Composición:
Usado en tratamiento:
Revisión médica por Oliinyk Elizabeth Ivanovna Última actualización de farmacia el 14.03.2022
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Los 20 mejores medicamentos con los mismos ingredientes:
Tratamiento de síntomas vasomotores moderados a severos debido a la menopausia
Tratamiento de síntomas moderados a severos de vulvar y atrofia vaginal debido a la menopausia
Limitación de uso
Cuando se prescribe únicamente para el tratamiento de síntomas moderados a severos de atrofia vulvar y vaginal debido a la menopausia, se deben considerar los productos vaginales tópicos.
Tratamiento del hipoestrogenismo debido al hipogonadismo, la castración o la insuficiencia ovárica primaria
Prevención de la osteoporosis posmenopáusica
Limitación de uso
Al prescribir únicamente para la prevención de la osteoporosis posmenopáusica, la terapia solo debe considerarse para mujeres con riesgo significativo de osteoporosis y medicamentos sin estrógeno.
Tratamiento de síntomas vasomotores moderados a severos debido a la menopausia
En general, cuando se prescribe estrógeno para una mujer posmenopáusica con útero, también se debe considerar que una progestina reduce el riesgo de cáncer de endometrio. Una mujer sin útero no necesita progestina. En algunos casos, sin embargo, las mujeres histerectomizadas con antecedentes de endometriosis pueden necesitar una progestina.
El uso de estrógeno solo, o en combinación con una progestina, debe realizarse con la dosis efectiva más baja y durante la menor duración, de acuerdo con los objetivos y riesgos del tratamiento para la mujer individual. Las mujeres posmenopáusicas deben reevaluarse periódicamente según sea clínicamente apropiado para determinar si el tratamiento aún es necesario.
Tratamiento de síntomas vasomotores moderados a severos debido a la menopausia
Comience la terapia con 0.025 mg por día aplicado a la piel una vez por semana. La terapia debe iniciarse con la dosis efectiva más baja y la duración más corta consistente con los objetivos del tratamiento. Los intentos de reducir o suspender el medicamento deben realizarse a intervalos de 3 a 6 meses.
Tratamiento de síntomas moderados a severos de vulvar y atrofia vaginal debido a la menopausia
Comience la terapia con 0.025 mg por día aplicado a la piel una vez por semana. La terapia debe iniciarse con la dosis efectiva más baja y la duración más corta consistente con los objetivos del tratamiento. Los intentos de reducir o suspender el medicamento deben realizarse a intervalos de 3 a 6 meses.
Tratamiento del hipoestrogenismo debido al hipogonadismo, la castración o la insuficiencia ovárica primaria
Comience la terapia con 0.025 mg por día aplicado a la piel una vez por semana. La dosis debe ajustarse según sea necesario para controlar los síntomas. Las respuestas clínicas (alivio de los síntomas) a la dosis efectiva más baja deben ser la guía para establecer la administración del sistema transdérmico Lindisc, especialmente en mujeres con un útero intacto.
Prevención de la osteoporosis posmenopáusica
Comience la terapia con 0.025 mg por día aplicado a la piel una vez por semana.
Aplicación del sistema transdérmico Lindisc
Selección del sitio
- El lado adhesivo de Lindisc debe colocarse en un área limpia y seca de la parte inferior del abdomen o en el cuadrante superior de la nalga.
- Lindisc no debe aplicarse a los senos o cerca de ellos.
- Los sitios de aplicación deben rotarse, con un intervalo de al menos 1 semana permitido entre las aplicaciones al mismo sitio.
- El área seleccionada no debe ser grasa, dañada o irritada. Se debe evitar la cintura, ya que la ropa ajustada puede eliminar el sistema transdérmico.
- También se debe evitar la aplicación a áreas donde sentarse desalojaría a Lindisc.
Aplicación
- Lindisc debe aplicarse inmediatamente después de abrir la bolsa y quitar el revestimiento protector.
- Lindisc debe presionarse firmemente en su lugar con los dedos durante al menos 10 segundos, asegurándose de que haya un buen contacto, especialmente alrededor de los bordes.
- Si el sistema se levanta, aplique presión para mantener la adhesión.
- En el caso de que un sistema se caiga, vuelva a aplicarlo a una ubicación diferente. Si el sistema no se puede volver a aplicar, se debe aplicar un nuevo sistema por el resto del intervalo de dosificación de 7 días.
- Solo se debe usar un sistema en cualquier momento durante el intervalo de dosificación de 7 días.
- No se ha estudiado nadar, bañarse o usar una sauna mientras se usa Lindisc, y estas actividades pueden disminuir la adhesión del sistema y la entrega de estradiol.
Eliminación del sistema transdérmico Lindisc
- La eliminación de Lindisc debe realizarse con cuidado y lentamente para evitar la irritación de la piel.
- Si queda algún adhesivo sobre la piel después de retirar el sistema Lindisc, permita que el área se seque durante 15 minutos. Luego, frotar suavemente el área con una crema o loción a base de aceite debe eliminar el residuo adhesivo.
- Los parches usados aún contienen algunas hormonas activas. Cada parche debe doblarse cuidadosamente por la mitad para que se pegue a sí mismo antes de tirarlo.
