Composition:
Utilisé dans le traitement:
Examiné médicalement par Oliinyk Elizabeth Ivanovna, Pharmacie Dernière mise à jour le 14.03.2022
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Top 20 des médicaments avec les mêmes ingrédients:
Traitement des symptômes vasomoteurs modérés à sévères dus à la ménopause
Traitement des symptômes modérés à sévères de l'atrophie vulvaire et vaginale due à la ménopause
Limitation d'utilisation
Lors de la prescription uniquement pour le traitement des symptômes modérés à sévères de l'atrophie vulvaire et vaginale due à la ménopause, les produits vaginaux topiques doivent être pris en compte.
Traitement de l'hypoestrogénisme dû à l'hypogonadisme, à la castration ou à l'échec ovarien primaire
Prévention de l'ostéoporose postménopausique
Limitation d'utilisation
Lors de la prescription uniquement pour la prévention de l'ostéoporose postménopausique, le traitement ne doit être envisagé que pour les femmes à risque important d'ostéoporose et les médicaments non œstrogènes doivent être soigneusement envisagés.
Traitement des symptômes vasomoteurs modérés à sévères dus à la ménopause
En règle générale, lorsque l'œstrogène est prescrit à une femme ménopausée avec un utérus, un progestatif doit également être envisagé pour réduire le risque de cancer de l'endomètre. Une femme sans utérus n'a pas besoin de progestatif. Dans certains cas, cependant, les femmes hystérectomisées ayant des antécédents d'endométriose peuvent avoir besoin d'un progestatif.
L'utilisation d'oestrogène seul, ou en combinaison avec un progestatif, doit être avec la dose efficace la plus faible et pour la durée la plus courte compatible avec les objectifs et les risques du traitement pour chaque femme. Les femmes ménopausées devraient être réévaluées périodiquement selon les besoins cliniques pour déterminer si un traitement est encore nécessaire.
Traitement des symptômes vasomoteurs modérés à sévères dus à la ménopause
Commencez le traitement avec 0,025 mg par jour appliqué sur la peau une fois par semaine. Le traitement doit être commencé à la dose efficace la plus faible et à la durée la plus courte compatible avec les objectifs du traitement. Les tentatives de réduction ou d'arrêt du médicament doivent être effectuées à des intervalles de 3 à 6 mois.
Traitement des symptômes modérés à sévères de l'atrophie vulvaire et vaginale due à la ménopause
Commencez le traitement avec 0,025 mg par jour appliqué sur la peau une fois par semaine. Le traitement doit être commencé à la dose efficace la plus faible et à la durée la plus courte compatible avec les objectifs du traitement. Les tentatives de réduction ou d'arrêt du médicament doivent être effectuées à des intervalles de 3 à 6 mois.
Traitement de l'hypoestrogénisme dû à l'hypogonadisme, à la castration ou à l'échec ovarien primaire
Commencez le traitement avec 0,025 mg par jour appliqué sur la peau une fois par semaine. La dose doit être ajustée si nécessaire pour contrôler les symptômes. Les réponses cliniques (soulagement des symptômes) à la dose efficace la plus faible doivent être le guide pour établir l'administration du système transdermique Lindisc, en particulier chez les femmes atteintes d'utérus intact.
Prévention de l'ostéoporose postménopausique
Commencez le traitement avec 0,025 mg par jour appliqué sur la peau une fois par semaine.
Application du système transdermique Lindisc
Sélection du site
- Le côté adhésif de Lindisc doit être placé sur une zone propre et sèche du bas-ventre ou du quadrant supérieur de la fesse.
- Lindisc ne doit pas être appliqué sur ou près des seins.
- Les sites d'application doivent être tournés, avec un intervalle d'au moins 1 semaine autorisé entre les applications sur le même site.
- La zone sélectionnée ne doit pas être grasse, endommagée ou irritée. La taille doit être évitée, car des vêtements serrés peuvent frotter le système transdermique.
