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Prometrium
Overview
What is Prometrium?
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.
What does Prometrium look like?
What are the available doses of Prometrium?
Sorry No records found.
What should I talk to my health care provider before I take Prometrium?
Sorry No records found
How should I use Prometrium?
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.
Prevention of Endometrial Hyperplasia:
Secondary Amenorrhea:
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.
What interacts with Prometrium?
- PROMETRIUM Capsules should not be used in women with any of the following conditions:
- PROMETRIUM Capsules should not be used in patients with known hypersensitivity to its ingredients. PROMETRIUM Capsules contain peanut oil and should never be used by patients allergic to peanuts.
- Undiagnosed abnormal genital bleeding.
- Known, suspected, or history of cancer of the breast.
- Active deep vein thrombosis, pulmonary embolism or history of these conditions.
- Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction).
- Liver dysfunction or disease.
- Known or suspected pregnancy. There is no indication for PROMETRIUM Capsules in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy. (See .)
What are the warnings of Prometrium?
There have been isolated reports of hypopigmentation after use of azelaic
acid. Since azelaic acid has not been well studied in patients with dark
complexion, these patients should be monitored for early signs of
hypopigmentation.
See .
Estrogen with progestin therapy has 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, estrogen
with progestin 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 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. (See .)
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. (See .)
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 CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep
venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA
compared to women receiving placebo. The rate of VTE was 34 per 10,000
women-years in the CE/MPA group compared to 16 per 10,000 women-years in the
placebo group. The increase in VTE risk was observed during the first year and
persisted. (See .)
If feasible, estrogens with progestins 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.
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 .) 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 the 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.
Discontinue medication pending examination if there is sudden
partial or complete loss of vision, or if there is a sudden onset of proptosis,
diplopia or migraine. If examination reveals papilledema or retinal vascular
lesions, medication should be withdrawn.
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 vs. 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 vs. placebo was 45 vs. 22 cases per 10,000 women-years, and
the absolute excess risk for CE/MPA was 23 cases per 10,000 women-years. It is
unknown whether these findings apply to younger postmenopausal women. (See and .)
What are the precautions of Prometrium?
Use of estrogens with a progestin may increase the risk of breast
cancer compared to estrogen alone.
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 vs. placebo was 1.58 (95%
confidence interval 0.77 – 3.24) but was not statistically significant. The
absolute risk for CE/MPA vs. placebo was 4.2 vs. 2.7 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.
See accompanying Patient Insert.
General: This product contains peanut oil and
should not be used if you are allergic to peanuts.
The following laboratory results may be altered by the use of estrogen-progestin combination drugs:
Fasting and 2-hour plasma insulin and glucose levels following an oral glucose tolerance test (OGTT) and fibrinogen levels were measured in patients receiving PROMETRIUM Capsules at a dose of 200 mg/day for 12 days per 28-day cycle in combination with conjugated estrogens 0.625 mg/day (n=120). summarizes these data. Plasma insulin levels 2 hours post-OGTT were decreased from baseline. The fasting plasma glucose and fasting plasma insulin levels were also decreased from baseline. Glucose levels 2 hours post-OGTT were increased slightly. There was no effect on fibrinogen levels.
For information on changes in lipid profile, see the .
| Parameter | |||||||
| Conjugated Estrogens 0.625 mg + PROMETRIUM Capsules 200 mg (cyclical) | a | Conjugated Estrogens 0.625 mg (only) | Placebo | ||||
| n= 173 to 176 | n=170 to 172 | n=171 | |||||
| MeanChange | Mean % Change | Mean Change | Mean % Change | Mean Change | Mean % Change | ||
| OGTT Insulin (pmol/L) | |||||||
| Glucose (mg/dL) | fasting2 hours | -3.03.6 | -2.95.2 | -2.75.0 | -2.77.8 | -1.02.1 | -0.93.9 |
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.
Reproductive studies have been performed in mice at doses up to 9 times the human oral dose, in rats at doses up to 44 times the human oral dose, in rabbits at a dose of 10 mcg/day delivered locally within the uterus by an implanted device, in guinea pigs at doses of approximately one-half the human oral dose and in rhesus monkeys at doses approximately the human dose, all based on body surface area, and have revealed little or no evidence of impaired fertility or harm to the fetus due to progesterone.
