estrogens. In other women, symptoms can be more severe.

• Treat moderate to severe menopausal changes in and around the vagina

You and your healthcare provider should talk regularly about whether you still need treatment with Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg to treat these problems. If you use Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg only to treat your menopausal changes in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you.

• Help reduce your chances of getting osteoporosis (thin weak bones)

Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break. If you use Estradiol/Norethindrone Acetate Tablets to prevent osteoporosis due to menopause, talk with your healthcare provider about whether a different treatment or medicine without estrogens might be better for you.

You and your healthcare provider should talk regularly about whether you still need treatment with Estradiol/Norethindrone Acetate Tablets.

Who should not use Estradiol/Norethindrone Acetate Tablets?

Do not use Estradiol/Norethindrone Acetate Tablets if you have had your uterus (womb) removed (hysterectomy).

Estradiol/Norethindrone Acetate Tablets contains a progestogen to decrease the chance of getting cancer of the uterus. If you do not have a uterus, you do not need a progestogen and you should not use Estradiol/Norethindrone Acetate Tablets.

Do not start using Estradiol/Norethindrone Acetate Tablets if you:

• have unusual vaginal bleeding

Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.

• have been diagnosed with a bleeding disorder
• currently have or have had certain cancers

Estrogens may increase the chance of getting certain types of cancers, including cancer of the breast or uterus (womb). If you have or have had cancer, talk with your healthcare provider about whether you should use Estradiol/Norethindrone Acetate Tablets.

• had a stroke or heart attack
• currently have or have had blood clots
• currently have or have had liver problems
• are allergic to Estradiol/Norethindrone Acetate Tablets or any of the ingredients in it.

See the list of ingredients in Estradiol/Norethindrone Acetate Tablets at the end of this leaflet.

Before you use Estradiol/Norethindrone Acetate Tablets, tell your healthcare provider about all of your medical conditions, including if you:

• have any unusual vaginal bleeding

Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.

• have any other medical conditions that may become worse while you are using Estradiol/Norethindrone Acetate Tablets

Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, angioedema (swelling of face and tongue), problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.

• are going to have surgery or will be on bed rest

Your healthcare provider will let you know if you need to stop using Estradiol/Norethindrone Acetate Tablets.

• are pregnant or think you may be pregnant

Estradiol/Norethindrone Acetate Tablets is not for pregnant women.

• are breast feeding

The hormones in Estradiol/Norethindrone Acetate Tablets can pass into your breast milk.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines may affect how Estradiol/Norethindrone Acetate Tablets works. Estradiol/Norethindrone Acetate Tablets may also affect how your other medicines work. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine.

How should I use Estradiol/Norethindrone Acetate Tablets?

• Use Estradiol/Norethindrone Acetate Tablets exactly as your healthcare provider tells you to use it.
• Take 1 tablet at the same time each day.
• You and your healthcare provider should talk regularly (every 3 to 6 months) about your dose and whether you still need treatment with Estradiol/Norethindrone Acetate Tablets.

Follow the instructions below to use your Estradiol/Norethindrone Acetate Tablets Dispenser.

What are the possible side effects of Estradiol/Norethindrone Acetate Tablets?

Side effects are grouped by how serious they are and how often they happen when you are treated.

Serious, but less common side effects include:

• heart attack
• stroke
• blood clots
• breast cancer
• cancer of the lining of the uterus (womb)
• cancer of the ovary
• dementia
• high or low blood calcium levels
• gallbladder disease
• visual abnormalities
• high blood pressure
• high levels of fat (triglycerides) in your blood
• liver problems
• changes in your thyroid hormone levels
• fluid retention
• cancer changes of endometriosis
• enlargement of benign tumors of the uterus ("fibroids")
• worsening swelling of face and tongue (angioedema) in women who have a history of angioedema
• changes in laboratory tests results such as bleeding times and high blood sugar levels

Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:

• new breast lumps
• unusual vaginal bleeding
• changes in vision or speech
• sudden new severe headaches
• severe pains in your chest or legs with or without shortness of breath, weakness and fatigue

Common side effects of Estradiol/Norethindrone Acetate Tablets include:

• irregular vaginal bleeding or spotting
• nausea
• stomach or abdominal cramps, bloating
• headache
• vomiting
• back pain
• breast pain
• diarrhea
• fluid retention
• vaginal yeast infection

These are not all the possible side effects of Estradiol/Norethindrone Acetate Tablets. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effects that bother you or do not go away.

You may report side effects to Breckenridge Pharmaceutical, Inc. at 1-800-367-3395 or to FDA at 1-800-FDA-1088.

What can I do to lower my chances of a serious side effect with Estradiol/Norethindrone Acetate Tablets?

• Talk with your healthcare provider regularly about whether you should continue using Estradiol/Norethindrone Acetate Tablets.
• If you have a uterus, talk with your healthcare provider about whether Estradiol/Norethindrone Acetate Tablets is right for you.
• In general, the addition of a progestogen is generally recommended for a woman with a uterus to reduce the chance of getting cancer of the uterus (womb).
• See your healthcare provider right away if you get vaginal bleeding while using Estradiol/Norethindrone Acetate Tablets.
• Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else.
• If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram (breast x-ray), you may need to have breast exams more often.
• If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease.
• Ask your healthcare provider for ways to lower your chances for getting heart disease.

How should I store Estradiol/Norethindrone Acetate Tablets?

• Store Estradiol/Norethindrone Acetate Tablets at room temperature between 68°F to 77°F (20°C to 25°C).
• Store Estradiol/Norethindrone Acetate Tablets in a dry place protected from light.

KEEP Estradiol/Norethindrone Acetate Tablets and all medicines out of the reach of children.

General information about the safe and effective use of Estradiol/Norethindrone Acetate Tablets.

Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use Estradiol/Norethindrone Acetate Tablets for conditions for which it was not prescribed. Do not give Estradiol/Norethindrone Acetate Tablets to other people, even if they have the same symptoms you have. It may harm them.

You can ask your healthcare provider or pharmacist for information about Estradiol/Norethindrone Acetate Tablets that is written for health professionals.

For more information go to www.bpirx.com or call 1-800-367-3395.

What are the ingredients in Estradiol/Norethindrone Acetate Tablets?

Active ingredients: estradiol and norethindrone acetate

Inactive Ingredients: lactose monohydrate, starch (corn), copovidone, talc, magnesium stearate, hypromellose, and triacetin.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Distributed by:

Breckenridge Pharmaceutical, Inc.

Berkeley Heights, NJ 07922

Manufactured by:

Pharmaceutics International, Inc.

Hunt Valley, MD 21031

Revised: 01/2024

Estrogen Plus Progestin Therapy

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/Norethindrone Acetate Tablets therapy with institution of appropriate symptomatic care.

1. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA. 2007;297:1465-1477.

2. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med. 2006;166:357-365.

3. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004;292:1573-1580.

4. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med. 2006;166:772-780.

5. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003;289:3234-3253.

6. 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.

7. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures. JAMA. 2003;290:1739-1748.

8. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:2947-2958.

9. 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.

10. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women's Health Initiative. Circulation. 2006;113:2425-2434.

Estradiol/Norethindrone Acetate Tablets 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), copovidone, talc, magnesium stearate, hypromellose and triacetin.

Estradiol/Norethindrone Acetate Tablets 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), copovidone, talc, magnesium stearate, hypromellose and triacetin.

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 C₁₈H₂₄O₂, ½ H₂O and a molecular weight of 281.4. The structural formula of E₂ 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 C₂₂H₂₈O₃ and molecular weight of 340.5. The structural formula of NETA is as follows:

Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg are available as white, convex, coated tablets debossed with "B" on one side and "474" on the other side.

(NDC 51991-474-28). It is supplied as 28 tablets in a calendar blister pack dispenser.

Estradiol/Norethindrone Acetate Tablets 0.5 mg/0.1 mg are available as white, convex, coated tablets debossed with "B" on one side and "623" on the other side.

(NDC 51991-623-28). It is supplied as 28 tablets in a calendar blister pack dispenser.

Estrogen-induced hypocalcemia may occur in women with hypoparathyroidism. Consider whether the benefits of estrogen therapy, including Estradiol/Norethindrone Acetate Tablets, outweigh the risks in such women.

Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. Discontinue estrogens, including Estradiol/Norethindrone Acetate Tablets if hypercalcemia occurs, and take appropriate measures to reduce the serum calcium level.

Estradiol/Norethindrone Acetate Tablets are not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population.

There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Estradiol/Norethindrone Acetate Tablets to determine whether those over 65 years of age differ from younger subjects in their response to Estradiol/Norethindrone Acetate Tablets.

Estradiol/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/Norethindrone Acetate Tablets
• Hepatic impairment or disease
• Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders

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)]

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.

Estrogens plus progestogens may cause some degree of fluid retention. Monitor any woman with a condition(s) that might predispose her to fluid retention, such as a cardiac or renal impairment. Discontinue estrogen plus progestogen therapy, including Estradiol/Norethindrone Acetate Tablets, with evidence of medically concerning fluid retention.

Generally, a serum estrogen concentration does not predict an individual woman's therapeutic response to Estradiol/Norethindrone Acetate tablets nor her risk for adverse outcomes. Likewise, exposure comparisions across different estrogen products to infer efficacy or safety for the individual woman may not be valid.

Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy.

In the WHI Memory Study (WHIMS) estrogen plus progestin ancillary study, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.