- Il convient également d'éviter toute application aux zones où la séance délogerait Lindisc.
Application
- Lindisc doit être appliqué immédiatement après avoir ouvert la pochette et retiré la doublure de protection.
- Lindisc doit être pressé fermement en place avec les doigts pendant au moins 10 secondes, en s'assurant qu'il y a un bon contact, en particulier sur les bords.
- Si le système se soulève, appliquez une pression pour maintenir l'adhérence.
- Dans le cas où un système devrait tomber, réappliquez-le à un autre emplacement. Si le système ne peut pas être réappliqué, un nouveau système doit être appliqué pour le reste de l'intervalle posologique de 7 jours.
- Un seul système doit être porté à la fois pendant l'intervalle posologique de 7 jours.
- La natation, le bain ou l'utilisation d'un sauna lors de l'utilisation de Lindisc n'a pas été étudié, et ces activités peuvent diminuer l'adhérence du système et la livraison d'estradiol.
Suppression du système transdermique Lindisc
- L'élimination du lindisc doit être effectuée avec soin et lentement pour éviter l'irritation de la peau.
- Si un adhésif reste sur la peau après le retrait du système Lindisc, laissez la zone sécher pendant 15 minutes. Ensuite, frotter doucement la zone avec une crème à base d'huile ou une lotion doit éliminer les résidus adhésifs.
- Les patchs utilisés contiennent encore des hormones actives. Chaque patch doit être soigneusement plié en deux pour qu'il colle à lui-même avant de le jeter.
En règle générale, lorsque l'œstrogène est prescrit à une femme ménopausée avec un utérus, un progestatif doit également être envisagé pour réduire le risque de cancer de l'endomètre.
Une femme sans utérus n'a pas besoin de progestatif. Dans certains cas, cependant, les femmes hystérectomisées ayant des antécédents d'endométriose peuvent avoir besoin d'un progestatif.
L'utilisation d'oestrogène seul, ou en combinaison avec un progestatif, doit être avec la dose efficace la plus faible et pour la durée la plus courte compatible avec les objectifs et les risques du traitement pour chaque femme. Les femmes ménopausées devraient être réévaluées périodiquement selon les besoins cliniques pour déterminer si un traitement est encore nécessaire.
Traitement des symptômes vasomoteurs modérés à sévères dus à la ménopause
Le lindisc doit être appliqué une fois par jour sur la peau du haut de la cuisse droite ou gauche. La surface d'application doit être d'environ 5 par 7 pouces (environ la taille de deux empreintes de palmier). Le contenu entier d'un paquet de dose unitaire doit être appliqué chaque jour. Pour éviter une irritation cutanée potentielle, le lindisc doit être appliqué sur le haut de la cuisse droite ou gauche les jours alternés. Le lindisc ne doit pas être appliqué sur le visage, les seins ou la peau irritée ou dans ou autour du vagin. Après l'application, le gel doit être laissé sécher avant de s'habiller. Le site d'application ne doit pas être lavé dans l'heure suivant l'application de Lindisc. Le contact du gel avec les yeux doit être évité. Les mains doivent être lavées après l'application.
En règle générale, les femmes doivent être démarrées à une dose de 0,25 gramme.
Lindisc est contre-indiqué chez les femmes présentant l'une des conditions suivantes:
- Saignement génital anormal non diagnostiqué
- Connu, suspecté ou antécédents de cancer du sein
- Néoplasie connue ou suspectée dépendante des œstrogènes
- DVT, PE actifs ou historique de ces conditions
- Maladie thromboembolique artérielle active (par exemple, AVC et IM), ou antécédents de ces conditions
- Réaction anaphylactique connue ou œdème de Quincke avec Lindisc
- Insuffisance hépatique ou maladie connue
- Protéine C, protéine S ou déficit en antithrombine connus, ou autres troubles thrombophiles connus
- Grossesse connue ou suspectée
Lindisc ne doit pas être utilisé chez les femmes présentant l'une des conditions suivantes:
- Saignement génital anormal non diagnostiqué
- Connu, suspecté ou antécédents de cancer du sein
- Néoplasie connue ou suspectée dépendante des œstrogènes
- DVT, PE ou historique actif de ces conditions
- Maladie thromboembolique artérielle active (par exemple, AVC et IM), ou antécédents de ces conditions
- Réaction anaphylactique connue ou œdème de Quincke à Lindisc
- Insuffisance hépatique ou maladie connue
- Protéine C, protéine S ou déficit en antithrombine connus, ou autres troubles thrombophiles connus
- Grossesse connue ou suspectée
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 n'a aucune influence ou qu'une influence négligeable sur l'aptitude à conduire des véhicules et à utiliser des machines.
