Disclaimer:
Medidex is not a provider of medical services and all information is provided for the convenience of the user. No medical decisions should be made based on the information provided on this website without first consulting a licensed healthcare provider.This website is intended for persons 18 years or older. No person under 18 should consult this website without the permission of a parent or guardian.
CombiPatch (estradiol/norethindrone acetate transdermal system)
Overview
What is CombiPatch (estradiol/norethindrone acetate transdermal system)?
CombiPatch (estradiol/norethindrone acetate transdermal system) is an adhesive-based matrix transdermal patch designed to release both estradiol, an estrogen, and norethindrone acetate (NETA), a progestational agent, continuously upon application to intact skin.
Two systems are available, providing the following delivery rates of estradiol and NETA.
Estradiol USP (estradiol) is a white to creamy white, odorless, crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17-diol. The molecular weight of estradiol is 272.39 and the molecular formula is CHO.
NETA USP is a white to creamy white, odorless, crystalline powder, chemically described as 17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one acetate. The molecular weight of NETA is 340.47 and the molecular formula is CHO.
The structural formulas for estradiol and NETA are:
CombiPatch is comprised of 3 layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are (1) a translucent polyolefin film backing, (2) an adhesive layer containing estradiol, NETA, acrylic adhesive, silicone adhesive, oleic acid NF, povidone USP and dipropylene glycol, and (3) a polyester release protective liner, which is attached to the adhesive surface and must be removed before the system can be used.
The active components of the system are estradiol USP and NETA USP. The remaining components of the system are pharmacologically inactive.
What does CombiPatch (estradiol/norethindrone acetate transdermal system) look like?
What are the available doses of CombiPatch (estradiol/norethindrone acetate transdermal system)?
Sorry No records found.
What should I talk to my health care provider before I take CombiPatch (estradiol/norethindrone acetate transdermal system)?
Sorry No records found
How should I use CombiPatch (estradiol/norethindrone acetate transdermal system)?
CombiPatch is indicated in a woman with a uterus for:
Generally, when estrogen therapy is prescribed for a postmenopausal woman with a uterus, a progestin should be considered to reduce the risk of endometrial cancer. A woman without a uterus generally does not need a progestin. In some cases, however, hysterectomized women with a history of endometriosis may need a progestin. Use of estrogen-alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be reevaluated periodically as clinically appropriate to determine whether treatment is still necessary. Adequate diagnostic measures, such as directed or random endometrial sampling, when indicated, should be undertaken to rule out malignancy in a postmenopausal woman with a uterus with undiagnosed persistent or recurring abnormal genital bleeding.
Initiation of Therapy
Patients should be started at the lowest dose. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. The lowest effective dose of CombiPatch has not been determined in clinical trials.
Women not currently using continuous estrogen or combination estrogen plus progestin therapy may start therapy with CombiPatch at any time. However, women currently using continuous estrogen or combination estrogen plus progestin therapy should complete the current cycle of therapy, before initiating CombiPatch 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 CombiPatch therapy.
Therapeutic Regimens
Combination estrogen plus progestin regimens are indicated for women with an intact uterus. Two CombiPatch (estradiol/NETA) transdermal delivery systems are available: 0.05 mg estradiol with 0.14 mg NETA per day (9 cm) and 0.05 mg estradiol with 0.25 mg NETA per day (16 cm). The lowest effective dose should be used. For all regimens, women should be reevaluated at 3- to 6-month intervals to determine if changes in hormone therapy or if continued hormone therapy is appropriate.
Continuous Combined Regimen
CombiPatch 0.05 mg estradiol/0.14 mg NETA per day (9 cm) matrix transdermal system is used for continuous uninterrupted treatment applied twice weekly on the lower abdomen. A new system should be applied to the skin every 3 to 4 days (twice weekly) during a 28-day cycle.
Additionally, a dose of 0.05 mg estradiol/0.25 mg NETA (16 cm system) is available if a greater progestin dose is desired. Irregular bleeding may occur particularly in the first six months, but generally decreases with time, and often to an amenorrheic state.
Continuous Sequential Regimen
CombiPatch can be applied as a sequential regimen in combination with an estradiol-only transdermal delivery system.
In this treatment regimen, a 0.05 mg per day (nominal delivery rate) estradiol transdermal system (Vivelle-Dot) is worn for the first 14 days of a 28-day cycle, replacing the system every 3 to 4 days (twice weekly) according to product directions.
