FDA label e7c2821a-12eb-4326-9b1c-ebe8f161cd3e

WARNINGS Progestins and estrogens should not be used for the prevention of cardiovascular disease. (See WARNINGS, Cardiovascular Disorders .) The Women's Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo. (See CLINICAL PHARMACOLOGY, Clinical Studies .) The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies .) Other doses of oral conjugated estrogens with medroxyprogesterone and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials. In the absence of comparable data and product-specific studies, the relevance of the WHI findings to other products has not been established. Therefore, the risks should be assumed to be similar for all estrogen and progestin products. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

WARNINGS See BOXED WARNINGS . Cardiovascular Disorders 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 Women's Health Initiative (WHI) study, an increase in the number of strokes was observed in women receiving CE compared to placebo. 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 CLINICAL PHARMACOLOGY, Clinical Studies .) 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 CLINICAL PHARMACOLOGY, Clinical Studies .) 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 Women's Health Initiative (WHI) study, an increase in VTE was observed in women receiving CE compared to placebo. 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 CLINICAL PHARMACOLOGY, Clinical Studies .) 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. Breast Cancer 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 CLINICAL PHARMACOLOGY, Clinical Studies .) 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. Vision Disorders 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. Dementia 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 CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use .)

ADVERSE REACTIONS See BOXED WARNINGS , 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. 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: Table 8 lists adverse experiences which were reported in greater than or equal to 2% of patients (regardless of relationship to treatment) who received cyclic PROMETRIUM Capsules, 200 mg daily (12 days per calendar month cycle) with daily 0.625 mg conjugated estrogen, in a multicenter, randomized, double-blind, placebo-controlled clinical trial in 875 postmenopausal women. TABLE 8 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 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 Secondary Amenorrhea: Table 9 lists adverse experiences which were reported in greater than or equal to 5% of patients receiving PROMETRIUM Capsules, 400 mg/day, in a multicenter, randomized, double-blind, placebo-controlled clinical trial in estrogen-primed (6 weeks) postmenopausal women receiving conjugated estrogens 0.625 mg/day and cyclic (10 days per calendar month cycle) PROMETRIUM Capsules at a dose of 400 mg/day, for three cycles. TABLE 9 Adverse Experiences (≥5%) Reported in Patients Using 400 mg/day in a Placebo-Controlled Trial in Estrogen-Primed Postmenopausal Women Adverse Experience PROMETRIUM 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 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: edema, edema peripheral Blood and Lymphatic System: lymphadenopathy Cardiac Disorders: angina pectoris, palpitation Ear and Labyrinth Disorders: earache Eye Disorders: abnormal vision Gastrointestinal System Disorders: constipation, dry mouth, dyspepsia, gastroenteritis, hemorrhagic rectum, hiatus hernia, vomiting General Disorders: chest pain, fever Infections: abscess, herpes simplex Injury, Poisoning and Procedural Complications: accidental injury Musculoskeletal and Connective Tissue Disorders: arthritis, leg cramps, muscle disorder, myalgia Nervous System Disorders: hypertonia, impaired concentration, somnolence, speech disorder Psychiatric Disorders: anxiety, confusion, insomnia, personality disorder Renal and Urinary Disorders: urinary tract infection Reproductive System Disorders: fungal vaginitis, leukorrhea, uterine fibroid, vaginal dryness, vaginitis Respiratory System Disorders: bronchitis, nasal congestion, pharyngitis, pneumonitis, sinusitis Skin and Subcutaneous Tissue Disorders: acne, verruca, wound debridement Vascular Disorders: hypertension 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: circulatory collapse, tachycardia Congenital, Familial, and Genetic Disorders: cleft lip, cleft palate, congenital heart disease, patent ductus arteriosus, ventricular septal defect Ear and Labyrinth Disorders: tinnitus, vertigo Eye Disorders: blurred vision, diplopia, visual disturbance Gastrointestinal Disorders: acute pancreatitis, dysphagia, swollen tongue General Disorders and Administration Site Conditions: abnormal gait, difficulty walking, feeling abnormal, feeling drunk Hepatobiliary Disorders: cholestasis, cholestatic hepatitis, jaundice, hepatitis, hepatic failure, hepatic necrosis, increased liver function tests Immune System Disorders: anaphylactic reaction, hypersensitivity Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyl transferase increased, hepatic enzyme increased, blood glucose increased, weight decreased, weight increased Musculoskeletal Disorders: arthralgia, muscle cramp Neoplasms Benign, Malignant, and Unspecified: endometrial carcinoma Nervous System Disorders: convulsion, depressed consciousness, dysarthria, loss of consciousness, paresthesia, sedation, stupor, syncope (with and without hypotension), transient ischemic attack Pregnancy, Puerperium, and Perinatal Conditions: intra-uterine death, spontaneous abortion Psychiatric Disorders: aggression, depersonalization, disorientation, suicidal ideation, Reproductive System and Breast Disorders: menorrhagia, menstrual disorder, metrorrhagia, ovarian cyst Respiratory, Thoracic, and Mediastinal Disorders: asthma, choking, dyspnea, face edema, throat tightness Skin and Subcutaneous Tissue Disorders: alopecia, pruritus, urticaria Vascular Disorders: hypertension, hypotension 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.