The following serious adverse reactions are discussed elsewhere in the labeling:
- Cardiovascular Disorders
- Malignant Neoplasms
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below reflect pooled data from 5 clinical trials of Lindisc. A total of 614 women were exposed to Lindisc for 3 months (193 women at 0.025 mg per day, 201 women at 0.05 mg per day, 194 women at 0.1 mg per day) in randomized, double-blind trials of clinical efficacy versus placebo and versus active comparator. All women were postmenopausal, had a serum estradiol level of less than 20 pg/mL, and a minimum of five moderate to severe hot flushes per week or a minimum of 15 hot flushes per week of any severity at baseline. Included in this table are an additional 25 postmenopausal hysterectomized women exposed to Lindisc 0.025 mg per day for 6 to 24 months (N=16 at 24 months) in a randomized, double-blind, placebo-controlled study of Lindisc for the prevention of osteoporosis.
Table 1: Treatment-Emergent Adverse Reactions Reported at a Frequency of ≥ 5 Percent and More Frequent in Women Receiving Lindisc
Body System Adverse Reactions | Lindisc | Placeboc (N=72) | ||
0.025 mg/daya (N=219) | 0.05 mg/dayb (N=201) | 0.1 mg/dayb (N=194) | ||
Body as a Whole | 21% | 39% | 37% | 29% |
Headache | 5% | 18% | 13% | 10% |
Pain | 1% | 8% | 11% | 7% |
Back Pain | 4% | 8% | 9% | 6% |
Edema | 0.5% | 13% | 10% | 6% |
Digestive System | 9% | 21% | 29% | 18% |
Abdominal Pain | 0% | 11% | 16% | 8% |
Nausea | 1% | 5% | 6% | 3% |
Flatulence | 1% | 3% | 7% | 1% |
Musculoskeletal System | 7% | 9% | 11% | 4% |
Arthralgia | 1% | 5% | 5% | 3% |
Nervous System | 13% | 10% | 11% | 1% |
Depression | 1% | 5% | 8% | 0% |
Urogenital System | 12% | 18% | 41% | 11% |
Breast Pain | 5% | 8% | 29% | 4% |
Leukorrhea | 1% | 6% | 7% | 1% |
Respiratory System | 15% | 26% | 29% | 14% |
URTI | 6% | 17% | 17% | 8% |
Pharyngitis | 0.5% | 3% | 7% | 3% |
Sinusitis | 4% | 4% | 5% | 3% |
Rhinitis | 2% | 4% | 6% | 1% |
Skin and Appendages | 19% | 12% | 12% | 15% |
Pruritus | 0.5% | 6% | 3% | 6% |
a) Adverse reactions occurring at rate of ≥ 5 percent in Lindisc trials of clinical efficacy versus placebo and versus active comparator; and trial of Lindisc versus placebo for the prevention of osteoporosis b) Adverse reactions occurring at rate of ≥ 5 percent in Lindisc trials of clinical efficacy versus placebo and versus active comparator c) Adverse reactions occurring in placebo group in Lindisc trial of clinical efficacy versus placebo |
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of the Lindisc transdermal system. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Genitourinary System
Changes in bleeding pattern, pelvic pain
Breast
Breast cancer, breast pain, breast tenderness
Cardiovascular
Changes in blood pressure, palpitations, hot flashes
Gastrointestinal
Vomiting, abdominal pain, abdominal distension, nausea
Skin
Alopecia, hyperhidrosis, night sweats, urticaria, rash
Eyes
Visual disturbances, contact lens intolerance,
Central Nervous System
Depression, migraine, paresthesia, dizziness, anxiety, irritability, mood swings, nervousness, insomnia, headache
Miscellaneous
Fatigue, menopausal symptoms, weight increase, application site reaction, anaphylactic reactions
The following serious adverse reactions are discussed elsewhere in the labeling:
- Cardiovascular Disorders.
