Ladiol

更年期障害による中等度から重度の血管運動症状の治療。

更年期障害によるバルバーと ⁇ の ⁇ 縮の中程度から重度の症状の治療。

使用の制限。

閉経による外陰性および ⁇ の ⁇ 縮の中等度から重度の症状の治療のみに処方する場合は、局所 ⁇ 製品を検討する必要があります。.

性腺機能低下症、去勢、または原発性卵巣不全による低エストロゲン症の治療。

閉経後骨粗しょう症の予防。

使用の制限。

閉経後の骨粗しょう症の予防のみを目的として処方する場合、骨粗しょう症の重大なリスクがある女性に対してのみ治療を検討する必要があり、非エストロゲン薬を慎重に検討する必要があります。.

更年期障害による中等度から重度の血管運動症状の治療。

一般に、子宮のある閉経後の女性にエストロゲンが処方されている場合、子宮内膜がんのリスクを減らすためにプロゲスチンも考慮する必要があります。. 子宮のない女性はプロゲスチンを必要としません。. ただし、子宮内膜症の病歴のある子宮摘出術を受けた女性には、プロゲスチンが必要な場合があります。.

エストロゲン単独の使用、またはプロゲスチンと組み合わせて使用 することは、最低有効量であり、個々の女性の治療目標とリスクと一致する最短期間である必要があります。. 閉経後の女性は、治療が依然として必要かどうかを判断するために、臨床的に適切なものとして定期的に再評価する必要があります。.

更年期障害による中等度から重度の血管運動症状の治療。

週に1回、皮膚に1日あたり0.025 mgを塗布して治療を開始します。. 治療は、最低有効用量と治療目標と一致する最短期間で開始する必要があります。. 薬をテーパーまたは中止する試みは、3〜6か月間隔で行う必要があります。.

更年期障害によるバルバーと ⁇ の ⁇ 縮の中程度から重度の症状の治療。

週に1回、皮膚に1日あたり0.025 mgを塗布して治療を開始します。. 治療は、最低有効用量と治療目標と一致する最短期間で開始する必要があります。. 薬をテーパーまたは中止する試みは、3〜6か月間隔で行う必要があります。.

性腺機能低下症、去勢、または原発性卵巣不全による低エストロゲン症の治療。

週に1回、皮膚に1日あたり0.025 mgを塗布して治療を開始します。. 症状を制御するために、必要に応じて用量を調整する必要があります。. 最低有効用量での臨床反応(症状の緩和)は、特に子宮が無傷の女性において、ラジオール経皮系の投与を確立するためのガイドであるべきです。.

閉経後骨粗しょう症の予防。

週に1回、皮膚に1日あたり0.025 mgを塗布して治療を開始します。.

ラジオール経皮システムの適用。

サイトの選択。

• ラジオールの接着剤側は、下腹部の清潔で乾燥した領域または ⁇ 部の上部象限に配置する必要があります。.
• ラジオールは乳房またはその近くに適用しないでください。.
• 申請の場所は、同じ場所への申請間で少なくとも1週間の間隔を空けて回転させる必要があります。.
• 選択した領域は、油性、損傷、または刺激を受けてはなりません。. タイトな服は経皮システムをこすり落とす可能性があるため、ウエストラインは避けてください。.
• 座るとラジオールが外れる領域への適用も避けるべきです。.

アプリケーション。

• ラジオールは、ポーチを開けて保護ライナーを取り外した直後に塗布する必要があります。.
• ラジオールは、指でしっかりと所定の位置に少なくとも10秒間押し、特にエッジの周りによく接触するようにします。.
• システムが持ち上げられた場合は、圧力をかけて接着を維持します。.
• システムが脱落した場合は、別の場所に再適用してください。. システムを再適用できない場合は、7日間の投与間隔の残りの期間に新しいシステムを適用する必要があります。.
• 7日間の投与間隔で一度に着用できるシステムは1つだけです。.
• ラジオールの使用中の水泳、入浴、またはサウナの使用は研究されておらず、これらの活動はシステムの接着性とエストラジオールの供給を低下させる可能性があります。.

ラジオール経皮システムの除去。

• ラジオールの除去は、皮膚の刺激を避けるために慎重かつゆっくりと行う必要があります。.
• ラジオールシステムの除去後に接着剤が皮膚に残っている場合は、領域を15分間乾燥させます。. 次に、油性クリームまたはローションで領域を軽くこすり、接着剤の残留物を除去します。.
• 使用済みのパッチにはまだいくつかの活性ホルモンが含まれています。. 各パッチは、捨てる前にそれ自体にくっついてしまうように、慎重に半分に折りたたむ必要があります。.

