Divina

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What are the side effects you encounter while taking this medicine?

Divina uses

Divina consists of Estradiol Valerate, Medroxyprogesterone Acetate.

Estradiol Valerate:


INDICATIONS AND USAGE

Divina (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

Divina (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 Divina (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 ).
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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.

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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 Divina.

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

Divina 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 Divina (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 Divina (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.

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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.

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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 Divina (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.

Divina (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 Divina (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 Divina (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 Divina (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

Divina ® (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

Divina (Estradiol Valerate)®

(estradiol valerate injection, USP)

Read this PATIENT INFORMATION before you start taking Divina (Estradiol Valerate) and read what you get each time you refill Divina (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 Divina (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 Divina (Estradiol Valerate).


What is Divina (Estradiol Valerate)?

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

What is Divina (Estradiol Valerate) used for?

Divina (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 Divina (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 Divina (Estradiol Valerate) to control these problems. If you use Divina (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 Divina (Estradiol Valerate)?

Do not start taking Divina (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 Divina (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 Divina (Estradiol Valerate) or any of its ingredients. See the end of this leaflet for a list of ingredients in Divina (Estradiol Valerate).
  • -think you may be pregnant.

Tell your healthcare provider:

  • -if you are breastfeeding. The hormone in Divina (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 Divina (Estradiol Valerate) works. Divina (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 Divina (Estradiol Valerate)?

Divina (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 Divina (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.

Divina (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 Divina (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 Divina (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 Divina (Estradiol Valerate)?

  • 1.Do not flush unused Divina (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 Divina (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 Divina (Estradiol Valerate)?

Talk with your healthcare provider regularly about whether you should continue taking Divina (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 Divina (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 Divina (Estradiol Valerate)

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

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

This leaflet provides a summary of the most important information about Divina (Estradiol Valerate). If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Divina (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 Divina (Estradiol Valerate)?

Divina (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 Divina (Estradiol Valerate) in a solution of chlorobutanol and sesame oil. The 20 mg/mL strength contains 20 mg Divina (Estradiol Valerate) in a solution of benzyl benzoate, benzyl alcohol, and castor oil. The 40 mg/mL strength contains 40 mg Divina (Estradiol Valerate) in a solution of benzyl benzoate, benzyl alcohol, and castor oil.

How should I store Divina (Estradiol Valerate)?

Store Divina (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

Divina (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

Divina (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

Divina (Estradiol Valerate)®

(estradiol valerate

injection, USP)

200 mg/5 mL

(40 mg/mL)

For Intramuscular Use Only

  • 5 mL Multiple Dose Vial

Medroxyprogesterone Acetate:


INDICATIONS AND USAGE

Divina (Medroxyprogesterone Acetate) Tablets USP are a progestin indicated for the treatment of secondary amenorrhea and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as fibroids or uterine cancer. Divina (Medroxyprogesterone Acetate) Tablets USP are also indicated to reduce the incidence of endometrial hyperplasia in nonhysterectomized postmenopausal women receiving daily oral conjugated estrogens 0.625 mg tablets.

CONTRAINDICATIONS

Divina (Medroxyprogesterone Acetate) Tablets USP should not be used in women with any of the following conditions:

  • Undiagnosed abnormal genital bleeding.
  • Known, suspected, or history of cancer of the breast.
  • Known or suspected estrogen- or progesterone-dependent neoplasia.
  • Active deep vein thrombosis, pulmonary embolism or a history of these conditions.
  • Active or recent (within the past year) arterial thromboembolic disease (for example, stroke and myocardial infarction).
  • Known liver dysfunction or disease.
  • Missed abortion.
  • As a diagnostic test for pregnancy.
  • Known hypersensitivity to the ingredients in Divina (Medroxyprogesterone Acetate) tablets.
  • Known or suspected pregnancy.