- Malignant Neoplasms.
Clinical Trials Experience
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.
Lindisc was studied at doses of 0.25, 0.5 and 1.0 gram per day in a 12-week, double-blind, placebo-controlled study that included a total of 495 postmenopausal women (86.5 percent Caucasian). The adverse events that occurred at a rate greater than 5 percent in any of the treatment groups are summarized in Table 1.
Table 1: Nuber (%) of Subjects with Common Adverse Reactions* in a 12-Week Placebo-Controlled Study of Lindisc
SYSTEM ORGAN CLASS Preferred Term | Lindisc | Placebo N=125 n(%) | ||
0.25 g/day N=122 n (%) | 0.5 g/day N=123 n (%) | 1.0 g/day N=125 n (%) | ||
INFECTIONS & INFESTATIONS | ||||
Nasopharyngitis | 7(5.7) | 5(4.1) | 6(4.8) | 5(4.0) |
Upper Respiratory Tract Infection | 7(5.7) | 3(2.4) | 2(1.6} | 2(1.6) |
Vaginal mycosis | 1 (0.8) | 3(2.4) | 8(6.4) | 4(3.2) |
REPRODUCTIVE SYSTEM & BREAST DISORDERS | ||||
Breast Tenderness | 3(2.5) | 7(5.7) | 11 (8.8) | 2(1.6) |
Metrorrhagia | 5(4.1) | 7(5.7) | 12(9.6) | 2(1.6) |
* Adverse reactions reported by >5 percent of patients in any treatment group. |
In a 12-week placebo-controlled study of Lindisc, application site reactions were seen in <1 percent of subjects.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Lindisc. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Genitourinary System
Amenorrhea, dysmenorrhea, ovarian cyst, vaginal discharge
Breasts
Gynecomastia
Cardiovascular
Palpitations, ventricular extrasystoles
Gastrointestinal
Flatulence
Skin
Rash pruritic, urticaria
Eyes
Retinal vein occlusion
Central Nervous System
Tremor
Miscellaneous
Arthralgia, application site rash, asthenia, chest discomfort, fatigue, feeling abnormal, heart rate increased, insomnia, malaise, muscle spasms, pain in extremity, weight increased
Additional postmarketing adverse reactions have been reported in patients receiving other forms of hormone therapy.
Overdosage of estrogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding in women. Treatment of overdose consists of discontinuation of Lindisc therapy with institution of appropriate symptomatic care.
Overdosage of estrogen may cause nausea and vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of Lindisc therapy with institution of appropriate symptomatic care.
Il n'y a pas de données pharmacodynamiques pour Lindisc.
Actuellement, aucune donnée pharmacodynamique n'est connue pour Lindisc.
Absorption
L'administration transdermique de Lindisc produit des concentrations sériques moyennes d'estradiol comparables à celles produites par les femmes préménopausées au début de la phase folliculaire du cycle ovulatoire. La pharmacocinétique de l'estradiol après l'application du système transdermique de Lindisc a été étudiée chez 197 femmes ménopausées en bonne santé dans six études. Dans cinq des études, le système transdermique de Lindisc a été appliqué à l'abdomen et, dans une sixième étude, l'application aux fesses et à l'abdomen a été comparée.
