Linoladiol n инструкции на русском языке

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

Linoladiol N 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

Linoladiol N 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 Linoladiol N transdermal system is administered to a nursing woman.

Pediatric Use

Linoladiol N 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 Linoladiol N to determine whether those over 65 years of age differ from younger subjects in their response to Linoladiol N.

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

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 Linoladiol N 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 Linoladiol N 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 Linoladiol N 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

Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.

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

• Linoladiol N should be applied once a day, around the same time each day
• Apply Linoladiol N to clean, dry, and unbroken (without cuts or scrapes) skin. If you take a bath or shower, be sure to apply your Linoladiol N after your skin is dry. The application site should be completely dry before dressing or swimming
• Apply Linoladiol N 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 Linoladiol N 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 Linoladiol N.

Figure C

Step 6: Allow the gel to dry completely before dressing.

Step 7: Dispose of the empty Linoladiol N packet in the trash.

Step 8: Wash your hands with soap and water immediately after applying Linoladiol N to remove any remaining gel and reduce the chance of transferring Linoladiol N 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

Linoladiol N 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

Linoladiol N 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 Linoladiol N is administered to a nursing woman.

Pediatric Use

Linoladiol N 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 Linoladiol N to determine whether those over 65 years of age differ from younger subjects in their response to Linoladiol N.

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 Linoladiol N has not been studied.

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of Linoladiol N 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.

• Половые гормоны и модуляторы половой системы
  • Эстрогены
    • Природные и полусинтетические эстрогены
      • Эстрадиол

• DDD^[*1] (Среднестатистическая поддерживающая суточная доза лекарства, применяющаяся по его основному показанию у взрослых): [0.3mg Adm.R:N; 2mg Adm.R:O; 1mg Adm.R:P. Note: depot short duration; 0.3mg Adm.R:P. Note: depot long duration; 5mg Adm.R:R; 50mcg Adm.R:TD. Note: «patch, refer to amount delivered per 24 hours»; 1mg Adm.R:TD. Note: gel; 1.53mg Adm.R:TD. Note: spray; 25mcg Adm.R:V; 7.5mcg Adm.R:V. Note: «vaginal ring, refers to amount delivered per 24 hours»]          Список сокращений
   

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# На 2023-Sep-04
ориентировочно, Вы можете купить «LINOLADIOL N CREME 50G» в городе Рига, Латвия по следующей цене:

• 12.97€  14.06$  11.09£  1498руб.  154.3SEK  58PLN  53.39₪ 

Mакcимально допустимая государством цена в Латвии (от сайта ZVA) Euro:

Перепроверить

Reģ. Nr.: I001070

 

* Данная таблица была скомпонована полностью автоматически, независимым от позиции рекламодателей способом, напрямую и без модификаций, ретранслируя открытые предложения доступные на указанные даты.Согласно нормативным актам, в Латвии, через интернет разрешается распространение только безрецептурных лекарств.

КРАТКА ХАРАКТЕРИСТИКА НА ПРОДУКТА/Linoladiol  N cream 0,01 g/100 g/

1. ТЪРГОВСКО ИМЕ

Linoladiol N 0.01 g/100 g cream
Линоладиол N 0.01 g/100 g крем

2. КОЛИЧЕСТВЕН И КАЧЕСТВЕН СЪСТАВ

Активно вещество:
естрадиол хемихидрат
100 g крем съдържа 0.01033 g естрадиол хемихидрат (еквивалент — на 0.01 g естрадиол).

3. ЛЕКАРСТВЕНА ФОРМА/Linoladiol  N cream 0,01 g/100 g/

Крем за вагинална употреба и локално приложение в областта на външните гениталии.
Бял, гладък крем.

4. КЛИНИЧНИ ДАННИ

4.1. Терапевтични показания

За лечение на атрофични вулвовагинални смущения дължащи се на естрогенна недостатъчност, т.е. атрофични вагинити, проблеми при полово общуване, вагинални стенози, атрофия на вулвата с парене и сърбеж.

4.2. Дозировка и начин на приложение

Път на въвеждане: крем за вагинална употреба и локално приложение в областта на външните гениталии.

Линоладиол N може да бъде прилаган с или без апликатор.

