Merigest

Estradiol Valerate:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Patient information
• Merigest (Estradiol Valerate) reviews

INDICATIONS AND USAGE

Merigest (Estradiol Valerate) (estradiol valerate injection, USP) is indicated in the:

• 1.Treatment of moderate to severe vasomotor symptoms associated with the menopause.
• 2.Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.
• 3.Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
• 4.Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).

CONTRAINDICATIONS

Merigest (Estradiol Valerate) should not be used in women with any of the following conditions:

• 1.Undiagnosed abnormal genital bleeding.
• 2.Known, suspected, or history of cancer of the breast.
• 3.Known or suspected estrogen-dependent neoplasia.
• 4.Active deep vein thrombosis, pulmonary embolism or a history of these conditions.
• 5.Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction).
• 6.Liver dysfunction or disease.
• 7.DELESTROGEN should not be used in patients with known hypersensitivity to its ingredients.
• 8.Known or suspected pregnancy. There is no indication for Merigest (Estradiol Valerate) in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy. (See PRECAUTIONS ).

WARNINGS

See BOXED WARNINGS.

The use of unopposed estrogens in women who have a uterus is associated with an increased risk of endometrial cancer.

1. Cardiovascular disorders

Estrogen and estrogen/progestin therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism. Should any of these occur or be suspected, estrogens should be discontinued immediately.

Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.

a. Coronary heart disease and stroke

In the Women's Health Initiative (WHI) study, an increase in the number of myocardial infarctions and strokes has been observed in women receiving CE compared to placebo. These observations are preliminary. (See CLINICAL PHARMACOLOGY, Clinical Studies ).

In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as non-fatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs. 30 per 10,000 women-years). The increase in risk was observed in year one and persisted.

In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs. 21 per 10,000 women-years). The increase in risk was observed after the first year and persisted.

In postmenopausal women with documented heart disease (n=2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with CE/MPA (0.625mg/2.5mg per day) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in HERS, HERS II, and overall.

Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.

b. Venous thromboembolism

In the Women's Health Initiative (WHI) study, an increase in VTE has been observed in women receiving CE compared to placebo. These observations are preliminary. (See CLINICAL PHARMACOLOGY, Clinical Studies .)

In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the CE/MPA group compared to 16 per 10,000 women-years in the placebo group. The increase in VTE risk was observed during the first year and persisted.

If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

2. Malignant neoplasms

a. Endometrial cancer

The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than one year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five to ten years or more and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

b. Breast cancer

The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women's Health Initiative substudy of CE/MPA (see CLINICAL PHARMACOLOGY, Clinical Studies ). The results from observational studies are generally consistent with those of the WHI clinical trial and report no significant variation in the risk of breast cancer among different estrogens or progestins, doses, or routes of administration.

The CE/MPA substudy of WHI reported an increased risk of breast cancer in women who took CE/MPA for a mean follow-up of 5.6 years. Observational studies have also reported an increased risk for estrogen/progestin combination hormone therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. In the WHI trial and from observational studies, the excess risk increased with duration of use. From observational studies, the risk appeared to return to baseline in about five years after stopping treatment. In addition, observational studies suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen/progestin combination therapy as compared to estrogen alone therapy.

In the CE/MPA substudy, 26% of the women reported prior use of estrogen alone and/or estrogen/progestin combination therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01-1.54), and the overall absolute risk was 41 vs. 33 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years for CE/MPA compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups.

The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.

3. Dementia

In the Women's Health Initiative Memory Study (WHIMS), 4,532 generally healthy postmenopausal women 65 years of age and older were studied, of whom 35% were 70 to 74 years of age and 18% were 75 or older. After an average follow-up of 4 years, 40 women being treated with CE/MPA (1.8%, n = 2,229) and 21 women in the placebo group (0.9%, n = 2,303) received diagnoses of probable dementia. The relative risk for CE/MPA versus placebo was 2.05 (95% confidence interval 1.21 – 3.48), and was similar for women with and without histories of menopausal hormone use before WHIMS. The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years, and the absolute excess risk for CE/MPA was 23 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use ).

It is unknown whether these findings apply to estrogen alone therapy.

4. Gallbladder disease

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

5. Hypercalcemia

Estrogen administration may lead to severe hypercalcemia in patients 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.

6. Visual abnormalities

Retinal vascular thrombosis has been reported in patients 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.