Le système de distribution transdermique Lindisc libère en continu de l'estradiol qui est transporté sur une peau intacte, ce qui entraîne des niveaux d'estradiol circulants soutenus pendant une période de traitement de 7 jours. La disponibilité systémique de l'estradiol après administration transdermique est environ 20 fois supérieure à celle après administration orale. Cette différence est due à l'absence de métabolisme de premier passage lorsque l'estradiol est administré par voie transdermique.
Dans une étude de biodisponibilité, le Lindisc 6,5 cm² a été étudié avec le Lindisc 12,5 cm² comme référence. Les taux moyens d'estradiol dans le sérum des deux tailles sont illustrés à la figure 1.
Figure 1: Sérum moyen 17β - Concentrations d'étradiol versus profil temporel suivant Application d'un système transdermique de 6,5 cm² et application d'un système transdermique à lindisc de 12,5 cm²
La proportionnalité de la dose a été démontrée pour le système transdermique Lindisc de 6,5 cm² par rapport au système transdermique Lindisc de 12,5 cm² dans une étude croisée de 2 semaines avec une période de lavage d'une semaine entre les systèmes bitransdermiques chez 24 femmes ménopausées.
La proportionnalité de la dose a également été démontrée pour le système transdermique Lindisc (12,5 cm² et 25 cm²) dans une étude d'une semaine menée auprès de 54 femmes ménopausées. Les niveaux moyens à l'état d'équilibre (Cavg) de l'estradiol lors de l'application de Lindisc 25 cm² et 12,5 cm² sur l'abdomen étaient respectivement d'environ 80 et 40 pg / ml.
Dans une étude de 3 semaines sur plusieurs applications chez 24 femmes ménopausées, le système transdermique Lindisc de 25 cm² a produit des concentrations maximales moyennes d'estradiol (Cmax) d'environ 100 pg / ml. Valeurs minimales à la fin de chaque intervalle d'usure (Cmin) étaient d'environ 35 pg / ml. Des courbes sériques presque identiques ont été observées chaque semaine, indiquant peu ou pas d'accumulation d'estradiol dans le corps. Les niveaux de pic et de creux de l'estrone sérique étaient respectivement de 60 et 40 pg / ml.
Dans une étude croisée randomisée à dose unique menée pour comparer l'effet du site d'application, 38 femmes ménopausées portaient un seul système transdermique Lindisc de 25 cm² pendant 1 semaine sur l'abdomen et les fesses. Les profils de concentration sérique d'estradiol sont illustrés à la figure 2. Les valeurs de Cmax et Cavg étaient respectivement de 25% et 17% plus élevées avec l'application de fesse qu'avec l'application abdominale.
Figure 2: Concentrations sériques moyennes (± SE) observées d'Estradiol pour une application d'une semaine du système transdermique de Lindisc (25 cm²) aux abdominaux et aux fesses de 38 femmes ménopausées
Le tableau 2 présente un résumé des paramètres pharmacocinétiques de l'estradiol déterminés lors de l'évaluation du système transdermique de Lindisc.
Tableau 2: Résumé pharmacocinétique (valeurs moyennes d'estradiol)
Taux de livraison de lindisc | Surface (cm²) | Site d'application | Non. des sujets | Dosage | Cmax (pg / mL) | C min (pg / ml) | Cavg (pg / mL) |
0,025 | 6.5 | Abdomen | 24 | Célibataire | 32 | 17 | 22 |
0,05 | 12.5 | Abdomen | 102 | Célibataire | 71 | 29 | 41 |
0,1 | 25 | Abdomen | 139 | Célibataire | 147 | 60 | 87 |
0,1 | 25 | Buttock | 38 | Célibataire | 174 | 71 | 106 |
L'écart type relatif de chaque paramètre pharmacocinétique après application à l'abdomen était en moyenne de 50%, ce qui indique la variabilité intersubjective considérable associée à l'administration transdermique de médicaments. L'écart type relatif de chaque paramètre pharmacocinétique après application sur la fesse était inférieur à celui après application à l'abdomen (par exemple, pour la Cmax 39% contre 62% et pour Cavg 35% contre 48%).