WARNINGS

1. Cardiovascular Disorders.

An increased risk of stroke, deep vein thrombosis, pulmonary embolism, and myocardial infarction has been reported with estrogen plus progestin therapy. Should any of these events occur or be suspected, estrogen plus 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 (for example, personal history or family history of venous thromboembolism [VTE]), obesity, and systemic lupus erythematosus should be managed appropriately.

a. Stroke

In the estrogen plus progestin substudy of the Women’s Health Initiative (WHI) a statistically significant increased risk of stroke was reported in women receiving daily conjugated estrogens (CE 0.625 mg) plus Divina (Medroxyprogesterone Acetate) (MPA 2.5 mg) compared to women receiving placebo (31 versus 24 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted.

b. Coronary heart disease

In the estrogen plus progestin substudy of WHI, no statistically significant increase of CHD events. An increase in relative risk was demonstrated in year one, and a trend toward decreasing relative risk was reported in years 2 through 5.

In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estro- gen/Progestin Replacement Study [HERS]), treatment with daily CE 0.625 mg/ MPA 2.5 mg 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 (2,321) 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.

c. Venous thromboembolism (VTE)

In the estrogen plus progestin substudy of WHI, a statistically significant two-fold greater rate of VTE, (DVT and pulmonary embolism [PE]), was reported in women receiving daily CE/MPA compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was observed during the first year and persisted.

2. Malignant Neoplasms

a. Breast cancer

The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer in some studies. Observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. The risk increased with duration of use and appeared to return to baseline in about 5 years after stopping treatment. Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogens or among different estrogen plus progestin combinations, doses, or routes of administration.

The most important randomized clinical trial providing information about this issue is the Women’s Health Initiative (WHI) substudy of daily conjugated estrogens (CE 0.625 mg) plus Divina (Medroxyprogesterone Acetate) (MPA 2.5 mg)

In the estrogen plus progestin substudy of WHI, after a mean follow-up of 5.6 years, the WHI substudy reported an increased risk of breast cancer in women who took daily CE/MPA. In this substudy, prior use of estrogen alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24 (95 percent nominal confidence interval [nCI], 1.01 to 1.54), and the absolute risk was 41 versus 33 cases per 10,000 women-years, for estrogen plus progestin compared with placebo, respectively. 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 versus 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 versus 36 cases per 10,000 women-years, for estrogen plus progestin 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 health care provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.

b. Endometrial cancer

An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12 times greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women using estrogen plus progestin therapy 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.

c. Ovarian cancer

The estrogen plus progestin substudy of WHI reported that daily CE/MPA 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 was 4.2 versus 2.7 cases per 10,000 women-years.

3. Dementia

In the estrogen plus progestin Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 4,532 postmenopausal women aged 65 to 79 years was randomized to daily conjugated estrogens (CE 0.625 mg) plus Divina (Medroxyprogesterone Acetate) (MPA 2.5 mg) or placebo.

After an average follow-up of 4 years, 40 women in the CE/MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE/MPA versus placebo was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women.

4. Visual Abnormalities

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, medication should be permanently discontinued.

PRECAUTIONS

A. General

  • 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, adverse effects on lipoprotein metabolism and impairment of glucose tolerance.

  • Undiagnosed abnormal vaginal bleeding

    In cases of undiagnosed abnormal vaginal bleeding, adequate diagnostic measures are indicated.

  • Elevated blood pressure

    Blood pressure should be monitored at regular intervals with estrogen plus progestin therapy.

  • Hypertriglyceridemia

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

  • Impaired liver function and past history of cholestatic jaundice

    Estrogens plus progestins 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.

  • Fluid Retention

    Progestins may cause some degree of fluid retention. Patients who have conditions which might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogen plus progestin are prescribed.

  • Hypocalcemia

    Estrogen plus progestin therapy should be used with caution in individuals with severe hypocalcemia.

  • Exacerbation of other conditions

    Estrogen plus progestin 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.

B. Patient Information

Physicians are advised to discuss the Patient Information leaflet with patients for whom they prescribe Divina (Medroxyprogesterone Acetate).