After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for the CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years ⁸ [see Use in Specific Populations (8.5), and Clinical Studies (14.6)].

In the WHIMS estrogen-alone ancillary study, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo. After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years⁸ [see Use in Specific Populations (8.5), and Clinical Studies (14.6)].

When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk of probable dementia was 1.76 (95 percent CI, 1.19-2.60). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women⁸ [see Use in Specific Populations (8.5), and Clinical Studies (14.6)].

Estradiol/Norethindrone Acetate Tablets are indicated for:

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

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.

Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue Estradiol/Norethindrone Acetate Tablets pending examination if there is a sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. Permanently discontinue estrogens, including Estradiol/Norethindrone Acetate Tablets, if examination reveals papilledema or retinal vascular lesions.

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

• Estrogens increase the risk of gall bladder disease (5.4)
• Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs (5.5, 5.6, 5.9, 5.10)
• Monitor thyroid function in women on thyroid replacement therapy (5.11, 5.18)

Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. Consider whether the benefits of estrogen therapy, including Estradiol/Norethindrone Acetate Tablets, outweigh the risks in such women.

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.

In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen.

Estradiol/Norethindrone Acetate Tablets are available in two strengths:

• Each tablet of Estradiol/Norethindrone Acetate 1 mg/ 0.5 mg contains 1 mg of estradiol and 0.5 mg of norethindrone acetate. The tablets are white, convex, coated tablets debossed with "B" on one side and "474" on the other side.
• Each tablet of Estradiol/Norethindrone Acetate 0.5 mg/ 0.1 mg contains 0.5 mg of estradiol and 0.1 mg of norethindrone acetate. The tablets are white, convex, coated tablets debossed with "B" on one side and "623" on the other side.

Increased risks of PE, DVT, stroke and MI are reported with estrogen plus progestin therapy. Increased risks of stroke and DVT are reported with estrogen-alone therapy. Immediately discontinue estrogen with or without progestogen therapy if any of these occur or is suspected.

Manage appropriately any risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus).

The following adverse reactions have been identified during post-approval use of Estradiol/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.

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/Norethindrone Acetate Tablets 1 mg/0.5 mg by investigators during clinical trials regardless of causality assessment are shown in Table 1.

Adverse reactions reported with Estradiol/Norethindrone Acetate Tablets 0.5 mg/0.1 mg by investigators during clinical trials regardless of causality assessment are shown in Table 2.

Advise women to read the FDA-approved patient labeling (Patient Information)

A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy.

Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T₄ and T₃ serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogen may require increased doses of their thyroid replacement therapy. Monitor thyroid function in these women during treatment with Estradiol/Norethindrone Acetate Tablets to maintain their free thyroid hormone levels in an acceptable range.

Estrogen therapy, including Estradiol/Norethindrone Acetate Tablets, may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas. Consider whether the benefits of estrogen therapy outweigh the risks in such women.

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. These substudies did not evaluate the effects of CE plus MPA or CE-alone on menopausal symptoms.

• Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity, increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
• Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T₄ levels (by column or by radioimmunoassay), or T₃ levels by radioimmunoassay. T₃ resin uptake is decreased, reflecting the elevated TBG. Free T₄ and free T₃ concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.
• Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/rennin substrate, alpha-1 antitrypsin, ceruloplasmin).
• Increased plasma high-density lipoprotein (HDL) and HDL₂ cholesterol subfraction concentration, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglyceride levels.
• Impaired glucose tolerance.

In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Discontinue Estradiol/Norethindrone Acetate Tablets if pancreatitis occurs.

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, 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases 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 study enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age (45 percent were 65 to 69 years of age, 36 percent were 70 to 74 years of age, 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included AD, VaD and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.3), and Use in Specific Populations (8.5)].

When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.3), and Use in Specific Populations (8.5) ].

Take a single Estradiol/Norethindrone Acetate tablet orally once daily for the prevention of postmenopausal osteoporosis.

• Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg
• Estradiol/Norethindrone Acetate Tablets 0.5 mg/0.1 mg

Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg reduced the incidence of estrogen-induced endometrial hyperplasia at 1 year in a randomized, controlled clinical trial. This trial enrolled 1,176 postmenopausal women who were randomized to one of 4 arms: 1 mg estradiol unopposed (n=296), 1 mg E₂ + 0.1 mg NETA (n=294), 1 mg E₂ + 0.25 mg NETA (n=291), and Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg (n=295). At the end of the study, endometrial biopsy results were available for 988 women. The results of the 1 mg estradiol unopposed arm compared to Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg are shown in Table 4.

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.

In a 12-week randomized clinical trial involving 92 subjects, Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg was compared to 1 mg of estradiol and to placebo. The mean number and intensity of hot flushes were significantly reduced from baseline to week 4 and 12 in both the Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg and the 1 mg estradiol group compared to placebo (see Figure 2).