Distribution
La distribution d'œstrogènes exogènes est similaire à celle des œstrogènes endogènes. Les œstrogènes sont largement distribués dans le corps et se trouvent généralement à des concentrations plus élevées dans les organes cibles de l'hormone sexuelle. Les œstrogènes circulent dans le sang largement lié au SHBG et à l'albumine.
Métabolisme
Les œstrogènes exogènes sont métabolisés de la même manière que les œstrogènes endogènes. Les œstrogènes circulants existent dans un équilibre dynamique d'interconversions métaboliques. Ces transformations se produisent principalement dans le foie. L'estradiol est converti de manière réversible en estrone, et les deux peuvent être convertis en estriol, qui est un métabolite urinaire majeur. Les œstrogènes subissent également une recirculation entérohépatique par conjugaison sulfate et glucuronide dans le foie, sécrétion biliaire de conjugués dans l'intestin et hydrolyse dans l'intestin suivie d'une réabsorption. Chez les femmes ménopausées, une proportion importante des œstrogènes circulants existe sous forme de conjugués sulfates, en particulier le sulfate d'estrone, qui sert de réservoir circulant pour la formation d'œstrogènes plus actifs.
Excrétion
L'estradiol, l'estrone et l'estriol sont excrétés dans l'urine avec les conjugués glucuronide et sulfate.
Adhésion
Une étude ouverte des potentiels d'adhésion des systèmes transdermiques placebo qui correspondent aux tailles de 6,5 cm² et 12,5 cm² de Lindisc a été menée chez 112 femmes en bonne santé de 45 à 75 ans. Chaque femme a appliqué les deux systèmes transdermiques chaque semaine, sur le haut de l'abdomen extérieur, pendant 3 semaines consécutives. Il convient de noter que le bas-ventre et le quadrant supérieur de la fesse sont les sites d'application approuvés pour le lindisc.
L'évaluation de l'adhérence a été effectuée visuellement les jours 2, 4, 5, 6, 7 de chaque semaine d'usure du système transdermique. Au total, 1 654 observations d'adhérence ont été effectuées pour 333 systèmes transdermiques de chaque taille.
De ces observations, environ 90% n'ont montré pratiquement aucun ascenseur pour les systèmes transdermiques de 6,5 cm² et 12,5 cm². Sur le nombre total de systèmes transdermiques appliqués, environ 5% ont montré un détachement complet pour chaque taille. Les potentiels d'adhérence des tailles de 18,75 cm² et 25 cm² des systèmes transdermiques (0,075 mg par jour et 0,1 mg par jour) n'ont pas été étudiés.
Absorption
L'estradiol diffuse sur une peau intacte et dans la circulation systémique par un processus d'absorption passive, la diffusion à travers la couche cornée étant le facteur limitant la vitesse.
Dans une étude de phase 1 de 14 jours sur plusieurs doses, Lindisc a démontré une pharmacocinétique de l'estradiol linéaire et approximativement proportionnelle à la dose à l'état d'équilibre pour l'ASC0-24 et la Cmax après un dosage une fois par jour sur la peau du haut droit ou gauche. cuisse (tableau 2).
Tableau 2: Paramètres pharmacocinétiques moyens (% CV) de l'estradiol (non corrigé pour la ligne de base) au jour 14 après plusieurs doses quotidiennes de lindisc 0,1%
Paramètre (unités) | 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) |
Rapport E2: E1 | 0,42 | 0,65 | 0,65 |
* Médiane (Mia Max). |
La concentration sérique d'estradiol à l'état d'équilibre est atteinte au jour 12 après l'application quotidienne de lindisc sur la peau du haut de la cuisse. Les taux sériques moyens (ET) d'estradiol après une administration quotidienne au jour 14 sont illustrés à la figure 1.