For the remaining 14 days of the 28-day cycle, CombiPatch 0.05 mg estradiol/0.14 mg NETA per day (9 cm) transdermal system should be worn continuously on the lower abdomen. The CombiPatch system should be replaced every 3 to 4 days (twice weekly) during this 14-day period in the 28-day cycle.
Additionally, a dose of 0.05 mg estradiol/0.25 mg NETA (16 cm system) is available if a greater progestin dose is desired. Women should be advised that monthly withdrawal bleeding often occurs.
Application of the System
Site Selection
CombiPatch should be placed on a smooth (fold-free), clean, dry area of the skin on the lower abdomen. 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
After opening the pouch, remove 1 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.
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 rub the area with an oil-based cream or lotion to remove the adhesive residue.
What interacts with CombiPatch (estradiol/norethindrone acetate transdermal system)?
- CombiPatch is contraindicated in women with any of the following conditions:
- Undiagnosed abnormal genital bleeding.
- Known, suspected, or history of breast cancer.
- Known or suspected estrogen-dependent neoplasia.
- Active DVT, PE, or history of these conditions.
- Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions.
- Known anaphylactic reaction or angioedema or hypersensitivity with CombiPatch.
- Known liver impairment or disease.
- Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders
- Known or suspected pregnancy.
What are the warnings of CombiPatch (estradiol/norethindrone acetate transdermal system)?
The occurrence of hypersensitivity reactions to allopurinol may be increased in patients with decreased renal function receiving thiazides and allopurinol concurrently. For this reason, in this clinical setting, such combinations should be administered with caution and patients should be observed closely.
1. Cardiovascular Disorders
An increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin therapy. An increased risk of stroke and DVT has been reported with estrogen-alone therapy. Should any of these occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately.
Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.
a. Stroke
In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years). (See ) The increase in risk was demonstrated after the first year and persisted. Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.
In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). (See ) The increase in risk was demonstrated in year 1 and persisted. Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately.
Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years).
b. Coronary Heart Disease
In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events (defined as nonfatal MI, silent MI, or CHD death) reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 (See ).
In the WHI estrogen-alone substudy, no overall effect on CHD events was reported in women receiving estrogen-alone compared to placebo. (See )
Subgroup analyses of women 50 to 59 years of age suggest a statistically nonsignificant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women less than 10 years since menopause (8 versus 16 per 10,000 women-years).
In postmenopausal women with documented heart disease (n=2,763, average 66.7 years of age), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established CHD. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred twenty-one (2,321) women from the original HERS trial agreed to participate in an open-label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in the HERS, the HERS II, and overall.
c. Venous Thromboembolism
In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE (DVT and PE) was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted. (See ) Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.
In the WHI estrogen-alone substudy, the risk of VTE was reported to be increased for women receiving daily CE (0.625 mg)-alone compared to women receiving placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women years). The increase in VTE risk was demonstrated during the first 2 years. (See ) Should a VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately.
If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.
2. Malignant Neoplasms
a. Breast Cancer
The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the 2 groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups. (See )
The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the WHI substudy of CE (0.625)-alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80). (See )
Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.
The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation.
All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.
b. Endometrial Cancer
An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among users of unopposed estrogen is about 2 to 12 times greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use with increased risks of 15- to 24-fold for 5 to 10 years or more and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.
Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
c. Ovarian Cancer
The WHI estrogen plus progestin substudy reported a statistically nonsignificant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent CI 0.77 to 3.24). The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years.
A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risks associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.50); there was no difference in the risk estimates by duration of the exposure (less than 5 years [median of 3 years]vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI 1.27-1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.
3. Probable Dementia
In the WHIMS estrogen plus progestin ancillary substudy of WHI, a population of 4,532 generally healthy postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.
After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. (See and , )
In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo. After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83 to 2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. (See and , )
When data from the 2 populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19 to 2.60). 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 , )
4. Gallbladder Disease
A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.
5. Hypercalcemia
Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.
6. Visual Abnormalities
Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.
7. Angioedema
Angioedema involving eye/eyelid, face, larynx, pharynx, tongue and extremity (hands, legs, ankles, and fingers) with or without urticaria requiring medical intervention has occurred in the postmarketing experience of using CombiPatch. If angioedema involves the tongue, glottis, or larynx, airway obstruction may occur. Women who develop angioedema anytime during the course of treatment with CombiPatch should not receive it again. Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.