Ако не е предписано друго, при заболяване на входа на вагината и външната генитална област, Линоладиол N (приблизително 1 сm от крема) се нанася на тънък слой върху кожата веднъж или два пъти на ден.

При вагинални заболявания, 1 пълен апликатор (= 2 g крем) се въвежда вечер, преди лягане. През първата седмица от лечението

Линоладиол N би трябвало да се прилага на всеки следващ ден т.е. през интервал от 48 ч, а след това два пъти седмично (поддържаща доза). След всяка употреба апликатора трябва да се почиства с топла вода.

Продължителността на лечението се определя от лекуващия лекар чрез редовни контролни прегледи. Особено при продължителна употреба трябва да се имат предвид следните наблюдения.

Продължителна употреба:
За безопасност на ендометриума — ако е предписано продължително лечение при жени в постменопауза, чиято матка е незасегната, то би трябвало дебелината на ендометриума чрез ултразвук, преди лечението и след това да се контролира на всеки 4-6 месеца. Ако има съмнения за ендрметриална пролиферация, един така наречен прогестин тест може да бъде направен (т.е. 1 mg норетистеронов ацетат на ден за 10-12 дни), за да се предизвика изкуствено кървене ако е необходимо.

В случаи на продължителна дневна интравагинална употреба на Линоладиол N се счита, че трябва да се дава прогестоген — перорално до 10-12 дни в месеца на жени, чийто ендометриум може все още да бъде стимулиран. Ако се появи неочаквано кървене, то лечението с Линоладиол N трябва да бъде прекратено докато не се изясни причината за това.

4.3. Противопоказания/Linoladiol  N cream 0,01 g/100 g/

Линоладиол N не може да бъде използван в следните случаи:
— известна свръхчувствителност към естрадиол хемихидрат, цетилстеарилов алкохол или към някое от помощните вещества на Линоладиол И,
— естроген-зависими тумори (предполагаеми или доказани),
— ендометриоза,
— недиагностицирано вагинално кървене и
— по време на бременност и кърмене.

4.4. Специални предупреждения и предпазни мерки при употреба,

Линоладиол N може да бъде прилаган с особена предпазливост само след изчерпателна клинична преценка на рисковете и ползите, в следните случаи:
— злокачествени естроген
— зависими тумори
— тумори на матката (лейомиома, маточна миома)
— остри дълбоки тромбози на вените
— остри тромбоемболични разстройства
— остри или хронични заболявания на черния дроб

Специални предупреждения:
Преди да се започне лечение с Линоладиол N е необходимо да се направи обща медицинска анамнеза (включително фамилна история).
Дебелината на ендометриума трябва да се измери чрез ултразвук при пациенти, които са били подложени на естроген възстановяваща терапия преди лечението, или които в момента са на такова лечение.
По време на лечение на жени в менопауза с Линоладиол N е възможно допълнително да се увеличат нивата на естрадиол в плазмата без да надвишат физиологичните граници. Ако продуктът се използва няколко месеца, то се препоръчва да се следи дебелината на ендометриума, преди лечението и на всеки 4-6 месеца след това.
Линоладиол N не би трябвало да се прилага непосредствено преди полов акт или като лубрикант, за да се избегнат възможни нежелани ефекти за партньора. При по-продължително прилагане се изисква наблюдение за възможни нежелани реакции. Като предпазна мярка, Линоладиол N не трябва да се използва при деца или подрастващи.
Цетил стеариловият алкохол може да причини локално кожно дразнене (т.е. контактен дерматит).

4.5. Взаимодействие с други лекарствени продукти и други взаимодействие

Не са известни взаимодействия при локално приложение.
При вагинално приложение взаимодействия не се очакват, тъй като прилаганите дози са редки (два пъти седмично) и това води до ниски плазмени нива на естрогените.
Следните взаимодействия не могат да бъдат категорично изключени при дневна интравагинална употреба на Линоладиол N  намаляване действието на антикоагулантите и антихиперглицемичните агенти. Намаляване ефективността на Линоладиол N чрез препарати, които индуцират микрозомни чернодробни ензими (т.е. барбитурати, рифампицин).

4.6. Бременност и кърмене

Линоладиол N е противопоказен да се използва по време на бременност и кърмене.

4.7. Ефекти върху способността за шофиране и работа с машини

Не се изискват специални предупреждения.

