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 ≥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|
| Placebo |
| (n=178) || (n=175) || (n=174) |
|Nausea / Vomiting||8||6||7|
|Swelling of Hands and Feet||6||9||9|
|Breast Excisional Biopsy||2||1||<1|
Secondary Amenorrhea: Table 9 lists adverse experiences which were reported in ≥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 |
| Abdominal Distention (Bloating)||8||8|
| Abdominal Pain (Cramping)||20||13|
| Back Pain||8||8|
| Musculoskeletal Pain||12||4|
| Breast Pain||16||8|
| Infection Viral||12||0|
The most common adverse experiences reported in ≥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 <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.