There may be an increased risk of minor birth defects in children whose mothers are exposed to progestins during the first trimester of pregnancy. The possible risk to the male baby is hypospadias, a condition in which the opening of the penis is on the underside rather than the tip of the penis. This condition occurs naturally in approximately 5 to 8 per 1,000 male births. The risk may be increased with exposure to Divina (Medroxyprogesterone Acetate). Enlargement of the clitoris and fusion of the labia may occur in female babies. However, a clear association between hypospadias, clitoral enlargement and labial fusion with use of Divina (Medroxyprogesterone Acetate) has not been established.

Inform the patient of the importance of reporting exposure to Divina (Medroxyprogesterone Acetate) in early pregnancy.

C. Drug/Laboratory Test Interactions

The following laboratory results may be altered by the use of estrogen plus progestin therapy:

  • 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 anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
  • Increased thyroid-binding globulin 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.

D. Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term intramuscular administration of Divina (Medroxyprogesterone Acetate) has been shown to produce mammary tumors in beagle dogs. There was no evidence of a carcinogenic effect associated with the oral administration of Divina (Medroxyprogesterone Acetate) to rats and mice. Divina (Medroxyprogesterone Acetate) was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays.

Divina (Medroxyprogesterone Acetate) at high doses is an antifertility drug and high doses would be expected to impair fertility until the cessation of treatment.

Long-term continuous administration of estrogen plus progestin therapy, has shown an increased risk of breast cancer and ovarian cancer.

E. Pregnancy

Teratogenic Effects

Pregnancy Category X

Divina should not be used during pregnancy.

There may be increased risks for hypospadias, clitoral enlargement and labial fusion in children whose mothers are exposed to Divina (Medroxyprogesterone Acetate) during the first trimester of pregnancy. However, a clear association between these conditions with use of Divina (Medroxyprogesterone Acetate) has not been established.

F. Nursing Mothers

Divina (Medroxyprogesterone Acetate) should not be used during lactation. Detectable amounts of progestin have been identified in the milk of nursing mothers receiving progestins.

G. Pediatric Use

Divina is not intended for pediatric use and no clinical data has been collected in children.

H. Geriatric Use

Of the total number of subjects in the estrogen plus progestin substudy of the Women’s Health Initiative (WHI), 44 percent (n = 7,320) were 65 years and older, while 6.6 percent (n = 1,095) were 75 years and older. In women 75 and older compared to women less than 75 years of age, there was a higher relative risk of non-fatal stroke and invasive breast cancer in the estrogen plus progestin group versus placebo. In women greater than 75 years of age, the increased risk of non-fatal stroke and invasive breast cancer observed in the estrogen plus progestin group compared to placebo was 75 versus 24 per 10,000 women-years and 52 versus 12 per 10,000 women-years, respectively.

In the estrogen plus progestin Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 4,532 postmenopausal women, aged 65 to 70 years, was randomized to receive daily CE 0.625 mg/MPA 2.5 mg or placebo. In the estrogen plus progestin group, after an average follow-up of 4 years, the relative risk (CE/MPA versus placebo) of probable dementia was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of developing probable dementia with CE/MPA was 45 versus 22 cases per 10,000 women-years compared with placebo.

Eighty-two percent of the cases of probable dementia occurred in women that were older than 70 in the CE/MPA group. The most common classification of probable dementia in the estrogen plus progestin and placebo groups was Alzheimer’s disease.

When data from the estrogen alone and estrogen plus progestin WHIMS substudies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19 to 2.60). Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women.

ADVERSE REACTIONS

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 following adverse reactions have been reported in women taking progestins, including Divina tablets, without concomitant estrogens treatment:

1. Genitourinary System

Abnormal uterine bleeding (irregular, increase, decrease), change in menstrual flow, breakthrough bleeding, spotting, amenorrhea, changes in cervical erosion and cervical secretions.

2. Breasts

Breast tenderness, mastodynia or galactorrhea has been reported.

3. Cardiovascular

Thromboembolic disorders including thrombophlebitis and pulmonary embolism have been reported.

4. Gastrointestinal

Nausea, cholestatic jaundice.

5. Skin

Sensitivity reactions consisting of urticaria, pruritus, edema and generalized rash have occurred. Acne, alopecia and hirsutism have been reported.

6. Eyes

Neuro-ocular lesions, for example, retinal thrombosis, and optic neuritis.

