PROMETRIUM®(progesterone, USP)Capsules 100 mgCapsules 200 mg

PROMETRIUM - progesterone capsule 
Abbott Products, Inc.

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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 CLINICAL STUDIES and WARNINGS, Cardiovascular disorders and Dementia.)

The Women's Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of stroke, deep vein thrombosis (DVT), pulmonary embolism, 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 CLINICAL STUDIES and WARNINGS, Cardiovascular disorders.)

The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer. (See CLINICAL STUDIES and WARNINGS, Malignant neoplasms, Breast Cancer.)

The Women's Health Initiative Memory Study (WHIMS) estrogen plus progestin ancillary study of the WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age or older.

DESCRIPTION

PROMETRIUM (progesterone, USP) Capsules contain micronized progesterone for oral administration. Progesterone has a molecular weight of 314.47 and a molecular formula of C21H30O2. 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:

Structural Formula

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.

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.

Pharmacokinetics

A. Absorption

After oral administration of progesterone as a micronized soft-gelatin capsule formulation, maximum serum concentrations were attained within 3 hours. The absolute bioavailability of micronized progesterone is not known. Table 1 summarizes the mean pharmacokinetic parameters in postmenopausal women after five oral daily doses of PROMETRIUM Capsules 100 mg as a micronized soft-gelatin capsule formulation.

TABLE 1. Pharmacokinetic Parameters of PROMETRIUM

a Mean ± S.D.

ParameterPROMETRIUM Capsules Daily Dose
100 mg200 mg300 mg
Cmax (ng/mL) 17.3 ± 21.9a38.1 ± 37.8 60.6 ± 72.5
Tmax (hr) 1.5 ± 0.8 2.3 ± 1.4 1.7 ± 0.6
AUC (0-10) (ng × hr/mL) 43.3 ± 30.8 101.2 ± 66.0 175.7 ± 170.3

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.

B. Distribution

Progesterone is approximately 96 percent to 99 percent bound to serum proteins, primarily to serum albumin (50 to 54 percent) and transcortin (43 to 48 percent).

C. Metabolism

Progesterone is metabolized primarily by the liver largely to pregnanediols and pregnanolones. Pregnanediols and pregnanolones are conjugated in the liver to glucuronide and sulfate metabolites. Progesterone metabolites which are excreted in the bile may be deconjugated and may be further metabolized in the gut via reduction, dehydroxylation, and epimerization.

D. Excretion

The glucuronide and sulfate conjugates of pregnanediol and pregnanolone are excreted in the bile and urine. Progesterone metabolites are eliminated mainly by the kidneys. Progesterone metabolites which are excreted in the bile may undergo enterohepatic recycling or may be excreted in the feces.

E. Special Populations

The pharmacokinetics of PROMETRIUM Capsules have not been assessed in low body weight or obese patients.

Race: There is insufficient information available from trials conducted with PROMETRIUM Capsules to compare progesterone pharmacokinetics in different racial groups.

Hepatic Insufficiency: The effects of hepatic impairment on PROMETRIUM Capsule pharmacokinetics have not been studied.

Renal Insufficiency: The effects of renal impairment on PROMETRIUM Capsule pharmacokinetics have not been studied.

F. Food–Drug Interaction

Concomitant food ingestion increased the bioavailability of PROMETRIUM Capsules relative to a fasting state when administered to postmenopausal women at a dose of 200 mg.

G. Drug Interactions

The metabolism of progesterone by human liver microsomes was inhibited by ketoconazole (IC50 <0.1 μM). Ketoconazole is a known inhibitor of cytochrome P450 3A4, hence these data suggest that ketoconazole or other known inhibitors of this enzyme may increase the bioavailability of progesterone. The clinical relevance of the in vitro findings is unknown.

Coadministration of conjugated estrogens and PROMETRIUM Capsules to 29 postmenopausal women over a 12-day period resulted in an increase in total estrone concentrations (Cmax 3.68 ng/mL to 4.93 ng/mL) and total equilin concentrations (Cmax 2.27 ng/mL to 3.22 ng/mL) and a decrease in circulating 17β estradiol concentrations (Cmax 0.037 ng/mL to 0.030 ng/mL). The half-life of the conjugated estrogens was similar with coadministration of PROMETRIUM Capsules. Table 2 summarizes the pharmacokinetic parameters.

