Esclim Side Effects, and Drug Interactions - Estradiol Transdermal

Esclim Side Effects, and Drug Interactions - Estradiol Transdermal

SIDE EFFECTS

See WARNINGS and Boxed Warning regarding the potential adverse effects on the fetus, the induction of malignant neoplasms, gallbladder disease, cardiovascular disease, elevated blood pressure, and hypercalcemia.

Skin irritation: In controlled clinical studies with Esclim, the most commonly reported adverse events were topical reactions of erythema and/or pruritus at the application site. In general these reactions caused patients little or no discomfort, and led to premature discontinuation of treatment in 0.9% (3/317) of patients in these trials. The rate of application site reactions, based on 8,135 applications of the 0.025, 0.05, and 0.1 Esclim systems in these trials was 6.1 per 100 applications (4.9, 5.4, 10.7 for the 3 Esclim doses respectively) compared to 6.2 in the placebo treated patients (2,014 applications).

In a placebo-controlled trial of Esclim 0.025, 0.05, and 0.1 conducted in 196 patients in the US, the adverse events reported by at least 5% of patients in 1 or more of the treatment groups are shown in Table 5.

Urogenital Adverse Events (See Precautions: Addition of a progestin): In the US placebo-controlled study, 72 patients were included who had intact uteri. As expected, after 12-13 weeks of continuous unopposed therapy, findings of endometrial hyperplasia (diagnosed either by endometrial biopsy and/or ultrasonography) were increased with increasing doses of estradiol (placebo: 0/18 patients; Esclim 0.025: 1/14 (7.1%); Esclim 0.05: 12/22 (54.5%); Esclim 0.1: 10/18 (55.6%). In the 86 patients who had not previously undergone a total hysterectomy, vaginal bleeding was also increased with increasing doses of estradiol [placebo: 2/21 patients (9.5%); Esclim 0.025: 6/19 (31.6%); Esclim 0.05: 14/25 (56.0%); Esclim 0.1: 12/21 (57.1%)].

In 2 long-term studies involving a total of 488 patients treated for a mean duration of 618 days and up to 3.5 years, the nature and incidence of adverse events did not change with prolonged duration of treatment.

The following additional adverse reactions have been reported with estrogen therapy:

1. Genitourinary System. Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding, spotting; increase in size of uterine leiomyomata; vaginal candidiasis; change in amount of cervical secretion.

2. Breasts. Tenderness, enlargement.

3. Gastrointestinal. Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; gallbladder disease.

4. Skin. Chloasma or melasma that may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism.

5. Eyes. Steepening of corneal curvature: intolerance to contact lenses.

6. Central Nervous System. Headache, migraine, dizziness; mental depression; chorea.

7. Miscellaneous. Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; changes in libido.

DRUG INTERACTIONS

Drug/Laboratory Tests Interactions

Some of these drug/laboratory test interactions have been observed only with estrogen–progestin combinations (oral contraceptives):

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) 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. 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 HDL–2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglyceride levels.

5. Impaired glucose tolerance.

6. Reduced response to metyrapone test.

7. Reduced serum folate concentration.