8. Severe Anaphylactic/Anaphylactoid Reactions
Cases of anaphylactic/anaphylactoid reactions, which developed anytime during the course of CombiPatch treatment and required emergency medical management, have been reported in the postmarketing setting. Involvement of skin (hives, pruritus, swollen lips-tongue-face) and either respiratory tract (respiratory compromise) or gastrointestinal tract (abdominal pain, vomiting) has been noted.
What are the precautions of CombiPatch (estradiol/norethindrone acetate transdermal system)?
A. General
1. Addition of a Progestin when a Woman has not had a Hysterectomy
Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.
There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.
2. Elevated Blood Pressure
In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen.
3. Hypertriglyceridemia
In women with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs.
4. Hepatic Impairment and/or Past History of Cholestatic Jaundice
Although transdermally administered estrogen therapy avoids first-pass hepatic metabolism, estrogens may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued.
5. Hypothyroidism
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T and T serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.
6. Fluid Retention
Estrogens plus progestins may cause some degree of fluid retention. Women with conditions which might be influenced by this factor, such as cardiac or renal impairment warrant careful observation when estrogens plus progestins are prescribed.
7. Hypocalcemia
Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.
8. Exacerbation of Endometriosis
A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.
9. Exacerbation of Other Conditions
Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.
B. Patient Information
Physicians are advised to discuss the content of the leaflet and with patients for whom they prescribe CombiPatch.
C. Laboratory Tests
Serum FSH and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy.
Laboratory parameters may be useful in guiding dosage for the treatment of hypoestrogenism due to hypogonadism, castration and primary ovarian failure.
D. Drug-Laboratory Test Interactions
1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex; and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III; decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
2. Increased TBG leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T levels (by column or by radioimmunoassay) or T levels by radioimmunoassay. T resin uptake is decreased, reflecting the elevated TBG. Free T and free T concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.
3. Other binding proteins may be elevated in serum (i.e., corticosteroid binding globulin [CBG], SHBG), leading to increased circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
4. Increased plasma high density lipoprotein (HDL) and HDL-2 subfraction concentrations, reduced low density lipoprotein (LDL) cholesterol concentration, increased triglycerides levels.
5. Impaired glucose tolerance.
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.
NETA was not mutagenic in a battery of or genetic toxicity assays.
F. Pregnancy
CombiPatch should not be used during pregnancy. (See .) 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.
G. Nursing Mothers
CombiPatch 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 and progestins have been identified in the breast milk of women receiving these drugs. Caution should be exercised when CombiPatch is administered to a nursing woman.
H. Pediatric Use
CombiPatch is not indicated in children. Clinical studies have not been conducted in the pediatric population.
I. Geriatric Use
There have not been sufficient numbers of geriatric women involved in studies utilizing CombiPatch to determine whether those over 65 years of age differ from younger subjects in their response to CombiPatch.
The Women’s Health Initiative Studies
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 )
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 )
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 plus progestin or estrogen-alone when compared to placebo. (See and , )
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 and , )
What are the side effects of CombiPatch (estradiol/norethindrone acetate transdermal system)?
See , , and .
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.
Postmarketing Experience
The following additional adverse reactions have been identified during post-approval use of CombiPatch. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Genitourinary System
Endometrial hyperplasia, endocervical polyp, uterine leiomyomata, fallopian tube cyst, uterine spasms.
Breast
Breast cancer.
Cardiovascular
Hypertension, varicose veins.
Gastrointestinal
Jaundice cholestatic, cholelithiasis, gall bladder disorder, transaminases increased.
Skin
Skin discoloration.
Central Nervous System
Affect lability, libido disorder, migraine, vertigo, paresthesia.
Miscellaneous
Angioedema, hypersensitivity, weight increased.
