ADVERSE REACTIONS
See BOX 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 with 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 1-year clinical trial that included 678 postmenopausal women treated with PREMPRO, 351 postmenopausal women treated with PREMPHASE, and 347 postmenopausal women treated with Premarin, the following adverse events occurred at a rate >/= 5% (see Table 9):
TABLE 9: ALL TREATMENT EMERGENT STUDY EVENTS REGARDLESS OF DRUG RELATIONSHIP REPORTED AT A FREQUENCY >/= 5%
|
Body System
|
PREMPRO
0.625 mg/2.5 mg
continuous
|
PREMPRO
0.625 mg/5.0 mg
continuous
|
PREMPHASE
0.625 mg/5.0 mg
sequential
|
PREMARIN
0.625 mg
daily
|
|
Adverse event
|
(n=340) |
(n=338) |
(n=351) |
(n=347) |
|
Body as a whole
|
|
abdominal pain
|
16%
|
21%
|
23%
|
17%
|
|
accidental injury
|
5%
|
4%
|
5%
|
5%
|
|
asthenia
|
6%
|
8%
|
10%
|
8%
|
|
back pain
|
14%
|
13%
|
16%
|
14%
|
|
flu syndrome
|
10%
|
13%
|
12%
|
14%
|
|
headache
|
36%
|
28%
|
37%
|
38%
|
|
infection
|
16%
|
16%
|
18%
|
14%
|
|
pain
|
11%
|
13%
|
12%
|
13%
|
|
pelvic pain
|
4%
|
5%
|
5%
|
5%
|
|
Digestive system
|
|
diarrhea
|
6%
|
6%
|
5%
|
10%
|
|
dyspepsia
|
6%
|
6%
|
5%
|
5%
|
|
flatulence
|
8%
|
9%
|
8%
|
5%
|
|
nausea
|
11%
|
9%
|
11%
|
11%
|
|
Metabolic and Nutritional
|
|
peripheral edema
|
4%
|
4%
|
3%
|
5%
|
|
Musculoskeletal system
|
|
arthralgia
|
9%
|
7%
|
9%
|
7%
|
|
leg cramps
|
3%
|
4%
|
5%
|
4%
|
|
Nervous system
|
|
depression
|
6%
|
11%
|
11%
|
10%
|
|
dizziness
|
5%
|
3%
|
4%
|
6%
|
|
hypertonia
|
4%
|
3%
|
3%
|
7%
|
|
Respiratory system
|
|
pharyngitis
|
11%
|
11%
|
13%
|
12%
|
|
rhinitis
|
8%
|
6%
|
8%
|
7%
|
|
sinusitis
|
8%
|
7%
|
7%
|
5%
|
|
Skin and appendages
|
|
pruritus
|
10%
|
8%
|
5%
|
4%
|
|
rash
|
4%
|
6%
|
4%
|
3%
|
|
Urogenital system
|
|
breast pain
|
33%
|
38%
|
32%
|
12%
|
|
cervix disorder
|
4%
|
4%
|
5%
|
5%
|
|
dysmenorrhea
|
8%
|
5%
|
13%
|
5%
|
|
leukorrhea
|
6%
|
5%
|
9%
|
8%
|
|
vaginal hemorrhage
|
2%
|
1%
|
3%
|
6%
|
|
vaginitis
|
7%
|
7%
|
5%
|
3%
|
|
During the first year of a 2-year clinical trial with 2333 postmenopausal women between 40 and 65 years of age (88% Caucasian), 2001 women received continuous regimens of either 0.625 mg of CE with or without 2.5 mg MPA, or 0.45 mg or 0.3 mg of CE with or without 1.5 mg MPA, and 332 received placebo tablets. Table 10 summarizes adverse events that occurred at a rate >/= 5% in at least 1 treatment group.
