Progesterone Drug Information
Generic name: PROGESTERONE
Progesterone [EPC]
Uses of Progesterone
Progesterone 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.
Dosage & Administration of Progesterone
Prevention of Endometrial Hyperplasia Progesterone 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 Progesterone capsules may be given as a single daily dose of 400 mg at bedtime for 10 days. Some women may experience difficulty swallowing progesterone capsules.
For these women, progesterone capsules should be taken with a glass of water while in the standing position.
Side Effects of Progesterone
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 progesterone capsules on the endometrium was studied in a total of 875 postmenopausal women.
Table 6. Adverse Experiences (≥2%) Reported in an 875 Patient Placebo-Controlled Trial in Postmenopausal Women Over a 3-Year Period Effects on Secondary Amenorrhea In a multicenter, randomized, double-blind, placebo-controlled clinical trial, the effects of progesterone 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 progesterone or placebo.
Table 7. Adverse Experiences (5%) Reported in Patients Using 400 mg/day in a Placebo-Controlled Trial in Estrogen-Primed Postmenopausal Women 8 0 In a multicenter, parallel-group, open label postmarketing dosing study consisting of three consecutive 28-day treatment cycles, 220 premenopausal women with secondary amenorrhea were randomized to receive daily conjugated estrogens therapy (0.625 mg conjugated estrogens) and progesterone capsules, 300 mg per day (n=113) or Progesterone capsules, 400 mg per day (n=107) for 10 days of each treatment cycle. Overall, the most frequently reported treatment-emergent adverse reactions, reported in greater than or equal to 5 percent of subjects, were nausea, fatigue, vaginal mycosis, nasopharyngitis, upper respiratory tract infection, headache, dizziness, breast tenderness, abdominal distension, acne, dysmenorrhea, mood swing, and urinary tract infection.
Postmarketing Experience: The following additional adverse reactions have been reported with progesterone 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, gammaglutamyl 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.
| Progesterone capsules 200 mg with Congugated Estrogens 0.625 mg | Placebo | |
|---|---|---|
| (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 |
| Adverse Experience | Progesterone Capsules 400 mg | 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 |
Warnings & Cautions for Progesterone
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 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, obesity, and systemic lupus erythematosus) should be managed appropriately. a. 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 coronary heart disease (CHD) events (defined as nonfatal myocardial infarction, silent MI, or CHD death) reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) 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 ), 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 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 In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE (DVT and pulmonary embolism ) 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. 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 in estrogen plus progestin users is the Women’s Health Initiative (WHI) substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up of 5.6 years, the estrogen plus progestin 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. 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. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were 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. (See CLINICAL STUDIES.) Consistent with the WHI clinical trials, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping).
Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. However, these studies have not generally found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration. 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 genital 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. 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 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 Retinal vascular thrombosis has been reported in patients receiving estrogen. Discontinue estrogen plus progestin therapy 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, estrogen plus progestin therapy should be permanently discontinued.
Pregnancy Safety for Progesterone
E. Pregnancy Progesterone 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.
Pediatric Use of Progesterone
G. Pediatric Use Progesterone capsules are not indicated in children. Clinical studies have not been conducted in the pediatric population.
Contraindications for Progesterone
Progesterone capsules should not be used in women with any of the following conditions: Progesterone capsules should not be used in patients with known hypersensitivity to its ingredients. Progesterone capsules contain peanut oil and should never be used by patients allergic to peanuts. Undiagnosed abnormal genital bleeding.
Known, suspected, or history of breast cancer. Active deep vein thrombosis, pulmonary embolism or history of these conditions. Active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions.
Known liver dysfunction or disease. Known or suspected pregnancy.
Overdosage Information for Progesterone
No studies on overdosage have been conducted in humans. In the case of overdosage, progesterone capsules should be discontinued and the patient should be treated symptomatically.
Clinical Studies of Progesterone
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: progesterone 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 progesterone 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 progesterone capsules plus conjugated estrogens treatment group throughout 36 months of treatment. TABLE 3.
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 progesterone capsules group (6 percent). 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 progesterone 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 0 0 graph1 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 progesterone capsules therapy resulted in 80 percent of women experiencing withdrawal bleeding within 7 days of the last dose of progesterone capsules, 300 mg/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 progesterone 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.
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 progesterone 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.
Women's Health Initiative Studies The Womens 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) alone or in combination with medroxyprogesterone acetate (MPA) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease, 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 substudies 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. 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 Years a,b 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. 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 WARNINGS, Probable dementia and PRECAUTIONS, Geriatric Use.)
| Most Advanced Biopsy Results Through 36 Months of Treatment | Treatment Group | |||||
|---|---|---|---|---|---|---|
| Conjugated Estrogens + Progesterone Capsules (cyclical) | Conjugated Estrogens (alone) | Placebo | ||||
| n=120 | n=119 | n=119 | ||||
| Number of patients | % of patients | Number of patients | % of patients | Number 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 |
| Event | Relative Risk CE/MPA versus Placebo (95% nCI c ) | CE/MPA n = 8,506 | Placebo n = 8,102 |
|---|---|---|---|
| Absolute Risk per 10,000 Women-Years | |||
| CHD events | 1.23 (0.99-1.53) | 41 | 34 |
| Non-fatal MI | 1.28 (1.00-1.63) | 31 | 25 |
| CHD death | 1.10 (0.70-1.75) | 8 | 8 |
| All stroke | 1.31 (1.03-1.88) | 33 | 25 |
| Ischemic stroke | 1.44 (1.09-1.90) | 26 | 18 |
| Deep vein thrombosis d | 1.95 (1.43-2.67) | 26 | 13 |
| Pulmonary embolism | 2.13 (1.45-3.11) | 18 | 8 |
| Invasive breast cancer e | 1.24 (1.01-1.54) | 41 | 33 |
| Colorectal cancer | 0.61 (0.42-0.87) | 10 | 16 |
| Endometrial cancer d | 0.81 (0.48-1.36) | 6 | 7 |
| Cervical cancer d | 1.44 (0.47-4.42) | 2 | 1 |
| Hip fracture | 0.67 (0.47-0.96) | 11 | 16 |
| Vertebral fractures d | 0.65 (0.46-0.92) | 11 | 17 |
| Lower arm/wrist fractures d | 0.71 (0.59-0.85) | 44 | 62 |
| Total fractures d | 0.76 (0.69-0.83) | 152 | 199 |
| Overall mortality f | 1.00 (0.83-1.19) | 52 | 52 |
| Global Index g | 1.13 (1.02-1.25) | 184 | 165 |
| a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. b Results are based on centrally adjudicated data. c Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. d Not included in Global Index. e Includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer. f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. g A subset of the events was combined in a global indexdefined 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. | |||
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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