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

Estrogen Plus Progestin Therapy

Patient Information

Norethindrone Acetate and Ethinyl Estradiol Tablets USP

0.5 mg/2.5 mc g and 1 mg/5 mcg

Read this Patient Information before you start taking norethindrone acetate and ethinyl estradiol 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 the most important information I should know about norethindrone acetate and ethinyl estradiol tablets (a combination of estrogen and progestin)?

• Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes or dementia (decline of brain function).
• Using estrogens with progestins may increase your chances of getting a heart attack, strokes, breast cancer, or blood clots.
• Using estrogens with progestins may increase your chance of getting dementia, based on a study of women 65 years of age or older.
• Do not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia.
• Using estrogen-alone may increase your chance of getting cancer of the uterus (womb).
• Using estrogen-alone may increase your chances of getting strokes or blood clots.
• Using estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age or older.
• You and your healthcare provider should talk regularly about whether you still need treatment with norethindrone acetate and ethinyl estradiol tablets.

What are norethindrone acetate and ethinyl estradiol tablets ?

Norethindrone acetate and ethinyl estradiol tablets are a prescription medicine that contains two kinds of hormones, an estrogen and a progestin.

What are norethindrone acetate and ethinyl estradiol tablets used for?

Norethindrone acetate and ethinyl estradiol 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 years 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 episodes of heat and sweating ("hot flashes" or "hot flushes"). In some women the symptoms are mild, and they will not need to take estrogens. In other women, symptoms can be more severe.
• Help reduce your chances of getting osteoporosis (thin weak bones)
  
  If you use norethindrone acetate and ethinyl estradiol tablets only to prevent osteoporosis from 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 norethindrone acetate and ethinyl estradiol tablets.

Who should not take norethindrone acetate and ethinyl estradiol tablets?

Do not take norethindrone acetate and ethinyl estradiol tablets if you have had your uterus (womb) removed (hysterectomy).

Norethindrone acetate and ethinyl estradiol tablets contain a progestin to decrease the chance of getting cancer of the uterus. If you do not have a uterus, you do not need a progestin and you should not take norethindrone acetate and ethinyl estradiol tablets.

Do not take norethindrone acetate and ethinyl estradiol 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.
• 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. If you have or have had cancer, talk with your healthcare provider about whether you should take norethindrone acetate and ethinyl estradiol tablets
• had a stroke or heart attack
• currently have or have had blood clots
• currently have or have had liver problems
• have been diagnosed with a bleeding disorder
• are allergic to norethindrone acetate and ethinyl estradiol tablets or any of its ingredients.
  
  See the list of ingredients in norethindrone acetate and ethinyl estradiol tablets at the end of this leaflet.
• think you may be pregnant
  
  Norethindrone acetate and ethinyl estradiol tablets are not for pregnant women. If you think you may be pregnant, you should have a pregnancy test and know the results. Do not take norethindrone acetate and ethinyl estradiol tablets if the test is positive and talk to your healthcare provider.

What should I tell my healthcare provider before I take norethindrone acetate and ethinyl estradiol tablets ?

Before you take norethindrone acetate and ethinyl estradiol tablets, tell your healthcare provider 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
  
  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), or 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 taking norethindrone acetate and ethinyl estradiol tablets.
• are breastfeeding
  
  The hormones in norethindrone acetate and ethinyl estradiol tablets can pass into your breast milk.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicines may affect how norethindrone acetate and ethinyl estradiol tablets work. Norethindrone acetate and ethinyl estradiol 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 a new medicine.

How should I take norethindrone acetate and ethinyl estradiol tablets?

• Take norethindrone acetate and ethinyl estradiol tablets exactly as your healthcare provider tells you to take it.
• Take 1 norethindrone acetate and ethinyl estradiol tablet at the same time each day.
• You and your healthcare provider should talk regularly (every 3 to 6 months) about the dose you are taking and whether or not you still need treatment with norethindrone acetate and ethinyl estradiol tablets.

What are the possible side effects of norethindrone acetate and ethinyl estradiol 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
• dementia
• breast cancer
• cancer of the lining of the uterus (womb)
• cancer of the ovary
• high blood pressure
• high blood sugar
• gallbladder disease
• liver problems
• changes in your thyroid hormone levels
• enlargement of benign tumors of the uterus ("fibroids")

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

Less serious, but common side effects include:

• headache
• breast pain
• irregular vaginal bleeding or spotting
• stomach or abdominal cramps, bloating
• hair loss
• fluid retention
• vaginal yeast infection

These are not all the possible side effects of norethindrone acetate and ethinyl estradiol tablets. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effects that bother you or does not go away.

To report SUSPECTED ADVERSE REACTIONS, contact Nivagen Pharmaceuticals Toll-free at 1-877-977-0687 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

What can I do to lower my chances of a serious side effect with norethindrone acetate and ethinyl estradiol tablets?

