(estradiol cypionate)
PRECAUTIONS
PRECAUTIONS
A. General
1. Addition of 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 (e.g., lowering HDL, raising LDL) and impairment of glucose tolerance.
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 estrogens 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 (TBG) 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, require careful observation when estrogens are prescribed.
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 (95% confidence interval 0.77 – 3.24) but was not statistically significant. The absolute risk for CE/MPA versus placebo was 20 versus 12 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen alone, in particular for ten or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations.
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.
B. PATIENT INFORMATION
Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe DEPO-Estradiol.
C. LABORATORY TESTS
Estrogen administration should be initiated at the lowest dose for the approved 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 anti-factor 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 (TBG) levels leading to increased circulating total thyroid hormone, 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 circulating corticosteroids and sex steroids, respectively. Free or biologically active hormone levels concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-anti-trypsin, ceruloplasmin).
- 4.
- Increased plasma HDL and HDL-2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.
- 5.
- Impaired glucose tolerance.
- 6.
- Reduced response to metyrapone test.
- 7.
- Reduced serum folate concentration.
E. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
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. (See BOXED WARINGS, WARNINGS and PRECAUTIONS.)
F. PREGNANCY
DEPO-Estradiol should not be used during pregnancy. See CONTRAINDICATIONS and Boxed WARNINGS.
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 DEPO-Estradiol is administered to a nursing woman.
H. GERIATRIC USE
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 women that were older than 70. (See WARNINGS, Dementia.)
PATIENT INFORMATION
PATIENT INFORMATION
DEPO-Estradiol®
Brand of estradiol cypionate injection, USP
Read this PATIENT INFORMATION before you start taking DEPO-Estradiol and read what you get each time you refill DEPO-Estradiol. 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 (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.
What is DEPO-Estradiol?
Depo-Estradiol 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 used for?
DEPO-Estradiol 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 to control these problems.
DEPO-Estradiol 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?
Do not start taking DEPO-Estradiol 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. - •
- had a stroke or heart attack in the past year.
- •
- currently have or have had blood clots.
- •
- are allergic to DEPO-Estradiol or any of its ingredients.
See the end of this leaflet for a list of ingredients in DEPO-Estradiol.
- •
- think you may be pregnant.
Tell your healthcare provider:
- •
- if you are breastfeeding.
The hormone in DEPO-Estradiol 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 medical conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, angioedema (swelling of face and tongue), hypertension (high blood pressure), 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 works. DEPO-ESTRADIOL 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?
Take DEPO-Estradiol 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.
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. 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?
- •
- Talk with your healthcare provider regularly about whether you should continue taking DEPO-ESTRADIOL. 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. 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
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take DEPO-Estradiol for conditions for which it was not prescribed. Do not give DEPO-Estradiol to other people, even if they have the same symptoms you have. It may harm them. Keep DEPO-Estradiol out of the reach of children.
This leaflet provides a summary of the most important information about DEPO-Estradiol. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about DEPO-Estradiol that is written for health professionals. You can get more information by calling the toll free number 1-800-438-1985. 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.
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