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
Activella Side Effects, and Drug Interactions - Estradiol/Norethindroneacetate
Activella Side Effects, and Drug Interactions - Estradiol/Norethindroneacetate
SIDE EFFECTS
(See WARNINGS regarding
induction of neoplasia, adverse effects on the fetus, increased incidence of
gallbladder disease, elevated blood pressure, thromboembolic disorders, cardiovascular
disease, visual abnormalities, and hypercalcemia and PRECAUTIONS
regarding cardiovascular disease.) Adverse events reported by investigators
in the Phase 3 studies regardless of causality assessment are shown in TABLE
5.
TABLE 5: ALL TREATMENT-EMERGENT ADVERSE EVENTS REGARDLESS OF
RELATIONSHIP REPORTED AT A FREQUENCY OF ³5% WITH
ACTIVELLA™
|
|
Endometrial Hyperplasia Study (12-Months)
|
Vasomotor Symptoms Study (3-Months)
|
Osteoporosis Study (2 years)
|
|
|
Activella™ 1 mg E2 (n=295) (n=296)
|
Activella™ Placebo (n=29)(n=34)
|
Activella™ Placebo (n=47)(n=48)
|
|
Body as a Whole
|
|
Back Pain
|
6%
|
5%
|
3%
|
3%
|
6%
|
4%
|
|
Headache
|
16%
|
16%
|
17%
|
18%
|
11%
|
6%
|
|
Digestive System
|
|
Nausea
|
3%
|
5%
|
10%
|
0%
|
11%
|
0%
|
|
Gastroenteritis
|
2%
|
2%
|
0%
|
0%
|
6%
|
4%
|
|
Nervous System
|
|
|
|
|
|
|
|
Insomnia
|
6%
|
4%
|
3%
|
3%
|
0%
|
8%
|
|
Emotional Lability
|
1%
|
1%
|
0%
|
0%
|
6%
|
0%
|
|
Respiratory System
|
|
Upper Respiratory
|
|
Tract Infection
|
18%
|
15%
|
10%
|
6%
|
15%
|
19%
|
|
Sinusitis
|
7%
|
11%
|
7%
|
0%
|
15%
|
10%
|
|
Metabolic and Nutritional
|
|
Weight Increase
|
0%
|
0%
|
0%
|
0%
|
9%
|
6%
|
|
Urogenital System
|
|
Breast Pain
|
24%
|
10%
|
21%
|
0%
|
17%
|
8%
|
|
Post-Menopausal
|
|
Bleeding
|
5%
|
15%
|
10%
|
3%
|
11%
|
0%
|
|
Uterine Fibroid
|
5%
|
4%
|
0%
|
0%
|
4%
|
8%
|
|
Ovarian Cyst
|
3%
|
2%
|
7%
|
0%
|
0%
|
8%
|
|
Resistance Mechanism
|
|
Infection Viral
|
4%
|
6%
|
0%
|
3%
|
6%
|
6%
|
|
Moniliasis Genital
|
4%
|
7%
|
0%
|
0%
|
6%
|
0%
|
|
Secondary Terms
|
|
Injury Accidental
|
4%
|
3%
|
3%
|
0%
|
17%*
|
4%*
|
|
Other Events
|
2%
|
3%
|
3%
|
0%
|
6%
|
4%
|
|
* including one upper extremity fracture in each group
|
The following 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, increase
in size of uterine leiomyomata, vaginal candidiasis, changes in amount of cervical
secretion, premenstrual-like syndrome, cystitis-like syndrome.
Breasts: tenderness, enlargement.
Gastrointestinal: nausea, vomiting, changes in appetite, cholestatic
jaundice, abdominal pain, flatulence, bloating, increased incidence of gallbladder
disease.
Skin: chloasma or melasma that may persist when drug is discontinued,
erythema multiforme, erythema nodosum, hemorrhagic eruption, loss of scalp hair,
hirsutism, itching, skin rash and pruritus.
Cardiovascular: changes in blood pressure, cerebrovascular
accidents, deep venous thrombosis and pulmonary embolism.
CNS: headache, migraine, dizziness, depression, chorea, insomnia,
nervousness.
Eyes: steepening of corneal curvature, intolerance to contact
lenses. Miscellaneous: increase or decrease in weight, aggravation of porphyria,
edema, changes in libido, fatigue, allergic reactions, back pain, arthral-gia,
myalgia.
DRUG/LABORATORY TEST INTERACTIONS
The following interactions have been observed with estrogen
therapy, and/or Activella™ (estradiol/norethin-drone acetate
tablets):
1. Activella™ decreases factor VII, plasminogen
activator inhibitor-1, and, to a lesser extent, antithrombin III activity.
2. Estrogen therapy increases thyroid-binding globulin (TBG)
leading to increased circulating total thyroid hormone, as measured by protein-bound
iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3
levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated
TBG. Free T4 and free T3 concentrations are unaltered.
3. Estrogen therapy may elevate other binding proteins in serum
i.e., corticosteroid-binding globulin (CBG), sex-hormone-binding globulin (SHBG),
leading to increased circulating corticosteroids and sex steroids respectively.
Free or biologically active hormone concentrations are unchanged. Other plasma
proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin,
cerulo-plasmin). In a 12-month clinical trial, SHBG was found to increase with
Activella™.
4. Estrogen therapy increases plasma HDL and HDL-2 subfraction
concentrations, reduces LDL cholesterol concentration, and increases triglyceride
levels. (For effects during Activella™ treatment, see CLINICAL
PHARMACOLOGY, Clinical Studies).
5. Activella™ treatment of healthy postmenopausal
women does not decrease glucose tolerance when assessed by an oral glucose tolerance
test; the insulin response decreases without any increase in the glucose serum
levels. Activella™ treatment does not deteriorate insulin sensitivity
in healthy postmenopausal women when assessed by an hyper-insulinemic euglycemic
clamp.
6. Estrogen therapy reduces response to metyrapone test.
7. Estrogen therapy reduces serum folate concentration.
CARCINOGENESIS, MUTAGENESIS, and IMPAIRMENT OF INFERTILITY
Long-term continuous administration of natural and synthetic
estrogens in certain animal species increases the frequency of carcinomas of
the breast, uterus, cervix, vagina, testis, and liver. (See CONTRAINDICATIONS
and WARNINGS.) PREGNANCY CATEGORY X:
Estrogens/progestins should not be used during pregnancy. (See CONTRAINDICATIONS
and WARNINGS.) NURSING MOTHERS: Detectable amounts of estradiol and norethindrone
acetate have been identified in the milk of mothers receiving these products
and has been reported to decrease the quantity and the quality of the milk.
As a general principle, the administration of any drug to nursing
mothers should be done only when clearly necessary since many drugs are excreted
in human milk.
PEDIATRIC USE
Safety and effectiveness in pediatric patients have not been
established.
GERIATRIC USE
Clinical studies of Activella™ (estradi-ol/norethindrone
acetate tablets) did not include sufficient number of subjects aged 65 and over
to determine if they responded differently from younger subjects. Other reported
clinical experience has not identified differences in responses between elderly
and younger subjects. In general, dose selection for an elderly patient should
be cautious, usually starting at the low end of the dosing range, reflecting
the greater frequency of decreased hepatic, renal, or cardiac function, and
of concomitant disease or other drug therapy.
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