Estradiol / Levonorgestrel

Pronunciation: ESS-truh-DIE-ole/LEE-voe-nor-JESS-truhl
Class: Estrogen and progestin combined

Trade Names:
Climara Pro
- Transdermal Patch estradiol 0.045 mg and levonorgestrel 0.015 mg per day

Pharmacology

Estrogens are essential in developing and maintaining female reproductive system and secondary sex characteristics.

Progestins transform proliferative endometrium into secretory endometrium.

Pharmacokinetics

Absorption

Estrogen: Max concentration reached in 2 to 2.5 days.

Levonorgestrel: Max concentration reached in 2.5 days.

Distribution

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.

Metabolism

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.

Elimination

Estradiol is excreted in the urine along with glucuronide and sulfate conjugates. Levonorgestrel and its metabolites are primarily excreted in the urine.

Indications and Usage

Treatment of moderate to severe vasomotor symptoms associated with menopause.

Contraindications

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.

Dosage and Administration

Adults

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.

General Advice

  • If patient previously has applied patch that needs to be changed, remove the old patch carefully and slowly to avoid irritating the skin. Carefully fold used patch in half and discard. If any adhesive remains on the skin after removal of the patch, allow the area to dry for 15 min, then gently rub the area with an oil-based cream or lotion to remove the adhesive residue.
  • Select site for application of new, or first patch, before opening storage pouch. Application site should be a smooth (fold-free), clean, dry area of the skin on the lower abdomen. Do not apply on the waistline, to or near the breasts, or areas where sitting could dislodge the patch. Ensure selected area is not oily (which can impair adherence of the system), damaged, or irritated.
  • Open storage pouch using tear notches and remove patch from storage pouch. Remove 1 side of the protective layer, taking care not to touch the adhesive part of the patch with the fingers. Immediately apply the patch to the selected area on the lower abdomen. Remove the second side of the protective liner and press the system firmly in place with the hand for at least 10 sec, making sure there is good contact, especially around the edges.
  • If patch becomes dislodged during bathing or other activities, the same patch may be reapplied to another area of the lower abdomen. If a dislodged patch does not adhere when it is reapplied, discard the patch and apply a new one, continuing with the original treatment schedule.

Storage/Stability

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.

Drug Interactions

Inducers of CYP2C, CYP2E, CYP3A4

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.

Laboratory Test Interactions

Increased

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.

Adverse Reactions

Cardiovascular

Hypertension (3%); deep and superficial venous thrombosis, MI, pulmonary embolism, stroke, thrombophlebitis.

CNS

Depression (6%); headache (5%); changes in libido, chorea, dizziness, exacerbation of epilepsy, irritability, migraine, mood disturbances, nervousness.

Dermatologic

Rash (2%); chloasma, erythema multiforme, erythema nodosum, hemorrhagic eruption, hirsutism, loss of scalp hair, melasma, pruritus.

EENT

Intolerance to contact lenses, retinal vascular thrombosis, steepening of corneal curvature.

GI

Abdominal pain, flatulence (4%); abdominal cramps, bloating, gallbladder disease, nausea, pancreatitis, vomiting.

Genitourinary

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.

Hepatic

Cholestatic jaundice.

Metabolic-Nutritional

Weight gain (3%); hypocalcemia, increased triglycerides, reduced carbohydrate tolerance, weight loss.

Musculoskeletal

Back pain (6%); arthralgia (4%); leg cramps.

Respiratory

Upper respiratory tract infection (13%); bronchitis, sinusitis (4%); exacerbation of asthma.

Miscellaneous

Application site reaction (41%); flu syndrome, pain (5%); edema (4%); accidental injury, infection (3%), aggravation of porphyria, anaphylactic/anaphylactoid reactions.

Precautions

Warnings

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.


Monitor

Baseline examinations

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.


Pregnancy

Category X .

Lactation

Secreted into breast milk.

Children

Not indicated for children.

Hepatic Function

Metabolism may be impaired; use with caution.