• Talk with your healthcare provider regularly about whether you should continue taking norethindrone acetate and ethinyl estradiol tablets.
• If you have a uterus, talk with your healthcare provider about whether the addition of a progestin is right for you.
• The addition of a progestin 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 develop vaginal bleeding while taking norethindrone acetate and ethinyl estradiol 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 use tobacco, you may have a higher chance for getting heart disease.

Ask your healthcare provider for ways to lower your chances of getting heart disease.

How should I store norethindrone acetate and ethinyl estradiol tablets?

• Store norethindrone acetate and ethinyl estradiol tablets at room temperature between 68° to 77° F (20° to 25° C).

Keep norethindrone acetate and ethinyl estradiol tablets out of the reach of children.

General information about the safe and effective use of norethindrone acetate and ethinyl estradiol tablets

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take norethindrone acetate and ethinyl estradiol tablets for conditions for which it was not prescribed.

Do not give norethindrone acetate and ethinyl estradiol tablets to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about norethindrone acetate and ethinyl estradiol tablets . If you would like more information, talk with your healthcare provider or pharmacist. You can ask your pharmacist or healthcare provider for information about norethindrone acetate and ethinyl estradiol tablets that is written for health professionals.

For more information call 1-877-977-0687.

What are the ingredients in norethindrone acetate and ethinyl estradiol tablets?

Active Ingredients: norethindrone acetate and ethinyl estradiol

Inactive Ingredients: Each white tablet also contains lactose monohydrate, pregelatinized starch, polyethylene glycol, magnesium stearate, ethyl cellulose, vitamin E, titanium dioxide, hypromelloses, macrogol/PEG, triacetin, polydextrose.

Each light yellow tablet also contains lactose monohydrate, pregelatinized starch, polyethylene glycol, magnesium stearate, ethyl cellulose, vitamin E, iron oxide yellow, iron oxide black, talc, polyvinyl alcohol, titanium dioxide, lecithin (soya).

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

Distributed by:

Nivagen Pharmaceuticals, Inc.

Sacramento, CA 95827, USA

Toll Free 1-877-977-0687

Manufactured by:

Novast Laboratories Ltd.

Nantong, China 226009

I0058

Iss. 08/2022 Rev D

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

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

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

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

Norethindrone acetate and ethinyl estradiol tablets are a continuous dosage regimen of a progestin-estrogen combination for oral administration.

The following two strengths of norethindrone acetate and ethinyl estradiol tablets are available:

• 0.5 mg/2.5 mcg: Each round light yellow tablet contains 0.5 mg norethindrone acetate and 2.5 mcg ethinyl estradiol; debossed with N1 on one side.
• 1 mg/5 mcg: Each round white tablet contains 1 mg norethindrone acetate and 5 mcg ethinyl estradiol; debossed with N2 on one side.

Each white tablet also contains lactose monohydrate, pregelatinized starch, polyethylene glycol, magnesium stearate, ethyl cellulose, vitamin E, titanium dioxide, hypromelloses, macrogol/PEG, triacetin, polydextrose.

Each light yellow tablet also contains lactose monohydrate, pregelatinized starch, polyethylene glycol, magnesium stearate, ethyl cellulose, vitamin E, iron oxide yellow, iron oxide black, talc, polyvinyl alcohol, titanium dioxide, lecithin (soya).

The structural formulas are as follows.

Norethindrone acetate and ethinyl estradiol tablets are available in the following strength and package sizes:

Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.

Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

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

There have not been sufficient numbers of geriatric women involved in clinical studies utilizing norethindrone acetate and ethinyl estradiol tablets to determine whether those over 65 years of age differ from younger subjects in their response to norethindrone acetate and ethinyl estradiol tablets.

Norethindrone acetate and ethinyl estradiol tablets are contraindicated in women with any of the following conditions:

• Undiagnosed abnormal genital bleeding
• Known, suspected, or history of breast cancer
• Known or suspected estrogen-dependent neoplasia
• Active DVT, PE or a history of these conditions
• Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions
• Known anaphylactic reaction or angioedema to Norethindrone acetate and Ethinyl estradiol tablets.
• Known liver impairment or disease
• Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders
• Known or suspected pregnancy

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. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

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)].

No drug-drug interaction studies have been conducted for norethindrone acetate and ethinyl estradiol tablets.

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

Estrogens plus progestins may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as cardiac or renal impairment, warrant careful observation when estrogens plus progestins are prescribed.

The effect of renal impairment on the pharmacokinetics of norethindrone acetate and ethinyl estradiol tablets have not been studied.

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

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

In the WHIMS estrogen plus progestin ancillary study of WHI, 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 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-years⁸ [see Use in Specific Populations (8.5), and Clinical Studies (14.6)].