7. Central Nervous System

Mental depression, insomnia, somnolence, dizziness, headache, nervousness.

8. Miscellaneous

Hypersensitivity reactions, rash (allergic) with and without pruritus, change in weight (increase or decrease), pyrexia, edema/fluid retention, fatigue, decreased glucose tolerance.

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

1. Genitourinary System

Abnormal uterine bleeding/spotting, or flow; breakthrough bleeding; spotting; dysmenorrheal/pelvic pain; 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 that 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/anaplylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides.

OVERDOSAGE

Overdosage of estrogen plus progestin therapy may cause nausea and vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of CE/MPA together with institution of appropriate symptomatic care.

DOSAGE AND ADMINISTRATION

Secondary Amenorrhea

Divina Tablets USP may be given in dosages of 5 or 10 mg daily for 5 to 10 days. A dose for inducing an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen is 10 mg of Divina (Medroxyprogesterone Acetate) daily for 10 days. In cases of secondary amenorrhea, therapy may be started at any time. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing Divina (Medroxyprogesterone Acetate) therapy.

Abnormal Uterine Bleeding Due to Hormonal Imbalance in the Absence of Organic Pathology

Beginning on the calculated 16th or 21st day of the menstrual cycle, 5 or 10 mg of Divina (Medroxyprogesterone Acetate) may be given daily for 5 to 10 days. To produce an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen, 10 mg of Divina (Medroxyprogesterone Acetate) daily for 10 days beginning on the 16th day of the cycle is suggested. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing therapy with Divina (Medroxyprogesterone Acetate). Patients with a past history of recurrent episodes of abnormal uterine bleeding may benefit from planned menstrual cycling with Divina (Medroxyprogesterone Acetate).

Reduction of Endometrial Hyperplasia in Postmenopausal Women Receiving Daily 0.625 mg Conjugated Estrogens

When estrogen is prescribed for a postmenopausal woman with a uterus, a 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 re-evaluated periodically as clinically appropriate (for example, 3-month to 6-month intervals) to determine if treatment is still necessary. 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.

Divina (Medroxyprogesterone Acetate) Tablets USP may be given in dosages of 5 or 10 mg daily for 12 to 14 consecutive days per month, in postmenopausal women receiving daily 0.625 mg conjugated estrogens, either beginning on the 1st day of the cycle or the 16th day of the cycle.

Patients should be started at the lowest dose.

The lowest effective dose of Divina (Medroxyprogesterone Acetate) has not been determined.

HOW SUPPLIED

Divina (Medroxyprogesterone Acetate) Tablets, USP are available as:

2.5 mg: White, round, scored, biconvex tablet. Debossed with 555/872 on the scored side and stylized b on the other side.
Available in bottles of:
100 Tablets
500 Tablets
5 mg: White, round, scored, biconvex tablet. Debossed with 555/873 on the scored side and stylized b on the other side.
Available in bottles of:
100 Tablets
500 Tablets
10 mg: White, round, scored, biconvex tablet. Debossed with 555/779 on the scored side and stylized b on the other side.
Available in bottles of:
100 Tablets
500 Tablets

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

Store at 20° to 25°C (68° to 77°F).

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

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Iss. 4/2010

PATIENT INFORMATION

Read this PATIENT INFORMATION before you start taking Divina (Medroxyprogesterone Acetate) and read the patient information each time you refill your Divina (Medroxyprogesterone Acetate) prescription. There may be new information. This information does not take the place of talking to your health care provider about your medical condition or your treatment.

WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT Divina (Medroxyprogesterone Acetate) (A PROGESTIN HORMONE)?


* Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your health care 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 chance of getting heart attacks, strokes, breast cancer, and blood clots.

* Using estrogens with or without progestins may increase your risk of dementia, based on a study of women age 65 years or older.

You and your health care provider should talk regularly about whether you still need treatment with Divina (Medroxyprogesterone Acetate).

What is Divina (Medroxyprogesterone Acetate)?

Divina (Medroxyprogesterone Acetate) is a medicine that contains Divina (Medroxyprogesterone Acetate), a progestin hormone.