In a study conducted in Europe a total of 577 postmenopausal women were randomly assigned to either Estradiol/Norethindrone Acetate Tablets 0.5 mg/0.1 mg, 0.5 mg E₂/0.25 mg NETA, or placebo for 24 weeks of treatment. The mean number and severity of hot flushes were significantly reduced at week 4 and week 12 in the Estradiol/Norethindrone Acetate Tablets 0.5 mg/0.1 mg (see Figure 3) and 0.5 mg E₂/0.25 mg NETA groups compared to placebo.

The results of two randomized, multicenter, calcium-supplemented (500 to 1,000 mg per day), placebo-controlled, 2 year clinical trials have shown that Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg and estradiol 0.5 mg are effective in preventing bone loss in postmenopausal women. A total of 462 postmenopausal women with intact uteri and baseline BMD values for lumbar spine within 2 standard deviations of the mean in healthy young women (T-score > -2.0) were enrolled. In a US trial, 327 postmenopausal women (mean time from menopause 2.5 to 3.1 years) with a mean age of 53 years were randomized to 7 groups (0.25 mg, 0.5 mg, and 1 mg of estradiol alone, 1 mg estradiol with 0.25 mg norethindrone acetate, 1 mg estradiol with 0.5 mg norethindrone acetate, and 2 mg estradiol with 1 mg norethindrone acetate, and placebo). In a European trial (EU trial), 135 postmenopausal women (mean time from menopause 8.4 to 9.3 years) with a mean age of 58 years were randomized to 1 mg estradiol with 0.25 mg norethindrone acetate, 1 mg estradiol with 0.5 mg norethindrone acetate, and placebo. Approximately 58 percent and 67 percent of the randomized subjects in the two clinical trials, respectively, completed the two clinical trials. BMD was measured using dual-energy x-ray absorptiometry (DXA).

A summary of the results comparing Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg and estradiol 0.5 mg to placebo from the two prevention trials is shown in Table 5.

The overall difference in mean percentage change in BMD at the lumbar spine in the US trial (1000 mg per day calcium) between Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg and placebo was 5.9 percent and between estradiol 0.5 mg and placebo was 4.4 percent. In the European trial (500 mg per day calcium), the overall difference in mean percentage change in BMD at the lumbar spine was 6.3 percent. Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg and estradiol 0.5 mg also increased BMD at the femoral neck and femoral trochanter compared to placebo. The increase in lumbar spine BMD in the US and European clinical trials for Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg and estradiol 0.5 mg is displayed in Figure 6.

NDC 51991-623-28

Estradiol /

Norethindrone Acetate Tablets

0.5 mg / 0.1 mg

breckenridge

A Towa

Company

Rx Only

28 Tablets

NDC 51991-474-28

Estradiol /

Norethindrone Acetate Tablets

1.0 mg / 0.5 mg

breckenridge

A Towa

Company

Rx Only

28 Tablets

Estrogens may be poorly metabolized in women with hepatic impairment. Exercise caution in any woman with a history of cholestatic jaundice associated with past estrogen use or with pregnancy. In the case of recurrence of cholestatic jaundice, discontinue Estradiol/Norethindrone Acetate Tablets.

During the initial months of therapy, irregular bleeding or spotting occurred with Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg treatment. However, bleeding tended to decrease over time, and after 12 months of treatment with Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg, about 86 percent of women were amenorrheic (see Figure 4).

Note: the percentage of patients who were amenorrheic in a given cycle and through cycle 13 is shown. If data were missing, the bleeding value from the last reported day was carried forward (LOCF).

In the clinical trial with Estradiol/Norethindrone Acetate Tablets 0.5 mg/0.1 mg, 88 percent of women were amenorrheic after 6 months of treatment (See Figure 5).

Studies of the addition of a progestogen for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestogens with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.

Take a single Estradiol/Norethindrone Acetate tablet orally once daily for the treatment of moderate to severe vasomotor symptoms due to menopause.

• Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg
• Estradiol/Norethindrone Acetate Tablets 0.5 mg/0.1 mg

Take a single Estradiol/Norethindrone Acetate tablet orally once daily for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause.

• Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg

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 deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) (5.1)
• The WHI estrogen plus progestin substudy reported increased risks 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 use 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 (5.2, 5.3)

Estrogen Plus Progestin Therapy

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/Norethindrone Acetate Tablets therapy with institution of appropriate symptomatic care.

1. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA. 2007;297:1465-1477.

2. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med. 2006;166:357-365.

3. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004;292:1573-1580.

4. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med. 2006;166:772-780.

5. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003;289:3234-3253.

6. 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.

7. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures. JAMA. 2003;290:1739-1748.

8. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:2947-2958.

9. 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.

10. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women's Health Initiative. Circulation. 2006;113:2425-2434.