In the WHIMS estrogen-alone ancillary study of WHI, 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 for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Since both ancillary substudies 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)].

The effect of hepatic impairment on the pharmacokinetics of norethindrone acetate and ethinyl estradiol tablets have not been studied.

Norethindrone acetate and Ethinyl estradiol tablets are an estrogen plus progestin indicated in a woman with a uterus for:

• Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause (1.1)
• Prevention of Postmenopausal Osteoporosis (1.2)

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, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. The pharmacologic effects of ethinyl estradiol are similar to those of endogenous estrogens.Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.Progestin compounds enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes. Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, bone, skeletal tissue and central nervous system. Progestins produce similar endometrial changes to those of the naturally occurring hormone progesterone.

Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.

In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs.

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

• Estrogens increase the risk of gallbladder 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.

Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary.

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.

The following two strengths of norethindrone acetate and ethinyl estradiol tablets are available:

• 0.5 mg/2.5 mcg: Each round light yellow tablet contains 0.5 mg norethindrone acetate and 2.5 mcg ethinyl estradiol; debossed with N1 on one side.
• 1 mg/5 mcg: Each round white tablet contains 1 mg norethindrone acetate and 5 mcg ethinyl estradiol; debossed with N2 on one side.

An increased risk of PE, DVT, stroke, and MI has been reported with estrogen plus progestin therapy. An increased risk of stroke and DVT has been reported with estrogen-alone therapy. Should any of these occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately.

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) should be managed appropriately.

The following additional adverse reactions have been identified during post-approval use of norethindrone acetate and ethinyl estradiol tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Nursing Mothers: Estrogen administration to nursing women has been shown to decrease the quantity and quality of breast milk (8.3)
• Geriatric Use: An increased risk of probable dementia in women over 65 years of age was reported in the Women's Health Initiative Memory ancillary studies of the Women's Health Initiative (5.3, 8.5)

Inform postmenopausal women of the importance of reporting abnormal vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions (5.2)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions reported by ≥5 percent of subjects in controlled clinical studies of norethindrone acetate and ethinyl estradiol tablets are shown in Table 1.

A 2-year, placebo-controlled, multicenter, randomized clinical trial was conducted to determine the safety and efficacy of norethindrone acetate and ethinyl estradiol on maintaining bone mineral density, protecting the endometrium, and to determine effects on lipids. A total of 1265 women were enrolled and randomized to either placebo, 0.2 mg NA/1 mcg EE, norethindrone acetate and ethinyl estradiol 0.5/2.5, norethindrone acetate and ethinyl estradiol 1/5 and 1 mg NA/10 mcg EE or matching unopposed EE doses (1, 2.5, 5, or 10 mcg) for a total of 9 treatment groups. All participants received 1000 mg of calcium supplementation daily. Of the 1265 women randomized to the various treatment arms of this study, 137 were randomized to placebo, 146 to norethindrone acetate and ethinyl estradiol 1/5, 136 to norethindrone acetate and ethinyl estradiol 0.5/2.5 and 141 to EE 5 mcg and 137 to EE 2.5 mcg. Of these, 134 placebo, 143 norethindrone acetate and ethinyl estradiol 1/5, 136 norethindrone acetate and ethinyl estradiol 0.5/2.5,139 EE 5 mcg and 137 EE 2.5 mcg had a baseline endometrial result. Baseline biopsies were classified as normal (in approximately 95% of subjects), or insufficient tissue (in approximately 5% of subjects). Follow-up biopsies were obtained in approximately 70-80% of patients in each arm after 12 and 24 months of therapy. Results for norethindrone acetate and ethinyl estradiol 1/5 and appropriate comparators are shown in Table 5.

See FDA-approved patient labeling (Patient Information)

A 12-week placebo-controlled, multicenter, randomized clinical trial was conducted in 266 symptomatic women who had at least 56 moderate to severe hot flushes during the week prior to randomization. On average, patients had 12 hot flushes per day upon study entry.

A total of 66 women were randomized to receive norethindrone acetate and ethinyl estradiol 1/5 and 66 women were randomized to the placebo group. Norethindrone acetate and ethinyl estradiol 1/5 was shown to be statistically better than placebo at weeks 4, and 12 for relief of the frequency of moderate to severe vasomotor symptoms (see Table 3). In Table 4, norethindrone acetate and ethinyl estradiol 1/5 was shown to be statistically better than placebo at weeks 4 and 12 for relief of the severity of moderate to severe vasomotor symptoms.

A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post- hysterectomy, the addition of progestin should be considered.