PRECAUTIONS

A. GENERAL

1. Addition of a progestin when a woman has not had a hysterectomy

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 a possible increased risk of breast cancer.

2. Elevated blood pressure

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. Blood pressure should be monitored at regular intervals with estrogen use.

3. Hypertriglyceridemia

In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.

4. Impaired liver function and past history of cholestatic jaundice

Estrogens may be poorly metabolized in patients with impaired liver function. For patients 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.

5. Hypothyroidism

Estrogen administration leads to increased thyroid-binding globulin levels. Patients 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. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

6. Fluid retention

Because estrogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.

7. Hypocalcemia

Estrogens should be used with caution in individuals with severe hypocalcemia.

8. Ovarian cancer

The CE/MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 but was not statistically significant. The absolute risk for CE/MPA versus placebo was 4.2 versus 2.7 cases per 10,000 women-years.

A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risks associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.50); there was no difference in the risk estimates by duration of the exposure (less than 5 years [median of 3 years] vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI 1.27-1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.

9. Exacerbation of endometriosis

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

10. Exacerbation of other conditions

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

11. Hypercoagulability

Some studies have shown that women taking estrogen replacement therapy have hypercoagulability, primarily related to decreased antithrombin activity. This effect appears dose- and duration-dependent and is less pronounced than that associated with oral contraceptive use. Also, postmenopausal women tend to have increased coagulation parameters at baseline compared to premenopausal women. There is some suggestion that low dose postmenopausal mestranol may increase the risk of thromboembolism, although the majority of studies report no such increase.

12. Uterine bleeding and mastodynia

Certain patients may develop undesirable manifestations of estrogenic stimulation, such as abnormal uterine bleeding and mastodynia.

B. Patient Information

Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe Merigest.

C. Laboratory Tests

Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response rather than by serum hormone levels (e.g., estradiol, FSH).

D. Drug/Laboratory Test Interactions

• 1.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.
• 2.Increased thyroid-binding globulin 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. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.
• 3.Other binding proteins may be elevated in serum (i.e., corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG)) leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
• 4.Increased plasma HDL and HDL₂ cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.
• 5.Impaired glucose tolerance.
• 6.Reduced response to metyrapone test.

E. Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. (See BOXED WARNINGS, WARNINGS and PRECAUTIONS ).

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.

F. Pregnancy

Merigest should not be used during pregnancy. (See CONTRAINDICATIONS ).

G. Nursing Mothers

Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when Merigest (Estradiol Valerate) is administered to a nursing woman.

H. Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Large and repeated doses of estrogen over an extended period of time may accelerate epiphyseal closure. Therefore, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended in patients in whom bone growth is not complete.

I. Geriatric Use

Clinical studies of Merigest (Estradiol Valerate) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

In the Women's Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n = 3,729) were 65 to 74 while 18% (n = 803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Alzheimer's disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of the women that were older than 70. (See WARNINGS, Dementia ).

It is unknown whether these findings apply to estrogen alone therapy.

ADVERSE REACTIONS

See BOXED WARNINGS, WARNINGS, and PRECAUTIONS .

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. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

The following additional adverse reactions have been reported with estrogen and/or progestin therapy.

• 1.Genitourinary system
  

  Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; dysmenorrhea, increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer.
  

• 2.Breasts
  

  Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer.
  

• 3.Cardiovascular
  

  Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure.
  

• 4.Gastrointestinal
  

  Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis, enlargement of hepatic hemangiomas.
  

• 5.Skin
  

  Chloasma or melasma, which may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash.
  

• 6.Eyes
  

  Retinal vascular thrombosis; intolerance to contact lenses.
  

• 7.Central Nervous System
  

  Headache; migraine; dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia.
  

• 8.Miscellaneous
  

  Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthalgias; leg cramps; changes in libido; urticaria, angioedema, anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides.

For medical advice about adverse reactions contact your medical professional. To report SUSPECTED ADVERSE REACTIONS, contact Par Pharmaceutical, Inc. at 1-800-828-9393 or FDA at 1-800-FDA-1088 (1-800-332-1088) or www.fda.gov/medwatch.

OVERDOSAGE

Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing drug products by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females.

DOSAGE AND ADMINISTRATION

When estrogen is prescribed for a postmenopausal woman with a uterus, progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. 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. Patients should be reevaluated periodically as clinically appropriate (e.g., 3-month to 6-month intervals) to determine if treatment is still necessary (See BOXED WARNINGS and WARNINGS ). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.

