(conjugated estrogens)
12 CLINICAL PHARMACOLOGY
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
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 in the 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 FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these gonadotropins seen in postmenopausal women.
12.3 Pharmacokinetics
Absorption
Conjugated estrogens are water-soluble and are absorbed from the gastrointestinal tract after release from the drug formulation. The PREMARIN tablet releases CE slowly over several hours. Table 2 summarizes the mean pharmacokinetic parameters for unconjugated and CE following administration of 1 × 0.625 mg and 1 × 1.25 mg tablets to healthy postmenopausal women.
Food effect: The pharmacokinetics of PREMARIN 0.45 mg and 1.25 mg tablets were assessed following a single dose with a high-fat breakfast and with fasting administration. The Cmax and AUC of estrogens were altered approximately 3–13%. The changes to Cmax and AUC are not considered clinically meaningful, therefore PREMARIN may be taken without regard to meals.
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 1 × 0.625 mg | ||||
PK Parameter Arithmetic Mean (%CV) | Cmax (pg/mL) | tmax (h) | t1/2 (h) | AUC (pg∙h/mL) |
Estrone | 87 (33) | 9.6 (33) | 50.7 (35) | 5557 (59) |
Baseline-adjusted estrone | 64 (42) | 9.6 (33) | 20.2 (40) | 1723 (52) |
Equilin | 31 (38) | 7.9 (32) | 12.9 (112) | 602 (54) |
Pharmacokinetic Profile of CE Following a Dose of 1 × 0.625 mg | ||||
PK Parameter Arithmetic Mean (%CV) | Cmax (ng/mL) | tmax (h) | t1/2 (h) | AUC (ng∙h/mL) |
Total Estrone | 2.7 (43) | 6.9 (25) | 26.7 (33) | 75 (52) |
Baseline-adjusted total estrone | 2.5 (45) | 6.9 (25) | 14.8 (35) | 46 (48) |
Total Equilin | 1.8 (56) | 5.6 (45) | 11.4 (31) | 27 (56) |
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 1 × 1.25 mg | ||||
PK Parameter Arithmetic Mean (%CV) | Cmax (pg/mL) | tmax (h) | t1/2 (h) | AUC (pg∙h/mL) |
Estrone | 124 (30) | 10.0 (32) | 38.1 (37) | 6332 (44) |
Baseline-adjusted estrone | 102 (35) | 10.0 (32) | 19.7 (48) | 3159 (53) |
Equilin | 59 (43) | 8.8 (36) | 10.9 (47) | 1182 (42) |
Pharmacokinetic Profile of CE Following a Dose of 1 × 1.25 mg | ||||
PK Parameter Arithmetic Mean (%CV) | Cmax (ng/mL) | tmax (h) | t1/2 (h) | AUC (ng∙h/mL) |
Total Estrone | 4.5 (39) | 8.2 (58) | 26.5 (40) | 109 (46) |
Baseline-adjusted total estrone | 4.3 (41) | 8.2 (58) | 17.5 (41) | 87 (44) |
Total equilin | 2.9 (42) | 6.8 (49) | 12.5 (34) | 48 (51) |
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 concentration in the sex hormone target organs. Estrogens circulate in the blood largely bound to 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 a 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 intestine 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.
PATIENT INFORMATION
PATIENT INFORMATION
PREMARIN®(prem-uh-rin)
(Conjugated estrogen tablets)
Read this PATIENT INFORMATION before you start taking PREMARIN and read what you get each time you refill your PREMARIN prescription. 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 PREMARIN (AN ESTROGEN MIXTURE)? |
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What is PREMARIN?
PREMARIN is a medicine that contains a mixture of estrogen hormones.
What is PREMARIN used for?
PREMARIN is used after menopause to:
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- Reduce moderate to severe hot flushes
Estrogens are hormones made by a woman's ovaries. The ovaries normally stop making estrogens when a woman is between 45 and 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 get very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating ("hot flushes"). In some women the symptoms are mild, and they will not need to take estrogens. In other women, symptoms can be more severe. - •
- Treat menopausal changes in and around the vagina
You and your healthcare provider should talk regularly about whether you still need treatment with PREMARIN to control these problems. If you use PREMARIN only to treat your menopausal changes in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you. - •
- Help reduce your chances of getting osteoporosis (thin weak bones)
Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break. If you use PREMARIN only to prevent osteoporosis due to menopause, talk with your healthcare provider about whether a different treatment or medicine without estrogens might be better for you.
Weight-bearing exercise, like walking or running, and taking calcium (1500 mg/day of elemental calcium) and vitamin D (400–800 IU/day) supplements may also lower your chances of getting postmenopausal osteoporosis. It is important to talk about exercise and supplements with your healthcare provider before starting them.
You and your healthcare provider should talk regularly about whether you still need treatment with PREMARIN.