4.8. Нежелани лекарствени реакции

Редки (>1/1 000 до < 1/100): може да се появи преходно, леко, локално дразнене (т.е. сърбеж, парене), както и и лек оток.

Много редки (< 1/10 000): кожна реакция на свръхчувствителност (алергична контактна екзема).
При по-продължителна употреба се изисква наблюдение за възможни системни нежелани реакции (т.е. болка в гърдите) и вагинално кървене.

4.9. Предозиране

Нежелани ефекти — такива като гастроинтестинални оплаквания, гадене и др. Могат да се появят само при случайно или умишлено приемане през устата на голямо количество Линоладиол N. Понеже нежеланите реакции отзвучават бързо и няма данни за предизвикване на сериозни смущения, не са необходими специални мерки.

5.ФАРМАКОЛОГИЧНИ СВОЙСТВА

5.1. Фармакодинамични свойства

Фармакотерапевтична група: обикновени, естествени и полу-синтетичени естрогени.
АТС код: G03CA03
Линоладиол N съдържа като активна субстанция естествения полов хормон 17β-естрадиол, в концентрация 0.01 %. Естрадиолът е най-мощният естествен естроген действащ вътреклетъчно. Освен типичното хормонално действие през репродуктивната възраст, естрадиол оказва характерно въздействие и върху кожата. В концентрация > 0.01% локално или системно приложен, естрадиола разширява капилярите и стимулира общото кръвооросяване. Естрогените стимулират пролиферацията на епителните клетки в гениталната област и уринарния тракт, както и увеличават синтезата на колаген в кожата.

Подобно на други стероидни хормони, естрадиолът действа непосредствено върху генетичната информация (ДНК) чрез специфични рецецептори.По този начин естрадиол повлиява на транскрипцията (синтезата на РНК и стимулира синтезирането на специфични протеини. Освен това, естрадиолът има бърз, негеномен ефект (сигнална трансдукция).

5.2. Фармакокинетични свойства

Когато се прилага вагинално, естрадиолът се абсорбира от вагиналния епител и навлиза в кръвообращението в измерими концентрации. Следните стойности за областта под кривата на плазмената концентрация (AUC) са били определени след приложение на еднократна доза от 2 g Линоладиол N, еквивалентно на 200 μg Е2: AUC _δ0→∞ = 887.5 pg/mlh;AUC_δ0→ = 799.5 pg/mlh;С_δmax =86.2 pg/ml.

След терапевтичен интервал от 48 часа (седмица 1), този резултат е 16.6 pg/ml при средните Е2 концентрации. Когато се прилага два пъти седмично средните плазмени концентрации са 11.1 и 8.33 pg/ml, съответно. Тези стойности са в границите на физиологичните нива на естардиол при жени в менопауза.

Средният геометричен полу-живот на Е2 е 5.05 часа, с широка индивидуална променливост. При други изследвания, слабо увеличение на нивото на естрадиол в плазмата от 6.4 pg/ml (1 ден) до 15.1 pg/ml (31 ден) е било наблюдавано след 4 седмично лечение с Линоладиол N. Стойностите на фоликулостимулиращият хормон (FSH), лутеинизиращият хормон (LH) както и и половият хормон-свързващ глобулин (SHBG) остават непроменени. Също така, дебелината на ендометриума, определена чрез ултразвуково измерване, преди и след лечението не показва изменения.

Естрадиол се метаболизира бързо в черния дроб и интестиналния тракт до естрон и последващо в естриол. Превръщането на естрадиол в естриол е необратимо. Над 95 % от естриола се отделя с урината, предимно под формата на глюкорониди.

5.3.Предклинични данни за безопастност

Остра и хронична токсичност:
Резултатите от проучвания с животни с естрогени могат да дадат само ограничени представи за употребата им при хора, тъй като съществуват значителните разлики между животински видове и тяхната всаимовръзка с хората.
След орално приложение, острата токсичност на естрадиол валерат е ниска, повече от 1 g/kg BW е поносима доза без сериозни симптоми. При повторни изследвания за токсичност на дозата са били получени серия от данни, в това число увеличена смъртност, хематологични нарушения, намаляване теглото на половите жлези и туморите на хипофизата. Базирайки се на досегашния опит, тези данни не могат да бъдат използвани за предвиждания в клиничната терапия.

