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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 that included 72 women treated with 0.625 mg and 2 x 0.625 mg Cenestin (synthetic conjugated estrogens) and 48 women treated with placebo, adverse events that occurred at a rate of > 5% are summarized in Table 5.

Table 5
Number (%) of Patients with Adverse Events With > 5% Occurrence Rate By Body System and Treatment Group

Body System
Adverse Event
Cenestin* 0.625 mg and 2 x 0.625 mg
n (%)
Placebo
n (%)
Total
n (%)
Number of Patients Who Received Medication 72 (100) 48 (100) 120 (100)
Number of Patients With Adverse Events 68 (94) 43 (90) 111 (93)
Number of Patients Without Any Adverse Events 4 (6) 5 (10) 9 (8)
Body As A Whole
    Abdominal Pain 20 (28) 11 (23) 31 (26)
    Asthenia 24 (33) 20 (42) 44 (37)
    Back Pain 10 (14) 6 (13) 16 (13)
    Fever 1 (1) 3 (6) 4 (3)
    Headache 49 (68) 32 (67) 81 (68)
    Infection 10 (14) 5 (10) 15 (13)
    Pain 8 (11) 9 (19) 17 (14)
Cardiovascular System
    Palpitation 15 (21) 13 (27) 28 (23)
Digestive System
    Constipation 4 (6) 2 (4) 6 (5)
    Diarrhea 4 (6) 0 (0) 4 (3)
    Dyspepsia 7 (10) 3 (6) 10 (8)
    Flatulence 21 (29) 14 (29) 35 (29)
    Nausea 13 (18) 9 (19) 22 (18)
    Vomiting 5 (7) 1 (2) 6 (5)
Metabolic and Nutritional
    Peripheral Edema 7 (10) 6 (13) 13 (11)
Musculoskeletal System
    Arthralgia 18 (25) 13 (27) 31 (26)
    Myalgia 20 (28) 15 (31) 35 (29)
Nervous System
    Depression 20 (28) 18 (38) 38 (32)
    Dizziness 8 (11) 5 (10) 13 (11)
    Hypertonia 4 (6) 0 (0) 4 (3)
    Insomnia 30 (42) 23 (48) 53 (44)
    Leg Cramps 7 (10) 3 (6) 10 (8)
    Nervousness 20 (28) 20 (42) 40 (33)
    Paresthesia 24 (33) 15 (31) 39 (33)
    Vertigo 12 (17) 12 (25) 24 (20)
Respiratory System
    Cough Increased 4 (6) 1 (2) 5 (4)
    Pharyngitis 6 (8) 4 (8) 10 (8)
    Rhinitis 6 (8) 7(15) 13 (11)
Skin and Appendages      
    Rash 3 (4) 3 (6) 6 (5)
Urogenital System
    Breast Pain 21 (29) 7 (15) 28 (23)
    Dysmenorrhea 4 (6) 3 (6) 7 (6)
    Metrorrhagia 10 (14) 3 (6) 13 (11)
* Combined results for 0.625 mg and 2 x 0.625 mg Cenestin Tablets

In a second 12-week clinical trial that included 52 women treated with 0.45 mg Cenestin (synthetic conjugated estrogens) and 51 women treated with placebo, adverse events that occurred at a rate of > 5% are summarized in Table 6

Table 6
Number (%) of Patients with a > 5% Occurrence Rate by Body System and Treatment Group

Body System and Term Cenestin 0.45 mg Control p-value
Any Adverse Event (%) 40 (75.5%) 39 (76.5%) 1.0000
Body as a whole 20 (37.7%) 24 (47.1%) 0.4275
    Asthenia 6 (11.3%) 7 (13.7%) 0.7731
    Headache 6 (11.3%) 8 (15.7%) 0.5748
    Infection 1 (1.9%) 6 (11.8%) 0.0576
    Pain 6 (11.3%) 1 (2.0%) 0.1128
    Pain abdominal 5 (9.4%) 3 (5.9%) 0.7159
Cardiovascular 5 (9.4%) 10 (19.6%) 0.1695
    Palpitations 3 (5.7%) 3 (5.9%) 1.0000
    Vasodilations 2 (3.8%) 4 (7.8%) 0.4324
Digestive 8 (15.1%) 7 (13.7%) 1.0000
    Nausea 5 (9.4%) 2 (3.9%) 0.4374
Metabolic and nutritional 5 (9.4%) 3 (5.9%) 0.7159
    Weight increase 3 (5.7%) 2 (3.9%) 1.0000
Musculoskeletal 5 (9.4%) 6 (11.8%) 0.7582
    Arthralgia 5 (9.4%) 5 (9.8%) 1.0000
    Myalgia 2 (3.8%) 6 (11.8%) 0.1566
Neurological 15 (28.3%) 19 (37.3%) 0.4044
    Anxiety 3 (5.7%) 1 (2.0%) 0.6179
    Depression 2 (3.8%) 7 (13.7%) 0.0895
    Insomnia 3 (5.7%) 5 (9.8%) 0.4839
    Nervousness 2 (3.8%) 7 (13.7%) 0.0895
    Paresthesia 4 (7.5%) 3 (5.9%) 1.0000
    Vertigo 3 (5.7%) 3 (5.9%) 1.0000
Respiratory 10 (18.9%) 6 (11.8%) 0.4173
    Upper Respiratory Tract Infection 7 (13.2%) 1 (2.0%) 0.0603
    Rhinitis 3 (5.7%) 2 (3.9%) 1.0000
    Pharyngitis 1 (1.9%) 3 (5.9%) 0.3581
Urogenital 19 (35.8%) 7 (13.7%) 0.0124
    Endometrial thickening 10 (18.9%) 4 (7.8%) 0.1503
    Vaginitis 4 (7.5%) 1 (2.0%) 0.3632
P-value by Fisher's Exact (2-tail) Test
If a subject experiences the same event more than once, the first occurrence is tabulated.

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

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.

Breasts

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

Cardiovascular

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

Gastrointestinal

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

Skin

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

Eyes

Retinal vascular thrombosis; intolerance to contact lenses.

Central nervous system

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

Miscellaneous

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