Estradiol/Norethindrone Acetate Tablets 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), copovidone, talc, magnesium stearate, hypromellose and triacetin.

Estradiol/Norethindrone Acetate Tablets 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), copovidone, talc, magnesium stearate, hypromellose and triacetin.

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 C₁₈H₂₄O₂, ½ H₂O and a molecular weight of 281.4. The structural formula of E₂ 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 C₂₂H₂₈O₃ and molecular weight of 340.5. The structural formula of NETA is as follows:

Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg are available as white, convex, coated tablets debossed with "B" on one side and "474" on the other side.

(NDC 51991-474-28). It is supplied as 28 tablets in a calendar blister pack dispenser.

Estradiol/Norethindrone Acetate Tablets 0.5 mg/0.1 mg are available as white, convex, coated tablets debossed with "B" on one side and "623" on the other side.

(NDC 51991-623-28). It is supplied as 28 tablets in a calendar blister pack dispenser.

Estrogen-induced hypocalcemia may occur in women with hypoparathyroidism. Consider whether the benefits of estrogen therapy, including Estradiol/Norethindrone Acetate Tablets, outweigh the risks in such women.

Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. Discontinue estrogens, including Estradiol/Norethindrone Acetate Tablets if hypercalcemia occurs, and take appropriate measures to reduce the serum calcium level.

Estradiol/Norethindrone Acetate Tablets are not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population.

There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Estradiol/Norethindrone Acetate Tablets to determine whether those over 65 years of age differ from younger subjects in their response to Estradiol/Norethindrone Acetate Tablets.

Estradiol/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/Norethindrone Acetate Tablets
• Hepatic impairment or disease
• Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders

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)]

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.

Read this Patient Information before you start using Estradiol/Norethindrone Acetate Tablets and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment.

What is Estradiol/Norethindrone Acetate Tablets?

Estradiol/Norethindrone Acetate Tablets are a prescription medicine that contains two kinds of hormones, an estrogen and a progestogen.

What is Estradiol/Norethindrone Acetate Tablets used for?

Estradiol/Norethindrone Acetate Tablets are used after menopause to:

• Reduce moderate to severe hot flushes

Estrogens are hormones made by a woman's ovaries. The ovaries normally stop making estrogens when a woman is between 45 and 55 yrs old. This drop in body estrogen levels causes the "change of life" or menopause, the end of monthly menstrual periods. Sometimes both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes "surgical menopause."

When estrogen levels begin dropping, some women get very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden, intense feelings of heat and sweating ("hot flashes" or "hot flushes"). In some women, the symptoms are mild, and they will not need to use estrogens. In other women, symptoms can be more severe.

• Treat moderate to severe menopausal changes in and around the vagina

You and your healthcare provider should talk regularly about whether you still need treatment with Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg to treat these problems. If you use Estradiol/Norethindrone Acetate Tablets 1.0 mg/0.5 mg only to treat your menopausal changes in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you.

• Help reduce your chances of getting osteoporosis (thin weak bones)

Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break. If you use Estradiol/Norethindrone Acetate Tablets to prevent osteoporosis due to menopause, talk with your healthcare provider about whether a different treatment or medicine without estrogens might be better for you.

You and your healthcare provider should talk regularly about whether you still need treatment with Estradiol/Norethindrone Acetate Tablets.

Who should not use Estradiol/Norethindrone Acetate Tablets?

Do not use Estradiol/Norethindrone Acetate Tablets if you have had your uterus (womb) removed (hysterectomy).

Estradiol/Norethindrone Acetate Tablets contains a progestogen to decrease the chance of getting cancer of the uterus. If you do not have a uterus, you do not need a progestogen and you should not use Estradiol/Norethindrone Acetate Tablets.

Do not start using Estradiol/Norethindrone Acetate Tablets if you:

• have unusual vaginal bleeding

Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.

• have been diagnosed with a bleeding disorder
• currently have or have had certain cancers

Estrogens may increase the chance of getting certain types of cancers, including cancer of the breast or uterus (womb). If you have or have had cancer, talk with your healthcare provider about whether you should use Estradiol/Norethindrone Acetate Tablets.

• had a stroke or heart attack
• currently have or have had blood clots
• currently have or have had liver problems
• are allergic to Estradiol/Norethindrone Acetate Tablets or any of the ingredients in it.

See the list of ingredients in Estradiol/Norethindrone Acetate Tablets at the end of this leaflet.

Before you use Estradiol/Norethindrone Acetate Tablets, tell your healthcare provider about all of your medical conditions, including if you:

• have any unusual vaginal bleeding

Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.

• have any other medical conditions that may become worse while you are using Estradiol/Norethindrone Acetate Tablets

Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, angioedema (swelling of face and tongue), problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.

• are going to have surgery or will be on bed rest

Your healthcare provider will let you know if you need to stop using Estradiol/Norethindrone Acetate Tablets.

• are pregnant or think you may be pregnant

Estradiol/Norethindrone Acetate Tablets is not for pregnant women.

• are breast feeding

The hormones in Estradiol/Norethindrone Acetate Tablets can pass into your breast milk.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines may affect how Estradiol/Norethindrone Acetate Tablets works. Estradiol/Norethindrone Acetate Tablets may also affect how your other medicines work. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine.

How should I use Estradiol/Norethindrone Acetate Tablets?

• Use Estradiol/Norethindrone Acetate Tablets exactly as your healthcare provider tells you to use it.
• Take 1 tablet at the same time each day.
• You and your healthcare provider should talk regularly (every 3 to 6 months) about your dose and whether you still need treatment with Estradiol/Norethindrone Acetate Tablets.

Follow the instructions below to use your Estradiol/Norethindrone Acetate Tablets Dispenser.

What are the possible side effects of Estradiol/Norethindrone Acetate Tablets?

Side effects are grouped by how serious they are and how often they happen when you are treated.

Serious, but less common side effects include:

• heart attack
• stroke
• blood clots
• breast cancer
• cancer of the lining of the uterus (womb)
• cancer of the ovary
• dementia
• high or low blood calcium levels
• gallbladder disease
• visual abnormalities
• high blood pressure
• high levels of fat (triglycerides) in your blood
• liver problems
• changes in your thyroid hormone levels
• fluid retention
• cancer changes of endometriosis
• enlargement of benign tumors of the uterus ("fibroids")
• worsening swelling of face and tongue (angioedema) in women who have a history of angioedema
• changes in laboratory tests results such as bleeding times and high blood sugar levels

Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:

• new breast lumps
• unusual vaginal bleeding
• changes in vision or speech
• sudden new severe headaches
• severe pains in your chest or legs with or without shortness of breath, weakness and fatigue

Common side effects of Estradiol/Norethindrone Acetate Tablets include:

• irregular vaginal bleeding or spotting
• nausea
• stomach or abdominal cramps, bloating
• headache
• vomiting
• back pain
• breast pain
• diarrhea
• fluid retention
• vaginal yeast infection

These are not all the possible side effects of Estradiol/Norethindrone Acetate Tablets. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effects that bother you or do not go away.

You may report side effects to Breckenridge Pharmaceutical, Inc. at 1-800-367-3395 or to FDA at 1-800-FDA-1088.

What can I do to lower my chances of a serious side effect with Estradiol/Norethindrone Acetate Tablets?

• Talk with your healthcare provider regularly about whether you should continue using Estradiol/Norethindrone Acetate Tablets.
• If you have a uterus, talk with your healthcare provider about whether Estradiol/Norethindrone Acetate Tablets is right for you.
• In general, the addition of a progestogen is generally recommended for a woman with a uterus to reduce the chance of getting cancer of the uterus (womb).
• See your healthcare provider right away if you get vaginal bleeding while using Estradiol/Norethindrone Acetate Tablets.
• Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else.
• If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram (breast x-ray), you may need to have breast exams more often.
• If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease.
• Ask your healthcare provider for ways to lower your chances for getting heart disease.

How should I store Estradiol/Norethindrone Acetate Tablets?

• Store Estradiol/Norethindrone Acetate Tablets at room temperature between 68°F to 77°F (20°C to 25°C).
• Store Estradiol/Norethindrone Acetate Tablets in a dry place protected from light.

KEEP Estradiol/Norethindrone Acetate Tablets and all medicines out of the reach of children.

General information about the safe and effective use of Estradiol/Norethindrone Acetate Tablets.

Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use Estradiol/Norethindrone Acetate Tablets for conditions for which it was not prescribed. Do not give Estradiol/Norethindrone Acetate Tablets to other people, even if they have the same symptoms you have. It may harm them.

You can ask your healthcare provider or pharmacist for information about Estradiol/Norethindrone Acetate Tablets that is written for health professionals.

For more information go to www.bpirx.com or call 1-800-367-3395.

What are the ingredients in Estradiol/Norethindrone Acetate Tablets?

Active ingredients: estradiol and norethindrone acetate

Inactive Ingredients: lactose monohydrate, starch (corn), copovidone, talc, magnesium stearate, hypromellose, and triacetin.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Distributed by:

Breckenridge Pharmaceutical, Inc.

Berkeley Heights, NJ 07922

Manufactured by:

Pharmaceutics International, Inc.

Hunt Valley, MD 21031

Revised: 01/2024

Estrogens plus progestogens may cause some degree of fluid retention. Monitor any woman with a condition(s) that might predispose her to fluid retention, such as a cardiac or renal impairment. Discontinue estrogen plus progestogen therapy, including Estradiol/Norethindrone Acetate Tablets, with evidence of medically concerning fluid retention.