Rare cases of congenital anomalies including cleft palate, cleft lip, hypospadia, ventricular septal defect, patent ductus arteriosus, and other congenital heart defects have been reported in the infants of women using progesterone, including PROMETRIUM Capsules, in early pregnancy. Definitive causality has not been established. Rare instances of fetal death and spontaneous abortion have been reported in pregnant women prescribed PROMETRIUM Capsules for unapproved indications including the prevention of such outcomes. Studies in humans cannot rule out the possibility of harm. Therefore, PROMETRIUM Capsules should be used during pregnancy only if indicated. (See .)
The administration of any drug to nursing mothers should be done only when clearly necessary since many drugs are excreted in human milk. Detectable amounts of progestin have been identified in the milk of nursing mothers receiving progestins. Caution should be exercised when PROMETRIUM Capsules are administered to a nursing woman.
PROMETRIUM Capsules are not indicated in children.
Clinical studies of PROMETRIUM Capsules did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
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 .)
- The pretreatment physical examination should include special reference to breast and pelvic organs, as well as Papanicolaou smear.
- Because progesterone may cause some degree of fluid retention, conditions which might be influenced by this factor, such as epilepsy, migraine, asthma, cardiac or renal dysfunction, require careful observation.
- In cases of breakthrough bleeding, as in any cases of irregular vaginal bleeding, nonfunctional causes should be considered. In cases of undiagnosed vaginal bleeding, adequate diagnostic measures are indicated.
- Patients who have a history of clinical depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree.
- Further studies are needed to determine any possible influence of prolonged progestin therapy on pituitary, ovarian, adrenal, hepatic or uterine functions.
- Although concomitant use of conjugated estrogens and PROMETRIUM Capsules did not result in a decrease in glucose tolerance, diabetic patients should be carefully observed while receiving estrogen-progestin therapy.
- The pathologist should be advised of progestin therapy when relevant specimens are submitted.
- Because of the occurrence of thrombotic disorders (thrombophlebitis, pulmonary embolism, retinal thrombosis, and cerebrovascular disorders) in patients taking estrogen-progestin combinations, the healthcare provider should be alert to the earliest manifestation of these disorders.
- Transient dizziness may occur in some patients. Use caution when driving a motor vehicle or operating machinery. A small percentage of women may experience the following symptoms upon initial therapy: extreme dizziness and/or drowsiness, blurred vision, slurred speech, difficulty walking, loss of consciousness, vertigo, confusion, disorientation, feeling drunk, and shortness of breath. For these women, consultation with their healthcare provider regarding their treatment is advised. Bedtime dosing may alleviate these symptoms.
- Rare instances of syncope and hypotension of possible orthostatic origin have been observed in patients taking PROMETRIUM Capsules.
What are the side effects of Prometrium?
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. The adverse reaction information from
clinical trials does, however, provide a basis for identifying the adverse
events that appear to be related to drug use and for approximate rates.
Endometrial Protection:
Secondary Amenorrhea:
The most common adverse experiences reported in greater than or equal to 5% of patients in all
PROMETRIUM Capsules dosage groups studied in this trial (100 mg/day to 400
mg/day) were: dizziness (16%), breast pain (11%), headache (10%), abdominal pain
(10%), fatigue (9%), viral infection (7%), abdominal distention (6%),
musculoskeletal pain (6%), emotional lability (6%), irritability (5%), and upper
respiratory tract infection (5%).
Other adverse events reported in less than 5% of patients taking PROMETRIUM
Capsules include:
Administration Site Conditions:
Blood and Lymphatic System:
Cardiac Disorders:
Ear and Labyrinth Disorders:
Eye Disorders:
Gastrointestinal System Disorders:
General Disorders:
Infections:
Injury, Poisoning and Procedural
Complications:
Musculoskeletal and Connective Tissue
Disorders:
Nervous System Disorders:
Psychiatric Disorders:
Renal and Urinary Disorders:
Reproductive System Disorders:
Respiratory System Disorders:
Skin and Subcutaneous Tissue Disorders:
Vascular Disorders:
The following adverse experiences have been reported with PROMETRIUM Capsules
in other U.S. clinical trials: increased sweating, asthenia, tooth disorder,
anorexia, increased appetite, nervousness, and breast enlargement.
In addition to the adverse events observed in clinical trials, the following
spontaneous adverse events have been reported during the marketing of PROMETRIUM
Capsules.