In the 2 year study, trabecular bone mineral density (BMD) was assessed at lumbar spine using quantitative computed tomography. A total of 419 postmenopausal primarily Caucasian women, aged 40 to 64 years, with intact uteri and non-osteoporotic bone mineral densities were randomized (1:1:1) to norethindrone acetate and ethinyl estradiol 1/5, norethindrone acetate and ethinyl estradiol 0.5/2.5 or placebo. Approximately 75 percent of the subjects in each group completed the two-year study. All patients received 1000 mg calcium in divided doses. Vitamin D was not supplemented.

As shown in Figure 3, women treated with norethindrone acetate and ethinyl estradiol 1/5 had an average increase of 3.1percent in lumbar spine BMD from baseline to Month 24. Women treated with placebo had average decreases of –6.3 percent in spinal BMD from baseline to Month 24. The differences in the changes from baseline to Month 24 in the norethindrone acetate and ethinyl estradiol 1/5 group compared with the placebo group were statistically significant.

Figure 3: Mean Percent Change (+ SE) From Baseline in Volumetric Bone Mineral Density* at Lumbar Spine Measured by Quantitative Computed Tomography after 12 and 24 Months of Treatment (Intent-to-Treat Population)

*It should be noted that when measured by QCT, BMD gains and losses are greater than when measured by dual X-ray absorptiometry (DXA). Therefore, the differences in the changes in BMD between the placebo and active drug treated groups will be larger when measured by QCT compared with DXA. Changes in BMD measured by DXA should not be compared with changes in BMD measured by QCT.

Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus and hepatic hemangiomas, and should be used with caution in women with these conditions.

The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE plus MPA or CE-alone on menopausal symptoms.

Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.

Increased 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. Norethindrone acetate and ethinyl estradiol tablets 1/5 was associated with an SHBG increase of 22 percent.

Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

Increased plasma high-density lipoprotein (HDL) and HDL₂ cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglycerides levels. Impaired glucose tolerance.

The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age, 35 percent were 70 to 74 years of age, and 18 percent were 75 years of age and older) to evaluate the effects of CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger post-menopausal women [see Warnings and Precautions (5.3), and Use in Specific Populations (8.5)].

The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo.

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

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

The cumulative incidence of amenorrhea, defined as no bleeding or spotting obtained from subject recall, was evaluated over 12 months for norethindrone acetate and ethinyl estradiol (NA/EE) 1/5 and placebo arms. Results are shown in Figure 2.

Norethindrone acetate and ethinyl estradiol tablets therapy consists of a single tablet taken orally once daily.

Combination hormonal products containing some synthetic estrogens (for example, ethinyl estradiol) may inhibit the metabolism of other compounds. Combination hormonal products have been shown to significantly decrease the plasma concentration of lamotrigine likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.

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.

3 Blister Cards of 28 Tablets each.

NDC 75834-130-29

Norethindrone Acetate and

Ethinyl Estradiol Tablets, USP

1 mg/5 mcg

Each light yellow tablet contains norethindrone acetate 1 mg

and ethinyl estradiol 5 mcg.

Each tablet dispenser contains 28 white tablets

This product (like all oral contraceptives) is intended to prevent pregnancy.

It does not protect against HIV infection (AIDS) and other sexually

transmitted diseases.

Rx Only

NIVAGEN

PHARMACEUTICALS

Studies of the addition of a progestin 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 progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.

3 Blister Cards of 28 Tablets each.

NDC 75834-129-29

Norethindrone Acetate and

Ethinyl Estradiol Tablets, USP

0.5 mg/2.5 mcg

Each light yellow tablet contains norethindrone acetate 0.5 mg

and ethinyl estradiol 2.5 mcg.

Each tablet dispenser contains 28 light yellow tablets

This product (like all oral contraceptives) is intended to prevent pregnancy.

It does not protect against HIV infection (AIDS) and other sexually

transmitted diseases.

Rx Only

NIVAGEN

PHARMACEUTICALS

Estrogens may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued.

Norethindrone acetate and ethinyl estradiol tablets therapy consists of a single tablet to be taken orally once daily.

Inform postmenopausal women of possible serious adverse reactions of estrogen plus progestin therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions (5.1, 5.2, 5.3)].

WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER AND PROBABLE DEMENTIA

See full prescribing information for complete boxed warning.

Estrogen Plus Progestin Therapy

• Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia (5.1, 5.3)
• The Women's Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of stroke, deep vein thrombosis (DVT), pulmonary embolism (PE), and myocardial infarction (MI) (5.1)
• The WHI estrogen plus progestin substudy reported an increased risk of invasive breast cancer (5.2)
• The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.3)

Estrogen-Alone Therapy

• There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens (5.2)
• Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia (5.1, 5.3)
• The WHI estrogen-alone substudy reported increased risks of stroke and DVT (5.1)
• The WHIMS estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.3)

Inform postmenopausal women of possible less serious but common adverse reactions of estrogen plus progestin therapy such as headache, breast pain and tenderness, nausea and vomiting.