Care should be taken to inject deeply into the upper, outer quadrant of the gluteal muscle following the usual precautions for intramuscular administration. By virtue of the low viscosity of the vehicles, the various preparations of Merigest (Estradiol Valerate) (estradiol valerate injection, USP) may be administered with a small gauge needle (i.e., 20 Gauge × 1 ½ inches long). Since the 40 mg potency provides a high concentration in a small volume, particular care should be observed to administer the full dose.

Merigest (Estradiol Valerate) should be visually inspected for particulate matter and color prior to administration; the solution is clear, colorless to pale yellow. Storage at low temperatures may result in the separation of some crystalline material which redissolves readily on warming.

Note: A dry needle and syringe should be used. Use of a wet needle or syringe may cause the solution to become cloudy; however, this does not affect the potency of the material.

Patients should be started at the lowest dose for the indication. The lowest effective dose of Merigest (Estradiol Valerate) has not been determined for any indication. Treated patients with an intact uterus should be monitored closely for signs of endometrial cancer, and appropriate diagnostic measures should be taken to rule out malignancy in the event of persistent or recurring abnormal vaginal bleeding. See PRECAUTIONS concerning addition of a progestin.

• 1.For treatment of moderate to severe vasomotor symptoms, vulvar and vaginal atrophy associated with the menopause, the lowest dose and regimen that will control symptoms should be chosen and medication should be discontinued as promptly as possible.
  

  
  

  The usual dosage is 10 to 20 mg Merigest (Estradiol Valerate) every four weeks.
  

  
  

  Attempts to discontinue or taper medication should be made at 3-month to 6-month intervals.
  

  
  

• 2.For treatment of female hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.
  

  
  

  The usual dosage is 10 to 20 mg Merigest (Estradiol Valerate) every four weeks.
  

  
  

• 3.For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation only.
  

  
  

  The usual dosage is 30 mg or more administered every one or two weeks.
  

  
  

HOW SUPPLIED

Merigest ^® (estradiol valerate injection, USP)

Multiple Dose Vials

• 10 mg/mL (5 mL): NDC 42023-110-01
• 20 mg/mL (5 mL): NDC 42023-111-01
• 40 mg/mL (5 mL): NDC 42023-112-01

STORAGE

Store between 20° to 25°C (68° to 77°F).

Keep out of reach of children.

PATIENT INFORMATION

Merigest (Estradiol Valerate)^®

(estradiol valerate injection, USP)

Read this PATIENT INFORMATION before you start taking Merigest (Estradiol Valerate) and read what you get each time you refill Merigest (Estradiol Valerate). There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT Merigest (Estradiol Valerate) (AN ESTROGEN HORMONE)?

• -Estrogens increase the chances of getting cancer of the uterus.
  

  Report any unusual vaginal bleeding right away while you are taking estrogens. 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.

• -Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or strokes.
  

  Using estrogens with or without progestins may increase your chances of getting heart attacks, strokes, breast cancer, and blood clots. Using estrogens with progestins may increase your risk of dementia. You and your healthcare provider should talk regularly about whether you still need treatment with Merigest (Estradiol Valerate).

What is Merigest (Estradiol Valerate)?

Merigest (Estradiol Valerate) is a medicine that contains estrogen hormones.

What is Merigest (Estradiol Valerate) used for?

Merigest (Estradiol Valerate) is used after menopause to:

• -reduce moderate to severe hot flashes. Estrogens are hormones made by a woman's ovaries. The ovaries normally stop making estrogens when a woman is between 45 to 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 the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feeling of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating ("hot flashes" or "hot flushes"). In some women, the symptoms are mild, and they will not need estrogens. In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether you still need treatment with Merigest (Estradiol Valerate).

• -treat moderate to severe dryness, itching, and burning in and around the vagina. You and your healthcare provider should talk regularly about whether you still need treatment with Merigest (Estradiol Valerate) to control these problems. If you use Merigest (Estradiol Valerate) only to treat your dryness, itching, and burning in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you.

Who should not take Merigest (Estradiol Valerate)?

Do not start taking Merigest (Estradiol Valerate) if you:

• -have unusual vaginal bleeding.
• -currently have or have had certain cancers. Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or had cancer, talk with your healthcare provider about whether you should take Merigest (Estradiol Valerate).
• -had a stroke or heart attack in the past year.
• -currently have or have had blood clots.
• -currently have or have had liver problems.
• -are allergic to Merigest (Estradiol Valerate) or any of its ingredients. See the end of this leaflet for a list of ingredients in Merigest (Estradiol Valerate).
• -think you may be pregnant.