| VASOMOTOR SYMPTOM STUDIES | |||
| CombiPatch | CombiPatch | Placebo | |
| n=113 | n=112 | n=107 | |
| Body as a Whole | 46% | 48% | 41% |
| Abdominal Pain | 7% | 6% | 4% |
| Accidental Injury | 4% | 5% | 8% |
| Asthenia | 8% | 12% | 4% |
| Back Pain | 11% | 9% | 5% |
| Flu Syndrome | 9% | 5% | 7% |
| Headache | 18% | 20% | 20% |
| Pain | 6% | 4% | 9% |
| Digestive | 19% | 23% | 24% |
| Diarrhea | 4% | 5% | 7% |
| Dyspepsia | 1% | 5% | 5% |
| Flatulence | 4% | 5% | 4% |
| Nausea | 11% | 8% | 7% |
| Nervous | 16% | 28% | 28% |
| Depression | 3% | 5% | 9% |
| Insomnia | 3% | 6% | 7% |
| Nervousness | 3% | 5% | 1% |
| Respiratory | 24% | 38% | 26% |
| Pharyngitis | 4% | 10% | 2% |
| Respiratory Disorder | 7% | 12% | 7% |
| Rhinitis | 7% | 13% | 9% |
| Sinusitis | 4% | 9% | 9% |
| Skin and Appendages | 8% | 17% | 16% |
| Application Site Reaction* | 2% | 6% | 4% |
| Urogenital | 54% | 63% | 28% |
| Breast Pain | 25% | 31% | 7% |
| Dysmenorrhea | 20% | 21% | 5% |
| Leukorrhea | 5% | 5% | 3% |
| Menstrual Disorder | 6% | 12% | 2% |
| Papanicolaou Smear Suspicious | 8% | 4% | 5% |
| Vaginitis | 6% | 13% | 5% |
| ENDOMETRIAL HYPERPLASIA STUDIES | |||
| CombiPatch | CombiPatch | Vivelle | |
| Body as a Whole | 61% | 60% | 59% |
| Abdominal Pain | 12% | 14% | 16% |
| Accidental Injury | 10% | 11% | 8% |
| Asthenia | 10% | 13% | 11% |
| Back Pain | 15% | 14% | 13% |
| Flu Syndrome | 14% | 10% | 7% |
| Headache | 25% | 17% | 21% |
| Infection | 5% | 3% | 3% |
| Pain | 19% | 15% | 13% |
| Digestive | 42% | 32% | 31% |
| Constipation | 2% | 5% | 3% |
| Diarrhea | 14% | 9% | 7% |
| Dyspepsia | 8% | 6% | 5% |
| Flatulence | 7% | 5% | 6% |
| Nausea | 8% | 12% | 11% |
| Tooth Disorder | 6% | 4% | 1% |
| Metabolic and Nutritional Disorders | 12% | 13% | 11% |
| Peripheral Edema | 6% | 6% | 5% |
| Musculoskeletal | 17% | 17% | 15% |
| Arthralgia | 6% | 6% | 5% |
| Nervous | 33% | 30% | 28% |
| Depression | 8% | 9% | 8% |
| Dizziness | 6% | 7% | 5% |
| Insomnia | 8% | 6% | 4% |
| Nervousness | 5% | 6% | 3% |
| Respiratory | 45% | 43% | 40% |
| Bronchitis | 5% | 3% | 4% |
| Pharyngitis | 9% | 9% | 8% |
| Respiratory Disorder | 13% | 9% | 13% |
| Rhinitis | 19% | 22% | 17% |
| Sinusitis | 10% | 12% | 12% |
| Skin and Appendages | 38% | 37% | 31% |
| Acne | 4% | 5% | 4% |
| Application Site Reaction* | 20% | 23% | 17% |
| Rash | 6% | 5% | 3% |
| Urogenital | 71% | 79% | 74% |
| Breast Enlargement | 2% | 7% | 2% |
| Breast Pain | 34% | 48% | 40% |
| Dysmenorrhea | 30% | 31% | 19% |
| Leukorrhea | 10% | 8% | 9% |
| Menorrhagia | 2% | 5% | 9% |
| Menstrual Disorder | 17% | 19% | 14% |
| Vaginal Hemorrhage | 3% | 6% | 12% |
| Vaginitis | 9% | 13% | 13% |
What should I look out for while using CombiPatch (estradiol/norethindrone acetate transdermal system)?
CombiPatch is contraindicated in women with any of the following conditions:
See
What might happen if I take too much CombiPatch (estradiol/norethindrone acetate transdermal system)?
Overdosage of estrogen or estrogen plus progestin 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 CombiPatch therapy with institution of appropriate symptomatic care
How should I store and handle CombiPatch (estradiol/norethindrone acetate transdermal system)?