Figure 1: Concentrations moyennes (SD) d'estradiol sérique (valeurs non corrigées pour la ligne de base) au jour 14 après plusieurs doses quotidiennes de lindisc 0,1%
L'effet des écrans solaires et autres lotions topiques sur l'exposition systémique du lindisc n'a pas été évalué. Des études menées à l'aide de produits approuvés par le gel d'oestrogène topique ont montré que les écrans solaires ont le potentiel de modifier l'exposition systémique des gels d'oestrogène appliqués par voie topique.
Distribution
La distribution d'œstrogènes exogènes est similaire à celle des œstrogènes endogènes. Les œstrogènes sont largement distribués dans le corps et se trouvent généralement à des concentrations plus élevées dans les organes cibles de l'hormone sexuelle. Les œstrogènes circulent dans le sang largement lié au SHBG et à l'albumine.
Métabolisme
Les œstrogènes exogènes sont métabolisés de la même manière que les œstrogènes endogènes. Les œstrogènes circulants existent dans un équilibre dynamique d'interconversions métaboliques. Ces transformations se produisent principalement dans le foie. L'estradiol est converti de manière réversible en estrone, et les deux peuvent être convertis en estriol, qui est un métabolite urinaire majeur. Les œstrogènes subissent également une recirculation entérohépatique par conjugaison sulfate et glucuronide dans le foie, sécrétion biliaire de conjugués dans l'intestin et hydrolyse dans l'intestin suivie d'une réabsorption. Chez les femmes ménopausées, une proportion importante des œstrogènes circulants existe sous forme de conjugués sulfates, en particulier le sulfate d'estrone, qui sert de réservoir circulant pour la formation d'œstrogènes plus actifs.
L'estradiol de Lindisc évite le métabolisme de premier passage et fournit des rapports estradiol / estrone à l'état d'équilibre dans la plage de 0,42 à 0,65.
Excrétion
L'estradiol, l'estrone et l'estriol sont excrétés dans l'urine avec les conjugués glucuronide et sulfate. La demi-vie terminale apparente de l'estradiol était d'environ 10 heures après l'administration de Lindisc.
Utilisation dans des populations spécifiques
Aucune étude pharmacocinétique n'a été menée dans des populations spécifiques, y compris des patients atteints d'insuffisance rénale ou hépatique.
Potentiel de transfert d'Estradiol
L'effet du transfert d'estradiol a été évalué chez des femmes ménopausées en bonne santé qui ont appliqué par voie topique 1,0 g de lindisc (dose unique) sur une cuisse. Une et 8 heures après l'application du gel, ils se sont livrés en contact direct de la cuisse au bras avec un partenaire pendant 15 minutes. Alors qu'une certaine élévation des niveaux d'estradiol au-dessus de la ligne de base a été observée chez les sujets masculins, le degré de transférabilité dans cette étude n'a pas été concluant.
Effets du lavage
L'effet du lavage au site d'application sur les niveaux de surface de la peau et les concentrations sériques d'estradiol a été déterminé chez 16 femmes ménopausées en bonne santé après application de 1,0 g de Lindisc sur une zone de 200 cm² sur la cuisse. Le lavage du site d'application avec du savon et de l'eau 1 heure après l'application a retiré toutes les quantités détectables d'estradiol de la surface de la peau et a entraîné une diminution de 30 à 38% de l'exposition totale moyenne de 24 heures à l'estradiol.
Le profil de toxicité de l'estradiol est bien établi. L'administration continue à long terme d'œstrogènes naturels et synthétiques dans certaines espèces animales augmente la fréquence des carcinomes du sein, de l'utérus, du col de l'utérus, du vagin, des testicules et du foie ainsi que la fréquence des tumeurs lymphoïdes et hypophysaires.
Sans objet.
Used transdermal patches should be folded in half with the adhesive side inwards, and discarded safely and out of the reach and sight of children. Any used or unused transdermal patches should be disposed of in accordance with local requirements or returned to the pharmacy, preferably in the original packaging.
However, we will provide data for each active ingredient