Tell your healthcare provider:

• -if you are breastfeeding. The hormone in Merigest (Estradiol Valerate) can pass into your milk.
• -about all of your medical problems. Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.
• -about all the medicines you take. This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how Merigest (Estradiol Valerate) works. Merigest (Estradiol Valerate) may also affect how your other medicines work.
• -if you are going to have surgery or will be on bed rest. You may need to stop taking estrogens.

How should I take Merigest (Estradiol Valerate)?

Merigest (Estradiol Valerate) should be injected deeply into the upper, outer quadrant of the gluteal muscle following the usual precautions for intramuscular administration. By virtue of the low viscosity of the vehicles, the various preparations of Merigest (Estradiol Valerate) (estradiol valerate injection, USP) may be administered with a small gauge needle (i.e., 20 Gauge × 1 ½ inches long). Since the 40 mg potency provides a high concentration in a small volume, particular care should be observed to administer the full dose.

Merigest (Estradiol Valerate) should be visually inspected for particulate matter and color prior to administration; the solution is clear, colorless to pale yellow. Storage at low temperatures may result in the separation of some crystalline material which redissolves readily on warming.

Note: A dry needle and syringe should be used. Use of a wet needle or syringe may cause the solution to become cloudy; however, this does not affect the potency of the material.

• 1.Start at the lowest dose and talk to your healthcare provider about how well that dose is working for you.
• 2.Estrogens should be used at the lowest dose possible for your treatment only as long as needed. The lowest effective dose of Merigest (Estradiol Valerate) has not been determined. You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about the dose you are taking and whether you still need treatment with Merigest (Estradiol Valerate).

How should I dispose of used syringes and needles?

• 1.Do not re-use needles or syringes.
• 2.Do not throw the needles and syringes in household waste. These should be discarded into an appropriate container (such as a sharps container) immediately after use. Refer to state or local laws and regulations for appropriate container requirements.
• 3.Make sure the container is tightly capped.
• 4.Strategically place the container so as to minimize handling and keep out of the reach of children.
• 5.Label the container indicating the presence of used needles/sharps.
• 6.For disposal of containers containing used needles and syringes refer to the state or local laws and regulations or as instructed by your healthcare provider or pharmacist.
• 7.Refer to your health care provider or pharmacist for guidance, and for additional information contact the Coalition for Safe Community Needle Disposal online at

http://www.safeneedledisposal.org or refer to the FDA website Needles and Other Sharps at http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/HomeHealthandConsumer/ConsumerProducts/Sharps/default.htm

How should I dispose of expired or unused Merigest (Estradiol Valerate)?

• 1.Do not flush unused Merigest (Estradiol Valerate) or pour down the sink or drain.
• 2.Refer to the state or local laws and regulations for the safest and proper disposal of injectable medications. Contact your city or county government’s household trash and recycling service to find out if a drug take-back program is available in your community. You can also refer to your health care provider or pharmacist for guidance.
• 3.For additional information refer to the following FDA websites:

Disposal of Unused Medicines: What You Should Know

http://www.fda.gov/drugs/resourcesforyou/consumers/buyingusingmedicinesafely/ensuringsafeuseofmedicine/safedisposalofmedicines/ucm186187.htm

How to Dispose of Unused Medicines http://www.fda.gov/downloads/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/UnderstandingOver-the-CounterMedicines/ucm107163.pdf

What are the possible side effects of estrogens?

Less common but serious side effects include:

• -Breast cancer
• -Cancer of the uterus
• -Stroke
• -Heart attack
• -Blood clots
• -Dementia
• -Gallbladder disease
• -Ovarian cancer

These are some of the warning signs of serious side effects:

• -Breast lumps
• -Unusual vaginal bleeding
• -Dizziness and faintness
• -Changes in speech
• -Severe headaches
• -Chest pain
• -Shortness of breath
• -Pains in your legs
• -Changes in vision
• -Vomiting

Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptom that concerns you.

Common side effects include:

• -Headache
• -Breast pain
• -Irregular vaginal bleeding or spotting
• -Stomach/abdominal cramps, bloating
• -Nausea and vomiting
• -Hair loss

Other side effects include:

• -High blood pressure
• -Liver problems
• -High blood sugar
• -Fluid retention
• -Enlargement of benign tumors of the uterus ("fibroids")
• -Vaginal yeast infection

These are not all the possible side effects of Merigest (Estradiol Valerate). For more information, ask your healthcare provider or pharmacist.

