The following additional adverse reactions have been identified during post-approval use of estradiol transdermal system. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Vaginal hemorrhage and abnormal withdrawal bleeding or flow, breakthrough bleeding, spotting, uterine leiomyomata, vaginitis, vaginal discharge, ovarian cancer, endometrial hyperplasia, dysmenorrhea.
Enlargement, pain, nipple discharge, fibrocystic breast changes, breast cancer.
Deep venous thrombosis, pulmonary embolism, thrombophlebitis.
Nausea, vomiting, abdominal cramps, bloating, cholelithiasis, liver function tests abnormal, diarrhea.
Application site reactions include localized bleeding, bruising, burning, discomfort, dryness, eczema, edema, erythema, erythema multiforme, erythema nodosum, inflammation, irritation, pain, papules and vesicles. Other skin reactions include paresthesia, skin discoloration, skin pigmentation, urticaria, swelling, loss of scalp hair, hirsutism, pruritus, and rash.
Intolerance to contact lenses.
Central Nervous System
Migraine, dizziness, chorea, nervousness, affect liability, irritability.
Decrease in weight, reduced carbohydrate tolerance, edema, arthralgias, leg cramps, changes in libido, purpura, hypersensitivity, anaphylactic reaction, anaphylactoid reaction, angioedema.
No drug interaction studies have been conducted with estradiol transdermal system.
In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John’s wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.
Estradiol transdermal system should not be used during pregnancy [see Contraindications (4)]. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.
Estradiol transdermal system should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens have been identified in the breast milk of women receiving estrogens. Caution should be exercised when estradiol transdermal system is administered to a nursing woman.
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 adult 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.
There have not been sufficient numbers of geriatric women involved in clinical studies utilizing estradiol transdermal system to determine whether those over 65 years of age differ from younger subjects in their response to estradiol transdermal system.
The Women’s Health Initiative Studies
In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Warnings and Precautions (5.1), and Clinical Studies (14.3)].
In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Warnings and Precautions (5.1), and Clinical Studies (14.3)].
The Women’s Health Initiative Memory Study
In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions (5.3), and Clinical Studies (14.4)].
Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.3), and Clinical Studies (14.4)].
The effect of renal impairment on the pharmacokinetics of estradiol transdermal system has not been studied.
The effect of hepatic impairment on the pharmacokinetics of estradiol transdermal system has not been studied.
Overdosage of estrogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of estradiol transdermal system therapy with institution of appropriate symptomatic care.
Estradiol transdermal system, USP contains estradiol, USP in a multipolymeric adhesive. The system is designed to release estradiol, USP continuously upon application to intact skin.
Five dosage strengths of estradiol transdermal system are available to provide nominal in vivo delivery rates of 0.025, 0.0375, 0.05, 0.075, or 0.1 mg of estradiol, USP per day via the skin. Each corresponding system has an active surface area of 1.89, 2.83, 3.78, 5.66, or 7.55 cm2 and contains 0.314, 0.470, 0.627, 0.940, or 1.253 mg of estradiol, USP, respectively. The composition of the systems per unit area is identical.
Estradiol, USP is a white to practically white powder, chemically described as estra-1,3,5 (10)- triene-3,17β-diol.
The structural formula is:
The molecular formula of estradiol, USP is C18 H24 02 . The molecular weight is 272.39.
Estradiol transdermal system is comprised of 3 layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are (1) polyester and ethylene vinyl acetate copolymer film (2) an adhesive formulation containing estradiol, acrylic adhesive, silicone adhesive, oleyl alcohol, NF, povidone, USP and dipropylene glycol, and (3) a polyester release liner which is attached to the adhesive surface and must be removed before the system can be used.
The active component of the system is estradiol, USP. The remaining components of the system are pharmacologically inactive.
FDA approved acceptance criteria for dissolution test specifications differ from USP.
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