Depo-Estradiol

See Boxed Warnings

Cardiovascular disorders

Estrogen and estrogen/progestin therapy have been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). 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.

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, and the study is continuing. (See CLINICAL PHARMACOLOGY, Clinical Studies.)

In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as nonfatal 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 (0.625 mg/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 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.

Venous thromboembolism (VTE)

In the Women's Health Initiative (WHI) study, in women receiving CE compared to placebo, the risk of VTE (including both DVT and PE) was increased 33% (28 vs. 21 per 10,000 person-years) although only the increased rate of DVT reached statistical significance (p = 0.03). (See CLINICAL PHARMACOLOGY, Clinical Studies.)

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

Malignant neoplasms

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 was 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.

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 (WHI) 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 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 hormone 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 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.

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. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use.)

Gallbladder disease

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

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.

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.

DEPO-Estradiol®
estradiol cypionate injection, USP

Read this PATIENT INFORMATION before you start taking DEPO-Estradiol (estradiol cypionate injection) and read what you get each time you refill DEPO-Estradiol (estradiol cypionate injection) . 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 DEPO-ESTRADIOL (estradiol cypionate injection) (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 uterine (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. You and your healthcare provider should talk regularly about whether you still need treatment with DEPO-Estradiol (estradiol cypionate injection) .

What is DEPO-Estradiol (estradiol cypionate injection) ?

Depo-Estradiol (estradiol cypionate injection) injection is an estrogen product. The information below is that which the U.S. Food and Drug Administration requires be provided for all patients taking estrogens. For further information ask your doctor.

What is DEPO-Estradiol (estradiol cypionate injection) used for?

DEPO-Estradiol (estradiol cypionate injection) is used during and after menopause to:

• reduce moderate or severe menopausal symptoms. 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 (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”). Using estrogen drugs can help the body adjust to lower estrogen levels and reduce these symptoms. Most women have only mild menopause symptoms or none at all and do not need estrogen drugs for these symptoms.
• treat moderate to severe itching, burning, and dryness in or around the vagina. You and your healthcare provider should talk regularly about whether you still need treatment with DEPO-Estradiol (estradiol cypionate injection) to control these problems.

DEPO-Estradiol (estradiol cypionate injection) is also used to:

• treat certain conditions in women before menopause if their ovaries do not make enough estrogen.

Who should not take DEPO-Estradiol (estradiol cypionate injection) ?

Do not start taking DEPO-Estradiol (estradiol cypionate injection) 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 DEPO-Estradiol (estradiol cypionate injection) .

• had a stroke or heart attack in the past year.
• currently have or have had blood clots.
• are allergic to DEPO-Estradiol (estradiol cypionate injection) or any of its ingredients.

See the end of this leaflet for a list of ingredients in DEPO-Estradiol (estradiol cypionate injection) .

• think you may be pregnant.

Tell your healthcare provider:

• if you are breastfeeding.

The hormone in DEPO-Estradiol (estradiol cypionate injection) 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, or 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 DEPO-ESTRADIOL (estradiol cypionate injection) works. DEPO-ESTRADIOL (estradiol cypionate injection) 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 DEPO-Estradiol (estradiol cypionate injection) ?

Take DEPO-Estradiol (estradiol cypionate injection) as directed by your healthcare provider.

Estrogens should be used only as long as needed. You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about whether you still need treatment with DEPO-ESTRADIOL (estradiol cypionate injection) .

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
• 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

Other side effects include:

• High blood pressure
• Liver problems
• High blood sugar
• Fluid retention
• Enlargement of benign tumors of the uterus (“fibroids”)
• Vaginal yeast infections
• Hair loss

These are not all the possible side effects of DEPO-Estradiol (estradiol cypionate injection) . For more information, ask your healthcare provider or pharmacist.

What can I do to lower my chances of getting a serious side effect with DEPO-Estradiol (estradiol cypionate injection) ?

• Talk with your healthcare provider regularly about whether you should continue taking DEPO-ESTRADIOL (estradiol cypionate injection) . 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 DEPO-ESTRADIOL (estradiol cypionate injection) . 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 examinations 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 DEPO-Estradiol (estradiol cypionate injection)

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take DEPO-Estradiol (estradiol cypionate injection) for conditions for which it was not prescribed. Do not give DEPO-Estradiol (estradiol cypionate injection) to other people, even if they have the same symptoms you have. It may harm them. Keep DEPO-Estradiol (estradiol cypionate injection) out of the reach of children.