TABLE 2. Mean (± S.D.) Pharmacokinetic Parameters for Estradiol, Estrone, and Equilin Following Coadministration of Conjugated Estrogens 0.625 mg and PROMETRIUM Capsules 200 mg for 12 Days to Postmenopausal Women

a Total estrogens is the sum of conjugated and unconjugated estrogen.

 Conjugated EstrogensConjugated Estrogens plus PROMETRIUM Capsules
DrugCmax
(ng/mL)
Tmax
(hr)
AUC(0-24h)
(ng × h/mL)
Cmax
(ng/mL)
Tmax
(hr)
AUC(0-24h)
(ng × h/mL)
Estradiol 0.037
± 0.048
12.7
± 9.1
0.676
± 0.737
0.030
± 0.032
17.32
± 1.21
0.561
± 0.572
Estrone
Totala
3.68
± 1.55
10.6
± 6.8
61.3
± 26.36
4.93
± 2.07
7.5
± 3.8
85.9
± 41.2
Equilin
Totala
2.27
± 0.95
6.0
± 4.0
28.8
± 13.0
3.22
± 1.13
5.3
± 2.6
38.1
± 20.2

CLINICAL STUDIES

Effects on the endometrium

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/day for 12 days per 28-day cycle in combination with conjugated estrogens 0.625 mg/day (n=120); conjugated estrogens 0.625 mg/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 Table 3. 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.

TABLE 3. Incidence of Endometrial Hyperplasia in Women Receiving 3 Years of Treatment

a Most advanced result to least advanced result:
Adenocarcinoma > atypical hyperplasia > complex hyperplasia > simple hyperplasia

Endometrial DiagnosisTreatment Group
 Conjugated Estrogens 0.625 mg + PROMETRIUM Capsules 200 mg
(cyclical)
Conjugated Estrogens 0.625 mg
(alone)
Placebo
 Number of patients% of patientsNumber of patients% of patientsNumber of patients% of patients
 n=117n=115n=116
HYPERPLASIAa 7 6 74 64 3 3
       Adenocarcinoma 0 0 0 0 1 1
       Atypical hyperplasia 1 1 14 12 0 0
       Complex hyperplasia 0 0 27 23 1 1
       Simple hyperplasia 6 5 33 29 1 1

The times to diagnosis of endometrial hyperplasia over 36 months of treatment are shown in Figure 1. 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).

Figure 1

Figure 1. Time to Hyperplasia in Women Receiving up to 36 Months of Treatment

The discontinuation rates due to hyperplasia over the 36 months of treatment are as shown in Table 4. 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.

TABLE 4. Discontinuation Rate Due to Hyperplasia Over 36 Months of Treatment
Most Advanced Biopsy Result Through 36 Months of TreatmentTreatment Group
 Conjugated Estrogens + PROMETRIUM Capsules
(cyclical)
Conjugated Estrogens (alone)Placebo
 n=120n=119n=119
 Number of patients% of
patients
Number of patients% of patientsNumber of patients% of patients
Adenocarcinoma 0 0 0 0 1 1
Atypical hyperplasia 1 1 10 8 0 0
Complex hyperplasia 0 0 21 18 1 1
Simple hyperplasia 1 1 13 11 0 0

Effects on secondary amenorrhea

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/day (n=20), compared to 10 percent of women experiencing withdrawal bleeding in the placebo group (n=21).

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/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).

Women's Health Initiative Studies

The Women's Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of either the use 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) (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. The study did not evaluate the effects of CE or CE plus MPA on menopausal symptoms.

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 age of 63 years, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 5. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

TABLE 5. Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Yearsa

a Results are based on centrally adjudicated data.

b Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.

c Not included in Global Index.

d Includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer.

e All deaths, except from breast or colorectal cancer, definite/probable CHD, PE or cerebrovascular disease.

f A subset of the events was combined in a “global index” defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes.