一般に、子宮のある閉経後の女性にエストロゲンが処方されている場合、子宮内膜がんのリスクを減らすためにプロゲスチンも考慮する必要があります。.

子宮のない女性はプロゲスチンを必要としません。. ただし、子宮内膜症の病歴のある子宮摘出術を受けた女性には、プロゲスチンが必要な場合があります。.

エストロゲン単独の使用、またはプロゲスチンと組み合わせて使用 することは、最低有効量であり、個々の女性の治療目標とリスクと一致する最短期間である必要があります。. 閉経後の女性は、治療が依然として必要かどうかを判断するために、臨床的に適切なものとして定期的に再評価する必要があります。.

更年期障害による中等度から重度の血管運動症状の治療。

ラジオールは、太ももの右または左の皮膚に1日1回塗布する必要があります。. 適用表面積は約5 x 7インチ(約2つのヤシのプリントのサイズ)にする必要があります。. 単位用量パケットの内容物全体を毎日適用する必要があります。. 潜在的な皮膚の炎症を避けるために、ラジオールは交互の日に右または左大 ⁇ に塗布する必要があります。. ラジオールは、顔、乳房、炎症を起こした皮膚、または ⁇ 内または ⁇ の周りに適用しないでください。. 塗布後、ゲルはドレッシングの前に乾燥させる必要があります。. 塗布部位は、ラジオールを塗布してから1時間以内に洗浄しないでください。. 目とのゲルの接触は避けてください。. 塗布後は手を洗ってください。.

一般に、女性は0.25グラムの投与量で開始する必要があります。.

ラジオールは、次の条件のいずれかの女性には禁 ⁇ です。

• 診断されていない異常な性器出血。
• 乳がんの既知、疑い、または病歴。
• エストロゲン依存性腫瘍として知られている、または疑われている。
• アクティブなDVT、PE、またはこれらの状態の歴史。
• 活動性動脈血栓塞栓性疾患(例えば、脳卒中およびMI)、またはこれらの状態の病歴。
• ラジオールによるアナフィラキシー反応または血管性浮腫の既知。
• 既知の肝障害または疾患。
• 既知のタンパク質C、タンパク質S、またはアンチトロンビン欠乏症、または他の既知の血栓性障害。
• 妊娠が知られている、または疑われている。

ラジオールは、次の条件のいずれかの女性には使用しないでください。

• 診断されていない異常な性器出血。
• 乳がんの既知、疑い、または病歴。
• エストロゲン依存性腫瘍として知られている、または疑われている。
• アクティブなDVT、PE、またはこれらの条件の歴史。
• 活動性動脈血栓塞栓性疾患(例えば、脳卒中およびMI)、またはこれらの状態の病歴。
• ラジオールに対するアナフィラキシー反応または血管性浮腫の既知。
• 既知の肝障害または疾患。
• 既知のタンパク質C、タンパク質S、またはアンチトロンビン欠乏症、または他の既知の血栓性障害。
• 妊娠が知られている、または疑われている。

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

Ladiol 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

Ladiol 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 Ladiol transdermal system is administered to a nursing woman.

Pediatric Use

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

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 Ladiol 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 Ladiol 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 Ladiol 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

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

Figure C

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

Step 7: Dispose of the empty Ladiol packet in the trash.

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

Ladiol 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

Ladiol 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 Ladiol is administered to a nursing woman.

Pediatric Use

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

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 Ladiol has not been studied.

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of Ladiol 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.

以下の深刻な副作用については、ラベルの他の場所で説明します。

• 心血管障害。
• 悪性新生物。

臨床試験の経験。

臨床試験はさまざまな条件下で行われるため、薬物の臨床試験で観察された副作用率は、他の薬物の臨床試験の率と直接比較することはできず、実際に観察された率を反映しない場合があります。.

以下に説明するデータは、Ladiolの5つの臨床試験からのプールされたデータを反映しています。. 臨床効果とプラセボの無作為化二重盲検試験で、合計614人の女性が3か月間ラジオールに曝露されました(1日あたり0.025 mgの193人の女性、1日あたり0.05 mgの201人の女性、1日あたり0.1 mgの194人の女性)。とアクティブなコンパレータ。. すべての女性は閉経後、血清エストラジオールレベルが20 pg / mL未満であり、週に最低5回の中等度から重度のほてり、またはベースラインでの重症度の週に最低15回のほてりがありました。. この表には、ラジオールの無作為化二重盲検プラセボ対照試験で、ラジオール0.025 mgを1日あたり6〜24か月間(N = 16で24か月)曝露した追加の25人の閉経後子宮摘出女性が含まれています。骨粗しょう症。.