Cardiac Disorders:
Congenital, Familial, and Genetic Disorders:
Ear and Labyrinth Disorders:
Eye Disorders:
Gastrointestinal Disorders:
General Disorders and Administration Site Conditions:
Hepatobiliary Disorders:
Immune System Disorders:
Investigations:
Musculoskeletal Disorders:
Neoplasms Benign, Malignant, and Unspecified:
Nervous System Disorders:
Pregnancy, Puerperium, and Perinatal Conditions:
Psychiatric Disorders:
Reproductive System and Breast Disorders:
Respiratory, Thoracic, and Mediastinal Disorders:
Skin and Subcutaneous Tissue Disorders:
Vascular Disorders:
The following additional adverse experiences have been observed in women
taking estrogen and/or progestins in general: breakthrough bleeding, spotting,
change in menstrual flow, amenorrhea, changes in weight (increase or decrease),
changes in the cervical squamo-columnar junction and cervical secretions,
cholestatic jaundice, anaphylactoid reactions and anaphylaxis, rash (allergic)
with and without pruritus, melasma or chloasma, that may persist when drug is
discontinued, dysmenorrhea, increase in size of uterine leiomyomata, ovarian
cancer, endometrial hyperplasia, endometrial cancer, galactorrhea, nipple
discharge, increased incidence of gallbladder disease, enlargement of hepatic
hemangiomas, erythema multiforme, erythema nodosum, hirsutism, hemorrhagic
eruption, intolerance to contact lenses, migraine, chorea, reduced carbohydrate
tolerance, aggravation of porphyria, changes in libido, hypocalcemia,
angioedema, exacerbation of asthma, increased triglycerides.
| PROMETRIUM Capsules 200 mg with Conjugated Estrogens 0.625 mg | Conjugated Estrogens 0.625 mg(only) | Placebo | |
| (n=178) | (n=175) | (n=174) | |
| Headache | 31 | 30 | 27 |
| Breast Tenderness | 27 | 16 | 6 |
| Joint Pain | 20 | 22 | 29 |
| Depression | 19 | 18 | 12 |
| Dizziness | 15 | 5 | 9 |
| Abdominal Bloating | 12 | 10 | 5 |
| Hot Flashes | 11 | 14 | 35 |
| Urinary Problems | 11 | 10 | 9 |
| Abdominal Pain | 10 | 13 | 10 |
| Vaginal Discharge | 10 | 10 | 3 |
| Nausea / Vomiting | 8 | 6 | 7 |
| Worry | 8 | 5 | 4 |
| Chest Pain | 7 | 4 | 5 |
| Diarrhea | 7 | 7 | 4 |
| Night Sweats | 7 | 5 | 17 |
| Breast Pain | 6 | 6 | 2 |
| Swelling of Hands and Feet | 6 | 9 | 9 |
| Vaginal Dryness | 6 | 8 | 10 |
| Constipation | 3 | 3 | 2 |
| Breast Carcinoma | 2 | less than 1 | less than 1 |
| Breast Excisional Biopsy | 2 | 1 | less than 1 |
| Cholecystectomy | 2 | less than 1 | less than 1 |
| Adverse Experience | Placebo | ||
| n=25 | n=24 | ||
| Percentage (%) of Patients | |||
| Fatigue | 8 | 4 | |
| Headache | 16 | 8 | |
| Dizziness | 24 | 4 | |
| Abdominal Distention (Bloating) | 8 | 8 | |
| Abdominal Pain (Cramping) | 20 | 13 | |
| Diarrhea | 8 | 4 | |
| Nausea | 8 | 0 | |
| Back Pain | 8 | 8 | |
| Musculoskeletal Pain | 12 | 4 | |
| Irritability | 8 | 4 | |
| Breast Pain | 16 | 8 | |
| Infection Viral | 12 | 0 | |
| Coughing | 8 | 0 |
What should I look out for while using Prometrium?
PROMETRIUM Capsules should not be used in women with any of the
following conditions:
See .
Estrogen with progestin therapy has 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, estrogen
with progestin 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 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. (See .)
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. (See .)
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 CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep
venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA
compared to women receiving placebo. The rate of VTE was 34 per 10,000
women-years in the CE/MPA group compared to 16 per 10,000 women-years in the
placebo group. The increase in VTE risk was observed during the first year and
persisted. (See .)