EventcRelative Risk
CE/MPA versus Placebo
(95% nCIb)
Placebo
n = 8,102
CE/MPA
n = 8,506
Absolute Risk per
10,000 Women-years
CHD events 1.23 (0.99-1.53) 34 41
    Non-fatal MI b1.28 (1.00-1.63)2531
    CHD death1.10 (0.70-1.75)88
       
All stroke 1.31 (1.03-1.88) 25 33
    Ischemic Stroke1.44 (1.09-1.90)1826
Deep vein thrombosis c1.95 (1.43-2.67) 13 26
Pulmonary embolism 2.13 (1.45-3.11) 8 18
Invasive breast cancer d1.24 (1.01-1.54) 33 41
Colorectal cancer 0.61 (0.42-0.87) 16 10
Endometrial cancer c0.82 (0.48-1.36) 7 6
Cervical cancer c1.44 (0.47-4.42) 1 2
Hip fracture 0.67 (0.47-0.96) 16 11
Vertebral fractures c0.68 (0.48-0.96) 17 12
Lower arm/wrist fractures c0.71 (0.59-0.85) 62 44
Total fractures c0.76 (0.69-0.83) 199 152
Overall mortality c, e1.00 (0.83-1.19) 52 52
Global Index f1.13 (1.02-1.25) 165 184

Women's Health Initiative Memory Study

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 with placebo.

After an average follow-up of 4 years, the relative risk of probable dementia for CE (0.625 mg) plus MPA (2.5 mg) 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. The most common classification of probable dementia in the treatment group and placebo group was Alzheimer's disease. 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 BOXED WARNING, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.)

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.

CONTRAINDICATIONS

PROMETRIUM Capsules should not be used in women with any of the following conditions:

  1. 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.
  2. Undiagnosed abnormal genital bleeding.
  3. Known, suspected, or history of breast cancer.
  4. Active deep vein thrombosis, pulmonary embolism or history of these conditions.
  5. Active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions.
  6. Known liver dysfunction or disease.
  7. Known or suspected pregnancy.

WARNINGS

See BOXED WARNING.

1. Cardiovascular disorders

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 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.

a. Stroke

In the Women's Health Initiative (WHI) estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in all women receiving daily conjugated estrogens (CE 0.625 mg) plus medroxyprogesterone acetate (MPA 2.5 mg) compared to placebo (33 versus 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. (See CLINICAL STUDIES.) Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.

b. Coronary Heart Disease

In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events (defined as nonfatal MI, silent MI, or CHD death) reported in women receiving daily CE/MPA compared to women receiving placebo (41 versus 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1 and a trend toward decreasing relative risk was reported in years 2 through 5. (See CLINICAL STUDIES.)

In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus 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 plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty-one (2,321) 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 plus MPA group and the placebo group in HERS, HERS II, and overall.

c. Venous Thromboembolism (VTE)

In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE (DVT and pulmonary embolism [PE]), was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years) and PE. Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was observed during the first year and persisted. (See CLINICAL STUDIES.) Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.

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.

2. Malignant neoplasms

a. Breast Cancer

The most important randomized clinical trial providing information about breast cancer is the Women's Health Initiative (WHI) substudy of daily CE (0.625 mg) plus MPA (2.5 mg). In the estrogen plus progestin substudy, after a mean follow-up of 5.6 years, the WHI substudy reported an increased risk of breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24 (95 percent nCI 1.01-1.54), and the absolute risk was 41 versus 33 cases per 10,000 women-years, for estrogen plus progestin 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 versus 25 cases per 10,000 women-years, for estrogen plus progestin 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 versus 36 cases per 10,000 women-years for estrogen plus progestin compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) 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.

b. Endometrial Cancer

An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women using estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

c. Ovarian Cancer

The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent nCI 0.77 – 3.24). The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen-only products, in particular for 5 or more years, has been associated with an increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association.