What can I do to lower my chances of a serious side effect with Merigest (Estradiol Valerate)?

Talk with your healthcare provider regularly about whether you should continue taking Merigest (Estradiol Valerate). If you have a uterus, talk to your healthcare provider about whether the addition of a progestin is right for you. See your healthcare provider right away if you get vaginal bleeding while taking Merigest (Estradiol Valerate). Have a 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, 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.

General information about safe and effective use of Merigest (Estradiol Valerate)

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take Merigest (Estradiol Valerate) for conditions for which it was not prescribed. Do not give Merigest (Estradiol Valerate) to other people, even if they have the same symptoms you have. It may harm them.

Keep Merigest (Estradiol Valerate) out of the reach of children.

This leaflet provides a summary of the most important information about Merigest (Estradiol Valerate). If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Merigest (Estradiol Valerate) that is written for health professionals. You can get more information by calling the toll free number 1-800-828-9393.

What are the ingredients in Merigest (Estradiol Valerate)?

Merigest (Estradiol Valerate) is supplied in three 5 mL multiple dose vials; 10 mg/mL, 20 mg/mL, and 40 mg/mL strengths. The 10 mg/mL strength contains 10 mg Merigest (Estradiol Valerate) in a solution of chlorobutanol and sesame oil. The 20 mg/mL strength contains 20 mg Merigest (Estradiol Valerate) in a solution of benzyl benzoate, benzyl alcohol, and castor oil. The 40 mg/mL strength contains 40 mg Merigest (Estradiol Valerate) in a solution of benzyl benzoate, benzyl alcohol, and castor oil.

How should I store Merigest (Estradiol Valerate)?

Store Merigest (Estradiol Valerate) at room temperature between 20° to 25°C (68° to 77°F).

Manufactured by:

Par Pharmaceutical, Inc.

Chestnut Ridge, NY 10977

Revised: 08/17

OS110J-1-90-03

3001078H

NDC 42023-110-01

Merigest (Estradiol Valerate)^®

(estradiol valerate

injection, USP)

50 mg/5 mL

(10 mg/mL)

For Intramuscular Use Only

5 mL Multiple Dose Vial

NDC 42023-111-01

Merigest (Estradiol Valerate) ^®

(estradiol valerate

injection, USP)

100 mg/5 mL

(20 mg/mL)

For Intramuscular Use Only

• 5 mL Multiple Dose Vial

NDC 42023-112-01

Merigest (Estradiol Valerate)^®

(estradiol valerate

injection, USP)

200 mg/5 mL

(40 mg/mL)

For Intramuscular Use Only

• 5 mL Multiple Dose Vial

Norethindrone:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• Patient information
• Merigest (Norethindrone) reviews

DESCRIPTION

Merigest (Norethindrone)^® (norethindrone acetate tablets USP) - 5 mg oral tablets.

Merigest (Norethindrone)^® (norethindrone acetate tablets USP), (17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one acetate), a synthetic, orally active progestin, is the acetic acid ester of Merigest (Norethindrone). It is a white, or creamy white, crystalline powder. The structural formula is as follows:

C₂₂H₂₈O₃ M.W. 340.46

Merigest (Norethindrone)^® (norethindrone acetate tablets USP) contain the following inactive ingredients: anhydrous lactose, magnesium stearate, and microcrystalline cellulose.

Merigest (Norethindrone) Acetate structural formula

CLINICAL PHARMACOLOGY

Merigest acetate induces secretory changes in an estrogen-primed endometrium. On a weight basis, it is twice as potent as Merigest (Norethindrone).

Pharmacokinetics

Absorption

Merigest acetate is completely and rapidly deacetylated to Merigest (Norethindrone) (NET) after oral administration, and the disposition of Merigest (Norethindrone) acetate is indistinguishable from that of orally administered Merigest (Norethindrone). Merigest (Norethindrone) acetate is rapidly absorbed from Merigest (Norethindrone) tablets, with maximum plasma concentration of Merigest (Norethindrone) generally occurring at about 2 hours post-dose. The pharmacokinetic parameters of Merigest (Norethindrone) following single oral administration of Merigest (Norethindrone) in 29 healthy female volunteers are summarized in Table 1.