表1:ラジオールを受け取る女性で5%以上の頻度で報告される治療緊急有害反応。

市販後の経験。

以下の副作用は、ラジオール経皮システムの承認後の使用中に確認されています。. これらの反応は不確実なサイズの集団から自発的に報告されるため、その頻度を確実に推定したり、薬物曝露との因果関係を確立したりすることは常に可能ではありません。.

Genitourinaryシステム。

出血パターンの変化、骨盤の痛み。

乳房。

乳がん、乳房の痛み、乳房の圧痛。

心血管。

血圧の変化、動 ⁇ 、ほてり。

消化器。

⁇ 吐、腹痛、腹部膨満、吐き気。

皮膚。

脱毛症、多汗症、寝汗、じんま疹、発疹。

目。

視覚障害、コンタクトレンズ不耐性、。

中央神経系。

うつ病、片頭痛、感覚異常、めまい、不安、イライラ、気分のむら、緊張、不眠症、頭痛。

その他。

疲労、更年期症状、体重増加、塗布部位の反応、アナフィラキシー反応。

以下の深刻な副作用については、ラベルの他の場所で説明します。

• 心血管障害。.
• 悪性新生物。.

臨床試験の経験。

臨床試験はさまざまな条件下で行われるため、薬物の臨床試験で観察された副作用率は、他の薬物の臨床試験の率と直接比較することはできず、実際に観察された率を反映しない場合があります。.

ラジオールは、合計495人の閉経後の女性(86.5%白人)を含む12週間の二重盲検プラセボ対照試験で、1日あたり0.25、0.5、1.0グラムの用量で研究されました。. いずれかの治療グループで5%を超える割合で発生した有害事象を表1にまとめます。.

表1:12週間のプラセボ対照ラジオール研究における一般的な有害反応*のある被験者のNuber(%)。

ラジオールの12週間のプラセボ対照試験では、被験者の1%未満で適用部位の反応が見られました。.

市販後の経験。

以下の副作用は、承認後のLadiolの使用中に確認されています。. これらの反応は不確実なサイズの集団から自発的に報告されるため、その頻度を確実に推定したり、薬物曝露との因果関係を確立したりすることは常に可能ではありません。.

Genitourinaryシステム。

無月経、月経困難症、卵巣 ⁇ 胞、 ⁇ 分 ⁇ 物。

乳房。

女性化乳房。

心血管。

動 ⁇ 、心室性開閉。

消化器。

⁇ 腸。

皮膚。

発疹 ⁇ 、じんま疹。

目。

網膜静脈閉塞。

中央神経系。

振戦。

その他。

関節痛、塗布部位の発疹、無力症、胸部不快感、疲労感、異常感、心拍数の増加、不眠症、 ⁇ 怠感、筋肉のけいれん、四肢の痛み、体重の増加。

他の形態のホルモン療法を受けている患者では、追加の市販後の副作用が報告されています。.

エストロゲンの過剰摂取は、吐き気、 ⁇ 吐、乳房の圧痛、腹痛、眠気と疲労、女性の離脱出血を引き起こす可能性があります。. 過剰摂取の治療は、適切な対症療法を行うことによるラジオール療法の中止から成ります。.

エストロゲンの過剰摂取は、吐き気と ⁇ 吐、乳房の圧痛、腹痛、眠気と疲労を引き起こし、女性で離脱出血が発生することがあります。. 過剰摂取の治療は、適切な対症療法を行うことによるラジオール療法の中止から成ります。.

ラジオールの薬力学的データはありません。.

現在、ラジオールについて知られている薬力学的データはありません。.

吸収。

ラジオールの経皮投与は、排卵周期の初期卵胞期に閉経前の女性が産生したものに匹敵するエストラジオールの平均血清濃度を生成します。. ラジオール経皮システムの適用後のエストラジオールの薬物動態は、6つの研究で197人の健康な閉経後の女性で調査されました。. 5つの研究では、ラジオール経皮システムが腹部に適用され、6番目の研究では、 ⁇ 部と腹部への適用が比較されました。.