<table width="100%" ID="i1be3ac73-2093-42e8-8898-b712679b795c"> <caption>TABLE 8 Adverse Experiences (&#x2265;2%) Reported in an 875 Patient Placebo-Controlled Trial in Postmenopausal Women Over a 3-Year Period [Percentage (%) of Patients Reporting]</caption> <col align="left" width="34%"/> <col align="left" width="30%"/> <col align="left" width="22%"/> <col align="left" width="12%"/> <thead> <tr> <td> </td> <td> <content styleCode="bold">PROMETRIUM Capsules 200 mg with Conjugated Estrogens 0.625 mg</content> </td> <td> <content styleCode="bold">Conjugated Estrogens 0.625 mg (only)</content> </td> <td> <content styleCode="bold">Placebo</content> </td> </tr> <tr> <td> </td> <td> <content styleCode="bold">(n=178)</content> </td> <td> <content styleCode="bold">(n=175)</content> </td> <td> <content styleCode="bold">(n=174)</content> </td> </tr> </thead> <tbody> <tr> <td>Headache</td> <td>31</td> <td>30</td> <td>27</td> </tr> <tr> <td>Breast Tenderness</td> <td>27</td> <td>16</td> <td>6</td> </tr> <tr> <td>Joint Pain</td> <td>20</td> <td>22</td> <td>29</td> </tr> <tr> <td>Depression</td> <td>19</td> <td>18</td> <td>12</td> </tr> <tr> <td>Dizziness</td> <td>15</td> <td>5</td> <td>9</td> </tr> <tr> <td>Abdominal Bloating</td> <td>12</td> <td>10</td> <td>5</td> </tr> <tr> <td>Hot Flashes</td> <td>11</td> <td>14</td> <td>35</td> </tr> <tr> <td>Urinary Problems</td> <td>11</td> <td>10</td> <td>9</td> </tr> <tr> <td>Abdominal Pain</td> <td>10</td> <td>13</td> <td>10</td> </tr> <tr> <td>Vaginal Discharge</td> <td>10</td> <td>10</td> <td>3</td> </tr> <tr> <td>Nausea / Vomiting</td> <td>8</td> <td>6</td> <td>7</td> </tr> <tr> <td>Worry</td> <td>8</td> <td>5</td> <td>4</td> </tr> <tr> <td>Chest Pain</td> <td>7</td> <td>4</td> <td>5</td> </tr> <tr> <td>Diarrhea</td> <td>7</td> <td>7</td> <td>4</td> </tr> <tr> <td>Night Sweats</td> <td>7</td> <td>5</td> <td>17</td> </tr> <tr> <td>Breast Pain</td> <td>6</td> <td>6</td> <td>2</td> </tr> <tr> <td>Swelling of Hands and Feet</td> <td>6</td> <td>9</td> <td>9</td> </tr> <tr> <td>Vaginal Dryness</td> <td>6</td> <td>8</td> <td>10</td> </tr> <tr> <td>Constipation</td> <td>3</td> <td>3</td> <td>2</td> </tr> <tr> <td>Breast Carcinoma</td> <td>2</td> <td>less than 1</td> <td>less than 1</td> </tr> <tr> <td>Breast Excisional Biopsy</td> <td>2</td> <td>1</td> <td>less than 1</td> </tr> <tr> <td>Cholecystectomy</td> <td>2</td> <td>less than 1</td> <td>less than 1</td> </tr> </tbody> </table>

<table width="100%" ID="i92398597-5483-4db3-8e5d-459d2d237a3b"> <caption>TABLE 9 Adverse Experiences (&#x2265;5%) Reported in Patients Using 400 mg/day in a Placebo-Controlled Trial in Estrogen-Primed Postmenopausal Women</caption> <col align="left" width="44%"/> <col align="left" width="32%"/> <col align="left" width="22%"/> <thead> <tr> <td> <content styleCode="bold">Adverse Experience</content> </td> <td> <content styleCode="bold">PROMETRIUM</content> <content styleCode="bold">Capsules 400 mg</content> </td> <td> <content styleCode="bold">Placebo</content> </td> </tr> <tr> <td> </td> <td> <content styleCode="bold">n=25</content> </td> <td> <content styleCode="bold">n=24</content> </td> </tr> <tr> <td> </td> <td> <content styleCode="bold">Percentage (%) of Patients</content> </td> </tr> </thead> <tbody> <tr> <td> Fatigue</td> <td>8</td> <td>4</td> </tr> <tr> <td> Headache</td> <td>16</td> <td>8</td> </tr> <tr> <td> Dizziness</td> <td>24</td> <td>4</td> </tr> <tr> <td> Abdominal Distention (Bloating)</td> <td>8</td> <td>8</td> </tr> <tr> <td> Abdominal Pain (Cramping)</td> <td>20</td> <td>13</td> </tr> <tr> <td> Diarrhea</td> <td>8</td> <td>4</td> </tr> <tr> <td> Nausea</td> <td>8</td> <td>0</td> </tr> <tr> <td> Back Pain</td> <td>8</td> <td>8</td> </tr> <tr> <td> Musculoskeletal Pain</td> <td>12</td> <td>4</td> </tr> <tr> <td> Irritability</td> <td>8</td> <td>4</td> </tr> <tr> <td> Breast Pain</td> <td>16</td> <td>8</td> </tr> <tr> <td> Infection Viral</td> <td>12</td> <td>0</td> </tr> <tr> <td> Coughing</td> <td>8</td> <td>0</td> </tr> </tbody> </table>