Figure 1. Mean Plasma Concentration Profile after a Single Dose of 5 mg Administered to 29 Healthy Female Volunteers under Fasting Conditions

Figure 1

Effect of Food

The effect of food administration on the pharmacokinetics of Merigest (Norethindrone) has not been studied.

Distribution

Merigest is 36% bound to sex hormone-binding globulin (SHBG) and 61% bound to albumin. Volume of distribution of Merigest (Norethindrone) is about 4 L/kg.

Metabolism

Merigest (Norethindrone) undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites.

Excretion

Plasma clearance value for Merigest is approximately 0.4 L/hr/kg. Merigest (Norethindrone) is excreted in both urine and feces, primarily as metabolites. The mean terminal elimination half-life of Merigest (Norethindrone) following a single dose administration of Merigest (Norethindrone) is approximately 9 hours.

Special Populations

Geriatrics

The effect of age on the pharmacokinetics of Merigest after Merigest (Norethindrone) administration has not been evaluated.

Race

The effect of race on the disposition of Merigest (Norethindrone) after Merigest (Norethindrone) administration has not been evaluated.

Renal Insufficiency

The effect of renal disease on the disposition of Merigest after Merigest (Norethindrone) administration has not been evaluated. In premenopausal women with chronic renal failure undergoing peritoneal dialysis who received multiple doses of an oral contraceptive containing ethinyl estradiol and Merigest (Norethindrone), plasma Merigest (Norethindrone) concentration was unchanged compared to concentrations in premenopausal women with normal renal function.

Hepatic Insufficiency

The effect of hepatic disease on the disposition of Merigest (Norethindrone) after Merigest (Norethindrone) administration has not been evaluated. However, Merigest (Norethindrone) is contraindicated in markedly impaired liver function or liver disease.

Drug Interactions

No pharmacokinetic drug interaction studies investigating any drug-drug interactions with Merigest (Norethindrone) have been conducted.

INDICATIONS AND USAGE

Merigest (Norethindrone) (norethindrone acetate tablets USP) is indicated for the treatment of secondary amenorrhea, endometriosis, and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as submucous fibroids or uterine cancer. Merigest (Norethindrone) (norethindrone acetate tablets USP) is not intended, recommended or approved to be used with concomitant estrogen therapy in postmenopausal women for endometrial protection.

CONTRAINDICATIONS

• Known or suspected pregnancy. There is no indication for Merigest (Norethindrone) in pregnancy. (See PRECAUTIONS .)
• Undiagnosed vaginal bleeding
• Known, suspected or history of cancer of the breast
• Active deep vein thrombosis, pulmonary embolism or history of these conditions
• Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction)
• Impaired liver function or liver disease
• As a diagnostic test for pregnancy
• Hypersensitivity to any of the drug components

WARNINGS

• Cardiovascular Disorders
  

  Patients with risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.

• Visual Abnormalities
  

  Discontinue medication pending examination if there is a sudden partial or complete loss of vision or if there is sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, medication should be discontinued.

PRECAUTIONS

General

• Because this drug may cause some degree of fluid retention, conditions which might be influenced by this factor, such as epilepsy, migraine, cardiac or renal dysfunctions, require careful observation.
• In cases of breakthrough bleeding, and in all cases of irregular bleeding per vagina, nonfunctional causes should be borne in mind. In cases of undiagnosed vaginal bleeding, adequate diagnostic measures are indicated.
• Patients who have a history of clinical depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree.
• Data suggest that progestin therapy may have adverse effects on lipid and carbohydrate metabolism. The choice of progestin, its dose, and its regimen may be important in minimizing these adverse effects, but these issues will require further study before they are clarified. Women with hyperlipidemias and/or diabetes should be monitored closely during progestin therapy.
• The pathologist should be advised of progestin therapy when relevant specimens are submitted.

Information for the Patient

Healthcare providers are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe Merigest.

Drug/Laboratory Tests Interactions

The following laboratory test results may be altered by the use of estrogen/progestin combination drugs:

• 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 X_a 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. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.
• Other binding proteins may be elevated in serum (i.e., corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG)) leading to increased circulating corticosteroid and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
• Increased plasma HDL and HDL₂ cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.
• Impaired glucose metabolism.
• Reduced response to metyrapone test.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Some beagle dogs treated with medroxyprogesterone acetate developed mammary nodules. Although nodules occasionally appeared in control animals, they were intermittent in nature, whereas nodules in treated animals were larger and more numerous, and persisted. There is no general agreement as to whether the nodules are benign or malignant. Their significance with respect to humans has not been established.