ラジオール経皮デリバリーシステムは、無傷の皮膚を横切って輸送されるエストラジオールを継続的に放出し、7日間の治療期間中に持続的な循環レベルのエストラジオールをもたらします。. 経皮投与後のエストラジオールの全身利用可能性は、経口投与後のそれよりも約20倍高い。. この違いは、経皮経路によってエストラジオールが投与された場合、最初の通過代謝がないためです。.

バイオアベイラビリティの研究では、Ladiol 6.5cm²がLadiol 12.5cm²を参考にして研究されました。. 2つのサイズの血清中の平均エストラジオールレベルを図1に示します。.

図1:6.5cm²の経皮システムの適用と12.5cm²の放射能経皮システムの適用後の平均血清17β-エストラジオール濃度対時間プロファイル。

2週間のクロスオーバー研究で、Ladiol 6.5cm²経皮システムと比較して、24人の閉経後の女性の2つの経皮システム間で1週間のウォッシュアウト期間を伴うLadiol 12.5cm²経皮システムで、用量比例が実証されました。.

閉経後の54人の女性を対象に実施された1週間の研究で、ラジオール経皮システム(12.5cm²および25cm²)についても用量比例が示されました。. 腹部に25cm²と12.5cm²のLadiolを適用した際のエストラジオールの平均定常状態レベル(Cavg)は、それぞれ約80と40 pg / mLでした。.

閉経後の女性24人を対象とした3週間の複数申請試験。, 25cm²のラジオール経皮システムは、平均ピークエストラジオール濃度を生成しました。 (Cmax。) 約100 pg / mL。各摩耗間隔の終わりのトラフ値。 (Cmin。) 約35 pg / mLでした。ほぼ同一の血清曲線が毎週見られました。, 体内のエストラジオールの蓄積がほとんどまたはまったくないことを示します。. 血清エストロンのピークレベルとトラフレベルは、それぞれ60および40 pg / mLでした。.

適用部位の効果を比較するために実施された単回投与の無作為化クロスオーバー研究では、閉経後の女性38人が腹部と ⁇ 部に1週間、単一のLadiol 25cm²経皮システムを着用しました。. エストラジオール血清濃度プロファイルを図2に示します。. CmaxとCavgの値は、腹部アプリケーションよりも ⁇ 部アプリケーションでそれぞれ25%と17%高くなりました。.

図2:閉経後の女性38人の腹部と ⁇ 部へのラジオール経皮システム(25cm²)の1週間の適用における観察された平均(±SE)エストラジオール血清濃度。

表2は、ラジオール経皮システムの評価中に決定されたエストラジオール薬物動態パラメーターの概要を示しています。.

表2:薬物動態の要約(平均エストラジオール値)。

腹部への適用後の各薬物動態パラメータの相対標準偏差は平均50%であり、これは経皮薬物送達に関連するかなりの被験者間変動を示しています。. ⁇ 部への適用後の各薬物動態パラメータの相対標準偏差は、腹部への適用後のそれよりも低かった(たとえば、Cmax 39%対62%、Cavg 35%対48%)。.

分布。

外因性エストロゲンの分布は、内因性エストロゲンの分布と似ています。. エストロゲンは体内に広く分布しており、一般に性ホルモンの標的臓器に高濃度で見られます。. エストロゲンは、主にSHBGとアルブミンに結合した血液中を循環します。.

代謝。

外因性エストロゲンは内因性エストロゲンと同じ方法で代謝されます。. 循環エストロゲンは、代謝相互変換の動的平衡に存在します。. これらの変換は主に肝臓で行われます。. エストラジオールは可逆的にエストロンに変換され、どちらも主要な尿中代謝物であるエストリオールに変換できます。. エストロゲンはまた、肝臓での硫酸塩とグルクロニドの抱合、腸への抱合体の胆 ⁇ 分 ⁇ 、および腸での加水分解とそれに続く再吸収を介して腸肝再循環を受けます。. 閉経後の女性では、循環エストロゲンのかなりの割合が硫酸塩抱合体として存在します。特にエストロネ硫酸塩は、より活性なエストロゲンの形成のための循環貯水池として機能します。.

排 ⁇ 。

エストラジオール、エストロン、およびエストリオールは、グルクロニドおよび硫酸塩の共役とともに尿中に排 ⁇ されます。.

癒着。

6.5cm²および12.5cm²のサイズのラジオールに対応するプラセボ経皮系の接着力のオープンラベル研究は、45〜75歳の112人の健康な女性で行われました。. 各女性は、両方の経皮システムを毎週、上腹部に3週間連続して適用しました。. ⁇ 部の下腹部と上腹部は、Ladiolの承認された適用部位であることに注意してください。.