Generally, a serum estrogen concentration does not predict an individual woman's therapeutic response to Estradiol/Norethindrone Acetate tablets nor her risk for adverse outcomes. Likewise, exposure comparisions across different estrogen products to infer efficacy or safety for the individual woman may not be valid.

Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy.

In the WHI Memory Study (WHIMS) estrogen plus progestin ancillary study, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.

After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for the CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years ⁸ [see Use in Specific Populations (8.5), and Clinical Studies (14.6)].

In the WHIMS estrogen-alone ancillary study, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo. After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years⁸ [see Use in Specific Populations (8.5), and Clinical Studies (14.6)].

When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk of probable dementia was 1.76 (95 percent CI, 1.19-2.60). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women⁸ [see Use in Specific Populations (8.5), and Clinical Studies (14.6)].

Estradiol/Norethindrone Acetate Tablets are indicated for:

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

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.

Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue Estradiol/Norethindrone Acetate Tablets pending examination if there is a sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. Permanently discontinue estrogens, including Estradiol/Norethindrone Acetate Tablets, if examination reveals papilledema or retinal vascular lesions.

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

• Estrogens increase the risk of gall bladder disease (5.4)
• Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs (5.5, 5.6, 5.9, 5.10)
• Monitor thyroid function in women on thyroid replacement therapy (5.11, 5.18)

Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. Consider whether the benefits of estrogen therapy, including Estradiol/Norethindrone Acetate Tablets, outweigh the risks in such women.

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.

In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen.

Estradiol/Norethindrone Acetate Tablets are available in two strengths:

• Each tablet of Estradiol/Norethindrone Acetate 1 mg/ 0.5 mg contains 1 mg of estradiol and 0.5 mg of norethindrone acetate. The tablets are white, convex, coated tablets debossed with "B" on one side and "474" on the other side.
• Each tablet of Estradiol/Norethindrone Acetate 0.5 mg/ 0.1 mg contains 0.5 mg of estradiol and 0.1 mg of norethindrone acetate. The tablets are white, convex, coated tablets debossed with "B" on one side and "623" on the other side.

Increased risks of PE, DVT, stroke and MI are reported with estrogen plus progestin therapy. Increased risks of stroke and DVT are reported with estrogen-alone therapy. Immediately discontinue estrogen with or without progestogen therapy if any of these occur or is suspected.

Manage appropriately any risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus).

The following adverse reactions have been identified during post-approval use of Estradiol/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.

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/Norethindrone Acetate Tablets 1 mg/0.5 mg by investigators during clinical trials regardless of causality assessment are shown in Table 1.

Adverse reactions reported with Estradiol/Norethindrone Acetate Tablets 0.5 mg/0.1 mg by investigators during clinical trials regardless of causality assessment are shown in Table 2.

Advise women to read the FDA-approved patient labeling (Patient Information)

A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy.

Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T₄ and T₃ serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogen may require increased doses of their thyroid replacement therapy. Monitor thyroid function in these women during treatment with Estradiol/Norethindrone Acetate Tablets to maintain their free thyroid hormone levels in an acceptable range.

Estrogen therapy, including Estradiol/Norethindrone Acetate Tablets, may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas. Consider whether the benefits of estrogen therapy outweigh the risks in such women.

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. These substudies did not evaluate the effects of CE plus MPA or CE-alone on menopausal symptoms.

• Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity, increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
• Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T₄ levels (by column or by radioimmunoassay), or T₃ levels by radioimmunoassay. T₃ resin uptake is decreased, reflecting the elevated TBG. Free T₄ and free T₃ concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.
• Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/rennin substrate, alpha-1 antitrypsin, ceruloplasmin).
• Increased plasma high-density lipoprotein (HDL) and HDL₂ cholesterol subfraction concentration, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglyceride levels.
• Impaired glucose tolerance.

In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Discontinue Estradiol/Norethindrone Acetate Tablets if pancreatitis occurs.

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, 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases 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 study enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age (45 percent were 65 to 69 years of age, 36 percent were 70 to 74 years of age, 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included AD, VaD and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.3), and Use in Specific Populations (8.5)].

When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.3), and Use in Specific Populations (8.5) ].

Take a single Estradiol/Norethindrone Acetate tablet orally once daily for the prevention of postmenopausal osteoporosis.

• Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg
• Estradiol/Norethindrone Acetate Tablets 0.5 mg/0.1 mg

Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg reduced the incidence of estrogen-induced endometrial hyperplasia at 1 year in a randomized, controlled clinical trial. This trial enrolled 1,176 postmenopausal women who were randomized to one of 4 arms: 1 mg estradiol unopposed (n=296), 1 mg E₂ + 0.1 mg NETA (n=294), 1 mg E₂ + 0.25 mg NETA (n=291), and Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg (n=295). At the end of the study, endometrial biopsy results were available for 988 women. The results of the 1 mg estradiol unopposed arm compared to Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg are shown in Table 4.

