Prometrium Information
Prometrium () Warning: Cardiovascular Disorders, Breast Cancer And Probable Dementia For Estrogen Plus Progestin Therapy
Estrogens plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia. (See and and .)
The Women's Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of deep vein thrombosis, pulmonary embolism, stroke and myocardial infarction in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo. (See and .)
The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See and and .)
The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer. (See and .)
In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA, and other combinations and dosage forms of estrogens and progestins.
Progestins with estrogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
Prometrium () Description
Prometrium () (progesterone, USP) Capsules contain micronized progesterone for oral administration. Progesterone has a molecular weight of 314.47 and a molecular formula of CHO. Progesterone (pregn-4-ene-3, 20-dione) is a white or creamy white, odorless, crystalline powder practically insoluble in water, soluble in alcohol, acetone and dioxane and sparingly soluble in vegetable oils, stable in air, melting between 126° and 131°C. The structural formula is:
Progesterone is synthesized from a starting material from a plant source and is chemically identical to progesterone of human ovarian origin. Prometrium () Capsules are available in multiple strengths to afford dosage flexibility for optimum management. Prometrium () Capsules contain 100 mg or 200 mg micronized progesterone.
The inactive ingredients for Prometrium () Capsules 100 mg include: peanut oil NF, gelatin NF, glycerin USP, lecithin NF, titanium dioxide USP, D&C Yellow No. 10, and FD&C Red No. 40.
The inactive ingredients for Prometrium () Capsules 200 mg include: peanut oil NF, gelatin NF, glycerin USP, lecithin NF, titanium dioxide USP, D&C Yellow No. 10, and FD&C Yellow No. 6.
Prometrium () Clinical Pharmacology
Prometrium () Capsules are an oral dosage form of micronized progesterone which is chemically identical to progesterone of ovarian origin. The oral bioavailability of progesterone is increased through micronization.
Prometrium () Clinical Studies
In a randomized, double-blind clinical trial, 358 postmenopausal women, each with an intact uterus, received treatment for up to 36 months. The treatment groups were: Prometrium () Capsules at the dose of 200 mg per day for 12 days per 28-day cycle in combination with conjugated estrogens 0.625 mg per day (n=120); conjugated estrogens 0.625 mg per day only (n=119); or placebo (n=119). The subjects in all three treatment groups were primarily Caucasian women (87 percent or more of each group). The results for the incidence of endometrial hyperplasia in women receiving up to 3 years of treatment are shown in . A comparison of the Prometrium () Capsules plus conjugated estrogens treatment group to the conjugated estrogens only group showed a significantly lower rate of hyperplasia (6 percent combination product versus 64 percent estrogen alone) in the Prometrium () Capsules plus conjugated estrogens treatment group throughout 36 months of treatment.
The times to diagnosis of endometrial hyperplasia over 36 months of treatment are shown in . This figure illustrates graphically that the proportion of patients with hyperplasia was significantly greater for the conjugated estrogens group (64 percent) compared to the conjugated estrogens plus Prometrium () Capsules group (6 percent).
The discontinuation rates due to hyperplasia over the 36 months of treatment are as shown in . For any degree of hyperplasia, the discontinuation rate for patients who received conjugated estrogens plus Prometrium () Capsules was similar to that of the placebo only group, while the discontinuation rate for patients who received conjugated estrogens alone was significantly higher. Women who permanently discontinued treatment due to hyperplasia were similar in demographics to the overall study population.
In a single-center, randomized, double-blind clinical study that included premenopausal women with secondary amenorrhea for at least 90 days, administration of 10 days of Prometrium () Capsules therapy resulted in 80 percent of women experiencing withdrawal bleeding within 7 days of the last dose of Prometrium () Capsules, 300 mg per day (n=20), compared to 10 percent of women experiencing withdrawal bleeding in the placebo group (n=21).
In a multicenter, parallel-group, open label, postmarketing dosing study that included premenopausal women with secondary amenorrhea for at least 90 days, administration of 10 days of Prometrium () Capsules during two 28-day treatment cycles, 300 mg per day (n=107) or 400 mg per day (n=99), resulted in 73.8 percent and 76.8 percent of women, respectively, experiencing withdrawal bleeding.
The rate of secretory transformation was evaluated in a multicenter, randomized, double-blind clinical study in estrogen-primed postmenopausal women. Prometrium () Capsules administered orally for 10 days at 400 mg per day (n=22) induced complete secretory changes in the endometrium in 45 percent of women compared to 0 percent in the placebo group (n=23).
A second multicenter, parallel-group, open label postmarketing dosing study in premenopausal women with secondary amenorrhea for at least 90 days also evaluated the rate of secretory transformation. All subjects received daily oral conjugated estrogens over 3 consecutive 28-day treatment cycles and Prometrium () Capsules, 300 mg per day (n=107) or 400 mg per day (n=99) for 10 days of each treatment cycle. The rate of complete secretory transformation was 21.5 percent and 28.3 percent, respectively.
The Women's Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral conjugated estrogens (CE) [0.625 mg]-alone or in combination with medroxyprogesterone acetate (MPA) [2.5 mg] compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease [(CHD) defined as nonfatal myocardial infarction (MI), silent MI and CHD death], with invasive breast cancer as the primary adverse outcome. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. These sub studies did not evaluate the effects of CE–alone or CE plus MPA on menopausal symptoms.
WHI Estrogen Plus Progestin Substudy
The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” The absolute excess risk of events in the “global index” was 19 per 10,000 women-years.
For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.
Results of the estrogen plus progestin substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in . These results reflect centrally adjudicated data after an average follow-up of 5.6 years.
Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified for age showed in women 50 to 59 years of age a non-significant trend toward reducing risk of overall mortality [hazard ratio (HR) 0.69 (95 percent CI, 0.44-1.07)].
