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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 approximating rates.

In a 12-week clinical trial, 209 postmenopausal women with vasomotor symptoms were treated with ENJUVIA (synthetic conjugated estrogens, b) . Adverse events that occurred in the study at a rate greater than or equal to 5% and greater than placebo, regardless of relationship to study drug, are summarized in Table 8.

Table 8. ENJUVIA (synthetic conjugated estrogens, b) Tablets - Number (%) of Patients Reporting Aderse Events* with ≥ 5% Occurrence Rate by Body System

Body System/Adverse Event* 0.3 mg
n=68
0.625 mg
n=72
1.25 mg
n=69
Placebo
n=72
Number of Patients in Safety Sample (%) 68 (100) 72 (100) 69 (100) 72 (100)
Number of Patients with Adverse Events (%) 49 (72) 55 (76) 56 (81) 51 (71)
Number of Patients without Adverse Events (%) 19 (28) 17 (24) 13 (19) 21 (29)
Body as a Whole        
  Abdominal Pain 3 (4) 11 (15) 3 (4) 7 (10)
  Accidental Injury 6 (8) 2 (3) 3 (4) 5 (7)
  Flu Syndrome 4 (6) 3 (4) 5 (7) 3 (4)
  Headache 10 (15) 18 (25) 11 (16) 15 (21)
  Pain 10 (15) 14 (19) 7 (10) 6 (8)
Digestive System        
  Flatulence 3 (4) 5 (7) 3 (4) 2 (3)
  Nausea 5 (7) 7 (10) 8 (12) 6 (8)
Nervous System        
  Dizziness 5 (7) 3 (4) 1 (1) 3 (4)
  Paresthesia 0 4 (6) 1 (1) 0
Respiratory System        
  Bronchitis 0 3 (4) 5(7) 3 (4)
  Rhinitis 3 (4) 4 (6) 5 (7) 4 (6)
  Sinusitis 2 (3) 3 (4) 5 (7) 2 (3)
Urogenital System        
  Breast Pain 0 9 (12) 10 (14) 3 (4)
  Dysmenorrhea 1 (2) 6 (8) 1 (1) 2 (3)
  Vaginitis 1 (2) 5 (7) 2 (3) 3 (4)
*Treatment-emergent adverse events, regardless of relationship to study drug

In a second 12-week clinical trial, 310 women with symptoms of vulvar and vaginal atrophy were treated (154 women with ENJUVIA (synthetic conjugated estrogens, b) 0.3 mg tablets and 156 women with placebo). The only adverse event that occurred at a rate of > 5% was headache; seven patients (4.55%) with ENJUVIA (synthetic conjugated estrogens, b) and twelve patients (7.69%) with placebo.

The following additional adverse reactions have been reported with estrogen and/or progestin therapy:

1. Genitourinary system

Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; dysmenorrhea; increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer.

2. Breasts

Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer.

3.Cardiovascular

Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure.

4. Gastrointestinal

Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis, enlargement of hepatic hemangiomas.

5. Skin

Chloasma or melasma that may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash.

6. Eyes

Retinal vascular thrombosis, intolerance to contact lenses.

7. Central Nervous System

Headache; migraine; dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia.

8. Miscellaneous

Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthralgias; leg cramps; changes in libido; urticaria, angioedema, anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides.