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Climara Pro Transdermal System (Berlex)
- Drugs index
Climara Pro (Estradiol/Levonorgestrel Transdermal System) is an adhesive-based matrix transdermal patch designed to release both estradiol and levonorgestrel, a progestational agent, continuously upon application to intact skin.
The 22 cm 2 Climara Pro system contains 4.40 mg estradiol and 1.39 mg levonorgestrel and provides a nominal delivery rate (mg per day) of 0.045 estradiol and 0.015 levonorgestrel.
Estradiol USP has a molecular weight of 272.39 and the molecular formula is C 18 H 24 O 2 .
Levonorgestrel USP has a molecular weight of 312.4 and a molecular formula of C 21 H 28 O 2 .
The structural formulas for estradiol and levonorgestrel are:
The Climara Pro system comprises 3 layers. Proceeding from the visible surface towards the surface attached to the skin, these layers are (1) a translucent polyethylene backing film, (2) an acrylate adhesive matrix containing estradiol and levonorgestrel, and (3) a protective liner of either siliconized or fluoropolymer coated polyester film. The protective liner is attached to the adhesive surface and must be removed before the system can be used.
The active components of the system are estradiol and levonorgestrel. The remaining components of the system (acrylate copolymer adhesive and polyvinylpyrrolidone/vinyl acetate copolymer) are pharmacologically inactive.
Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.
Levonorgestrel inhibits gonadotropin production resulting in retardation of follicular growth and inhibition of ovulation.
Studies to assess the potency of progestins using estrogen-primed postmenopausal endometrial biochemistry and morphologic features have shown that levonorgestrel counteracts the proliferative effects of estrogens on the endometrium.
Absorption: Administration of Climara Pro to postmenopausal women produces mean maximum estradiol concentrations in serum in about 2 to 2.5 days. Estradiol concentrations equivalent to the normal ranges observed at the early follicular phase in premenopausal women are achieved within 12-24 hours after the first application.
In one study, steady state estradiol concentrations in serum were measured during week 4 in 44 healthy, postmenopausal women during four consecutive Climara Pro applications of two formulations (0.045 mg estradiol/0.030 mg levonorgestrel and 0.045 mg estradiol/0.015 mg levonorgestrel) to the abdomen (each dose was applied for four 7-day periods). Both formulations were bioequivalent in terms of estradiol and estrone C max and AUC parameters. A summary of Climara Pro single and multiple applications estradiol, estrone and levonorgestrel pharmacokinetic parameters is shown in Table 1.
All mean parameters are arithmetic means except T max which is expressed as the median.
At steady state, Climara Pro maintains during the application period an average serum estradiol concentration of 35.7 pg/mL as depicted in Figure 1.
Following the application of the Climara Pro transdermal system, levonorgestrel concentrations are maximum in about 2.5 days. At steady state, Climara Pro maintains during the application period an average serum levonorgestrel concentration of 166 pg/mL as depicted in Figure 2. The mean levonorgestrel pharmacokinetic parameters of Climara Pro are summarized in Table 1.
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.
Levonorgestrel in serum is bound to both SHBG and albumin. Following four consecutive weekly applications of Climara Pro mean (± SD) SHBG concentrations declined from a predose value of 47.5 (25.8) to 41.2 (22.4) nmol/L at week 4.
Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intesine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
The most important metabolic pathway for levonorgestrel occurs in the reduction of the 4- and the 3-oxo-group as well as hydroxylations at positions 2(alpha), 1(beta), and 16(beta), followed by conjugation. Most of the metabolites that circulate in the blood are sulfates of 3, 5(beta)-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. Some of the parent levonorgestrel also circulates as the 17(beta)-sulfate. In-vitro studies on the biotransformation of levonorgestrel in human skin did not indicate any significant metabolism of levonorgestrel during skin penetration.
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Following patch removal, serum estradiol concentrations decline rapidly with a mean (± SD) terminal half-life of 3.0 ± 0.67 hours.
Levonorgestrel and its metabolites are primarily excreted in the urine. Mean (± SD) terminal half-life for levonorgestrel was determined to be 28 ± 6.4 hours.
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 preparations (Hypericum perforatum), 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.
Hydroxylation of levonorgestrel is a conversion step which is mediated by cytochrome P450 enzymes. Based on in-vitro and in-vivo studies, it can be assumed that CYP3A, CYP2E and CYP2C are involved in the metabolism of levonorgestrel. Likewise, inducers or inhibitors of these enzymes may either, respectively, decrease the therapeutic effects or result in side effects.
Climara Pro has been studied only in healthy postmenopausal women.
Effects on vasomotor symptoms
The efficacy of 0.045 mg estradiol/0.030 mg levonorgestrel administered weekly versus placebo in the relief of moderate to severe vasomotor symptoms in post-menopausal women was studied in one 12-week clinical trial (n=183, average age 52.1 ± 4.93, 82.0% Caucasian). The 0.045 mg estradiol/0.030 mg levonorgestrel dosage strength was shown to be statistically better than placebo at weeks 4 and 12 for relief of both the number and severity of moderate to severe hot flushes. See Tables 2 and 3. Climara Pro and the 0.045 mg estradiol/0.030 mg levonorgestrel dosage strength are bioequivalent in terms of estradiol delivery. (See CLINICAL PHARMACOLOGY , Pharmacokinetics .)
Effects on the endometrium
In a 1-year clinical trial of 412 postmenopausal women (with intact uteri) treated with a continuous regimen of Climara Pro or with a continuous estradiol-only transdermal system, results of evaluable endometrial biopsies show that no hyperplasia was seen with Climara Pro. Table 4 below summarizes these results (Intent-to-Treat populations).
Effects on uterine bleeding or spotting
The effects of Climara Pro on uterine bleeding or spotting, as recorded using an interactive voice response system, were evaluated in one 12-month clinical trial. Results are shown in Figure 3.
Percent based upon the number of subjects with data
Last non-missing cycle carried forward through cycle 13
Bleeding associated with endometrial biopsies not included
Women's Health Initiative Studies
The Women's Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of 0.625 mg conjugated estrogens (CE) per day alone or the use of 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.
The CE-only substudy is continuing and results have not been reported. The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index." Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 5 below:
For those outcomes included in the "global index," absolute excess risks per 10,000 person-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the "global index" was 19 per 10,000 person-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNING , WARNINGS , and PRECAUTIONS .)
INDICATIONS AND USAGE
In women with an intact uterus, Climara Pro is indicated for the following:
Estrogens/progestins combined should not be used in women with any of the following conditions:
See BOXED WARNING .
B. PATIENT INFORMATION
Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe Climara Pro.
C. LABORATORY TESTS
Estrogen administration should be initiated at the lowest dose for the approved indication and then guided by clinical response, rather than by serum hormone levels (e.g., estradiol, FSH).
D. DRUG/LABORATORY TEST INTERACTIONS
E. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. (See BOXED WARNING , CONTRAINDICATIONS , and WARNINGS .)
Climara Pro should not be used during pregnancy. (See CONTRAINDICATIONS .)
G. NURSING MOTHERS
Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogen and progestin have been identified in the milk of mothers receiving these drugs. Caution should be exercised when Climara Pro is administered to a nursing woman.
H. PEDIATRIC USE
Climara Pro is not indicated in children.
I. GERIATRIC USE
There have not been sufficient numbers of geriatric patients involved in studies utilizing Climara Pro to determine whether those over 65 years of age differ from younger subjects in their response to Climara Pro.
See BOXED WARNING , WARNINGS and PRECAUTIONS .
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. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
Irritation potential of Climara Pro was assessed in a 3-week irritation study. The study compared the irritation of a Climara Pro placebo patch (22 cm 2 ) to a Climara® placebo (25 cm 2 ). Visual assessments of irritation were made on Day 7 of each wear period, approximately 30 minutes after patch removal using a 7-point scale (0 = no evidence of irritation; 1 = minimal erythema, barely perceptible; 2 = definite erythema, readily visible, or minimal edema, or minimal papular response; 3-7 = erythema and papules, edema, vesicles, strong extensive reaction).
The mean irritation scores were 0.13 (week 1), 0.12 (week 2), and 0.06 (week 3) for the Climara Pro placebo. The mean scores for the Climara placebo were 0.20 (week 1), 0.26 (week 2), 0.12 (week 3). There were no irritation scores greater than 2 at any timepoint in any subject.
In controlled clinical trials, withdrawals due to application site reactions occurred in 6 (2.1%) of subjects in the 12-week symptom study and in 71 (8.5%) of subjects in the 1-year endometrial protection study.
The following additional adverse reactions have been reported with estrogen and/or estrogen/progestin therapy:
Overdosage may cause nausea, and withdrawal bleeding may occur in females. Serious ill effects have not been reported following acute ingestion of large doses of estrogen/progestin-containing oral contraceptives by young children.
DOSAGE AND ADMINISTRATION
When estrogen is prescribed for a postmenopausal woman with a uterus, progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be limited to the lowest effective dose available and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be reevaluated periodically as clinically appropriate (e.g., 3-month to 6-month intervals) to determine if treatment is still necessary. (See BOXED WARNING and WARNINGS .) For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
One Climara Pro transdermal system is available for the treatment of moderate to severe vasomotor symptoms associated with the menopause. Climara Pro delivers 0.045 mg of estradiol per day and 0.015 mg of levonorgestrel per day. The lowest effective estradiol/levonorgestrel dose for the treatment of moderate to severe vasomotor symptoms has not been determined. (See BOXED WARNING and WARNINGS .)
Initiation of Therapy:
Women not currently using continuous estrogen or combination estrogen/progestin therapy may start therapy with Climara Pro at any time. However, women currently using continuous estrogen or combination estrogen/progestin therapy should complete the current cycle of therapy, before initiating Climara Pro therapy. Women often experience withdrawal bleeding at the completion of the cycle. The first day of this bleeding would be an appropriate time to begin Climara Pro therapy.
A Climara Pro 0.045 mg / 0.015 mg (22 sq cm) matrix transdermal system is worn continuously on the lower abdomen. A new system should be applied weekly during a 28-day cycle.
Application of the System: Site Selection: Climara Pro should be placed on a smooth (fold free), clean, dry area of the skin on the lower abdomen. Climara Pro should not be applied to or near the breasts. The area selected should not be oily (which can impair adherence of the system), damaged, or irritated. The waistline should be avoided, since tight clothing may rub the system off or modify drug delivery. The sites of application must be rotated, with an interval of at least one week allowed between applications to the same site.
Application of the system: After opening the pouch, remove one side of the protective liner, taking care not to touch the adhesive part of the transdermal delivery system with the fingers. Immediately apply the transdermal delivery system to a smooth (fold free) area of skin 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 seconds, making sure there is good contact, especially around the edges.
Care should be taken that the system does not become dislodged during bathing and other activities. If a system should fall off, the same system may be reapplied to another area of the lower abdomen. If necessary, a new transdermal system may be applied, in which case, the original treatment schedule should be continued. Only one system should be worn at any one time during one week dosing interval.
Once in place, the transdermal system should not be exposed to the sun for prolonged periods of time.
Removal of the System: Removal of the system should be done carefully and slowly to avoid irritation of the skin. Should any adhesive remain on the skin after removal of the system, allow the area to dry for 15 minutes. Then gently rubbing the area with an oil-based cream or lotion should remove the adhesive residue.
Used patches still contain some active hormones. Each patch should be carefully folded in half so that it sticks to itself before throwing it away.
Climara Pro (Estradiol/Levonorgestrel Transdermal System) 0.045 mg/day estradiol and 0.015 mg/day levonorgestrel - each 22 cm 2 system contains 4.40 mg of estradiol and 1.39 mg of levonorgestrel.
Individual Carton of 4 systems
Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F) [See USP controlled Room Temperature].
Do not store unpouched.
Updated November 19, 2003
(Estradiol/Levonorgestrel Transdermal System)
Read this PATIENT INFORMATION before you start taking Climara Pro and read what you get each time you refill Climara Pro. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
What is Climara Pro?
Climara Pro is a medicine that contains two kinds of hormones, estrogen and a progestin.
What is Climara Pro used for?
Climara Pro is used after menopause to:
Who should not use Climara Pro?
Do not use Climara Pro if you have had your uterus removed (hysterectomy).
Climara Pro contains a progestin to decrease the chances of getting cancer of the uterus. If you do not have a uterus, you do not need a progestin and you should not use Climara Pro.
Do not start using Climara Pro if you:
Tell your healthcare provider:
How The Patch Works
The Climara Pro patch releases two hormones, estradiol and levonorgestrel, which flow through the skin into the bloodstream.
How and Where to Apply the Climara Pro Patch
Each Climara Pro patch is individually sealed in a protective pouch. To open the pouch, hold it up with the Climara Pro name facing you. Tear left to right using the top tear notch. Tear from bottom to top using the side tear notch. Pull the pouch open. Carefully remove the Climara Pro patch. You will notice that the patch is attached to a thicker, hard-plastic liner and that the patch itself is oval.
Apply the adhesive side of the Climara Pro patch to a clean, dry area of the lower abdomen. Do not apply the Climara Pro patch to your breasts. The sites of application must be rotated, with an interval of at least 1 week allowed between applications to a particular site. The area selected should not be oily, damaged, or irritated. Avoid the waistline, since tight clothing may rub and remove the patch. Application to areas where sitting would dislodge the patch should also be avoided. Apply the patch immediately after opening the pouch and removing the protective liner. Press the patch firmly in place with the fingers for about 10 seconds, making sure there is good contact, especially around the edges.
The Climara Pro patch should be worn continuously for one week. You may wish to experiment with different locations when applying a new patch, to find ones that are most comfortable for you and where clothing will not rub on the patch.
When to Apply the Climara Pro Patch
The Climara Pro patch should be changed once weekly. Remove the used patch. Carefully fold it in half so that it sticks to itself because used patches still contain active hormones and discard it. Any adhesive that might remain on your skin can be easily rubbed off. Then place the new Climara Pro patch on a different skin site. (The same skin site should not be used again for at least 1 week after removal of the patch.)
Contact with water when you are bathing, swimming, or showering may affect the patch. If the patch falls off, the same patch may be reapplied to another area of the lower abdomen. Make sure that there is good contact, especially around the edges. If the patch will not stick completely to your skin, put a new patch on a different area of the lower abdomen. Do not apply two patches at the same time.
Once in place, the transdermal system should not be exposed to the sun for prolonged periods of time.
Estrogens should be used only as long as needed. You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about whether you still need treatment with Climara Pro.
What are the possible side effects of estrogens?
Less common but serious side effects include:
These are some of the warning signs of serious side effects:
Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptom that concerns you.
Common side effects include:
Other side effects include:
These are not all the possible side effects of Climara Pro. For more information, ask your healthcare provider or pharmacist.
What can I do to lower my chances of a serious side effect with Climara Pro?
General information about safe and effective use of Climara Pro
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Climara Pro for conditions for which it was not prescribed. Do not give Climara Pro to other people, even if they have the same symptoms you have. It may harm them.
Keep Climara Pro out of the reach of children.
This leaflet provides a summary of the most important information about Climara Pro. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Climara Pro that is written for health professionals. You can get more information by calling the toll free number (1-888-237-5394).
What are the ingredients in Climara Pro?
The active ingredients in Climara Pro are estradiol and levonorgestrel. Climara Pro also contains acrylate copolymer adhesive and polyvinylpyrrolidone/vinyl acetate copolymer.
Do not store above 86°F (30°C).
Do not store unpouched.
© 2005, Berlex. All rights reserved.
Made In USA
Berlex, Montville, NJ 07045
St. Paul, MN 55144
6050701-635100 February 2005