Store at room temperature 68°F to 77°F (20°C to 25°C); excursions permitted between 15°C and 30°C (59°F and 86°F). Do not store unpouched. Apply immediately upon removal from the protective pouch.Used transdermal systems still contain active hormone. To discard, fold the sticky side of the transdermal system together, place it in a sturdy child-proof container, and place this container in the trash. Used transdermal systems should not be flushed in the toilet.Store at room temperature 68°F to 77°F (20°C to 25°C); excursions permitted between 15°C and 30°C (59°F and 86°F). Do not store unpouched. Apply immediately upon removal from the protective pouch.Used transdermal systems still contain active hormone. To discard, fold the sticky side of the transdermal system together, place it in a sturdy child-proof container, and place this container in the trash. Used transdermal systems should not be flushed in the toilet.Store at room temperature 68°F to 77°F (20°C to 25°C); excursions permitted between 15°C and 30°C (59°F and 86°F). Do not store unpouched. Apply immediately upon removal from the protective pouch.Used transdermal systems still contain active hormone. To discard, fold the sticky side of the transdermal system together, place it in a sturdy child-proof container, and place this container in the trash. Used transdermal systems should not be flushed in the toilet.CombiPatch estradiol/NETA transdermal delivery system is available in:Storage ConditionsPrior to dispensing to the patient, store refrigerated 2°C to 8°C (36°F to 46°F). After dispensing to the patient, CombiPatch can be stored at room temperature between 66°F to 77°F (20°C to 25°C) for up to 6 months. When CombiPatch is dispensed to the patient, place an expiration date on the label. The date should not exceed either 6 months from the date of sale or the expiration date, whichever comes first.Store the systems in the foil pouch.Do not store the system in areas where extreme temperatures can occur.Keep this and all medicines out of the reach of children.Vivelle® is a registered trademark of Novartis Corporation. & Vivelle-Dot is a registered trademark of Novartis AG.CombiPatch estradiol/NETA transdermal delivery system is available in:Storage ConditionsPrior to dispensing to the patient, store refrigerated 2°C to 8°C (36°F to 46°F). After dispensing to the patient, CombiPatch can be stored at room temperature between 66°F to 77°F (20°C to 25°C) for up to 6 months. When CombiPatch is dispensed to the patient, place an expiration date on the label. The date should not exceed either 6 months from the date of sale or the expiration date, whichever comes first.Store the systems in the foil pouch.Do not store the system in areas where extreme temperatures can occur.Keep this and all medicines out of the reach of children.Vivelle® is a registered trademark of Novartis Corporation. & Vivelle-Dot is a registered trademark of Novartis AG.CombiPatch estradiol/NETA transdermal delivery system is available in:Storage ConditionsPrior to dispensing to the patient, store refrigerated 2°C to 8°C (36°F to 46°F). After dispensing to the patient, CombiPatch can be stored at room temperature between 66°F to 77°F (20°C to 25°C) for up to 6 months. When CombiPatch is dispensed to the patient, place an expiration date on the label. The date should not exceed either 6 months from the date of sale or the expiration date, whichever comes first.Store the systems in the foil pouch.Do not store the system in areas where extreme temperatures can occur.Keep this and all medicines out of the reach of children.Vivelle® is a registered trademark of Novartis Corporation. & Vivelle-Dot is a registered trademark of Novartis AG.CombiPatch estradiol/NETA transdermal delivery system is available in:Storage ConditionsPrior to dispensing to the patient, store refrigerated 2°C to 8°C (36°F to 46°F). After dispensing to the patient, CombiPatch can be stored at room temperature between 66°F to 77°F (20°C to 25°C) for up to 6 months. When CombiPatch is dispensed to the patient, place an expiration date on the label. The date should not exceed either 6 months from the date of sale or the expiration date, whichever comes first.Store the systems in the foil pouch.Do not store the system in areas where extreme temperatures can occur.Keep this and all medicines out of the reach of children.Vivelle® is a registered trademark of Novartis Corporation. & Vivelle-Dot is a registered trademark of Novartis AG.CombiPatch estradiol/NETA transdermal delivery system is available in:Storage ConditionsPrior to dispensing to the patient, store refrigerated 2°C to 8°C (36°F to 46°F). After dispensing to the patient, CombiPatch can be stored at room temperature between 66°F to 77°F (20°C to 25°C) for up to 6 months. When CombiPatch is dispensed to the patient, place an expiration date on the label. The date should not exceed either 6 months from the date of sale or the expiration date, whichever comes first.Store the systems in the foil pouch.Do not store the system in areas where extreme temperatures can occur.Keep this and all medicines out of the reach of children.Vivelle® is a registered trademark of Novartis Corporation. & Vivelle-Dot is a registered trademark of Novartis AG.CombiPatch estradiol/NETA transdermal delivery system is available in:Storage ConditionsPrior to dispensing to the patient, store refrigerated 2°C to 8°C (36°F to 46°F). After dispensing to the patient, CombiPatch can be stored at room temperature between 66°F to 77°F (20°C to 25°C) for up to 6 months. When CombiPatch is dispensed to the patient, place an expiration date on the label. The date should not exceed either 6 months from the date of sale or the expiration date, whichever comes first.Store the systems in the foil pouch.Do not store the system in areas where extreme temperatures can occur.Keep this and all medicines out of the reach of children.Vivelle® is a registered trademark of Novartis Corporation. & Vivelle-Dot is a registered trademark of Novartis AG.CombiPatch estradiol/NETA transdermal delivery system is available in:Storage ConditionsPrior to dispensing to the patient, store refrigerated 2°C to 8°C (36°F to 46°F). After dispensing to the patient, CombiPatch can be stored at room temperature between 66°F to 77°F (20°C to 25°C) for up to 6 months. When CombiPatch is dispensed to the patient, place an expiration date on the label. The date should not exceed either 6 months from the date of sale or the expiration date, whichever comes first.Store the systems in the foil pouch.Do not store the system in areas where extreme temperatures can occur.Keep this and all medicines out of the reach of children.Vivelle® is a registered trademark of Novartis Corporation. & Vivelle-Dot is a registered trademark of Novartis AG.
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
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 in the 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, 2 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.
Non-Clinical Toxicology
CombiPatch is contraindicated in women with any of the following conditions:See
When tamoxifen is used in combination with coumarin-type anticoagulants, a significant increase in anticoagulant effect may occur. Where such coadministration exists, careful monitoring of the patient's prothrombin time is recommended.
In the NSABP P-1 trial, women who required coumarin-type anticoagulants for any reason were ineligible for participation in the trial (see ).
There is an increased risk of thromboembolic events occurring when cytotoxic agents are used in combination with tamoxifen.
Tamoxifen reduced letrozole plasma concentrations by 37%. The effect of tamoxifen on metabolism and excretion of other antineoplastic drugs, such as cyclophosphamide and other drugs that require mixed function oxidases for activation, is not known. Tamoxifen and N-desmethyl tamoxifen plasma concentrations have been shown to be reduced when coadministered with rifampin or aminoglutethimide. Induction of CYP3A4-mediated metabolism is considered to be the mechanism by which these reductions occur; other CYP3A4 inducing agents have not been studied to confirm this effect.
One patient receiving tamoxifen with concomitant phenobarbital exhibited a steady-state serum level of tamoxifen lower than that observed for other patients (i.e., 26 ng/mL vs. mean value of 122 ng/mL). However, the clinical significance of this finding is not known. Rifampin induced the metabolism of tamoxifen and significantly reduced the plasma concentrations of tamoxifen in 10 patients. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not tamoxifen.
Concomitant bromocriptine therapy has been shown to elevate serum tamoxifen and N-desmethyl tamoxifen.
Based on clinical and pharmacokinetic results from the anastrozole adjuvant trial, tamoxifen citrate should not be administered with anastrozole (see ).
1. Addition of a Progestin when a Woman has not had a Hysterectomy
Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.
There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.
2. Elevated Blood Pressure
In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen.
3. Hypertriglyceridemia
In women with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs.
4. Hepatic Impairment and/or Past History of Cholestatic Jaundice
Although transdermally administered estrogen therapy avoids first-pass hepatic metabolism, estrogens may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued.
5. Hypothyroidism
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T and T serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.
6. Fluid Retention
Estrogens plus progestins may cause some degree of fluid retention. Women with conditions which might be influenced by this factor, such as cardiac or renal impairment warrant careful observation when estrogens plus progestins are prescribed.
7. Hypocalcemia
Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.
8. Exacerbation of Endometriosis
A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.
9. Exacerbation of Other Conditions
Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.
See , , and .
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.
Postmarketing Experience
The following additional adverse reactions have been identified during post-approval use of CombiPatch. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Genitourinary System
Endometrial hyperplasia, endocervical polyp, uterine leiomyomata, fallopian tube cyst, uterine spasms.
Breast
Breast cancer.
Cardiovascular
Hypertension, varicose veins.
Gastrointestinal
Jaundice cholestatic, cholelithiasis, gall bladder disorder, transaminases increased.
Skin
Skin discoloration.
Central Nervous System
Affect lability, libido disorder, migraine, vertigo, paresthesia.
Miscellaneous
Angioedema, hypersensitivity, weight increased.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
While we update our database periodically, we cannot guarantee it is always updated to the latest version.
Review
Read user comments about the side effects, benefits, and effectiveness of losartan oral.
Overall User Ratings
516Total User Reviews
User Reviews
Learn about
User Reviews
Professional
Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
Tips
Interactions
Interactions
A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).