Premarin Side Effects & Drug Interactions

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Premarin - Side Effects & Drug Interactions [Conjugated Estrogens]

Global Index c 1.15 (1.03-1.28) 151 170
Deep vein thrombosis d 2.07 (1.49-2.87) 13 26
Vertebral fractures d 0.66 (0.44-0.98) 15 9
Other osteoporotic fractures d 0.77 (0.69-0.86) 170 131
a: adapted from JAMA, 2002; 288: 321-333
b: includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer
c: a subset of the events was combined in a "global index," defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes
d: not included in Global Index
* nominal confidence intervals unadjusted for multiple looks and multiple comparisons.

For those outcomes included in the "global index," absolute excess risks per 10,000 person-years in the group treated with Prempro were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the "global index" was 19 per 10,000 person-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and
PRECAUTIONS.)

Drug/ Laboratory Test Interactions

1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.

2. Increased thyroid binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels 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. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.

3. Other binding proteins may be elevated 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, ceruloplasmin).

4. Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentrations, increased triglyceride levels.

5. Impaired glucose tolerance.

6. Reduced response to metyrapone test.

E. Carcinogenesis, Mutagenesis, Impairment of Fertility

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 BOXED WARNINGS, CONTRAINDICATIONS, andWARNINGS).

F. Pregnancy

Premarin should not be used during pregnancy. (See CONTRAINDICATIONS).

G. Nursing Mothers

Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when Premarin is administered to a nursing woman.

H. Pediatric Use

Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay. Safety and effectiveness in pediatric patients have not otherwise been established. Large and repeated doses of estrogen over an extended time period have been shown to accelerate epiphyseal closure, which could result in short stature if treatment is initiated before the completion of physiologic puberty in normally developing children. If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended during estrogen administration.

Estrogen treatment of prepubertal girls also induces premature breast development and vaginal cornification, and may induce vaginal bleeding. In boys, estrogen treatment may modify the normal pubertal process and induce gynecomastia. See INDICATIONS and DOSAGE AND ADMINISTRATION sections.

I. Geriatric Use

Of the total number of subjects in the Prempro substudy of the Women's Health Initiative study, 44% (n= 7,320) were 65 years and over, while 6.6% (n= 1,095) were 75 and over (see CLINICAL PHARMACOLOGY, Clinical Studies). No significant differences in safety were observed between subjects 65 years and over compared to younger subjects. There was a higher incidence of stroke and invasive breast cancer in women 75 and over compared to younger subjects.

With respect to efficacy in the approved indications, there have not been sufficient numbers of geriatric patients involved in studies utilizing Premarin to determine whether those over 65 years of age differ from younger subjects in their response to Premarin.