En general, cuando se prescribe estrógeno para una mujer posmenopáusica con útero, también se debe considerar que una progestina reduce el riesgo de cáncer de endometrio.
Una mujer sin útero no necesita progestina. En algunos casos, sin embargo, las mujeres histerectomizadas con antecedentes de endometriosis pueden necesitar una progestina.
El uso de estrógeno solo, o en combinación con una progestina, debe realizarse con la dosis efectiva más baja y durante la menor duración, de acuerdo con los objetivos y riesgos del tratamiento para la mujer individual. Las mujeres posmenopáusicas deben ser reevaluadas periódicamente según sea clínicamente apropiado para determinar si el tratamiento aún es necesario.
Tratamiento de síntomas vasomotores moderados a severos debido a la menopausia
Lindisc debe aplicarse una vez al día sobre la piel de la parte superior derecha o izquierda del muslo. El área de superficie de aplicación debe ser de aproximadamente 5 por 7 pulgadas (aproximadamente del tamaño de dos huellas de palma). Todo el contenido de un paquete de dosis unitarias debe aplicarse cada día. Para evitar irritación potencial de la piel, Lindisc debe aplicarse en la parte superior derecha o izquierda del muslo en días alternos. Lindisc no debe aplicarse en la cara, los senos o la piel irritada o dentro o alrededor de la vagina. Después de la aplicación, se debe dejar que el gel se seque antes de vestirse. El sitio de aplicación no debe lavarse dentro de 1 hora después de aplicar Lindisc. Se debe evitar el contacto del gel con los ojos. Las manos deben lavarse después de la aplicación.
En general, las mujeres deben comenzar con la dosis de 0.25 gramos.
Lindisc está contraindicado en mujeres con cualquiera de las siguientes condiciones:
- Sangrado genital anormal no diagnosticado
- Conocido, sospechoso o antecedentes de cáncer de seno
- Neoplasia dependiente de estrógenos conocida o sospechada
- DVT activo, PE o un historial de estas condiciones
- Enfermedad tromboembólica arterial activa (por ejemplo, accidente cerebrovascular y IM), o antecedentes de estas afecciones
- Reacción anafiláctica conocida o angioedema con Lindisc
- Insuficiencia hepática o enfermedad conocida
- Proteína C conocida, proteína S o deficiencia de antitrombina u otros trastornos trombofílicos conocidos
- Embarazo conocido o sospechoso
Lindisc no debe usarse en mujeres con cualquiera de las siguientes condiciones:
- Sangrado genital anormal no diagnosticado
- Conocido, sospechoso o antecedentes de cáncer de seno
- Neoplasia dependiente de estrógenos conocida o sospechada
- DVT activo, PE o historial de estas condiciones
- Enfermedad tromboembólica arterial activa (por ejemplo, accidente cerebrovascular y IM), o antecedentes de estas afecciones
- Reacción anafiláctica conocida o angioedema a Lindisc
- Insuficiencia hepática o enfermedad conocida
- Proteína C conocida, proteína S o deficiencia de antitrombina u otros trastornos trombofílicos conocidos
- Embarazo conocido o sospechoso
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Cardiovascular Disorders
An increased risk of stroke and DVT has been reported with estrogen-alone therapy. An increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin 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.
Stroke
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). 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).1
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). The increase in risk was demonstrated after the first year and persisted.1 Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.
Coronary Heart Disease
In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo2.
Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years).1
In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events 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).1 An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5.
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 coronary heart disease. 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. A total of 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 HERS, HERS II, and overall.
Venous Thromboembolism
In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) was increased for women receiving daily CE (0.625 mg)-alone compared to 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 years3. Should a VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately.
In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving 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 persisted4. Should a VTE occur or be suspected, estrogen plus progestin 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.
Malignant Neoplasms
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 unopposed estrogen users 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 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. 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 in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
Breast Cancer
The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the WHI substudy of daily CE (0.625 mg)-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]5.
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 two groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups6.
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 generally 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.
Ovarian Cancer
The WHI estrogen plus progestin substudy reported a statistically non-significant 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, 0.77-3.24). The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years.7 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 to 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.
Probable Dementia
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, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years8.
In the WHIMS estrogen plus progestin ancillary study, a population of 4,532 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 of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years8.
When data from the two 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, 1.19-2.60). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8.
Gallbladder Disease
A 2-to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.
Hypercalcemia
Estrogen administration may lead to severe hypercalcemia in women 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.
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.
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.
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 estrogens on blood pressure was not seen.
Hypertriglyceridemia
In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs.
Hepatic Impairment And/Or Past History Of Cholestatic Jaundice
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.
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 T4 and T3 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.
Fluid Retention
Estrogens may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as a cardiac or renal impairment, warrant careful observation when estrogen-alone is prescribed.
Hypocalcemia
Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.
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.
Hereditary Angioedema
Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.
Exacerbation Of Other Conditions
Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.
Laboratory Tests
Serum follicle stimulating hormone (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.
Drug-Laboratory Test Interactions
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 antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
Increased TBG levels leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.
Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total 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-l-antitrypsin, ceruloplasmin).
Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, and increased triglyceride levels.
Impaired glucose tolerance.
Patient Counseling Information
See FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use)
Vaginal Bleeding
Inform postmenopausal women of the importance of reporting vaginal bleeding to their healthcare provider as soon as possible.
Possible Serious Adverse Reactions With Estrogen-Alone Therapy
Inform postmenopausal women of possible serious adverse reactions of estrogen-alone therapy including cardiovascular disorders, malignant neoplasms, and probable dementia.
Possible Less Serious But Common Adverse Reactions With Estrogen-Alone Therapy
Inform postmenopausal women of possible less serious but common adverse reactions of estrogen-alone therapy such as headache, breast pain and tenderness, nausea and vomiting.
Nonclinical Toxicology
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.
Use In Specific Populations
Pregnancy
Lindisc should not be used during pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as oral contraceptives inadvertently during early pregnancy.
Nursing Mothers
Lindisc 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 have been identified in the breast milk of women receiving estrogen therapy. Caution should be exercised when the Lindisc transdermal system is administered to a nursing woman.
Pediatric Use
Lindisc is not indicated in children. Clinical studies have not been conducted in the pediatric population.
Geriatric Use
There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Lindisc to determine whether those over 65 years of age differ from younger subjects in their response to Lindisc.
The Women’s Health Initiative Studies
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.
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-alone or estrogen plus progestin when compared to placebo.
Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8.
Renal Impairment
In postmenopausal women with end stage renal disease (ESRD) receiving maintenance hemodialysis, total estradiol serum levels are higher than in normal subjects at baseline and following oral doses of estradiol. Therefore, conventional transdermal estradiol doses used in individuals with normal renal function may be excessive for postmenopausal women with ESRD receiving maintenance hemodialysis.
Hepatic Impairment
Estrogens may be poorly metabolized in patients with impaired liver function and should be administered with caution.
REFERENCES
1. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA. 2007;297:1465-1477.
2. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med. 2006;166:357-365.
3. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med. 2006;166:772-780.
4. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004;292:1573-1580.
5. Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women With Hysterectomy. JAMA. 2006;295:1647-1657.
6. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003;289:3234-3253.
7. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures. JAMA. 2003;290:1739-1748.
8. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:2947-2958.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Cardiovascular Disorders
An increased risk of stroke and DVT has been reported with estrogen-alone therapy. An increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin 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.
Stroke
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). 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).1
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). The increase in risk was demonstrated after the first year and persisted.1 Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.
Coronary Heart Disease
In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo2.
Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE [0.625 mg] alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years).1
In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events 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).1 An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5.
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 coronary heart disease. 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 and 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 HERS, HERS II, and overall.
Venous Thromboembolism
In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) was increased for women receiving daily CE (0.625 mg)-alone compared to 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 years3. Should a VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately.
In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving 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 persisted4. Should a VTE occur or be suspected, estrogen plus progestin 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.
Malignant Neoplasms
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 unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risk 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 postmenopausal estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
Breast Cancer
The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the WHI substudy of daily CE (0.625 mg)-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]5.
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 two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups6.
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 generally 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.
Ovarian Cancer
The WHI estrogen plus progestin substudy reported a statistically non-significant 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, 0.77–3.24]. The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years.7
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 1.271.48), 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.
Probable Dementia
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, 0.83–2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years8.
In the WHIMS estrogen plus progestin ancillary study, a population of 4,532 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 of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21–3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years8.
When data from the two 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, 1.19–2.60). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8.
Gallbladder Disease
A 2-to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.
Hypercalcemia
Estrogen administration may lead to severe hypercalcemia in women 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.
Visual Abnormalities
Retinal vascular thrombosis has been reported in patients 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.
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.
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 estrogens on blood pressure was not seen.
Hypertriglyceridemia
In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs.
Hepatic Impairment And/Or Past History Of Cholestatic Jaundice
Estrogens may be poorly metabolized in patients 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.
Hypothyroidism
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG bymaking more thyroid hormone, thus maintaining free T4 and T3 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 to maintain their free thyroid hormone levels in an acceptable range.
Fluid Retention
Estrogens may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as a cardiac or renal impairment, warrant careful observation when estrogen-alone is prescribed.
Hypocalcemia
Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.
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.
Hereditary Angioedema
Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.
Exacerbation Of Other Conditions
Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.
Photosensitivity/Photoallergy
The effects of direct sun exposure to Lindisc application sites have not been evaluated in clinical trials.
Application Of Sunscreen And Topical Solutions
Studies conducted using other approved topical estrogen gel products have shown that sunscreens have the potential for changing the systemic exposure of topically applied estrogen gels.
The effect of sunscreens and other topical lotions on the systemic exposure of Lindisc has not been evaluated in clinical trials.
Flammability Of Alcohol-Based Gels
Alcohol based gels are flammable. Avoid fire, flame, or smoking until the gel has dried. Occlusion of the area where the topical drug product is applied with clothing or other barriers is not recommended until the gel is completely dried.
