Trade Names:Climara Pro- Transdermal Patch estradiol 0.045 mg and levonorgestrel 0.015 mg per day
Estrogens are essential in developing and maintaining female reproductive system and secondary sex characteristics.
Progestins transform proliferative endometrium into secretory endometrium.
Estrogen: Max concentration reached in 2 to 2.5 days.
Levonorgestrel: Max concentration reached in 2.5 days.
Estrogens are widely distributed and are generally found in higher concentrations in the sex hormone target organs. Levonorgestrel binds to sex hormone-binding globulin and albumin.
Estrogen: Metabolic conversion occurs primarily in the liver but also at local target tissue sites. Also undergoes enterohepatic recirculation.
Levonorgestrel: In vitro studies did not indicate any significant metabolism of levonorgestrel during skin penetration.
Estradiol is excreted in the urine along with glucuronide and sulfate conjugates. Levonorgestrel and its metabolites are primarily excreted in the urine.
Treatment of moderate to severe vasomotor symptoms associated with menopause.
Undiagnosed abnormal genital bleeding; known, suspected, or history of breast cancer; known or suspected estrogen-dependent neoplasm; active deep vein thrombosis, pulmonary embolism, or history of these conditions; active or recent (eg, within past year) arterial thromboembolic disease (eg, stroke, MI); liver dysfunction or disease; known or suspected pregnancy; hypersensitivity to any component of the product.
Transdermal Apply a new system to the lower abdomen weekly during a 28-day cycle. Rotate application site, with an interval of at least 1 wk allowed between applications to the same site.
Store transdermal delivery system in original pouch at controlled room temperature (59° to 86°F). Do not remove delivery system from pouch until immediately before application.
Levonorgestrel concentration may be decreased, reducing the efficacy.Inducers of CYP3A4 (eg, carbamazepine, phenobarbital, rifampin, St. John's wort)
Estradiol concentration may be decreased, reducing the efficacy and changing the uterine bleeding profile.Inhibitors of CYP2C, CYP2E, CYP3A4
May elevate levonorgestrel concentrations, increasing the risk of adverse reactions.Inhibitors of CYP3A4 (eg, clarithromycin, erythromycin, grapefruit juice, itraconazole, ketoconazole, ritonavir)
May elevate estradiol concentrations, increasing the risk of adverse reactions.
PT, activated partial thromboplastin time, platelet aggregation time, platelet count; factors II, VII antigen, VIII antigen, VIII coagulation activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; levels of fibrinogen activity; plasminogen antigen and activity; thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine; corticosteroid-binding globulin; sex hormone-binding globulin; angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin; TG, plasma HDL, and levels of various other lipids and lipoproteins may be affected.Decreased
Levels of anti-factors Xa and antithrombin III; antithrombin III activity; T3 resin uptake is decreased, reflecting elevated TBG; impaired glucose tolerance, reduced response to metyrapone test; reduced serum folate concentration, reduced LDL concentration.
Hypertension (3%); deep and superficial venous thrombosis, MI, pulmonary embolism, stroke, thrombophlebitis.
Depression (6%); headache (5%); changes in libido, chorea, dizziness, exacerbation of epilepsy, irritability, migraine, mood disturbances, nervousness.
Rash (2%); chloasma, erythema multiforme, erythema nodosum, hemorrhagic eruption, hirsutism, loss of scalp hair, melasma, pruritus.
Intolerance to contact lenses, retinal vascular thrombosis, steepening of corneal curvature.
Abdominal pain, flatulence (4%); abdominal cramps, bloating, gallbladder disease, nausea, pancreatitis, vomiting.
Vaginal bleeding (37%); breast pain (19%); UTI (3%); vaginitis (2%); abnormal withdrawal bleeding or flow, breakthrough bleeding, breast cancer, fibrocystic breast changes, breast tenderness or enlargement, change in amount of cervical secretion, changes in cervical ectropion, changes in vaginal bleeding pattern, endometrial cancer, endometrial hyperplasia, spotting, galactorrhea, increased size of uterine leiomyomata, nipple discharge, ovarian cancer, vaginal candidiasis.