Pregnancy

Category X

Merigest acetate is contraindicated during pregnancy as it may cause fetal harm when administered to pregnant women. Several reports suggest an association between intrauterine exposure to progestational drugs in the first trimester of pregnancy and congenital abnormalities in male and female fetuses. Some progestational drugs induce mild virilization of the external genitalia of female fetuses.

Nursing Mothers

Detectable amounts of progestins have been identified in the milk of mothers receiving them. Caution should be exercised when progestins are administered to a nursing woman.

Pediatric Use

Merigest (Norethindrone) tablets are not indicated in children.

ADVERSE REACTIONS

See WARNINGS and PRECAUTIONS .

The following adverse reactions have been observed in women taking progestins:

• Breakthrough bleeding
• Spotting
• Change in menstrual flow
• Amenorrhea
• Edema
• Changes in weight (decreases, increases)
• Changes in the cervical squamo-columnar junction and cervical secretions
• Cholestatic jaundice
• Rash (allergic) with and without pruritus
• Melasma or chloasma
• Clinical depression
• Acne
• Breast enlargement/tenderness
• Headache/migraine
• Urticaria
• Abnormalities of liver tests (i.e., AST, ALT, Bilirubin)
• Decreased HDL cholesterol and increased LDL/HDL ratio
• Mood swings
• Nausea
• Insomnia
• Anaphylactic/anaphylactoid reactions
• Thrombotic and thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, retinal vascular thrombosis, cerebral thrombosis and embolism)
• Optic neuritis (which may lead to partial or complete loss of vision)

DOSAGE AND ADMINISTRATION

Therapy with Merigest must be adapted to the specific indications and therapeutic response of the individual patient.

Secondary amenorrhea, abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology

2.5 to 10 mg Merigest (Norethindrone) may be given daily for 5 to 10 days to produce secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen.

Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing Merigest (Norethindrone) therapy. Patients with a past history of recurrent episodes of abnormal uterine bleeding may benefit from planned menstrual cycling with Merigest (Norethindrone).

Endometriosis

Initial daily dosage of 5 mg Merigest (Norethindrone) for two weeks. Dosage should be increased by 2.5 mg per day every two weeks until 15 mg per day of Merigest (Norethindrone) is reached. Therapy may be held at this level for six to nine months or until annoying breakthrough bleeding demands temporary termination.

HOW SUPPLIED

Merigest (Norethindrone)^® (norethindrone acetate tablets USP) is available as:

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Store at 20º to 25ºC (68º to 77ºF).

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

TEVA WOMEN’S HEALTH, INC.

Subsidiary of TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Rev. A 10/2015

PATIENT INFORMATION

Merigest (Norethindrone)^®

(norethindrone acetate tablets USP)

Read this PATIENT INFORMATION before you start taking Merigest (Norethindrone) and read what you get each time you refill Merigest (Norethindrone). There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition.

What is the most important information I should know about Merigest (Norethindrone) (A Progestin Hormone)?

• Do not use Merigest (Norethindrone) if you are pregnant, breastfeeding or are trying to conceive.
• Do not use Merigest (Norethindrone) if you have had a previous blood clot, stroke, or heart attack.
• Do not use Merigest (Norethindrone) if you are postmenopausal.

What is Merigest (Norethindrone)?

Merigest (Norethindrone) is similar to the progesterone hormones naturally produced by the body. Your healthcare provider may provide Merigest (Norethindrone) as individual tablets.

What are Merigest (Norethindrone) used for?

Merigest (Norethindrone) are used for the treatment of secondary amenorrhea (absence of menstrual periods in women who have previously had a menstrual period who are not pregnant), the treatment of endometriosis, and the treatment of irregular menstrual periods due to hormone imbalance.

Who should not take Merigest (Norethindrone)?

You should not take Merigest (Norethindrone) if you are postmenopausal, pregnant or breastfeeding.