If feasible, estrogens with progestins 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.
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 .) 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 the 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.
Discontinue medication pending examination if there is sudden
partial or complete loss of vision, or if there is a sudden onset of proptosis,
diplopia or migraine. If examination reveals papilledema or retinal vascular
lesions, medication should be withdrawn.
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 vs. 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 vs. placebo was 45 vs. 22 cases per 10,000 women-years, and
the absolute excess risk for CE/MPA was 23 cases per 10,000 women-years. It is
unknown whether these findings apply to younger postmenopausal women. (See and .)
What might happen if I take too much Prometrium?
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.
How should I store and handle Prometrium?
GEODON for Injection should be stored at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [See USP Controlled Room Temperature] in dry form. Protect from light. Following reconstitution, GEODON for Injection can be stored, when protected from light, for up to 24 hours at 15°–30°C (59°–86°F) or up to 7 days refrigerated, 2°–8°C (36°–46°F).PROMETRIUM® (progesterone, USP) Capsules 100 mg are round, peach-colored capsules branded with black imprint “SV.”PROMETRIUM® (progesterone, USP) Capsules 200 mg are oval, pale yellow-colored capsules branded with black imprint “SV2.”Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].Protect from excessive moisture.Dispense in tight, light-resistant container as defined in USP/NF, accompanied by a Patient Insert.Keep out of reach of children.PROMETRIUM® (progesterone, USP) Capsules 100 mg are round, peach-colored capsules branded with black imprint “SV.”PROMETRIUM® (progesterone, USP) Capsules 200 mg are oval, pale yellow-colored capsules branded with black imprint “SV2.”Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].Protect from excessive moisture.Dispense in tight, light-resistant container as defined in USP/NF, accompanied by a Patient Insert.Keep out of reach of children.PROMETRIUM® (progesterone, USP) Capsules 100 mg are round, peach-colored capsules branded with black imprint “SV.”PROMETRIUM® (progesterone, USP) Capsules 200 mg are oval, pale yellow-colored capsules branded with black imprint “SV2.”Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].Protect from excessive moisture.Dispense in tight, light-resistant container as defined in USP/NF, accompanied by a Patient Insert.Keep out of reach of children.PROMETRIUM® (progesterone, USP) Capsules 100 mg are round, peach-colored capsules branded with black imprint “SV.”PROMETRIUM® (progesterone, USP) Capsules 200 mg are oval, pale yellow-colored capsules branded with black imprint “SV2.”Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].Protect from excessive moisture.Dispense in tight, light-resistant container as defined in USP/NF, accompanied by a Patient Insert.Keep out of reach of children.PROMETRIUM® (progesterone, USP) Capsules 100 mg are round, peach-colored capsules branded with black imprint “SV.”PROMETRIUM® (progesterone, USP) Capsules 200 mg are oval, pale yellow-colored capsules branded with black imprint “SV2.”Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].Protect from excessive moisture.Dispense in tight, light-resistant container as defined in USP/NF, accompanied by a Patient Insert.Keep out of reach of children.PROMETRIUM® (progesterone, USP) Capsules 100 mg are round, peach-colored capsules branded with black imprint “SV.”PROMETRIUM® (progesterone, USP) Capsules 200 mg are oval, pale yellow-colored capsules branded with black imprint “SV2.”Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].Protect from excessive moisture.Dispense in tight, light-resistant container as defined in USP/NF, accompanied by a Patient Insert.Keep out of reach of children.
Clinical Information
Chemical Structure
No Image foundClinical 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.
Absorption:
a Mean ± S.D.
Serum progesterone concentrations appeared linear and dose proportional
following multiple dose administration of PROMETRIUM Capsules 100 mg over the
dose range 100 mg/day to 300 mg/day in postmenopausal women. Although doses
greater than 300 mg/day were not studied in females, serum concentrations from a
study in male volunteers appeared linear and dose proportional between
100 mg/day and 400 mg/day. The pharmacokinetic parameters in male volunteers
were generally consistent with those seen in postmenopausal women.
Distribution:
Metabolism:
Excretion:
Special Populations:
Race:
Hepatic Insufficiency:
Renal Insufficiency:
Food–Drug Interaction:
Non-Clinical Toxicology
PROMETRIUM Capsules should not be used in women with any of the following conditions:See .