Potential For Estradiol Transfer And Effects Of Washing
There is a potential for drug transfer from one individual to the other following physical contact of Lindisc application sites. In a study to evaluate transferability to males from their female contacts, there was some elevation of estradiol levels over baseline in the male subjects; however, the degree of transferability in this study was inconclusive. Patients are advised to avoid skin contact with other subjects until the gel is completely dried. The site of application should be covered (clothed) after drying.
Washing the application site with soap and water 1 hour after application resulted in a 30 to 38 percent decrease in the mean total 24-hour exposure to estradiol. Therefore, patients should refrain from washing the application site for at least one hour after application.
Laboratory Tests
Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms.
Drug -Laboratory Test Interactions
Increased thyroid binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels, as measured by protein-bound iodine (PBI),T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.
Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total 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-lantitrypsin, ceruloplasmin).
Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglyceride levels.
Impaired glucose tolerance.
Patient Counseling Information
See FDA-Approved Patient Labeling.
Vaginal Bleeding
Inform postmenopausal women of the importance of reporting vaginal bleeding to their healthcare provider as soon as possible.
Possible Serious Adverse Reactions With Estrogen-Alone Therapy
Inform postmenopausal women of possible serious adverse reactions of estrogen-alone therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia.
Possible Less Serious But More Common Adverse Reactions With Estrogen-Alone Therapy
Inform postmenopausal women of possible less serious but common adverse reactions of estrogen-alone therapy such as headaches, breast pain and tenderness, nausea and vomiting.
Instructions For Use
- Lindisc should be applied once a day, around the same time each day
- Apply Lindisc to clean, dry, and unbroken (without cuts or scrapes) skin. If you take a bath or shower, be sure to apply your Lindisc after your skin is dry. The application site should be completely dry before dressing or swimming
- Apply Lindisc to either your left or right upper thigh. Change between your left and right upper thigh each day to help prevent skin irritation
TO APPLY:
Step 1: Wash and dry your hands thoroughly.
Step 2: Sit in a comfortable position.
Step 3: Cut or tear the Lindisc packet as shown in Figure A.
Figure A
Step 4: Using your thumb and index finger, squeeze the entire contents of the packet onto the skin of the upper thigh as shown in Figure B.
Figure B
Step 5: Gently spread the gel in a thin layer on your upper thigh over an area of about 5 by 7 inches, or two palm prints as shown in Figure C. It is not necessary to massage or rub in Lindisc.
Figure C
Step 6: Allow the gel to dry completely before dressing.
Step 7: Dispose of the empty Lindisc packet in the trash.
Step 8: Wash your hands with soap and water immediately after applying Lindisc to remove any remaining gel and reduce the chance of transferring Lindisc to other people.
Nonclinical Toxicology
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.
Use In Specific Populations
Pregnancy
Lindisc should not be used during pregnancy. 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.
Nursing Mothers
Lindisc 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 have been identified in the breast milk of women receiving estrogen therapy. Caution should be exercised when Lindisc is administered to a nursing woman.
Pediatric Use
Lindisc is not indicated in children. Clinical studies have not been conducted in the pediatric population.
Geriatric Use
There have not been sufficient numbers of geriatric women involved in studies utilizing Lindisc to determine whether those over 65 years of age differ from younger subjects in their response to Lindisc.
The Women's Health Initiative Studies
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.
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.
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-alone or estrogen plus progestin when compared to placebo.
Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8.
Renal Impairment
The effect of renal impairment on the pharmacokinetics of Lindisc has not been studied.
Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of Lindisc has not been studied.
REFERENCES
1. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA.2007;297:1465–1477.
2. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med. 2006;166:357–365.
3. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus.Arch Int Med. 2006;166:772–780.
4. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004;292:1573–1580.
5. Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women With Hysterectomy. JAMA. 2006;295:1647–1657.
6. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003;289:3234–3253.
7. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures. JAMA. 2003;290:1739–1748.
8. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:2947–2958.
Lindisc tiene una influencia nula o insignificante sobre la capacidad para conducir y utilizar máquinas.
Las siguientes reacciones adversas graves se analizan en otra parte del etiquetado:
- Trastornos cardiovasculares
- Neoplasias malignas
Experiencia en ensayos clínicos
Debido a que los ensayos clínicos se llevan a cabo en condiciones muy variables, las tasas de reacciones adversas observadas en los ensayos clínicos de un medicamento no se pueden comparar directamente con las tasas en los ensayos clínicos de otro medicamento y pueden no reflejar las tasas observadas en la práctica.
Los datos descritos a continuación reflejan datos agrupados de 5 ensayos clínicos de Lindisc. Un total de 614 mujeres estuvieron expuestas a Lindisc durante 3 meses (193 mujeres a 0.025 mg por día, 201 mujeres a 0.05 mg por día, 194 mujeres a 0.1 mg por día) en ensayos aleatorios doble ciego de eficacia clínica versus placebo y comparador activo. Todas las mujeres eran posmenopáusicas, tenían un nivel de estradiol en suero de menos de 20 pg / ml, y un mínimo de cinco sofocos moderados a severos por semana o un mínimo de 15 sofocos por semana de cualquier gravedad al inicio del estudio. En esta tabla se incluyen 25 mujeres histerectomizadas posmenopáusicas adicionales expuestas a Lindisc 0.025 mg por día durante 6 a 24 meses (N = 16 a los 24 meses) en un estudio aleatorizado, doble ciego, controlado con placebo de Lindisc para la prevención de la osteoporosis.