What is Divina (Medroxyprogesterone Acetate) used for?

Medroxyprogesterone Acetate is used to:

  • Treat menstrual periods that have stopped or to treat abnormal uterine bleeding. Women with a uterus who are not pregnant, who stop having regular menstrual periods or who begin to have irregular menstrual periods may have a drop in their progesterone level. Talk with your health care provider about whether Divina (Medroxyprogesterone Acetate) is right for you.
  • Reduce your chances of getting cancer of the uterus. In postmenopausal women with a uterus who use estrogens, taking progestin in combination with estrogen will reduce your chances of getting cancer of the uterus.

Who should not take Divina (Medroxyprogesterone Acetate)?

Do not start taking Divina (Medroxyprogesterone Acetate) if you:

  • Have undiagnosed vaginal bleeding
  • Currently have or have had certain cancers

Estrogen plus progestin may increase your chance of getting certain cancers, including cancer of the breast. If you have or have had cancer, talk with your health care provider about whether you should use Divina (Medroxyprogesterone Acetate).

  • Had a stroke or heart attack in the past year
  • Currently have or have had blood clots
  • Currently have or have had liver problems
  • Think you may be pregnant

Tell your health care provider if you think that you may be pregnant or having a miscarriage. There may be an increased risk of minor birth defects in children whose mothers take this drug during the first 4 months of pregnancy. If you take Divina (Medroxyprogesterone Acetate) and later find out you were pregnant when you took it, be sure to discuss this with your doctor as soon as possible.

Divina (Medroxyprogesterone Acetate) should not be used as a test for pregnancy.

  • Are allergic to any of the ingredients in Divina (Medroxyprogesterone Acetate).

Tell your health care provider:

  • If you are breastfeeding. The hormone in Divina (Medroxyprogesterone Acetate) can pass into your breast milk.
  • About all of your medical problems. Your health care provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing); epilepsy (seizures); migraine headaches; endometriosis (severe pelvic pain); lupus; problems with your heart, liver, thyroid, or kidneys; or if you 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 Divina (Medroxyprogesterone Acetate) works. Divina (Medroxyprogesterone Acetate) may also affect how other medicines work.
  • If you are going to have surgery or will be on bed rest. If you are taking estrogen in addition to Divina (Medroxyprogesterone Acetate), you may need to stop taking estrogen and Divina (Medroxyprogesterone Acetate).

How should I take Divina (Medroxyprogesterone Acetate)?

Start at the lowest dose and talk to your health care provider about how well that dose is working for you. The lowest effective dose of Divina (Medroxyprogesterone Acetate) has not been determined.

You and your health care provider should talk regularly (every 3 to 6 months) about the dose you are taking and whether you still need treatment with Divina (Medroxyprogesterone Acetate).

  • Absence of menstrual period: Divina (Medroxyprogesterone Acetate) may be given in doses ranging from 5 to 10 mg daily for 5 to 10 days.
  • Abnormal Uterine Bleeding: Divina (Medroxyprogesterone Acetate) may be given in doses ranging from 5 to 10 mg daily for 5 to 10 days.
  • Overgrowth of the lining of the uterus: When used in combination with oral conjugated estrogens in postmenopausal women with a uterus, Divina (Medroxyprogesterone Acetate) may be given in doses ranging from 5 or 10 mg daily for 12 to 14 straight days per month.

What are the possible side effects of Divina (Medroxyprogesterone Acetate)?

The following side effects have been reported with the use of Divina (Medroxyprogesterone Acetate) alone:

  • Breast tenderness
  • Breast milk secretion
  • Breakthrough bleeding
  • Spotting (minor vaginal bleeding)
  • Irregular periods
  • Amenorrhea (absence of menstrual periods)
  • Vaginal secretions
  • Headaches
  • Nervousness
  • Dizziness
  • Depression
  • Insomnia, sleepiness, fatigue
  • Premenstrual syndrome-like symptoms
  • Thrombophlebitis (inflamed veins)
  • Blood clot
  • Itching, hives, skin rash
  • Acne
  • Hair loss, hair growth
  • Abdominal discomfort
  • Nausea
  • Bloating
  • Fever
  • Increase in weight
  • Swelling
  • Changes in vision and sensitivity to contact lenses

The following side effects have been reported with the use of Divina (Medroxyprogesterone Acetate) with an estrogen.