Мутагенност и канцерогенност:
Повечето от изследванията за мутагенност на естрадиола са били отрицателни. Малко на брой тестове са доказали, че когато се прилагат високи концентрации, могат да се индуцират хромозомни мутации (анеуплоидия и структурни промени). По време на in vitro тестове за определяне на канцерогенния ефект естрадиолът е причинил клетъчни трансформации. Не е изяснено до каква степен тези ефекти се дължат на туморна мутагенност, наблюдавани при, изследвания с животни.

При орално приложение на естрадиол валерат при плъхове се е наблюдавало увеличавано въздействие върху аденом на хипофизата — както и върху доброкачествени или злокачествени тумори на млечните жлези по време на две годишно изследване.

Естрадиолът и неговите естери обикновено увеличават честотата на туморите на хипофизата и млечните жлези при мишки и плъхове, бъбречните тумори при хамстери, както и урогениталните, тестикуларните и лимфоидните тумори при мишки. Също така, при изследвания върху животние с естери на естрадиол, е бил намерен един повишен ефект от химически предизвикани чернодробни тумори.

Би трябвало да се счита, че продължителната употреба на естрогени може също така да бъде свързана с повишен риск от поява на тумори при хора. От дълго време се дискутира увеличената заболеваемост на карцином на ендометриума при жени с матка и дали тя се дължи на употребата на естрогени.

Освен това продължителната естрогенна употреба може да бъде свързана с увеличен риск от развитие на злокачествени тумори на млечните жлези. При определен риск, трябва да се има предвид връзката между приложената доза естроген и физиологичната секреция. При жени в детеродна възраст, средно 100 — 300 μg естрадиол се произвежда на всеки 24 часа при дневен цикъл 1-14 дни, докато 80- 100 μg естрадиол се отделя на всеки 24 часа при дневен цикъл 15-28 дни. 1 g Линоладиол N крем съдържа 100 μg естрадиол. Канцерогенният риск на Линоладиол N може да се счита за незначително нисък.

Репродуктивна токсичност:
Когато естрадиол валерат се прилага подкожно или мускулно може да има ембриолетален ефект дори и при много ниски дози. На 19 ден след прилагане на естрадиол при плъхове са били наблюдавани малформации на урогениталния тракт. Вагинални и/или маточни тумори са се развили при мишки след подкожно post partum приложение на естрадиол. Засега ограниченият опит с хора показва, че няма малформации при употреба на естрадиол по време на бременност и кърмене.

6.ФАРМАЦЕВТИЧНИ ДАННИ

6.1.Списък на помощните вещества

Бензилов алкохол, цетилов палмитат, цетил стеарилов алкохол, натриев цитрат дихидрат, октилдодеканол, полисорбат 60, сорбитанов стеарат, пречистена вода.

6.2.Несъвместимости

Няма

6.3. Срок на годност

3 години

6.4. Специални условия на съхранение

Да се съхранява при температура под 25 С°.

6.5 Данни за опаковката

Алуминиева туба с капачка от полиетилен с висока плътност. Туби с 50g крем за вагинална употреба и локално приложение външно в областта на гениталиите. Опаковката съдържа апликатор.

6.6 Специфични предпазни мерки при изхвърляне на използван лекарствен продукт или отпадъчни материали от него

Няма специални изисквания

7. ПРИТЕЖАТЕЛ НА РАЗРЕШЕНИЕТО ЗА УПОТРЕБА

Dr. August Wolff GmbH & Co. KG — Arzneimittel Sudbrackstrasse 56, D-33611 Bielefeld, Германия тел.:+ 49 (0)521 8808-05; факс:+ 49 (0)521 8808-334; e-mail: info(g),wolff-arzneimittel.de

8. РЕГИСТРАЦИОНЕН НОМЕР

9700437

9. ДАТА HA АКТУАЛИЗИРАНЕ HA ТЕКСТА

януари 2008

10. ВНОСИТЕЛ:

„Химтренд-Комет» ООД
Бул. «Цар Борис ПГ № 12, бл.59-партер, 1612 София Тел:/Факс: 02/953 13 10; e-mail: chimtrd(g),vahoo.com

11. НАЧИН НА ПРЕДЛАГАНЕ

Само по лекарско предписание