3. Probable Dementia

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 CLINICAL STUDIES and PRECAUTIONS, Geriatric Use.)

4. Vision abnormalities

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 permanently discontinued.

PRECAUTIONS

A. General

1. Addition of a progestin when a woman has not had a hysterectomy

Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.

There are, however, possible risks that may be associated with the use of progestins with estrogens compared with estrogen-alone regimens. These include a possible increased risk of breast cancer.

2. Fluid Retention

Progesterone may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation.

3. Dizziness and Drowsiness

PROMETRIUM Capsules may cause transient dizziness and drowsiness and should be used with caution when driving a motor vehicle or operating machinery. PROMETRIUM Capsules should be taken as a single daily dose at bedtime.

B. Patient Information

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.

C. Drug-Laboratory Test Interactions

The following laboratory results may be altered by the use of estrogen-progestin combination drugs:

  • Increased sulfobromophthalein retention and other hepatic function tests.
  • Coagulation tests: increase in prothrombin factors VII, VIII, IX and X.
  • Pregnanediol determination.
  • Thyroid function: increase in PBI, and butanol extractable protein bound iodine and decrease in T3 uptake values.

D. Carcinogenesis, Mutagenesis, Impairment of Fertility

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 in vitro studies for point mutations or for chromosomal damage. In vivo 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.

E. Pregnancy

PROMETRIUM Capsules should not be used during pregnancy. (See CONTRAINDICATIONS.)

Pregnancy Category B: 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.

F. Nursing Mothers

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.

G. Pediatric Use

PROMETRIUM Capsules are not indicated for pediatric use and no clinical data have been collected in children.

H. Geriatric Use

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.

The Women's Health Initiative Study

In the Women's Health Initiative (WHI) estrogen plus progestin substudy, there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age. (See WARNINGS, Cardiovascular disorders and Malignant neoplasms.)

The Women's Health Initiative Memory Study

In the Women's Health Initiative Memory Study (WHIMS) of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in the estrogen plus progestin ancillary study when compared to placebo. (See WARNINGS, Probable Dementia.)

ADVERSE REACTIONS

See BOXED WARNING, WARNINGS and PRECAUTIONS.

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. Table 6 lists adverse experiences 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.

TABLE 6. Adverse Experiences (≥ 2%) Reported in an 875 Patient Placebo-Controlled Trial in Postmenopausal Women Over a 3-Year Period [Percentage (%) of Patients Reporting]
 PROMETRIUM Capsules 200 mg with Conjugated Estrogens 0.625 mgPlacebo
 (n=178)(n=174)
Headache 31 27
Breast Tenderness 27 6
Joint Pain 20 29
Depression 19 12
Dizziness 15 9
Abdominal Bloating 12 5
Hot Flashes 11 35
Urinary Problems 11 9
Abdominal Pain 10 10
Vaginal Discharge 10 3
Nausea / Vomiting 8 7
Worry 8 4
Chest Pain 7 5
Diarrhea 7 4
Night Sweats 7 17
Breast Pain 6 2
Swelling of Hands and Feet 6 9
Vaginal Dryness 6 10
Constipation 3 2
Breast Carcinoma 2 <1
Breast Excisional Biopsy 2 <1
Cholecystectomy 2 <1

Effects on Secondary Amenorrhea

In a multicenter, randomized, double-blind, placebo-controlled clinical trial, the effects of PROMETRIUM on secondary amenorrhea was studied in 49 estrogen-primed postmenopausal women. Table 7 lists adverse experiences greater than or equal to 5 percent of women who received PROMETRIUM or placebo.

TABLE 7. Adverse Experiences (≥ 5%) Reported in Patients Using 400 mg/day in a Placebo-Controlled Trial in Estrogen-Primed Postmenopausal Women
Adverse ExperiencePROMETRIUM
Capsules 400 mg
Placebo
 n=25n=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

In an open label, multicenter, parallel group, postmarketing dosing study consisting of three consecutive 28-day treatment cycles, 220 women with secondary amenorrhea were randomized to PROMETRIUM 300 mg/day (n = 113) or PROMETRIUM 400 mg/day (n = 107). They received daily estrogen therapy (0.625 mg conjugated estrogen). Eight (8) patients (5 at 400 mg/day; 3 at 300 mg/day) were found to have abnormal PAP smears classified by the investigator as clinically significant. Further evaluation found that 6 of the 8 results were infectious in nature (i.e., Candida, HPV, bacterial vaginosis, Trichomonas).