Estrogen Plus Progestin Therapy

Patient Information

Norethindrone Acetate and Ethinyl Estradiol Tablets USP

0.5 mg/2.5 mc g and 1 mg/5 mcg

Read this Patient Information before you start taking norethindrone acetate and ethinyl estradiol 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 the most important information I should know about norethindrone acetate and ethinyl estradiol tablets (a combination of estrogen and progestin)?

• Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes or dementia (decline of brain function).
• Using estrogens with progestins may increase your chances of getting a heart attack, strokes, breast cancer, or blood clots.
• Using estrogens with progestins may increase your chance of getting dementia, based on a study of women 65 years of age or older.
• Do not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia.
• Using estrogen-alone may increase your chance of getting cancer of the uterus (womb).
• Using estrogen-alone may increase your chances of getting strokes or blood clots.
• Using estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age or older.
• You and your healthcare provider should talk regularly about whether you still need treatment with norethindrone acetate and ethinyl estradiol tablets.

What are norethindrone acetate and ethinyl estradiol tablets ?

Norethindrone acetate and ethinyl estradiol tablets are a prescription medicine that contains two kinds of hormones, an estrogen and a progestin.

What are norethindrone acetate and ethinyl estradiol tablets used for?

Norethindrone acetate and ethinyl estradiol 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 years 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 episodes of heat and sweating ("hot flashes" or "hot flushes"). In some women the symptoms are mild, and they will not need to take estrogens. In other women, symptoms can be more severe.
• Help reduce your chances of getting osteoporosis (thin weak bones)
  
  If you use norethindrone acetate and ethinyl estradiol tablets only to prevent osteoporosis from 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 norethindrone acetate and ethinyl estradiol tablets.

Who should not take norethindrone acetate and ethinyl estradiol tablets?

Do not take norethindrone acetate and ethinyl estradiol tablets if you have had your uterus (womb) removed (hysterectomy).

Norethindrone acetate and ethinyl estradiol tablets contain a progestin to decrease the chance of getting cancer of the uterus. If you do not have a uterus, you do not need a progestin and you should not take norethindrone acetate and ethinyl estradiol tablets.

Do not take norethindrone acetate and ethinyl estradiol 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.
• 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. If you have or have had cancer, talk with your healthcare provider about whether you should take norethindrone acetate and ethinyl estradiol tablets
• had a stroke or heart attack
• currently have or have had blood clots
• currently have or have had liver problems
• have been diagnosed with a bleeding disorder
• are allergic to norethindrone acetate and ethinyl estradiol tablets or any of its ingredients.
  
  See the list of ingredients in norethindrone acetate and ethinyl estradiol tablets at the end of this leaflet.
• think you may be pregnant
  
  Norethindrone acetate and ethinyl estradiol tablets are not for pregnant women. If you think you may be pregnant, you should have a pregnancy test and know the results. Do not take norethindrone acetate and ethinyl estradiol tablets if the test is positive and talk to your healthcare provider.

What should I tell my healthcare provider before I take norethindrone acetate and ethinyl estradiol tablets ?

Before you take norethindrone acetate and ethinyl estradiol tablets, tell your healthcare provider 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
  
  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), or 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 taking norethindrone acetate and ethinyl estradiol tablets.
• are breastfeeding
  
  The hormones in norethindrone acetate and ethinyl estradiol tablets can pass into your breast milk.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicines may affect how norethindrone acetate and ethinyl estradiol tablets work. Norethindrone acetate and ethinyl estradiol 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 a new medicine.

How should I take norethindrone acetate and ethinyl estradiol tablets?

• Take norethindrone acetate and ethinyl estradiol tablets exactly as your healthcare provider tells you to take it.
• Take 1 norethindrone acetate and ethinyl estradiol tablet at the same time each day.
• You and your healthcare provider should talk regularly (every 3 to 6 months) about the dose you are taking and whether or not you still need treatment with norethindrone acetate and ethinyl estradiol tablets.

What are the possible side effects of norethindrone acetate and ethinyl estradiol 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
• dementia
• breast cancer
• cancer of the lining of the uterus (womb)
• cancer of the ovary
• high blood pressure
• high blood sugar
• gallbladder disease
• liver problems
• changes in your thyroid hormone levels
• enlargement of benign tumors of the uterus ("fibroids")

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

Less serious, but common side effects include:

• headache
• breast pain
• irregular vaginal bleeding or spotting
• stomach or abdominal cramps, bloating
• hair loss
• fluid retention
• vaginal yeast infection

These are not all the possible side effects of norethindrone acetate and ethinyl estradiol tablets. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effects that bother you or does not go away.

To report SUSPECTED ADVERSE REACTIONS, contact Nivagen Pharmaceuticals Toll-free at 1-877-977-0687 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

What can I do to lower my chances of a serious side effect with norethindrone acetate and ethinyl estradiol tablets?