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

Serious but less common side effects of estrogen include:

  • Breast cancer
  • Cancer of the uterus
  • Stroke
  • Heart attack
  • Blood clots
  • Dementia
  • Gallbladder disease
  • Ovarian cancer
  • High blood pressure
  • Liver problems
  • High blood sugar
  • Enlargement of benign tumors of the uterus (“fibroids”)

Some of the warning signs of these serious side effects include:

  • 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
  • Yellowing of the skin, eyes or nail beds

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

Less serious but common side effects include:

  • Headache
  • Breast pain
  • Irregular vaginal bleeding or spotting
  • Stomach/abdominal cramps, bloating
  • Nausea and vomiting
  • Hair loss
  • Fluid retention
  • Vaginal yeast infection

These are not all the possible side effects of Divina (Medroxyprogesterone Acetate) with or without estrogen. For more information, ask your health care provider or pharmacist.

What can I do to lower my chances of a serious side effect with Divina (Medroxyprogesterone Acetate)?

  • Talk with your health care provider regularly about whether you should continue taking Divina (Medroxyprogesterone Acetate). The addition of a progestin is generally recommended for women with a uterus to reduce the chance of getting cancer of the uterus.
  • See your health care provider right away if you get vaginal bleeding while taking Divina (Medroxyprogesterone Acetate).
  • Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your health care provider tells you otherwise. 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 a higher chance of getting heart disease. Ask your health care provider for ways to lower your chance of getting heart disease.

General information about safe and effective use of Divina (Medroxyprogesterone Acetate)

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

Keep Divina (Medroxyprogesterone Acetate) out of the reach of children.

This leaflet provides a summary of the most important information about Divina (Medroxyprogesterone Acetate). If you would like more information, talk with your health care provider or pharmacist. You can ask for information about Divina (Medroxyprogesterone Acetate) that is written for health professionals.

What are the ingredients in Divina (Medroxyprogesterone Acetate)?

Each Divina (Medroxyprogesterone Acetate) Tablet USP for oral administration contains 2.5 mg, 5 mg or 10 mg of Divina (Medroxyprogesterone Acetate).

Inactive ingredients: crospovidone, lactose monohydrate, magnesium stearate, methylcellulose, pregelatinized starch, and sodium lauryl sulfate.

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Iss. 4/2010

Medroxy - Progesterone 2.5mg

Structural Formula

Divina pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Divina available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Divina destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Divina Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Divina pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."DELESTROGEN (ESTRADIOL VALERATE) INJECTION [PAR PHARMACEUTICAL, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."MEDROXYPROGESTERONE ACETATE TABLET [BRYANT RANCH PREPACK]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."MEDROXYPROGESTERONE ACETATE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Divina?

Depending on the reaction of the Divina after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Divina not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Divina addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Divina, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Divina consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

Visitor reported useful

No survey data has been collected yet

Visitor reported side effects

No survey data has been collected yet

Visitor reported price estimates

No survey data has been collected yet

Visitor reported frequency of use

No survey data has been collected yet

One visitor reported doses

What is the dose of Divina drug you are taking?
According to the survey conducted among sdrugs.com website users, the maximum number of people are using the following dose 6-10mg. Few medications come in only one or two doses. Few are specific for adult dose and child dose. The dose of the medicine given to the patient depends on the severity of the symptom/disease. There can be dose adjustments made by the doctor, based on the progression of the disease. Follow-up is important.
Visitors%
6-10mg1
100.0%

Visitor reported time for results

No survey data has been collected yet

Visitor reported administration

No survey data has been collected yet

Six visitors reported age

Visitors%
30-452
33.3%
16-292
33.3%
46-601
16.7%
6-151
16.7%

Visitor reviews


There are no reviews yet. Be the first to write one!


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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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