(estradiol cypionate)
CLINICAL PHARMACOLOGY
CLINICAL PHARMACOLOGY
Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.
Absorption
When conjugated with aryl and alkyl groups for parenteral administration, the rate of absorption of oily preparations is slowed with a prolonged duration of action, such that a single intramuscular injection of estradiol valerate or estradiol cypionate is absorbed over several weeks.
Distribution
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.
Metabolism
Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.
Drug Interactions
In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John's Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.
Estrogen drug products administered by non oral routes are not subject to first-pass metabolism, but also undergo significant hepatic uptake, metabolism, and enterohepatic recycling.
Clinical Studies
Women's Health Initiative Studies
The Women's Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of 0.625 mg conjugated estrogens (CE) per day alone or the use of oral 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.
The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index." Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 1 below:
| Event † | Relative Risk CE/MPA vs placebo at 5.2 Years (95% CI‡) | Placebo n = 8102 | CE/MPA n = 8506 |
|---|---|---|---|
| Absolute Risk per 10,000 Person-years | |||
| |||
CHD events | 1.29 (1.02–1.63) | 30 | 37 |
Non-fatal MI | 1.32 (1.02–1.72) | 23 | 30 |
CHD death | 1.18 (0.70–1.97) | 6 | 7 |
Invasive breast cancer § | 1.26 (1.00–1.59) | 30 | 38 |
Stroke | 1.41 (1.07–1.85) | 21 | 29 |
Pulmonary embolism | 2.13 (1.39–3.25) | 8 | 16 |
Colorectal cancer | 0.63 (0.43–0.92) | 16 | 10 |
Endometrial cancer | 0.83 (0.47–1.47) | 6 | 5 |
Hip fracture | 0.66 (0.45–0.98) | 15 | 10 |
Death due to causes other than the events above | 0.92 (0.74–1.14) | 40 | 37 |
Global index † | 1.15 (1.03–1.28) | 151 | 170 |
| |||
Deep vein thrombosis ¶ | 2.07 (1.49–2.87) | 13 | 26 |
Vertebral fractures ¶ | 0.66 (0.44–0.98) | 15 | 9 |
Other osteoporotic fractures ¶ | 0.77 (0.69–0.86) | 170 | 131 |
For those outcomes included in the "global index," the absolute excess risks per 10,000 person-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the "global index" was 19 per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS and PRECAUTIONS.)
Women's Health Initiative Memory Study
The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.
After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and WARNINGS, Dementia.)
Comparative clinical studies have demonstrated that estradiol cypionate produces estrogenic effects that are qualitatively the same as those produced by other estradiol esters. In menopausal women, the average duration of estrogenic effect (as measured by vaginal smear) following a single injection of 5 mg of estradiol cypionate was found to be approximately 3 to 4 weeks. Relief of vasomotor symptoms was observed to occur within 1 to 5 days and to be maintained for 1 to 8 weeks, with an average of approximately 5 weeks.
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:
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- 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:
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- 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:
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- have unusual vaginal bleeding.
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- 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.
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- currently have or have had blood clots.
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- are allergic to DEPO-Estradiol or any of its ingredients.
See the end of this leaflet for a list of ingredients in DEPO-Estradiol.
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- think you may be pregnant.
Tell your healthcare provider:
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- if you are breastfeeding.
The hormone in DEPO-Estradiol can pass into your milk.
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- 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:
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- Breast cancer
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- Cancer of the uterus
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- Stroke
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- Heart attack
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- Blood clots
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- Gallbladder disease
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- Ovarian cancer
These are some of the warning signs of serious side effects:
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- Breast lumps
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- Unusual vaginal bleeding
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- Dizziness and faintness
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- Changes in speech
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- Severe headaches
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- Chest pain
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- Shortness of breath
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- Pains in your legs
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- Changes in vision
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- 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:
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- Headache
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- Breast pain
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- Irregular vaginal bleeding or spotting
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- Stomach/abdominal cramps, bloating
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- Nausea and vomiting
Other side effects include:
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- High blood pressure
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- Liver problems
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- High blood sugar
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- Fluid retention
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- Enlargement of benign tumors of the uterus ("fibroids")
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- Vaginal yeast infections
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- 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?
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- 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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