Tabla 1: Reacciones adversas emergentes del tratamiento informadas a una frecuencia de ≥ 5 por ciento y más frecuentes en mujeres que reciben Lindisc
Sistema del cuerpo Reacciones adversas | Lindisc | Placeboc (N = 72) | ||
0.025 mg / díaa (N = 219) | 0.05 mg / díab (N = 201) | 0.1 mg / díab (N = 194) | ||
El cuerpo como un todo | 21% | 39% | 37% | 29% |
Dolor de cabeza | 5% | 18% | 13% | 10% |
Dolor | 1% | 8% | 11% | 7% |
Dolor de espalda | 4% | 8% | 9% | 6% |
Edema | 0.5% | 13% | 10% | 6% |
Sistema digestivo | 9% | 21% | 29% | 18% |
Dolor abdominal | 0% | 11% | dieciséis% | 8% |
Náuseas | 1% | 5% | 6% | 3% |
Flatulencia | 1% | 3% | 7% | 1% |
Sistema musculoesquelético | 7% | 9% | 11% | 4% |
Artralgia | 1% | 5% | 5% | 3% |
Sistema nervioso | 13% | 10% | 11% | 1% |
Depresión | 1% | 5% | 8% | 0% |
Sistema urogenital | 12% | 18% | 41% | 11% |
Dolor en los senos | 5% | 8% | 29% | 4% |
Leukorrhea | 1% | 6% | 7% | 1% |
Sistema respiratorio | 15% | 26% | 29% | 14% |
URTI | 6% | 17% | 17% | 8% |
Faringitis | 0.5% | 3% | 7% | 3% |
Sinusitis | 4% | 4% | 5% | 3% |
Rinitis | 2% | 4% | 6% | 1% |
Piel y apéndices | 19% | 12% | 12% | 15% |
Prurito | 0.5% | 6% | 3% | 6% |
a) Reacciones adversas que ocurren a una tasa de ≥ 5 por ciento en ensayos de Lindisc de eficacia clínica versus placebo y comparador activo; y ensayo de Lindisc versus placebo para la prevención de la osteoporosis b) Reacciones adversas que ocurren a una tasa de ≥ 5 por ciento en ensayos de Lindisc de eficacia clínica versus placebo y comparador activo versus c) Reacciones adversas que ocurren en el grupo placebo en el ensayo Lindisc de eficacia clínica versus placebo |
Experiencia de postmarketing
Se han identificado las siguientes reacciones adversas durante el uso posterior a la aprobación del sistema transdérmico Lindisc. Debido a que estas reacciones se informan voluntariamente de una población de tamaño incierto, no siempre es posible estimar de manera confiable su frecuencia o establecer una relación causal con la exposición a drogas.
Sistema genitourinario
Cambios en el patrón de sangrado, dolor pélvico
Pecho
Cáncer de mama, dolor de mama, sensibilidad de los senos
Cardiovascular
Cambios en la presión arterial, palpitaciones, sofocos
Gastrointestinal
Vómitos, dolor abdominal, distensión abdominal, náuseas
Piel
Alopecia, hiperhidrosis, sudores nocturnos, urticaria, erupción cutánea
Ojos
Alteraciones visuales, intolerancia a las lentes de contacto
Sistema nervioso central
Depresión, migraña, parestesia, mareos, ansiedad, irritabilidad, cambios de humor, nerviosismo, insomnio, dolor de cabeza
Varios
Fatiga, síntomas menopáusicos, aumento de peso, reacción en el lugar de aplicación, reacciones anafilácticas
Las siguientes reacciones adversas graves se analizan en otra parte del etiquetado:
- Trastornos cardiovasculares.
- Neoplasias malignas.
Experiencia en ensayos clínicos
Debido a que los ensayos clínicos se llevan a cabo en condiciones muy variables, las tasas de reacciones adversas observadas en los ensayos clínicos de un medicamento no se pueden comparar directamente con las tasas en los ensayos clínicos de otro medicamento y pueden no reflejar las tasas observadas en la práctica.
Lindisc se estudió a dosis de 0.25, 0.5 y 1.0 gramos por día en un estudio de 12 semanas, doble ciego, controlado con placebo que incluyó un total de 495 mujeres posmenopáusicas (86.5 por ciento caucásicas). Los eventos adversos que ocurrieron a una tasa superior al 5 por ciento en cualquiera de los grupos de tratamiento se resumen en la Tabla 1.