Estrogen with progestin therapy has 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, estrogen with progestin 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 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. (See .)
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. (See .)
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 CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the CE/MPA group compared to 16 per 10,000 women-years in the placebo group. The increase in VTE risk was observed during the first year and persisted. (See .)
If feasible, estrogens with progestins 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.
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 .) 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 the 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.
Discontinue medication pending examination if there is sudden partial or complete loss of vision, or if there is a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, medication should be withdrawn.
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 vs. 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 vs. placebo was 45 vs. 22 cases per 10,000 women-years, and the absolute excess risk for CE/MPA was 23 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See and .)
Drug Interactions
The use of MAO inhibitors or tricyclic antidepressants with hydrocodone preparations may increase the effect of either the antidepressant or hydrocodone.
Use of estrogens with a progestin may increase the risk of breast cancer compared to estrogen alone.
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 vs. placebo was 1.58 (95% confidence interval 0.77 – 3.24) but was not statistically significant. The absolute risk for CE/MPA vs. placebo was 4.2 vs. 2.7 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.
See accompanying Patient Insert.
General: This product contains peanut oil and should not be used if you are allergic to peanuts.
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. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximate rates.
Endometrial Protection:
Secondary Amenorrhea:
The most common adverse experiences reported in greater than or equal to 5% of patients in all PROMETRIUM Capsules dosage groups studied in this trial (100 mg/day to 400 mg/day) were: dizziness (16%), breast pain (11%), headache (10%), abdominal pain (10%), fatigue (9%), viral infection (7%), abdominal distention (6%), musculoskeletal pain (6%), emotional lability (6%), irritability (5%), and upper respiratory tract infection (5%).
Other adverse events reported in less than 5% of patients taking PROMETRIUM Capsules include:
Administration Site Conditions:
Blood and Lymphatic System:
Cardiac Disorders:
Ear and Labyrinth Disorders:
Eye Disorders:
Gastrointestinal System Disorders:
General Disorders:
Infections:
Injury, Poisoning and Procedural Complications:
Musculoskeletal and Connective Tissue Disorders:
Nervous System Disorders:
Psychiatric Disorders:
Renal and Urinary Disorders:
Reproductive System Disorders:
Respiratory System Disorders:
Skin and Subcutaneous Tissue Disorders:
Vascular Disorders:
The following adverse experiences have been reported with PROMETRIUM Capsules in other U.S. clinical trials: increased sweating, asthenia, tooth disorder, anorexia, increased appetite, nervousness, and breast enlargement.
In addition to the adverse events observed in clinical trials, the following spontaneous adverse events have been reported during the marketing of PROMETRIUM Capsules.
Cardiac Disorders:
Congenital, Familial, and Genetic Disorders:
Ear and Labyrinth Disorders:
Eye Disorders:
Gastrointestinal Disorders:
General Disorders and Administration Site Conditions:
Hepatobiliary Disorders:
Immune System Disorders:
Investigations:
Musculoskeletal Disorders:
Neoplasms Benign, Malignant, and Unspecified:
Nervous System Disorders:
Pregnancy, Puerperium, and Perinatal Conditions:
Psychiatric Disorders:
Reproductive System and Breast Disorders:
Respiratory, Thoracic, and Mediastinal Disorders:
Skin and Subcutaneous Tissue Disorders:
Vascular Disorders:
The following additional adverse experiences have been observed in women taking estrogen and/or progestins in general: breakthrough bleeding, spotting, change in menstrual flow, amenorrhea, changes in weight (increase or decrease), changes in the cervical squamo-columnar junction and cervical secretions, cholestatic jaundice, anaphylactoid reactions and anaphylaxis, rash (allergic) with and without pruritus, melasma or chloasma, that may persist when drug is discontinued, dysmenorrhea, increase in size of uterine leiomyomata, ovarian cancer, endometrial hyperplasia, endometrial cancer, galactorrhea, nipple discharge, increased incidence of gallbladder disease, enlargement of hepatic hemangiomas, erythema multiforme, erythema nodosum, hirsutism, hemorrhagic eruption, intolerance to contact lenses, migraine, chorea, reduced carbohydrate tolerance, aggravation of porphyria, changes in libido, hypocalcemia, angioedema, exacerbation of asthma, increased triglycerides.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
While we update our database periodically, we cannot guarantee it is always updated to the latest version.
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