You should not take Merigest (Norethindrone) if you have the following conditions:

• Known or suspected pregnancy. Merigest (Norethindrone) are not indicated during pregnancy as it may cause fetal harm when administered to pregnant women. There is an increased risk of minor birth defects in children whose mothers take Merigest (Norethindrone) during the first 4 months of pregnancy (mild masculinization of the external genitalia of the female fetus, as well as hypospadias in the male fetus). If you take Merigest (Norethindrone) and later find out you were pregnant, talk with your healthcare provider right away.
• History of blood clots in the legs, lungs, eyes, brain, or elsewhere, or a past history of these conditions
• Liver impairment or disease
• Known or suspected cancer of the breast. If you have or had cancer of the breast, talk with your healthcare provider about whether you should take Merigest (Norethindrone).
• Undiagnosed vaginal bleeding
• Hypersensitivity to Merigest (Norethindrone). See the end of this leaflet for a list of all of the ingredients in Merigest (Norethindrone).

What are the risks associated with Merigest (Norethindrone)?

• Risk to the Fetus

Merigest (Norethindrone) should not be used if you are pregnant. Merigest (Norethindrone) are contraindicated during pregnancy as it may cause fetal harm when administered to pregnant women. There is an increased risk of minor birth defects in children whose mothers take this drug during the first 4 months of pregnancy. Several reports suggest an association between mothers who take these drugs in the first trimester of pregnancy and congenital abnormalities in male and female babies. Although it is not clear that these events were drug related, you should check with your healthcare provider about the risks to your unborn child of any medication taken during pregnancy.

You should avoid using Merigest (Norethindrone) during pregnancy. If you take Merigest (Norethindrone) and later find you were pregnant when you took it, be sure to discuss this with your healthcare provider as soon as possible.

• Abnormal Blood Clotting

Use of progestational drugs, such as Merigest (Norethindrone), has been associated with changes in the blood-clotting system. These changes allow the blood to clot more easily, possibly allowing clots to form in the bloodstream. If blood clots do form in your bloodstream, they can cut off the blood supply to vital organs, causing serious problems. These problems may include a stroke (by cutting off blood to part of the brain), a heart attack (by cutting off blood to part of the heart), a pulmonary embolus (by cutting off blood to part of the lungs), visual loss or blindness (by cutting off blood vessels in the eye), or other problems. Any of these conditions may cause death or serious long-term disability. Call your healthcare provider right away if you suspect you have any of these conditions. He or she may advise you to stop using the drug.

• Eye Abnormalities

Discontinue Merigest (Norethindrone) tablets and call your healthcare provider right away if you experience sudden partial or complete loss of vision, blurred vision, or sudden onset of bulging eyes, double vision, or migraine.

These are some of the warning signs of serious side effects with progestin therapy

• Breast lumps
• Dizziness and faintness
• Changes in speech
• Severe headaches
• Chest pain
• Shortness of breath
• Pains in your legs
• Changes in vision

Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptom that concerns you.

Common side effects include

• Headache
• Breast pain
• Irregular vaginal bleeding or spotting
• Stomach/abdominal cramps/bloating
• Nausea and vomiting
• Hair loss

Other side effects include

• High blood pressure
• Liver problems
• High blood sugar
• Fluid retention
• Enlargements of benign tumors of the uterus (“fibroids”)
• Vaginal yeast infections
• Mental depression

These are not all the possible side effects of progestin and/or estrogen therapy. For more information, ask your healthcare provider or pharmacist.

What can I do to lower my chances of getting a serious side effect with Merigest (Norethindrone)?

• Talk with your healthcare provider regularly about whether you should continue taking Merigest (Norethindrone).
• Have a 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, 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 of getting heart attacks.

General information about the safe and effective use of Merigest (Norethindrone)

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take Merigest (Norethindrone) for conditions for which it was not prescribed. Do not give Merigest (Norethindrone) tablets to other people, even if they have the same symptoms you have. It may harm them.

Keep Merigest (Norethindrone) out of the reach of children.

This leaflet provides a summary of the most important information about progestin and/or estrogen therapy. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Merigest (Norethindrone) that is written for health professionals.

What are the ingredients in Merigest (Norethindrone)?

Merigest (Norethindrone) contain the following inactive ingredients: anhydrous lactose, magnesium stearate, and microcrystalline cellulose.

TEVA WOMEN’S HEALTH, INC.

Subsidiary of TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Rev. A 10/2015

NDC 51285-424-10

Aygestin®

(norethindrone acetate

tablets USP)

ORALLY ACTIVE PROGESTIN

5 mg

PHARMACIST: PLEASE DISPENSE WITH

ATTACHED PATIENT INFORMATION LEAFLET.

Rx only

50 TABLETS

TEVA

TEVA WOMEN’S HEALTH