Estradiol (Page 4 of 10)

5.8 Elevated Blood Pressure

In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen.

5.9 Exacerbation of Hypertriglyceridemia

In women with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Discontinue estradiol transdermal system if pancreatitis occurs.

5.10 Hepatic Impairment and/or Past History of Cholestatic Jaundice

Estrogens may be poorly metabolized in women with hepatic impairment. Exercise caution in any woman with a history of cholestatic jaundice associated with past estrogen use or with pregnancy. In the case of recurrence of cholestatic jaundice, discontinue estradiol transdermal system.

5.11 Exacerbation of Hypothyroidism

Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. Monitor thyroid function in these women during treatment with estradiol transdermal system to maintain their free thyroid hormone levels in an acceptable range.

5.12 Fluid Retention

Estrogens may cause some degree of fluid retention. Monitor any woman with a condition(s) that might predispose her to fluid retention, such as cardiac or renal impairment. Discontinue estrogen-alone therapy, including estradiol transdermal system, with evidence of medically concerning fluid retention.

5.13 Hypocalcemia

Estrogen induced hypocalcemia may occur in women with hypoparathyroidism. Consider whether the benefits of estrogen therapy, including estradiol transdermal system, outweigh the risks in such women.

5.14 Exacerbation of Endometriosis

A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. Consider the addition of progestogen therapy for women known to have residual endometriosis post-hysterectomy.

5.15 Severe Anaphylactic/Anaphylactoid Reactions and Angioedema

A few cases of anaphylactic/anaphylactoid reactions are reported in the postmarketing use of estradiol transdermal system. Involvement of skin (hives, pruritus, swollen lips-tongue-face) and either respiratory tract (respiratory compromise) or gastrointestinal tract (abdominal pain, vomiting) are noted.

Angioedema involving eye/eyelid, face, larynx, pharynx, tongue and extremity (hands, legs, ankles, and fingers) with or without urticaria requiring medical intervention are reported in the postmarketing use of estradiol transdermal system. Angioedema involving the tongue, glottis, or larynx, may result in airway obstruction. Do not give estradiol transdermal system to any woman who develops angioedema during treatment with estradiol transdermal system.
Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. Consider whether the benefits of estrogen therapy outweigh the risks in such women.

5.16 Exacerbation of Other Conditions

Estrogen therapy, including estradiol transdermal system, may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraines, porphyria, systemic lupus erythematosus, and hepatic hemangiomas. Consider whether the benefits of estrogen therapy outweigh the risks in such women.

5.17 Laboratory Tests

Serum follicle-stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy.

Laboratory parameters may be useful in guiding dosage for the treatment of hypoestrogenism due to hypogonadism, castration and primary ovarian failure.

5.18 Drug-Laboratory Test Interactions

  • 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.
  • Increased thyroid-binding globulin (TBG) 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. Women on thyroid replacement therapy may require higher doses of thyroid hormone.
  • Other binding proteins may be elevated in serum, for example, corticosteroid-binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
  • Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, and increased triglycerides levels.
  • Impaired glucose tolerance.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in labeling:

6.1 Clinical Trials Experience

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.

There were no clinical trials conducted with estradiol transdermal system. Estradiol transdermal system is bioequivalent to the original formulation of estradiol transdermal system. The following adverse reactions have been reported with the original formulation of estradiol transdermal system therapy:

Table 1. Summary of Most Frequently Reported Adverse Reactions Regardless of Relationship Reported at a Frequency ≥5 Percent

Estradiol 0.025 mg/day (N=47) N (%)

Estradiol 0.0375 mg/day (N=130) N (%)

Estradiol 0.05 mg/day (N=103) N (%)

Estradiol 0.075 mg/day (N=46) N (%)

Estradiol 0.1 mg/day (N=132) N (%)

Placebo (N=157) N (%)

Gastrointestinal disorders

Constipation

2 (4.3)

5 (3.8)

4 (3.9)

3 (6.5)

2 (1.5)

4 (2.5)

Dyspepsia

4 (8.5)

12 (9.2)

3 (2.9)

2 (4.3)

0

10 (6.4)

Nausea

2 (4.3)

8 (6.2)

4 (3.9)

0

7 (5.3)

5 (3.2)

General disorders and administration site conditions***

Influenza-like illness

3 (6.4)

6 (4.6)

8 (7.8)

0

3 (2.3)

10 (6.4)

Pain NOS*

0

8 (6.2)

0

2 (4.3)

7 (5.3)

7 (4.5)

Infections and infestations

Influenza

4 (8.5)

4 (3.1)

6 (5.8)

0

10 (7.6)

14 (8.9)

Nasopharyngitis

3 (6.4)

16 (12.3)

10 (9.7)

9 (19.6)

11 (8.3)

24 (15.3)

Sinusitis NOS*

4 (8.5)

17 (13.1)

13 (12.6)

3 (6.5)

7 (5.3)

16 (10.2)

Upper respiratory tract infection NOS*

3 (6.4)

8 (6.2)

11 (10.7)

4 (8.7)

6 (4.5)

9 (5.7)

Investigations

Weight increased

4 (8.5)

5 (3.8)

2 (1.9)

2 (4.3)

0

3 (1.9)

Musculoskeletal and connective tissue disorders

Arthralgia

0

11 (8.5)

4 (3.9)

2 (4.3)

5 (3.8)

9 (5.7)

Back pain

4 (8.5)

10 (7.7)

9 (8.7)

4 (8.7)

14 (10.6)

10 (6.4)

Neck pain

3 (6.4)

4 (3.1)

4 (3.9)

0

6 (4.5)

2 (1.3)

Pain in limb

0

10 (7.7)

7 (6.8)

2 (4.3)

6 (4.5)

9 (5.7)

Nervous system disorders

Headache NOS*

7 (14.9)

35 (26.9)

32 (31.1)

23 (50.0)

34 (25.8)

37 (23.6)

Sinus headache

0

12 (9.2)

5 (4.9)

5 (10.9)

2 (1.5)

8 (5.1)

Psychiatric disorders

Anxiety NEC**

3 (6.4)

5 (3.8)

0

0

2 (1.5)

4 (2.5)

Depression

5 (10.6)

4 (3.1)

7 (6.8)

0

4 (3.0)

6 (3.8)

Insomnia

3 (6.4)

6 (4.6)

4 (3.9)

2 (4.3)

2 (1.5)

9 (5.7)

Reproductive system and breast disorders

Breast tenderness

8 (17.0)

10 (7.7)

8 (7.8)

3 (6.5)

17 (12.9)

0

Dysmenorrhea

0

0

0

3 (6.5)

0

0

Intermenstrual bleeding

3 (6.4)

9 (6.9)

6 (5.8)

0

14 (10.6)

7 (4.5)

Respiratory, thoracic and mediastinal disorders

Sinus congestion

0

4 (3.1)

3 (2.9)

3 (6.5)

6 (4.5)

7 (4.5)

Vascular disorders

Hot flushes NOS*

3 (6.4)

0

3 (2.9)

0

0

6 (3.8)

Hypertension NOS*

2 (4.3)

0

3 (2.9)

0

0

2 (1.3)

Represents milligrams of estradiol delivered daily by each system

* NOS represents not otherwise specified

** NEC represents not elsewhere classified

*** Application site erythema and application site irritation were observed in a small number of patients (3.2% or less of patients across treatment groups)

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