Tabla 1: Nuber (%) de sujetos con reacciones adversas comunes * en un estudio controlado por placebo de 12 semanas de Lindisc
SISTEMA ORGAN CLASE Término preferido | Lindisc | Placebo N = 125 n (%) | ||
0.25 g / día N = 122 n (%) | 0.5 g / día N = 123 n (%) | 1.0 g / día N = 125 n (%) | ||
INFECCIONES E INFESTACIONES | ||||
Nasofaringitis | 7 (5.7) | 5 (4.1) | 6 (4.8) | 5 (4.0) |
Infección del tracto respiratorio superior | 7 (5.7) | 3 (2.4) | 2 (1.6} | 2 (1.6) |
Micosis vaginal | 1 (0.8) | 3 (2.4) | 8 (6.4) | 4 (3.2) |
SISTEMA REPRODUCTIVO Y TRASTADORES DE MAMA | ||||
Sombrerería mamaria | 3 (2.5) | 7 (5.7) | 11 (8.8) | 2 (1.6) |
Metrorragia | 5 (4.1) | 7 (5.7) | 12 (9.6) | 2 (1.6) |
* Reacciones adversas informadas por> 5 por ciento de los pacientes en cualquier grupo de tratamiento. |
En un estudio de Lindisc controlado con placebo de 12 semanas, se observaron reacciones en el sitio de aplicación en <1 por ciento de los sujetos.
Experiencia de postmarketing
Se han identificado las siguientes reacciones adversas durante el uso posterior a la aprobación de Lindisc. Debido a que estas reacciones se informan voluntariamente de una población de tamaño incierto, no siempre es posible estimar de manera confiable su frecuencia o establecer una relación causal con la exposición a drogas.
Sistema genitourinario
Amenorrea, dismenorrea, quiste ovárico, flujo vaginal
Senos
Ginecomastia
Cardiovascular
Palpitaciones, extrasístoles ventriculares
Gastrointestinal
Flatulencia
Piel
Sarpullido pruriginoso, urticaria
Ojos
Oclusión venosa retiniana
Sistema nervioso central
Temblor
Varios
Artralgia, erupción cutánea en el lugar de aplicación, astenia, molestias en el pecho, fatiga, sensación anormal, aumento de la frecuencia cardíaca, insomnio, malestar, espasmos musculares, dolor en las extremidades, aumento de peso
Se han informado reacciones adversas posteriores a la comercialización en pacientes que reciben otras formas de terapia hormonal.
La sobredosis de estrógeno puede causar náuseas, vómitos, sensibilidad en los senos, dolor abdominal, somnolencia y fatiga, y hemorragia por abstinencia en las mujeres. El tratamiento de la sobredosis consiste en la interrupción de la terapia con Lindisc con la institución de una atención sintomática adecuada.
La sobredosis de estrógeno puede causar náuseas y vómitos, sensibilidad en los senos, dolor abdominal, somnolencia y fatiga, y puede producirse sangrado por abstinencia en las mujeres. El tratamiento de la sobredosis consiste en la interrupción de la terapia con Lindisc con la institución de una atención sintomática adecuada.
No hay datos farmacodinámicos para Lindisc.
Actualmente, no hay datos farmacodinámicos conocidos para Lindisc.
Absorción
La administración transdérmica de Lindisc produce concentraciones séricas medias de estradiol comparables a las producidas por mujeres premenopáusicas en la fase folicular temprana del ciclo ovulatorio. La farmacocinética del estradiol después de la aplicación del sistema transdérmico Lindisc se investigó en 197 mujeres posmenopáusicas sanas en seis estudios. En cinco de los estudios, se aplicó el sistema transdérmico Lindisc al abdomen, y en un sexto estudio, se comparó la aplicación a las nalgas y el abdomen.
El sistema de suministro transdérmico Lindisc libera continuamente estradiol que se transporta a través de la piel intacta, lo que lleva a niveles circulantes sostenidos de estradiol durante un período de tratamiento de 7 días. La disponibilidad sistémica de estradiol después de la administración transdérmica es aproximadamente 20 veces mayor que la de la administración oral. Esta diferencia se debe a la ausencia de metabolismo de primer paso cuando el estradiol viene dado por la ruta transdérmica.
En un estudio de biodisponibilidad, se estudió el Lindisc 6.5 cm² con el Lindisc 12.5 cm² como referencia. Los niveles medios de estradiol en suero de los dos tamaños se muestran en la Figura 1.
Figura 1: Concentraciones medias de suero 17β-estradiol versus perfil de tiempo después de la aplicación de un sistema transdérmico de 6.5 cm² y la aplicación de un sistema transdérmico Lindisc de 12.5 cm²
Se demostró la proporcionalidad de la dosis para el sistema transdérmico Lindisc de 6,5 cm² en comparación con el sistema transdérmico Lindisc de 12,5 cm² en un estudio cruzado de 2 semanas con un período de lavado de 1 semana entre los sistemas transdérmicos dos en 24 mujeres posmenopáusicas.
También se demostró la proporcionalidad de la dosis para el sistema transdérmico Lindisc (12.5 cm² y 25 cm²) en un estudio de 1 semana realizado en 54 mujeres posmenopáusicas. Los niveles medios en estado estacionario (Cavg) del estradiol durante la aplicación de Lindisc 25 cm² y 12.5 cm² en el abdomen fueron de aproximadamente 80 y 40 pg / ml, respectivamente.
En un estudio de aplicación múltiple de 3 semanas en 24 mujeres posmenopáusicas, El sistema transdérmico Lindisc de 25 cm² produjo concentraciones medias máximas de estradiol (Cmax) de aproximadamente 100 pg / ml. Valores de canal al final de cada intervalo de desgaste (Cmin) fueron aproximadamente 35 pg / ml. Se observaron curvas de suero casi idénticas cada semana, indicando poca o ninguna acumulación de estradiol en el cuerpo. Los niveles máximos y mínimos de estrona sérica fueron 60 y 40 pg / ml, respectivamente.