• Talk with your healthcare provider regularly about whether you should continue taking norethindrone acetate and ethinyl estradiol tablets.
• If you have a uterus, talk with your healthcare provider about whether the addition of a progestin is right for you.
• The addition of a progestin 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 develop vaginal bleeding while taking norethindrone acetate and ethinyl estradiol 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 use tobacco, you may have a higher chance for getting heart disease.

Ask your healthcare provider for ways to lower your chances of getting heart disease.

How should I store norethindrone acetate and ethinyl estradiol tablets?

• Store norethindrone acetate and ethinyl estradiol tablets at room temperature between 68° to 77° F (20° to 25° C).

Keep norethindrone acetate and ethinyl estradiol tablets out of the reach of children.

General information about the safe and effective use of norethindrone acetate and ethinyl estradiol tablets

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take norethindrone acetate and ethinyl estradiol tablets for conditions for which it was not prescribed.

Do not give norethindrone acetate and ethinyl estradiol tablets to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about norethindrone acetate and ethinyl estradiol tablets . If you would like more information, talk with your healthcare provider or pharmacist. You can ask your pharmacist or healthcare provider for information about norethindrone acetate and ethinyl estradiol tablets that is written for health professionals.

For more information call 1-877-977-0687.

What are the ingredients in norethindrone acetate and ethinyl estradiol tablets?

Active Ingredients: norethindrone acetate and ethinyl estradiol

Inactive Ingredients: Each white tablet also contains lactose monohydrate, pregelatinized starch, polyethylene glycol, magnesium stearate, ethyl cellulose, vitamin E, titanium dioxide, hypromelloses, macrogol/PEG, triacetin, polydextrose.

Each light yellow tablet also contains lactose monohydrate, pregelatinized starch, polyethylene glycol, magnesium stearate, ethyl cellulose, vitamin E, iron oxide yellow, iron oxide black, talc, polyvinyl alcohol, titanium dioxide, lecithin (soya).

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

Distributed by:

Nivagen Pharmaceuticals, Inc.

Sacramento, CA 95827, USA

Toll Free 1-877-977-0687

Manufactured by:

Novast Laboratories Ltd.

Nantong, China 226009

I0058

Iss. 08/2022 Rev D

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

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

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

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

Norethindrone acetate and ethinyl estradiol tablets are a continuous dosage regimen of a progestin-estrogen combination for oral administration.

The following two strengths of norethindrone acetate and ethinyl estradiol tablets are available:

• 0.5 mg/2.5 mcg: Each round light yellow tablet contains 0.5 mg norethindrone acetate and 2.5 mcg ethinyl estradiol; debossed with N1 on one side.
• 1 mg/5 mcg: Each round white tablet contains 1 mg norethindrone acetate and 5 mcg ethinyl estradiol; debossed with N2 on one side.

Each white tablet also contains lactose monohydrate, pregelatinized starch, polyethylene glycol, magnesium stearate, ethyl cellulose, vitamin E, titanium dioxide, hypromelloses, macrogol/PEG, triacetin, polydextrose.

Each light yellow tablet also contains lactose monohydrate, pregelatinized starch, polyethylene glycol, magnesium stearate, ethyl cellulose, vitamin E, iron oxide yellow, iron oxide black, talc, polyvinyl alcohol, titanium dioxide, lecithin (soya).

The structural formulas are as follows.

Norethindrone acetate and ethinyl estradiol tablets are available in the following strength and package sizes:

Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.

Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

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

There have not been sufficient numbers of geriatric women involved in clinical studies utilizing norethindrone acetate and ethinyl estradiol tablets to determine whether those over 65 years of age differ from younger subjects in their response to norethindrone acetate and ethinyl estradiol tablets.

Norethindrone acetate and ethinyl estradiol tablets are contraindicated in women with any of the following conditions:

• Undiagnosed abnormal genital bleeding
• Known, suspected, or history of breast cancer
• Known or suspected estrogen-dependent neoplasia
• Active DVT, PE or a history of these conditions
• Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions
• Known anaphylactic reaction or angioedema to Norethindrone acetate and Ethinyl estradiol tablets.
• Known liver impairment or disease
• Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders
• Known or suspected pregnancy

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. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

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)].

No drug-drug interaction studies have been conducted for norethindrone acetate and ethinyl estradiol tablets.

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

Estrogens plus progestins may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as cardiac or renal impairment, warrant careful observation when estrogens plus progestins are prescribed.

The effect of renal impairment on the pharmacokinetics of norethindrone acetate and ethinyl estradiol tablets have not been studied.

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

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

In the WHIMS estrogen plus progestin ancillary study of WHI, 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 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-years⁸ [see Use in Specific Populations (8.5), and Clinical Studies (14.6)].