TABLE 10. PERCENT OF PATIENTS WITH TREATMENT EMERGENT STUDY EVENTS REGARDLESS OF DRUG
RELATIONSHIP REPORTED AT A FREQUENCY >/= 5% DURING STUDY YEAR 1
|
Body System
|
Premarin
0.625 mg
daily
|
Prempro
0.625 mg/2.5 mg
continuous
|
Premarin
0.45 mg
daily
|
Prempro
0.45 mg/1.5 mg
continuous
|
Premarin
0.3 mg
daily
|
Prempro
0.3 mg/1.5 mg
continuous
|
Placebo
daily
|
|
Adverse event
|
(n=348) |
(n=331) |
(n=338) |
(n=331) |
(n=326) |
(n=327) |
(n=332) |
|
Any adverse event
|
93%
|
92%
|
90%
|
89%
|
90%
|
90%
|
85%
|
|
Body as a whole
|
|
abdominal pain
|
16%
|
17%
|
15%
|
16%
|
17%
|
13%
|
11%
|
|
accidental injury
|
6%
|
10%
|
12%
|
9%
|
6%
|
9%
|
9%
|
|
asthenia
|
7%
|
8%
|
7%
|
8%
|
8%
|
6%
|
5%
|
|
back pain
|
14%
|
12%
|
13%
|
13%
|
13%
|
12%
|
12%
|
|
flu syndrome
|
11%
|
8%
|
11%
|
11%
|
10%
|
10%
|
11%
|
|
headache
|
26%
|
28%
|
32%
|
29%
|
29%
|
33%
|
28%
|
|
infection
|
18%
|
21%
|
22%
|
19%
|
23%
|
18%
|
22%
|
|
pain
|
17%
|
14%
|
18%
|
15%
|
20%
|
20%
|
18%
|
|
Digestive system
|
|
diarrhea
|
6%
|
7%
|
7%
|
7%
|
6%
|
6%
|
6%
|
|
dyspepsia
|
9%
|
8%
|
9%
|
8%
|
11%
|
8%
|
14%
|
|
flatulence
|
7%
|
7%
|
7%
|
8%
|
6%
|
5%
|
3%
|
|
nausea
|
9%
|
7%
|
7%
|
10%
|
6%
|
8%
|
9%
|
|
Musculoskeletal system
|
|
arthralgia
|
14%
|
9%
|
12%
|
13%
|
7%
|
10%
|
12%
|
|
leg cramps
|
5%
|
7%
|
7%
|
5%
|
3%
|
4%
|
2%
|
|
myalgia
|
5%
|
5%
|
5%
|
5%
|
9%
|
4%
|
8%
|
|
Nervous system
|
|
anxiety
|
5%
|
4%
|
4%
|
5%
|
4%
|
2%
|
4%
|
|
depression
|
7%
|
11%
|
8%
|
5%
|
5%
|
8%
|
7%
|
|
dizziness
|
6%
|
3%
|
6%
|
5%
|
4%
|
5%
|
5%
|
|
insomnia
|
6%
|
6%
|
7%
|
7%
|
7%
|
6%
|
10%
|
|
nervousness
|
3%
|
3%
|
5%
|
2%
|
2%
|
2%
|
2%
|
|
Respiratory system
|
|
cough increased
|
4%
|
8%
|
7%
|
5%
|
4%
|
6%
|
4%
|
|
pharyngitis
|
10%
|
11%
|
10%
|
8%
|
12%
|
9%
|
11%
|
|
rhinitis
|
6%
|
8%
|
9%
|
9%
|
10%
|
10%
|
13%
|
|
sinusitis
|
6%
|
8%
|
11%
|
8%
|
7%
|
10%
|
7%
|
|
upper respiratory infection
|
12%
|
10%
|
10%
|
9%
|
9%
|
11%
|
11%
|
|
Skin and appendages
|
|
pruritus
|
4%
|
4%
|
5%
|
5%
|
5%
|
5%
|
2%
|
|
Urogenital system
|
|
breast enlargement
|
<1%
|
5%
|
1%
|
3%
|
2%
|
2%
|
<1%
|
|
breast pain
|
11%
|
26%
|
12%
|
21%
|
7%
|
13%
|
9%
|
|
dysmenorrhea
|
4%
|
5%
|
3%
|
6%
|
1%
|
3%
|
<1%
|
|
leukorrhea
|
5%
|
4%
|
7%
|
5%
|
4%
|
3%
|
3%
|
|
vaginal hemorrhage
|
14%
|
6%
|
4%
|
4%
|
2%
|
2%
|
0%
|
|
vaginal moniliasis
|
6%
|
8%
|
5%
|
7%
|
5%
|
4%
|
2%
|
|
vaginitis
|
7%
|
5%
|
6%
|
6%
|
5%
|
4%
|
1%
|
|
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, change in amount of cervical secretion, premenstrual-like syndrome, cystitis-like syndrome, increase in size of uterine leiomyomata, vaginal candidiasis, amenorrhea, changes in cervical erosion, 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, cholestatic jaundice, changes in appetite, vomiting, abdominal cramps, bloating, increased incidence of gallbladder disease, pancreatitis, enlargement of hepatic hemangiomas. - Skin
Chloasma or melasma that may persist when drug is discontinued, erythema multiforme, erythema nodosum, hemorrhagic eruption, loss of scalp hair, hirsutism, itching, urticaria, pruritus, generalized rash, rash (allergic) with and without pruritus, acne.
- Eyes
Neuro-ocular lesions, e.g., retinal vascular thrombosis and optic neuritis, intolerance of contact lenses. - Central Nervous System (CNS)
Headache, dizziness, mental depression, mood disturbances, anxiety, irritability, nervousness, migraine, chorea, insomnia, somnolence, exacerbation of epilepsy, dementia.
- Miscellaneous
Increase or decrease in weight, edema, changes in libido, fatigue, backache, reduced carbohydrate tolerance, aggravation of porphyria, pyrexia, urticaria, angioedema, anaphylactoid/anaphylactic reactions, hypocalcemia, exacerbation of asthma, increased triglycerides.
|