En un estudio cruzado aleatorizado de dosis única realizado para comparar el efecto del sitio de aplicación, 38 mujeres posmenopáusicas usaron un solo sistema transdérmico Lindisc de 25 cm² durante 1 semana en el abdomen y las nalgas. Los perfiles de concentración sérica de estradiol se muestran en la Figura 2. Los valores de Cmax y Cavg fueron, respectivamente, un 25 por ciento y un 17 por ciento más altos con la aplicación de glúteos que con la aplicación de abdomen.
Figura 2: Concentraciones de suero de estradiol medias observadas (± SE) durante una semana Aplicación del sistema transdérmico Lindisc (25 cm²) al abdomen y las nalgas de 38 mujeres posmenopáusicas
La Tabla 2 proporciona un resumen de los parámetros farmacocinéticos de estradiol determinados durante la evaluación del sistema transdérmico de Lindisc.
Tabla 2: Resumen farmacocinético (valores medios de estradiol)
Tasa de entrega de Lindisc | Superficie (cm²) | Sitio de aplicaciones | No. de sujetos | Dosificación | Cmax (pg / ml) | C min (pg / ml) | Cavg (pg / ml) |
0.025 | 6.5 | Abdomen | 24 | Soltero | 32 | 17 | 22 |
0.05 | 12.5 | Abdomen | 102) | Soltero | 71 | 29 | 41 |
0.1 | 25 | Abdomen | 139) | Soltero | 147) | 60 | 87 |
0.1 | 25 | Marimacho | 38 | Soltero | 174) | 71 | 106) |
La desviación estándar relativa de cada parámetro farmacocinético después de la aplicación al abdomen promedió el 50 por ciento, lo que indica la considerable variabilidad entre sujetos asociada con el suministro de fármacos transdérmicos. La desviación estándar relativa de cada parámetro farmacocinético después de la aplicación en la nalga fue menor que la posterior a la aplicación en el abdomen (por ejemplo, para Cmax 39 por ciento versus 62 por ciento, y para Cavg 35 por ciento versus 48 por ciento).
Distribución
La distribución de estrógenos exógenos es similar a la de los estrógenos endógenos. Los estrógenos se distribuyen ampliamente en el cuerpo y generalmente se encuentran en concentraciones más altas en los órganos diana de la hormona sexual. Los estrógenos circulan en la sangre en gran medida unidos a SHBG y albúmina.
Metabolismo
Los estrógenos exógenos se metabolizan de la misma manera que los estrógenos endógenos. Los estrógenos circulantes existen en un equilibrio dinámico de las interconversiones metabólicas. Estas transformaciones tienen lugar principalmente en el hígado. El estradiol se convierte reversiblemente en estrona, y ambos se pueden convertir en estriol, que es un metabolito urinario principal. Los estrógenos también sufren recirculación enterohepática a través de sulfato y conjugación de glucurónido en el hígado, secreción biliar de conjugados en el intestino e hidrólisis en el intestino seguido de reabsorción. En mujeres posmenopáusicas, existe una proporción significativa de los estrógenos circulantes como conjugados de sulfato, especialmente sulfato de estrona, que sirve como reservorio circulante para la formación de estrógenos más activos.
Excreción
El estradiol, la estrona y el estriol se excretan en la orina junto con los conjugados de glucurónido y sulfato.
Adhesión
Se realizó un estudio abierto de los potenciales de adhesión de los sistemas transdérmicos placebo que corresponden a los tamaños de 6.5 cm² y 12.5 cm² de Lindisc en 112 mujeres sanas de 45 a 75 años de edad. Cada mujer aplicó ambos sistemas transdérmicos semanalmente, en la parte superior del abdomen externo, durante 3 semanas consecutivas. Cabe señalar que la parte inferior del abdomen y el cuadrante superior de la nalga son los sitios de aplicación aprobados para Lindisc.
La evaluación de adhesión se realizó visualmente en los días 2, 4, 5, 6, 7 de cada semana de desgaste del sistema transdérmico. Se realizaron un total de 1.654 observaciones de adhesión para 333 sistemas transdérmicos de cada tamaño.
De estas observaciones, aproximadamente el 90 por ciento no mostró esencialmente elevación para los sistemas transdérmicos de 6.5 cm² y 12.5 cm². Del número total de sistemas transdérmicos aplicados, aproximadamente el 5 por ciento mostró un desprendimiento completo para cada tamaño. No se han estudiado los potenciales de adhesión de los tamaños de 18,75 cm² y 25 cm² de los sistemas transdérmicos (0,075 mg por día y 0,1 mg por día).
Absorción
El estradiol se difunde a través de la piel intacta y hacia la circulación sistémica mediante un proceso de absorción pasiva, siendo la difusión a través del estrato córneo el factor limitante de la velocidad.