This leaflet provides a summary of the most important information about DEPO-Estradiol (estradiol cypionate injection) . If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about DEPO-Estradiol (estradiol cypionate injection) that is written for health professionals. You can get more information by calling the toll free number 1-888-691-6813. You are cautioned to discuss very carefully with your doctor or healthcare provider all the possible risks and benefits of long-term estrogen and progestin treatment as they affect you personally.

Depo-Estradiol is a prescription medication used to treat symptoms of menopause including hot flashes and vaginal dryness. It is also used to treat conditions in which a woman's ovaries do not produce enough estrogen naturally (hypoestrogenism).

Depo-Estradiol is a form of the hormone estrogen. It replaces estrogen that is not naturally produced by the ovaries.

This medication is available in an injectable form to be given directly into a muscle (IM) by a healthcare professional.

Common side effects of Depo-Estradiol include 

Serious side effects have been reported with Depo-Estradiol. See the “Drug Precautions” section.

Common side effects of Depo-Estradiol include the following:

• headache
• breast pain or tenderness
• nausea
• vomiting
• constipation
• gas
• heartburn
• weight gain or loss
• hair loss
• swelling or itching of the vagina
• vaginal discharge
• painful menstrual periods
• anxiety
• depression
• changes in mood
• change in sexual desire
• back, neck, or muscle pain
• runny nose or congestion
• cough
• unwanted hair growth
• difficulty wearing contact lenses

This is not a complete list of Depo-Estradiol side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Use  this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on the following:

• the condition being treated
• other medical conditions you have
• other medications you are taking
• how you respond to this medication

The recommended dose range of Depo-Estradiol (estradiol cypionate) intramuscular injection for the treatment of menopause symptoms is 1 to 5 mg injected every 3 to 4 weeks.

The recommended dose range of Depo-Estradiol (estradiol cypionate) intramuscular injection for the treatment of female hypoestrogenism due to hypogonadism 1.5 to 2 mg injected at monthly intervals.

 

If Depo-Estradiol is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Follow your doctor's instructions about any restrictions on food, beverages, or activity while you are using estradiol injection.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Chest pain or pressure.
• Shortness of breath.
• Coughing up blood.
• Swelling, warmth, numbness, change of color, or pain in a leg or arm.
• Very bad headache.
• Very bad dizziness or passing out.
• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
• Very upset stomach or throwing up.
• Very bad belly pain.
• Back pain.
• Bulging eyes.
• Change in how contact lenses feel in the eyes.
• Loss of eyesight.
• Change in eyesight.
• A lump in the breast, breast soreness, or nipple discharge.
• Breast pain.
• Vaginal itching or discharge.
• Vaginal bleeding that is not normal.
• Low mood (depression).
• Mood changes.
• Memory problems or loss.
• Fever.
• Not able to pass urine or change in how much urine is passed.
• Pain when passing urine.
• Swelling.

See BOXED WARNINGS, WARNINGS and PRECAUTIONS.

The following additional adverse reactions have been reported with estrogens 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 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; steepening of corneal curvature; 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; changes in libido; arthralgias; leg cramps; anaphylactoid/anaphylactic reactions including urticaria and angioedema; hypocalcemia; exacerbation of asthma; increased triglycerides.

NDC 0009-0271-01
Rx only

1–5 mL Vial

Depo®-Estradiol
estradiol cypionate
injection, USP

5 mg/mL

For intramuscular use only

Pfizer Injectables

Depo-Estradiol  estradiol cypionate injection

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0009-0271 Route of Administration INTRAMUSCULAR DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ESTRADIOL CYPIONATE (ESTRADIOL) ESTRADIOL CYPIONATE 5 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength COTTONSEED OIL 913 mg  in 1 mL CHLOROBUTANOL 5.4 mg  in 1 mL

Packaging # Item Code Package Description 1 NDC:0009-0271-01 1 VIAL in 1 CARTON 1 5 mL in 1 VIAL

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA085470 08/15/1979

Labeler - Pharmacia and Upjohn Company LLC (618054084)

Establishment
Name	Address	ID/FEI	Operations
Pharmacia and Upjohn Company LLC		618054084	ANALYSIS(0009-0271), API MANUFACTURE(0009-0271), LABEL(0009-0271), MANUFACTURE(0009-0271), PACK(0009-0271)

Revised: 11/2016   Pharmacia and Upjohn Company LLC