A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Prempro Side Effects, and Drug Interactions - Conjugated estrogens/medroxyprogesterone acetate
Prempro Side Effects, and Drug Interactions - Conjugated estrogens/medroxyprogesterone acetate
SIDE EFFECTS
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 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 ³
5%
|
|
|
PREMPRO 0.625 mg/2.5 mg continuous (n=340)
|
PREMPRO 0.625 mg/5.0 mg continuous (n=338)
|
PREMPHASE 0.625 mg/5.0 mg sequential (n=351)
|
PREMARIN 0.625 mg daily (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 adverse reactions also 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, 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.
2. Breasts
Tenderness, enlargement, pain, nipple discharge, galactorrhea, fibrocystic breast changes, breast cancer.
3. Gastrointestinal
Nausea, cholestatic jaundice, changes in appetite, vomiting,
abdominal cramps, bloating, increased incidence of gallbladder disease, pancreatitis, enlargement of hepatic hemangiomas.
4. 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.
5. Cardiovascular
Change in blood pressure, deep and superficial venous thrombosis/thrombophlebitis,
pulmonary embolism, myocardial infarction, cerebral thrombosis and embolism.
6. CNS
Headache, dizziness, mental depression, mood disturbances,
anxiety, irritability, nervousness, migraine, chorea, insomnia, somnolence, exacerbation of epilepsy, dementia.
7. Eyes
Neuro-ocular lesions, eg, retinal thrombosis and optic neuritis, intolerance of contact lenses.
8. 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.
Drug interactions
Data from a single-dose drug-drug interaction study involving
conjugated estrogens and medroxyprogesterone acetate indicate that the pharmacokinetic
disposition of both drugs is not altered when the drugs are coadministered.
No other clinical drug-drug interaction studies have been conducted with conjugated
estrogens.
In vitro and in vivo studies have shown that estrogens are
metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or
inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4
such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital,
carbamazepine, and rifampicin may reduce plasma concentrations of estrogens,
possibly resulting in a decrease in therapeutic effects and/or changes in the
uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin,
ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma
concentrations of estrogens and may result in side effects.
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