In the WHIMS estrogen-alone ancillary study of WHI, 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 for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Since both ancillary substudies 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)].

The effect of hepatic impairment on the pharmacokinetics of norethindrone acetate and ethinyl estradiol tablets have not been studied.

Norethindrone acetate and Ethinyl estradiol tablets are an estrogen plus progestin indicated in a woman with a uterus for:

• Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause (1.1)
• Prevention of Postmenopausal Osteoporosis (1.2)

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, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. The pharmacologic effects of ethinyl estradiol are similar to those of endogenous estrogens.Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.Progestin compounds enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes. Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, bone, skeletal tissue and central nervous system. Progestins produce similar endometrial changes to those of the naturally occurring hormone progesterone.

Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.

In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs.

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

• Estrogens increase the risk of gallbladder 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.

Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary.

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.

The following two strengths of norethindrone acetate and ethinyl estradiol tablets are available:

• 0.5 mg/2.5 mcg: Each round light yellow tablet contains 0.5 mg norethindrone acetate and 2.5 mcg ethinyl estradiol; debossed with N1 on one side.
• 1 mg/5 mcg: Each round white tablet contains 1 mg norethindrone acetate and 5 mcg ethinyl estradiol; debossed with N2 on one side.

An increased risk of PE, DVT, stroke, and MI has been reported with estrogen plus progestin therapy. An increased risk of stroke and DVT has been reported with estrogen-alone therapy. Should any of these occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately.

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) should be managed appropriately.

The following additional adverse reactions have been identified during post-approval use of norethindrone acetate and ethinyl estradiol tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Nursing Mothers: Estrogen administration to nursing women has been shown to decrease the quantity and quality of breast milk (8.3)
• Geriatric Use: An increased risk of probable dementia in women over 65 years of age was reported in the Women's Health Initiative Memory ancillary studies of the Women's Health Initiative (5.3, 8.5)

Inform postmenopausal women of the importance of reporting abnormal vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions (5.2)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions reported by ≥5 percent of subjects in controlled clinical studies of norethindrone acetate and ethinyl estradiol tablets are shown in Table 1.

A 2-year, placebo-controlled, multicenter, randomized clinical trial was conducted to determine the safety and efficacy of norethindrone acetate and ethinyl estradiol on maintaining bone mineral density, protecting the endometrium, and to determine effects on lipids. A total of 1265 women were enrolled and randomized to either placebo, 0.2 mg NA/1 mcg EE, norethindrone acetate and ethinyl estradiol 0.5/2.5, norethindrone acetate and ethinyl estradiol 1/5 and 1 mg NA/10 mcg EE or matching unopposed EE doses (1, 2.5, 5, or 10 mcg) for a total of 9 treatment groups. All participants received 1000 mg of calcium supplementation daily. Of the 1265 women randomized to the various treatment arms of this study, 137 were randomized to placebo, 146 to norethindrone acetate and ethinyl estradiol 1/5, 136 to norethindrone acetate and ethinyl estradiol 0.5/2.5 and 141 to EE 5 mcg and 137 to EE 2.5 mcg. Of these, 134 placebo, 143 norethindrone acetate and ethinyl estradiol 1/5, 136 norethindrone acetate and ethinyl estradiol 0.5/2.5,139 EE 5 mcg and 137 EE 2.5 mcg had a baseline endometrial result. Baseline biopsies were classified as normal (in approximately 95% of subjects), or insufficient tissue (in approximately 5% of subjects). Follow-up biopsies were obtained in approximately 70-80% of patients in each arm after 12 and 24 months of therapy. Results for norethindrone acetate and ethinyl estradiol 1/5 and appropriate comparators are shown in Table 5.

See FDA-approved patient labeling (Patient Information)

A 12-week placebo-controlled, multicenter, randomized clinical trial was conducted in 266 symptomatic women who had at least 56 moderate to severe hot flushes during the week prior to randomization. On average, patients had 12 hot flushes per day upon study entry.

A total of 66 women were randomized to receive norethindrone acetate and ethinyl estradiol 1/5 and 66 women were randomized to the placebo group. Norethindrone acetate and ethinyl estradiol 1/5 was shown to be statistically better than placebo at weeks 4, and 12 for relief of the frequency of moderate to severe vasomotor symptoms (see Table 3). In Table 4, norethindrone acetate and ethinyl estradiol 1/5 was shown to be statistically better than placebo at weeks 4 and 12 for relief of the severity of moderate to severe vasomotor symptoms.

A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post- hysterectomy, the addition of progestin should be considered.

