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.

Adverse events reported by investigators in the Phase 3 studies regardless of causality assessment are shown in Table 5.

TABLE 5

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

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, changes in amount of cervical secretion; changes in cervical ectropion; pre-menstrual-like syndrome, cystitis-like syndrome, ovarian cancer, endometrial hyperplasia, endometrial cancer.

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

Cerebrovascular accidents, deep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, myocardial infarction, stroke, increase in blood pressure.

Nausea, vomiting, changes in appetite, cholestatic jaundice, abdominal pain/cramps, flatulence, bloating, increased incidence of gallbladder disease, pancreatitis; enlargement of hepatic hemangiomas.

Chloasma or melasma that may persist when drug is discontinued, erythema multiforme, erythema nodosum, hemorrhagic eruption, loss of scalp hair, seborrhea, hirsutism, itching, skin rash and pruritus.

Retinal vascular thrombosis, intolerance to contact lenses.

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

Increase or decrease in weight, aggravation of porphyria, edema, leg cramps, changes in libido, fatigue, reduced carbohydrate tolerance, anaphylactoid/anaphylactic reactions, hypocalcemia, exacerbation of asthma, increased triglycerides, back pain, arthralgia, myalgia.

The following interactions have been observed with estrogen therapy, and/or Activella:

1. Activella decreases factor VII, plasminogen activator inhibitor-1, and, to a lesser extent, antithrombin III 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., corticosteriod binding globulin (CBG), sex hormone-binding globulin (SHBG) leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/rennin substrate, alpha-1 antitrypsin, ceruloplasmin).

4.Activella reduces LDL and total cholesterol concentration, and decreases HDL without changes to HDL/LDL ratio. Activella does not increase triglycerides.

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 reduce insulin sensitivity in healthy postmenopausal women when assessed by an hyperinsulinemic euglycemic clamp.

6.Reduced response to metyrapone test.

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