Special Risk Patients

Because asthma, diabetes mellitus, epilepsy, hepatic hemangiomas, migraine, porphyria, and systemic lupus erythematosus may be exacerbated by estrogens, use with caution.

Cholestatic jaundice history

Use with caution and discontinue if there is recurrence.

CV effects

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).

Breast cancer

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.

Elevated BP

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.

Endometrial cancer

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.

Endometriosis

May be exacerbated with administration of estrogen.

Familial hyperlipoproteinemia

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.

Fluid retention

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).

Gallbladder disease

The risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogen is increased 2- to 4-fold.

Glucose intolerance

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.

Hypocalcemia

Use with caution.

Hypothyroidism

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.

Ovarian cancer

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.

Surgery/Immobilization

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.

Tapering/Withdrawal

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.

Visual abnormalities

Retinal vascular thrombosis may occur, leading to diplopia, loss of vision, migraine, or sudden onset of proptosis.

Overdosage

Symptoms

Nausea, withdrawal bleeding.

Patient Information

  • Advise patient to review patient information leaflet before starting therapy and with each refill.
  • Advise patient to regularly (eg, every 3 to 6 mo) talk with health care provider about using the patch or switching to different agents that provide lower doses of estrogen and progestin.
  • Instruct patient to apply patch as prescribed and not change the frequency of application or stop taking unless advised by health care provider.
  • Advise patient that patch (transdermal delivery system) is applied weekly to the lower abdomen and worn continuously during the 7-day treatment period. Instruct patient to rotate application sites, with an interval of at least 1 wk allowed between applications to the same site.
  • Advise patient who currently is using continuous estrogen or combination estrogen/progestin therapy to complete the current cycle of therapy before initiating therapy with the transdermal delivery system.
  • Instruct patient to remove previously applied patch before applying new patch. Advise patient to remove the old patch carefully and slowly to avoid irritating the skin and then carefully fold used patch in half and discard. If any adhesive remains on the skin after removal of the patch, advise patient to allow the area to dry for 15 min, then gently rub the area with an oil-based cream or lotion to remove the adhesive residue.
  • Instruct patient to select site for application of patch before opening storage pouch. Advise patient to select an application site on the lower abdomen that is smooth (fold free), clean, dry, and not oily (which can impair adherence of the patch), damaged, or irritated. Caution patient not to apply on the waistline, to or near the breasts, or areas where sitting could dislodge the patch.
  • Instruct patient on proper method of applying patch: open storage pouch using tear notches and remove patch from storage pouch; remove 1 side of the protective layer, taking care not to touch the adhesive part of the patch with the fingers, and immediately apply the patch to the selected area on the lower abdomen; remove the second side of the protective liner and press the system firmly in place with the hand for at least 10 sec, making sure there is good contact, especially around the edges.
  • Advise patient that if patch becomes dislodged during bathing or other activities, it may be reapplied to another area of the lower abdomen. If a dislodged patch does not adhere when it is reapplied, advise patient to discard the patch and apply a new patch, continuing with the original weekly treatment schedule.
  • Advise patient that applied patch should not be exposed to the sun for long periods of time.
  • Instruct patients with diabetes to monitor blood glucose more frequently when therapy is started and to inform health care provider of significant changes in readings.
  • Review the following nonhormonal modalities that help prevent osteoporosis: 1,500 mg/day of calcium, vitamin D supplementation, exercise.
  • Teach patient proper method of breast self-examination and advise patient to perform monthly.
  • Instruct patient to immediately report any of the following to health care provider: abnormal vaginal bleeding, chest pain, difficulty breathing or unexplained shortness of breath, breast lumps, dizziness or fainting, pain in groin or calves, severe abdominal pain or swelling, severe depression, sudden severe headache, vision or speech problems, weakness or numbness of arms or legs, yellowing of skin or eyes.
  • Advise patient that follow-up visits and examinations, including Pap smear at least once a year, will be required to monitor therapy and to keep appointments.

Copyright © 2009 Wolters Kluwer Health.

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