In the 2 year study, trabecular bone mineral density (BMD) was assessed at lumbar spine using quantitative computed tomography. A total of 419 postmenopausal primarily Caucasian women, aged 40 to 64 years, with intact uteri and non-osteoporotic bone mineral densities were randomized (1:1:1) to norethindrone acetate and ethinyl estradiol 1/5, norethindrone acetate and ethinyl estradiol 0.5/2.5 or placebo. Approximately 75 percent of the subjects in each group completed the two-year study. All patients received 1000 mg calcium in divided doses. Vitamin D was not supplemented.

As shown in Figure 3, women treated with norethindrone acetate and ethinyl estradiol 1/5 had an average increase of 3.1percent in lumbar spine BMD from baseline to Month 24. Women treated with placebo had average decreases of –6.3 percent in spinal BMD from baseline to Month 24. The differences in the changes from baseline to Month 24 in the norethindrone acetate and ethinyl estradiol 1/5 group compared with the placebo group were statistically significant.

Figure 3: Mean Percent Change (+ SE) From Baseline in Volumetric Bone Mineral Density* at Lumbar Spine Measured by Quantitative Computed Tomography after 12 and 24 Months of Treatment (Intent-to-Treat Population)

*It should be noted that when measured by QCT, BMD gains and losses are greater than when measured by dual X-ray absorptiometry (DXA). Therefore, the differences in the changes in BMD between the placebo and active drug treated groups will be larger when measured by QCT compared with DXA. Changes in BMD measured by DXA should not be compared with changes in BMD measured by QCT.

Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus and hepatic hemangiomas, and should be used with caution in women with these conditions.

The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE plus MPA or CE-alone on menopausal symptoms.

Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.

Increased 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. Norethindrone acetate and ethinyl estradiol tablets 1/5 was associated with an SHBG increase of 22 percent.

Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

Increased plasma high-density lipoprotein (HDL) and HDL₂ cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglycerides levels. Impaired glucose tolerance.

The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age, 35 percent were 70 to 74 years of age, and 18 percent were 75 years of age and older) to evaluate the effects of CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger post-menopausal women [see Warnings and Precautions (5.3), and Use in Specific Populations (8.5)].

The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo.

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

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

The cumulative incidence of amenorrhea, defined as no bleeding or spotting obtained from subject recall, was evaluated over 12 months for norethindrone acetate and ethinyl estradiol (NA/EE) 1/5 and placebo arms. Results are shown in Figure 2.

Norethindrone acetate and ethinyl estradiol tablets therapy consists of a single tablet taken orally once daily.

Combination hormonal products containing some synthetic estrogens (for example, ethinyl estradiol) may inhibit the metabolism of other compounds. Combination hormonal products have been shown to significantly decrease the plasma concentration of lamotrigine likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.

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.

3 Blister Cards of 28 Tablets each.

NDC 75834-130-29

Norethindrone Acetate and

Ethinyl Estradiol Tablets, USP

1 mg/5 mcg

Each light yellow tablet contains norethindrone acetate 1 mg

and ethinyl estradiol 5 mcg.

Each tablet dispenser contains 28 white tablets

This product (like all oral contraceptives) is intended to prevent pregnancy.

It does not protect against HIV infection (AIDS) and other sexually

transmitted diseases.

Rx Only

NIVAGEN

PHARMACEUTICALS

Studies of the addition of a progestin 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 progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.

3 Blister Cards of 28 Tablets each.

NDC 75834-129-29

Norethindrone Acetate and

Ethinyl Estradiol Tablets, USP

0.5 mg/2.5 mcg

Each light yellow tablet contains norethindrone acetate 0.5 mg

and ethinyl estradiol 2.5 mcg.

Each tablet dispenser contains 28 light yellow tablets

This product (like all oral contraceptives) is intended to prevent pregnancy.

It does not protect against HIV infection (AIDS) and other sexually

transmitted diseases.

Rx Only

NIVAGEN

PHARMACEUTICALS

Estrogens may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued.

Norethindrone acetate and ethinyl estradiol tablets therapy consists of a single tablet to be taken orally once daily.

Inform postmenopausal women of possible serious adverse reactions of estrogen plus progestin therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions (5.1, 5.2, 5.3)].

WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER AND PROBABLE DEMENTIA

See full prescribing information for complete boxed warning.

Estrogen Plus Progestin Therapy

• Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia (5.1, 5.3)
• The Women's Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of stroke, deep vein thrombosis (DVT), pulmonary embolism (PE), and myocardial infarction (MI) (5.1)
• The WHI estrogen plus progestin substudy reported an increased risk of invasive breast cancer (5.2)
• The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.3)

Estrogen-Alone Therapy

• There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens (5.2)
• Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia (5.1, 5.3)
• The WHI estrogen-alone substudy reported increased risks of stroke and DVT (5.1)
• The WHIMS estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.3)

Inform postmenopausal women of possible less serious but common adverse reactions of estrogen plus progestin therapy such as headache, breast pain and tenderness, nausea and vomiting.