接着評価は、経皮システムの摩耗の毎週2、4、5、6、7日目に視覚的に行われました。. 各サイズの333の経皮システムに対して、合計1,654の付着観測が行われました。.

これらの観察のうち、約90%は、6.5cm²と12.5cm²の両方の経皮システムに本質的にリフトがないことを示しました。. 適用された経皮システムの総数のうち、約5%が各サイズの完全な分離を示しました。. 18.75cm²および25cm²の経皮システム(1日あたり0.075 mgおよび1日あたり0.1 mg)の接着の可能性は研究されていません。.

吸収。

エストラジオールは、無傷の皮膚全体に拡散し、受動的吸収プロセスによって体循環に拡散します。角質層全体に拡散することが速度制限因子です。.

14日間のフェーズ1の複数回投与試験で、Ladiolは、右または左上大 ⁇ の皮膚に1日1回投与した後、AUC0-24とCmaxの両方で定常状態で直線的でほぼ用量比例的なエストラジオールの薬物動態を示しました(表2)。.

表2:Ladiolの複数日投与後の14日目のエストラジオール(ベースラインでは修正されていない)の平均(%CV)薬物動態パラメーター0.1%。

エストラジオールの定常血清濃度は、大 ⁇ 上部の皮膚にラジオールを毎日塗布した後、12日目までに達成されます。. 14日目に1日1回投与した後の平均(SD)血清エストラジオールレベルを図1に示します。.

図1:ラジオールの複数日投与後の14日目の平均(SD)血清エストラジオール濃度(ベースラインでは未補正の値)0.1%。

ラジオールの全身曝露に対する日焼け止めやその他の局所ローションの影響は評価されていません。. 局所エストロゲンゲル承認製品を使用して実施された研究は、日焼け止めが局所的に適用されたエストロゲンゲルの全身曝露を変化させる可能性があることを示しています。.

分布。

外因性エストロゲンの分布は、内因性エストロゲンの分布と似ています。. エストロゲンは体内に広く分布しており、一般に性ホルモンの標的臓器に高濃度で見られます。. エストロゲンは、主にSHBGとアルブミンに結合した血液中を循環します。.

代謝。

外因性エストロゲンは内因性エストロゲンと同じ方法で代謝されます。. 循環エストロゲンは、代謝相互変換の動的平衡に存在します。. これらの変換は主に肝臓で行われます。. エストラジオールは可逆的にエストロンに変換され、どちらも主要な尿中代謝物であるエストリオールに変換できます。. エストロゲンはまた、肝臓での硫酸塩とグルクロニドの抱合、腸への抱合体の胆 ⁇ 分 ⁇ 、および腸での加水分解とそれに続く再吸収を介して腸肝再循環を受けます。. 閉経後の女性では、循環エストロゲンのかなりの割合が硫酸塩抱合体として存在します。特にエストロネ硫酸塩は、より活性なエストロゲンの形成のための循環貯水池として機能します。.

ラジオールのエストラジオールは、初回通過代謝を回避し、0.42から0.65の範囲の定常状態でエストラジオールとエストロンの比率を提供します。.

排 ⁇ 。

エストラジオール、エストロン、およびエストリオールは、グルクロニドおよび硫酸塩の共役とともに尿中に排 ⁇ されます。. エストラジオールの見かけの終末半減期は、ラジオールの投与後約10時間でした。.

特定の集団で使用します。

腎機能障害または肝機能障害のある患者を含む特定の集団では、薬物動態研究は行われませんでした。.

エストラジオール移植の可能性。

エストラジオール移植の効果は、大 ⁇ 1頭に1.0 gのラジオール(単回投与)を局所的に塗布した閉経後の健康な女性で評価されました。. ゲルを塗布してから1時間8時間後、パートナーと15分間直接太ももに接触しました。. 男性の被験者では、ベースラインを超えるエストラジオールレベルの上昇が見られましたが、この研究の転移性の程度は決定的ではありませんでした。.

洗浄の影響。

エストラジオールの皮膚表面レベルと血清濃度に対する塗布部位の洗浄の影響は、大 ⁇ 部の200cm²の面積に1.0 gのラジオールを塗布した後、閉経後の健康な女性16人で決定されました。. 塗布後1時間で塗布部位を石 ⁇ と水で洗浄すると、検出可能な量のエストラジオールが皮膚の表面からすべて除去され、エストラジオールへの平均合計24時間の曝露が30〜38%減少しました。.