PREMARIN is also used to:
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- Treat certain conditions in women before menopause if their ovaries do not make enough estrogen naturally.
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- Ease symptoms of certain cancers that have spread through the body, in men and women
Who should not take PREMARIN?
Do not take PREMARIN 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 chance of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should use PREMARIN. - •
- Had a stroke or heart attack
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- Currently have or have had blood clots
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- Currently have or have had liver problems
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- Have been diagnosed with a bleeding disorder
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- Are allergic to PREMARIN or any of its ingredients
See the end of this leaflet for a list of ingredients in PREMARIN.
Tell your healthcare provider
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- If you have any unusual vaginal bleeding
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. - •
- 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), diabetes, 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 PREMARIN works. PREMARIN may also affect how your other medicines work. - •
- If you are going to have surgery or will be on bedrest
You may need to stop taking PREMARIN. - •
- If you are pregnant or think you may be pregnant
PREMARIN is not for pregnant women.
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- If you are breastfeeding
The hormones in PREMARIN can pass into your breast milk.
How should I take PREMARIN?
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- Take one PREMARIN tablet at the same time each day
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- If you miss a dose, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your normal schedule. Do not take 2 doses at the same time.
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- Estrogens should be used at the lowest dose possible for your treatment only as long as needed. 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 PREMARIN.
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- If you see something that resembles a tablet in your stool, talk to your healthcare provider.
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- Take PREMARIN with or without food.
What are the possible side effects of PREMARIN?
Side effects are grouped by how serious they are and how often they happen when you are treated.
Serious, but less common side effects include:
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- Heart attack
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- Stroke
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- Blood clots
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- Breast cancer
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- Cancer of the lining of the uterus (womb)
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- Cancer of the ovary
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- Dementia
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- High or low blood calcium
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- Gallbladder disease
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- Visual abnormalities
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- High blood pressure
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- High levels of fat (triglycerides) in your blood
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- Liver problems
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- Changes in your thyroid hormone levels
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- Fluid retention
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- Cancer changes of endometriosis
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- Enlargement of benign tumors of the uterus ("fibroids")
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- Severe allergic reactions
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- Changes in certain laboratory test results, such as high blood sugar
Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:
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- New breast lumps
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- Unusual vaginal bleeding
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- Changes in vision or speech
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- Sudden new severe headaches
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- Severe pains in your chest or legs with or without shortness of breath, weakness and fatigue
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- Swelling of the face, lips, and tongue with or without red itchy bumps
Common side effects of PREMARIN 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
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- Hair loss
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- Fluid retention
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- Vaginal yeast infection
These are not all the possible side effects of PREMARIN. For more information, ask your healthcare provider or pharmacist for advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
What can I do to lower my chances of getting a serious side effect with PREMARIN?
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- Talk with your healthcare provider regularly about whether you should continue taking PREMARIN
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- If you have a uterus, talk to your healthcare provider about whether the addition of a progestin is right for you. The addition of a progestin is generally recommended for women with a uterus to reduce the chance of getting cancer of the uterus (womb).
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- See your health care provider right away if you get vaginal bleeding while taking PREMARIN
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- Have a pelvic exam, 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.
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- If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease. Ask your healthcare provider for ways to lower your chances of getting heart disease.
General information about the safe and effective use of PREMARIN
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take PREMARIN for conditions for which it was not prescribed. Do not give PREMARIN to other people, even if they have the same symptoms you have. It may harm them.
Keep PREMARIN out of the reach of children
This leaflet provides a summary of the most important information about PREMARIN. If you would like more information, talk with your healthcare provider or pharmacist.
What are the ingredients in PREMARIN?
PREMARIN contains a mixture of conjugated estrogens, which are a mixture of sodium estrone sulfate and sodium equilin sulfate and other components including sodium sulfate conjugates, 17 α-dihydroequilin, 17 α-estradiol, and 17 β-dihydroequilin.
PREMARIN 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, and 1.25 mg tablets also contain the following inactive ingredients: calcium phosphate tribasic, hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, sucrose and titanium dioxide.
The tablets come in different strengths and each strength tablet is a different color. The color ingredients are:
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- 0.3 mg tablet (green color): D&C Yellow No. 10 and FD&C Blue No. 2.
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- 0.45 mg tablet (blue color): FD&C Blue No. 2.
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- 0.625 mg tablet (maroon color): FD&C Blue No. 2 and FD&C Red No. 40.
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- 0.9 mg tablet (white color): D&C Red No. 30 and D&C Red No. 7.
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- 1.25 mg tablet (yellow color): black iron oxide, D&C Yellow No. 10, and FD&C Yellow No. 6.
The appearance of these tablets is a trademark of Wyeth LLC.
Store at Controlled Room Temperature 20° – 25°C (68° – 77°F).
This product's labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com.
LAB-0515-7.0
Revised 04/2025
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