En un estudio de dosis múltiples de 14 días, Fase 1, Lindisc demostró una farmacocinética de estradiol lineal y aproximadamente proporcional a la dosis en estado estacionario para AUC0-24 y Cmax después de una administración diaria de la piel del muslo superior derecho o izquierdo ( Tabla 2).
Tabla 2: Parámetros farmacocinéticos medios (% CV) para Estradiol (no corregidos para el valor inicial) el día 14 después de múltiples dosis diarias de Lindisc 0.1%
Parámetro (unidades) | Lindisc 0.25 g | Lindisc 0.5 g | Lindisc 1.0 g |
AUC0-24 (pg • h / mL) | 236 (94) | 504 (149) | 732 (81) |
Cmax (pg / ml) | 14,7 (84) | 28,4 (139) | 51,5 (86) |
Cavg (pg / ml) | 9.8 (92) | 21 (148) | 30,5 (81) |
tmax (h) | 16 (0,72) | 10 (0,72) | 8 (0,48) |
E2: relación E1 | 0,42 | 0.65 | 0.65 |
* Mediana (Mia Max). |
La concentración sérica de estradiol en estado estacionario se logra el día 12 después de la aplicación diaria de Lindisc en la piel de la parte superior del muslo. Los niveles medios de estradiol en suero (DE) después de una dosis diaria en el día 14 se muestran en la Figura 1.
Figura 1: Concentraciones medias (DE) de estradiol sérico (valores no corregidos para la línea de base) el día 14 después de múltiples dosis diarias de Lindisc 0.1%
No se ha evaluado el efecto de los protectores solares y otras lociones tópicas sobre la exposición sistémica de Lindisc. Los estudios realizados con productos aprobados por gel de estrógeno tópico han demostrado que los protectores solares tienen el potencial de cambiar la exposición sistémica de los geles de estrógeno aplicados tópicamente.
Distribución
La distribución de estrógenos exógenos es similar a la de los estrógenos endógenos. Los estrógenos se distribuyen ampliamente en el cuerpo y generalmente se encuentran en concentraciones más altas en los órganos diana de la hormona sexual. Los estrógenos circulan en la sangre en gran medida unidos a SHBG y albúmina.
Metabolismo
Los estrógenos exógenos se metabolizan de la misma manera que los estrógenos endógenos. Los estrógenos circulantes existen en un equilibrio dinámico de las interconversiones metabólicas. Estas transformaciones tienen lugar principalmente en el hígado. El estradiol se convierte reversiblemente en estrona, y ambos se pueden convertir en estriol, que es un metabolito urinario principal. Los estrógenos también sufren recirculación enterohepática a través de sulfato y conjugación de glucurónido en el hígado, secreción biliar de conjugados en el intestino e hidrólisis en el intestino seguido de reabsorción. En mujeres posmenopáusicas, existe una proporción significativa de los estrógenos circulantes como conjugados de sulfato, especialmente sulfato de estrona, que sirve como reservorio circulante para la formación de estrógenos más activos.
El estradiol de Lindisc evita el metabolismo de primer paso y proporciona relaciones de estradiol a estrona en estado estacionario en el rango de 0.42 a 0.65.
Excreción
El estradiol, la estrona y el estriol se excretan en la orina junto con los conjugados de glucurónido y sulfato. La vida media terminal aparente del estradiol fue de aproximadamente 10 horas después de la administración de Lindisc.
Uso en poblaciones específicas
No se realizaron estudios farmacocinéticos en poblaciones específicas, incluidos pacientes con insuficiencia renal o hepática.
Potencial para la transferencia de estradiol
El efecto de la transferencia de estradiol se evaluó en mujeres posmenopáusicas sanas que aplicaron tópicamente 1.0 g de Lindisc (dosis única) en un muslo. Una y 8 horas después de la aplicación del gel, entablaron contacto directo de muslo a brazo con un compañero durante 15 minutos. Si bien se observó cierta elevación de los niveles de estradiol sobre el valor inicial en los sujetos masculinos, el grado de transferibilidad en este estudio no fue concluyente.
Efectos del lavado
El efecto del lavado en el sitio de aplicación sobre los niveles de superficie de la piel y las concentraciones séricas de estradiol se determinó en 16 mujeres posmenopáusicas sanas después de la aplicación de 1.0 g de Lindisc a un área de 200 cm² en el muslo. Lavar el sitio de aplicación con agua y jabón 1 hora después de la aplicación eliminó todas las cantidades detectables de estradiol de la superficie de la piel y resultó en una disminución del 30 al 38 por ciento en la exposición total media de 24 horas al estradiol.
El perfil de toxicidad del estradiol ha sido bien establecido. La administración continua a largo plazo de estrógenos naturales y sintéticos en ciertas especies animales aumenta la frecuencia de carcinomas de mama, útero, cuello uterino, vagina, testículo e hígado, así como la frecuencia de tumores linfoides y pituitarios.
No aplica.
Los parches transdérmicos usados deben doblarse por la mitad con el lado adhesivo hacia adentro y desecharse de manera segura y fuera del alcance y de la vista de los niños. Cualquier parche transdérmico usado o no usado debe eliminarse de acuerdo con los requisitos locales o devolverse a la farmacia, preferiblemente en el embalaje original.
However, we will provide data for each active ingredient