Postmarketing Experience:

The following additional adverse reactions have been reported with PROMETRIUM Capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Genitourinary System: endometrial carcinoma, hypospadia, intra-uterine death, menorrhagia, menstrual disorder, metrorrhagia, ovarian cyst, spontaneous abortion.

Cardiovascular: circulatory collapse, congenital heart disease (including ventricular septal defect and patent ductus arteriosus), hypertension, hypotension, tachycardia.

Gastrointestinal: acute pancreatitis, cholestasis, cholestatic hepatitis, dysphagia, hepatic failure, hepatic necrosis, hepatitis, increased liver function tests (including alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyl transferase increased), jaundice, swollen tongue.

Skin: alopecia, pruritus, urticaria.

Eyes: blurred vision, diplopia, visual disturbance.

Central Nervous System: aggression, convulsion, depersonalization, depressed consciousness, disorientation, dysarthria, loss of consciousness, paresthesia, sedation, stupor, syncope (with and without hypotension), transient ischemic attack, suicidal ideation.

During initial therapy, a few women have experienced a constellation of many or all of the following symptoms: extreme dizziness and/or drowsiness, blurred vision, slurred speech, difficulty walking, loss of consciousness, vertigo, confusion, disorientation, feeling drunk, and shortness of breath.

Miscellaneous: abnormal gait, anaphylactic reaction, arthralgia, blood glucose increased, choking, cleft lip, cleft palate, difficulty walking, dyspnea, face edema, feeling abnormal, feeling drunk, hypersensitivity, asthma, muscle cramp, throat tightness, tinnitus, vertigo, weight decreased, weight increased.

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.

DOSAGE AND ADMINISTRATION

Prevention of Endometrial Hyperplasia

PROMETRIUM Capsules should be given as a single daily dose at bedtime, 200 mg orally for 12 days sequentially per 28-day cycle, to postmenopausal women with a uterus who are receiving daily conjugated estrogens tablets.

Treatment of Secondary Amenorrhea

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.

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)

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.

Manufactured by:
Catalent Pharma Solutions
St. Petersburg, FL 33716

Marketed by:
Abbott Laboratories
North Chicago, IL 60064, U.S.A.

© 2010 Abbott Laboratories

All rights reserved.

500032 3E Rev Mar 2010

PATIENT INFORMATION

PROMETRIUM® (progesterone, USP)
Capsules 100 mg
Capsules 200 mg

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.

WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT PROMETRIUM CAPSULES (A Progesterone Hormone)?
  • Progesterone with or without estrogens should not be used to prevent heart disease, heart attacks, strokes, or dementia.
  • Using estrogens with or without progestins may increase your chance of getting heart attacks, strokes, breast cancer, and blood clots. Using estrogens with or without progestins may increase your chance of getting dementia, based on a study of women age 65 and older. You and your healthcare provider should talk regularly about whether you still need treatment with PROMETRIUM Capsules.

THIS PRODUCT CONTAINS PEANUT OIL AND SHOULD NOT BE USED IF YOU ARE ALLERGIC TO PEANUTS.

What is PROMETRIUM Capsules?

PROMETRIUM Capsules contain the female hormone called progesterone.

What is PROMETRIUM Capsules used for?

Treatment of Menstrual Irregularities

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.

Protection of the Endometrium (Lining of the Uterus)

PROMETRIUM Capsules are used in combination with estrogen-containing medications in postmenopausal women with a uterus. Taking estrogens alone increases the chance of developing a condition called endometrial hyperplasia, that may lead to cancer of the lining of the uterus. The addition of a progestin is generally recommended for women with a uterus to reduce the chance of getting cancer of the uterus.