Weight gain (3%); hypocalcemia, increased triglycerides, reduced carbohydrate tolerance, weight loss.
Back pain (6%); arthralgia (4%); leg cramps.
Upper respiratory tract infection (13%); bronchitis, sinusitis (4%); exacerbation of asthma.
Application site reaction (41%); flu syndrome, pain (5%); edema (4%); accidental injury, infection (3%), aggravation of porphyria, anaphylactic/anaphylactoid reactions.
The Women's Health Initiative study reported increased risks of MI, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women during 5 yr of treatment with oral conjugated estrogens combined with medroxyprogesterone acetate. Although the combination of estradiol/levonorgestrel was not studied, in the absence of comparable date, these risks should be assumed to be similar. Because of these risks, prescribe estrogens with or without progestins at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman.
Ensure breast, abdominal, and pelvic examination, and Pap smear have been completed and documented before starting therapy and annually thereafter during prolonged therapy.Side effects
Immediately inform health care provider if any of the following are noted: pain, swelling, redness, or warmth in calves; sudden severe headache; chest pain; shortness of breath or difficulty breathing; visual disturbances; weakness or numbness of arms or legs; signs of liver dysfunction (eg, dark urine, jaundice); abdominal pain or tenderness; abdominal mass; signs of depression.
Category X .
Secreted into breast milk.
Not indicated for children.
Metabolism may be impaired; use with caution.
Because asthma, diabetes mellitus, epilepsy, hepatic hemangiomas, migraine, porphyria, and systemic lupus erythematosus may be exacerbated by estrogens, use with caution.
Use with caution and discontinue if there is recurrence.
Estrogen and estrogen/progestin therapy has been associated with an increased risk of CV events such as MI and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism).
Estrogen and estrogen/progestin therapy in postmenopausal women has been associated with an increased risk of breast cancer. The increased risk is apparent after 4 yr of treatment.
Substantial increases in BP have been attributed to idiosyncratic reactions to estrogens. Assess BP at beginning of therapy and periodically during treatment. Notify health care provider of significant increases.
Use of unopposed estrogens in women with intact uteri has been associated with increased risk of endometrial cancer. The increased risk is related to the dose and duration of estrogen therapy.
May be exacerbated with administration of estrogen.
In patients with familial defects of lipoprotein metabolism, oral estrogen therapy may be associated with elevations of plasma triglycerides, leading to pancreatitis or other complications.
Because estrogen and estrogen/progestin may cause fluid retention, use with caution in patients whose condition may be influenced by fluid retention (eg, cardiac or renal dysfunction).
The risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogen is increased 2- to 4-fold.
Monitor blood sugar in diabetic patient when therapy is started. Report significant changes to health care provider. A worsening of glucose tolerance has been observed.
Use with caution.
Estrogen use leads to increased thyroid-binding globulin levels. Patients dependent on thyroid hormone replacement therapy who are receiving estrogens may require increased doses of thyroid replacement therapy. Ensure thyroid function is monitored periodically in patient with hypothyroidism, and that thyroid replacement dose is adjusted, if necessary, to maintain free thyroid levels in an acceptable range.
Use of estrogen-only products has been associated with an increased risk of ovarian cancer. Data are insufficient to determine whether there is an increased risk with estrogen/progestin combination therapy.
Consider discontinuing therapy during periods of prolonged immobilization and, if possible, 4 to 6 wk before surgery that is associated with an increased risk of thromboembolic disease.
Ensure attempts are made every 3 to 6 mo to discontinue therapy or change to different agents that provide lower doses of estrogen and progestin.
Retinal vascular thrombosis may occur, leading to diplopia, loss of vision, migraine, or sudden onset of proptosis.
Nausea, withdrawal bleeding.
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