The estrogen plus progestin Women's Health Initiative Memory Study (WHIMS), an ancillary study of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age; 35 percent were 70 to 74 years of age; and 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.
After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21 – 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See and .)
Prometrium () Indications And Usage
Prometrium () Capsules are indicated for use in the prevention of endometrial hyperplasia in nonhysterectomized postmenopausal women who are receiving conjugated estrogens tablets. They are also indicated for use in secondary amenorrhea.
Prometrium () Contraindications
Prometrium () Capsules should not be used in women with any of the following conditions:
Prometrium () Warnings
See .
An increased risk of pulmonary embolism, deep vein thrombosis (DVT), stroke, and myocardial infarction has been reported with estrogen plus progestin therapy. Should any of these occur or be suspected, estrogen with 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.
In the estrogen plus progestin Women's Health Initiative Memory Study (WHIMS), an ancillary study of WHI, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.
In the WHIMS estrogen plus progestin ancillary study, after an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for estrogen plus progestin versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus 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 and .)
Prometrium () Precautions
General: This product contains peanut oil and should not be used if you are allergic to peanuts.
Physicians are advised to discuss the contents of the Patient Information leaflet with patients for whom they prescribe Prometrium () Capsules.
Progesterone has not been tested for carcinogenicity in animals by the oral route of administration. When implanted into female mice, progesterone produced mammary carcinomas, ovarian granulosa cell tumors and endometrial stromal sarcomas. In dogs, long-term intramuscular injections produced nodular hyperplasia and benign and malignant mammary tumors. Subcutaneous or intramuscular injections of progesterone decreased the latency period and increased the incidence of mammary tumors in rats previously treated with a chemical carcinogen.
Progesterone did not show evidence of genotoxicity in studies for point mutations or for chromosomal damage. studies for chromosome damage have yielded positive results in mice at oral doses of 1000 mg/kg and 2000 mg/kg. Exogenously administered progesterone has been shown to inhibit ovulation in a number of species and it is expected that high doses given for an extended duration would impair fertility until the cessation of treatment.
Prometrium () Adverse Reactions
See , and .
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.
In a multicenter, randomized, double-blind, placebo-controlled clinical trial, the effects of Prometrium () Capsules on the endometrium was studied in a total of 875 postmenopausal women. lists adverse reactions greater than or equal to 2 percent of women who received cyclic Prometrium () Capsules 200 mg daily (12 days per calendar month cycle) with 0.625 mg conjugated estrogens or placebo.
Prometrium () Overdosage
No studies on overdosage have been conducted in humans. In the case of overdosage, Prometrium () Capsules should be discontinued and the patient should be treated symptomatically.
Prometrium () Dosage And Administration
Prometrium () Capsules may be given as a single daily dose of 400 mg at bedtime for 10 days.
Some women may experience difficulty swallowing Prometrium () Capsules. For these women, Prometrium () Capsules should be taken with a glass of water while in the standing position.
Prometrium () How Supplied
Prometrium () (progesterone, USP) Capsules 100 mg are round, peach-colored capsules branded with black imprint “SV.”NDC 0032-1708-01 (Bottle of 100)
Prometrium () (progesterone, USP) Capsules 200 mg are oval, pale yellow-colored capsules branded with black imprint “SV2.”NDC 0032-1711-01 (Bottle of 100)
© 2011 Abbott Laboratories
All rights reserved.
Revised: 11/2011
Prometrium () Patient Information
Read this PATIENT INFORMATION before you start taking Prometrium () Capsules and read what you get each time you refill your Prometrium () Capsules 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.
Prometrium () Capsules contain the female hormone called progesterone.
Prometrium () Capsules are used for the treatment of secondary amenorrhea (absence of menstrual periods in women who have previously had a menstrual period) due to a decrease in progesterone. When you do not produce enough progesterone, menstrual irregularities can occur. If your healthcare provider has determined your body does not produce enough progesterone on its own, Prometrium () Capsules may be prescribed to provide the progesterone you need.
Prometrium () Capsules are used in combination with estrogen-containing medications in a postmenopausal woman with a uterus (womb). Taking estrogen-alone increases the chance of developing a condition called endometrial hyperplasia that may lead to cancer of the lining of the uterus (womb). The addition of a progestin is generally recommended for a woman with a uterus to reduce the chance of getting cancer of the uterus (womb).
Do not start taking Prometrium () Capsules if you:
Side effects are grouped by how serious they are and how often they happen when you are treated:
Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptoms that concern you.
These are not all the possible side effects of Prometrium () Capsules. For more information, ask your healthcare provider or pharmacist for advice about side effects. You may report side effects to Abbott Laboratories at 1-800-241-1643 or to FDA at 1-800-FDA-1088.
This leaflet provides a summary of the most important information about Prometrium () Capsules. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Prometrium () Capsules that is written for health professionals. You can get more information by calling the toll free number 1-800-241-1643.
Active ingredient: 100 mg or 200 mg micronized progesterone
The inactive ingredients for Prometrium () Capsules 100 mg include: peanut oil NF, gelatin NF, glycerin USP, lecithin NF, titanium dioxide USP, D&C Yellow No. 10, and FD&C Red No. 40.
The inactive ingredients for Prometrium () Capsules 200 mg include: peanut oil NF, gelatin NF, glycerin USP, lecithin NF, titanium dioxide USP, D&C Yellow No. 10, and FD&C Yellow No. 6.
Prometrium () Capsules 100 mg are round, peach-colored capsules branded with black imprint “SV.”
Prometrium () Capsules 200 mg are oval, pale yellow-colored capsules branded with black imprint “SV2.”
© 2011 Abbott Laboratories.All rights reserved.
Revised: 11/2011
Prometrium ()