Who should not take PROMETRIUM Capsules?

Do not start taking PROMETRIUM Capsules if you:

Tell your healthcare provider:

How should I take PROMETRIUM Capsules?

  1. Prevention of Endometrial Hyperplasia: Postmenopausal women with a uterus who are taking estrogens should take a single daily dose of 200 mg PROMETRIUM Capsules at bedtime for 12 continuous days per 28-day cycle.
  2. Secondary Amenorrhea: PROMETRIUM Capsules may be given as a single daily dose of 400 mg at bedtime for 10 days.
  3. PROMETRIUM Capsules are to be taken at bedtime as some women become very drowsy and/or dizzy after taking PROMETRIUM Capsules. In a small percentage of these women, these effects may be increased including blurred vision, difficulty speaking, difficulty walking, and feeling abnormal. If you experience these symptoms, discuss them with your healthcare provider immediately. Taking PROMETRIUM Capsules at bedtime may minimize the impact of these symptoms.

If you experience difficulty in swallowing PROMETRIUM Capsules, it is recommended that you take your daily dose at bedtime with a glass of water while in the standing position.

What are the possible side effects of PROMETRIUM Capsules?

The following 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:

Less serious but common side effects include:

These are not all the possible side effects of PROMETRIUM Capsules. For more information, ask your healthcare provider or pharmacist.

Some of the warning signs of serious side effects include:

Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptoms that concern you.

What can I do to lower my chances of getting a serious side effect with PROMETRIUM Capsules?

General information about safe and effective use of PROMETRIUM Capsules

Keep PROMETRIUM Capsules out of the reach of children.

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.

What are the ingredients in PROMETRIUM Capsules?

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.

HOW SUPPLIED

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.”

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.

Manufactured by:
Catalent Pharma Solutions
St. Petersburg, FL 33716

Marketed by:
Abbott Laboratories
North Chicago, IL 60064, U.S.A.

© 2010 Abbott Laboratories.
All rights reserved.

500033 3E Rev Mar 2010

NDC 0032–1708–01

100 Capsules

PROMETRIUM® (progesterone, USP) Capsules

100 mg

Rx only

DO NOT USE IF ALLERGIC TO PEANUTS

Abbott

prometrium 100 mg capsules

NDC 0032–1711–01

100 Capsules

PROMETRIUM® (progesterone, USP) Capsules

200 mg

Rx only

DO NOT USE IF ALLERGIC TO PEANUTS

Abbott

prometrium 200 mg capsules

PROMETRIUM 
progesterone capsule
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0032-1708
Route of AdministrationORALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
progesterone (progesterone) progesterone100 mg
Inactive Ingredients
Ingredient NameStrength
peanut oil 
gelatin 
glycerin 
lecithin, soybean 
titanium dioxide 
D&C yellow no. 10 
FD&C red no. 40 
Product Characteristics
ColorORANGE (peach) Score no score
ShapeROUND (ROUND) Size13mm
FlavorImprint Code SV
Contains    
Packaging
#Item CodePackage DescriptionMultilevel Packaging
1NDC:0032-1708-01100 CAPSULE ( CAPSULE) in 1 BOTTLENone

Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA01978107/30/2010

PROMETRIUM 
progesterone capsule
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0032-1711
Route of AdministrationORALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
progesterone (progesterone) progesterone200 mg
Inactive Ingredients
Ingredient NameStrength
peanut oil 
gelatin 
glycerin 
lecithin, soybean 
titanium dioxide 
D&C yellow no. 10 
FD&C yellow no. 6 
Product Characteristics
ColorYELLOW (Pale Yellow) Score no score
ShapeOVAL (OVAL) Size15mm
FlavorImprint Code SV2
Contains    
Packaging
#Item CodePackage DescriptionMultilevel Packaging
1NDC:0032-1711-01100 CAPSULE ( CAPSULE) in 1 BOTTLENone

Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA01978107/30/2010

Labeler - Abbott Products, Inc. (003309358)

Revised: 07/2011 Abbott Products, Inc.