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.

In a 12-week randomized clinical trial involving 92 subjects, Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg was compared to 1 mg of estradiol and to placebo. The mean number and intensity of hot flushes were significantly reduced from baseline to week 4 and 12 in both the Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg and the 1 mg estradiol group compared to placebo (see Figure 2).

In a study conducted in Europe a total of 577 postmenopausal women were randomly assigned to either Estradiol/Norethindrone Acetate Tablets 0.5 mg/0.1 mg, 0.5 mg E₂/0.25 mg NETA, or placebo for 24 weeks of treatment. The mean number and severity of hot flushes were significantly reduced at week 4 and week 12 in the Estradiol/Norethindrone Acetate Tablets 0.5 mg/0.1 mg (see Figure 3) and 0.5 mg E₂/0.25 mg NETA groups compared to placebo.

The results of two randomized, multicenter, calcium-supplemented (500 to 1,000 mg per day), placebo-controlled, 2 year clinical trials have shown that Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg and estradiol 0.5 mg are effective in preventing bone loss in postmenopausal women. A total of 462 postmenopausal women with intact uteri and baseline BMD values for lumbar spine within 2 standard deviations of the mean in healthy young women (T-score > -2.0) were enrolled. In a US trial, 327 postmenopausal women (mean time from menopause 2.5 to 3.1 years) with a mean age of 53 years were randomized to 7 groups (0.25 mg, 0.5 mg, and 1 mg of estradiol alone, 1 mg estradiol with 0.25 mg norethindrone acetate, 1 mg estradiol with 0.5 mg norethindrone acetate, and 2 mg estradiol with 1 mg norethindrone acetate, and placebo). In a European trial (EU trial), 135 postmenopausal women (mean time from menopause 8.4 to 9.3 years) with a mean age of 58 years were randomized to 1 mg estradiol with 0.25 mg norethindrone acetate, 1 mg estradiol with 0.5 mg norethindrone acetate, and placebo. Approximately 58 percent and 67 percent of the randomized subjects in the two clinical trials, respectively, completed the two clinical trials. BMD was measured using dual-energy x-ray absorptiometry (DXA).

A summary of the results comparing Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg and estradiol 0.5 mg to placebo from the two prevention trials is shown in Table 5.

The overall difference in mean percentage change in BMD at the lumbar spine in the US trial (1000 mg per day calcium) between Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg and placebo was 5.9 percent and between estradiol 0.5 mg and placebo was 4.4 percent. In the European trial (500 mg per day calcium), the overall difference in mean percentage change in BMD at the lumbar spine was 6.3 percent. Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg and estradiol 0.5 mg also increased BMD at the femoral neck and femoral trochanter compared to placebo. The increase in lumbar spine BMD in the US and European clinical trials for Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg and estradiol 0.5 mg is displayed in Figure 6.

NDC 51991-623-28

Estradiol /

Norethindrone Acetate Tablets

0.5 mg / 0.1 mg

breckenridge

A Towa

Company

Rx Only

28 Tablets

NDC 51991-474-28

Estradiol /

Norethindrone Acetate Tablets

1.0 mg / 0.5 mg

breckenridge

A Towa

Company

Rx Only

28 Tablets

Estrogens may be poorly metabolized in women with hepatic impairment. Exercise caution in any woman with a history of cholestatic jaundice associated with past estrogen use or with pregnancy. In the case of recurrence of cholestatic jaundice, discontinue Estradiol/Norethindrone Acetate Tablets.

During the initial months of therapy, irregular bleeding or spotting occurred with Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg treatment. However, bleeding tended to decrease over time, and after 12 months of treatment with Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg, about 86 percent of women were amenorrheic (see Figure 4).

Note: the percentage of patients who were amenorrheic in a given cycle and through cycle 13 is shown. If data were missing, the bleeding value from the last reported day was carried forward (LOCF).

In the clinical trial with Estradiol/Norethindrone Acetate Tablets 0.5 mg/0.1 mg, 88 percent of women were amenorrheic after 6 months of treatment (See Figure 5).

Studies of the addition of a progestogen for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestogens with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.

Take a single Estradiol/Norethindrone Acetate tablet orally once daily for the treatment of moderate to severe vasomotor symptoms due to menopause.

• Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg
• Estradiol/Norethindrone Acetate Tablets 0.5 mg/0.1 mg

Take a single Estradiol/Norethindrone Acetate tablet orally once daily for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause.

• Estradiol/Norethindrone Acetate Tablets 1 mg/0.5 mg

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 deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) (5.1)
• The WHI estrogen plus progestin substudy reported increased risks 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 use 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 (5.2, 5.3)