CLIMARA PRO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for CLIMARA PRO (CLIMARA PRO).
CLIMARA PRO contains estradiol, an estrogen, and levonorgestrel, a progestin. Estrogens act by binding to nuclear receptors (ERα and ERβ) which act as transcription factors to regulate gene expression, leading to effects such as proliferation of the endometrium and relief of menopausal symptoms. Levonorgestrel is a progestin that induces endometrial transformation and shedding, counteracting estrogen-induced endometrial hyperplasia. The combination provides hormone replacement therapy with reduced risk of endometrial hyperplasia.
| Metabolism | Estradiol: metabolized primarily in the liver via conversion to estrone and estriol, and further conjugated to glucuronides and sulfates; undergoes enterohepatic recirculation. Levonorgestrel: metabolized by CYP3A4 to reduced and hydroxylated metabolites, which are excreted as glucuronide and sulfate conjugates. |
| Excretion | Estradiol and estradiol valerate are metabolized primarily in the liver to estrone, estriol, and glucuronide/sulfate conjugates. Excretion occurs predominantly via the kidneys (>90% as conjugated metabolites), with less than 5% excreted unchanged in urine. Fecal excretion accounts for approximately 5-10%. |
| Half-life | The terminal elimination half-life of estradiol from Climara Pro (estradiol/levonorgestrel transdermal system) is approximately 2-3 hours for estradiol, but due to continuous transdermal delivery, steady-state concentrations are maintained with twice-weekly application. The half-life of levonorgestrel is longer, around 17-20 hours. |
| Protein binding | Estradiol is approximately 98-99% bound to plasma proteins, primarily to sex hormone-binding globulin (SHBG) and albumin. Levonorgestrel is about 98-99% bound, mainly to SHBG and albumin. |
| Volume of Distribution | Estradiol: Vd ~1.2 L/kg (varies with body composition). Levonorgestrel: Vd ~2.5 L/kg. The large Vd indicates extensive distribution into tissues, including adipose tissue. |
| Bioavailability | Transdermal administration of Climara Pro bypasses first-pass hepatic metabolism, resulting in systemic bioavailability of approximately 100% relative to intravenous administration for the released drug. Oral estradiol bioavailability is <5% due to extensive first-pass metabolism. |
| Onset of Action | Following transdermal application, detectable serum estradiol levels appear within 2-4 hours, but therapeutic effects (e.g., relief of vasomotor symptoms) may require 2-4 weeks of consistent use. |
| Duration of Action | Each system is designed to deliver continuous drug for 7 days. Clinical effects (e.g., reduced hot flushes) persist as long as the system is replaced weekly. After removal, serum estradiol levels decline to baseline within 24-48 hours. |
One patch applied transdermally once weekly, delivering 0.05 mg estradiol and 0.25 mg levonorgestrel per day.
| Dosage form | FILM, EXTENDED RELEASE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Not studied in severe renal impairment; use with caution. |
| Liver impairment | Contraindicated in patients with severe hepatic disease (Child-Pugh class C). For mild to moderate impairment (Child-Pugh A or B), use with caution and monitor liver function; no specific dose adjustments established. |
| Pediatric use | Not indicated for use in pediatric patients. |
| Geriatric use | Use the lowest effective dose for the shortest duration. Consider alternative therapies due to increased risk of cardiovascular events, dementia, and breast cancer in women >65 years. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for CLIMARA PRO (CLIMARA PRO).
| Breastfeeding | Estradiol and levonorgestrel are excreted in breast milk. M/P ratio: estradiol 1.9, levonorgestrel not specified. May reduce milk production and quality. Contraindicated in breastfeeding. |
| Teratogenic Risk | Estradiol and levonorgestrel combination: First trimester - increased risk of congenital anomalies including cardiac defects and limb reduction; second and third trimesters - risk of urogenital abnormalities and feminization of male fetus. Avoid use in pregnancy. |
| Fetal Monitoring |
■ FDA Black Box Warning
Estrogens plus progestin therapy should not be used to prevent cardiovascular disease or dementia. Increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis have been reported. The Women's Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg), relative to placebo. The WHI Memory Study (WHIMS) reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE 0.625 mg combined with MPA 2.5 mg, relative to placebo.
| Serious Effects |
["Undiagnosed abnormal genital bleeding","Known, suspected, or history of breast cancer","Known or suspected estrogen-dependent neoplasia","Active or past history of venous thromboembolism (e.g., deep vein thrombosis, pulmonary embolism)","Active or recent arterial thromboembolic disease (e.g., stroke, myocardial infarction)","Known thrombophilic disorders (e.g., protein C, protein S, or antithrombin deficiency)","Known or suspected pregnancy","Liver disease or impaired liver function (aspartate aminotransferase [AST], alanine aminotransferase [ALT], bilirubin, or alkaline phosphatase elevations)","Known hypersensitivity to estradiol, levonorgestrel, or any component of the product"]
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| Monitor fetal growth and development with ultrasound; assess for signs of estrogen-related adverse effects like cholestasis. Maternal monitoring: liver function, blood pressure, and glucose tolerance. |
| Fertility Effects | Suppresses ovulation and may impair fertility during use; reversible upon discontinuation. No permanent effects on fertility. |
| Precautions |
| ["Cardiovascular disorders: increased risk of stroke, DVT, pulmonary embolism, and myocardial infarction","Malignant neoplasms: increased risk of endometrial cancer (with use without progestin), breast cancer, and ovarian cancer","Dementia: increased risk of probable dementia in women aged 65 and older","Cholelithiasis and cholecystitis","Gallbladder disease","Hypercalcemia in women with breast cancer and bone metastases","Visual abnormalities (e.g., retinal vascular thrombosis)","Fluid retention","Hypertension","Hypertriglyceridemia","Hepatic hemangiomas","Hypothyroidism (may require increased thyroid replacement dose)","Porphyria","Systemic lupus erythematosus","Uterine leiomyomata","Endometriosis","Asthma","Diabetes mellitus","Migraine headache"] |