奥培米芬片 OSPHENA (ospemifene) FDA药品说明书翻译.pdf

FULL PRESCRIBING INFORMATION WARNING ENDOMETRIAL CANCER AND CARDIOVASCULAR DISORDERS 警告 子宫内膜癌和心血管疾病警告 子宫内膜癌和心血管疾病 Endometrial Cancer 子宫内膜癌子宫内膜癌 OSPHENA is an estrogen agonist antagonist with tissue selective effects In the endometrium OSPHENA has estrogen agonistic effects There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens Adding a progestin to estrogen therapy reduces the risk of endometrial hyperplasia which may be a precursor to endometrial cancer Adequate diagnostic measures including directed and random endometrial sampling when indicated should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding see Warnings and Precautions 5 2 本药本药是一种具有组织选择性作用的雌激素激动药和拮抗药 在子宫内膜中 具有雌激素激是一种具有组织选择性作用的雌激素激动药和拮抗药 在子宫内膜中 具有雌激素激 动作用 使用非对抗性雌激素的女性动作用 使用非对抗性雌激素的女性 有子宫有子宫 患子宫内膜癌的风险增加患子宫内膜癌的风险增加 雌激素治疗时合用 雌激素治疗时合用 孕激素可降低孕激素可降低子宫内膜增生的风险 而子宫内膜增生可能是子宫内膜癌的先兆 子宫内膜增生的风险 而子宫内膜增生可能是子宫内膜癌的先兆 未经未经确诊确诊 的持续或复发性生殖器的持续或复发性生殖器异常异常出血的绝经后妇女应采取适当的诊断措施以排除恶性肿瘤 包出血的绝经后妇女应采取适当的诊断措施以排除恶性肿瘤 包 括定向和随机的子宫内膜取样 括定向和随机的子宫内膜取样 Cardiovascular Disorders 心血管疾病心血管疾病 There is a reported increased risk of stroke and deep vein thrombosis DVT in postmenopausal women 50 to 79 years of age who received daily oral conjugated estrogens CE 0 625 mg alone therapy over 7 1 years as part of the Women s Health Initiative WHI see Warnings and Precautions 5 1 有绝经后妇女有绝经后妇女 50 79 岁岁 遵从妇女健康倡议 遵从妇女健康倡议 WHI 每日接受口服结合雌激素每日接受口服结合雌激素 CE 0 625mg 单药治疗单药治疗 7 1 年 卒中和深静脉血栓形成年 卒中和深静脉血栓形成 DVT 风险增加的报道 风险增加的报道 In the clinical trials for OSPHENA duration of treatment up to 15 months the incidence rates of thromboembolic and hemorrhagic stroke were 0 72 and 1 45 per thousand women respectively in OSPHENA 60 mg treatment group and 1 04 and 0 in placebo see Warnings and Precautions 5 1 The incidence of DVT was 1 45 per thousand women in OSPHENA 60 mg treatment group and 1 04 per thousand women in placebo see Warnings and Precautions 5 1 OSPHENA should be prescribed for the shortest duration consistent with treatment goals and risks for the individual woman 临床试验临床试验 治疗时间达治疗时间达 15 个月个月 受试者为女性 受试者为女性 中 本药中 本药 60mg 治疗组血栓栓塞性卒中和出治疗组血栓栓塞性卒中和出 血性卒中的发生血性卒中的发生率分别为率分别为 0 72 和 和 1 45 安慰剂组为 安慰剂组为 1 04 和 和 0 本药 本药 60mg 治疗组治疗组 DVT 发生率为发生率为 1 45 安慰剂组为 安慰剂组为 1 04 本药处方应以最短的治疗时间满足治疗目的和 本药处方应以最短的治疗时间满足治疗目的和 风险 风险 1 INDICATIONS AND USAGE 适应症和用适应症和用途途 OSPHENA is indicated for the treatment of moderate to severe dyspareunia a symptom of vulvar and vaginal atrophy due to menopause 用于治疗中至重度性交困难 以缓解因绝经引起的外阴和阴道内萎缩症状 2 DOSAGE AND ADMINISTRATION 用法用量用法用量 OSPHENA is an estrogen agonist antagonist which has agonistic effects on the endometrium Generally when a product with estrogen agonistic effects on the endometrium is prescribed for a postmenopausal woman with a uterus a progestin should be considered to reduce the risk of endometrial cancer A woman without a uterus does not need a progestin see Warnings and Precautions 5 2 本药是一种对子宫内膜有激动作用的雌激素激动药和拮抗药 通常绝经后妇女使用对子宫内 膜有雌激素激动作用的药物 应考虑合用孕激素以降低子宫内膜癌的风险 没有子宫的妇女 不需合用孕激素 Use of OSPHENA should be for the shortest duration consistent with treatment goals and risks for the individual woman Postmenopausal women should be re evaluated periodically as clinically appropriate to determine if treatment is still necessary 使用本药应以最短的治疗时间满足治疗目的和风险 绝经后妇女应定期重新进行临床评价 以确定是否还需继续治疗 2 1 Treatment of Moderate to Severe Dyspareunia a Symptom of Vulvar and Vaginal Atrophy due to Menopause 中至重度性交困难中至重度性交困难 Take one 60 mg tablet with food once daily 一次60mg 一日1次 与食物同服 3 DOSAGE FORMS AND STRENGTHS 剂型和规格剂型和规格 OSPHENA tablets are white to off white oval biconvex film coated tablets containing 60 mg of ospemifene and engraved with 60 on one side 奥培米芬片 60mg 4 CONTRAINDICATIONS 禁忌症禁忌症 OSPHENA is contraindicated in women with any of the following conditions Undiagnosed abnormal genital bleeding Known or suspected estrogen dependent neoplasia Active DVT pulmonary embolism PE or a history of these conditions Active arterial thromboembolic disease for example stroke and myocardial infarctions MI or a history of these conditions OSPHENA is contraindicated in women who are or may become pregnant OSPHENA may cause fetal harm when administered to a pregnant woman Ospemifene was embryo fetal lethal with labor difficulties and increased pup deaths in rats at doses below clinical exposures and embryo fetal lethal in rabbits at 10 times the clinical exposure based on mg m 2 If this drug is used during pregnancy or if a woman becomes pregnant while taking this drug she should be apprised of the potential hazard to a fetus 有下列情况的女性禁用本药 1 未经确诊的生殖器异常出血者 2 已知或疑为雌激素依耐性肿瘤患者 3 活动性DVT或有其病史者 4 活动性动脉血栓栓塞病 如卒中和心肌梗死 或有其病史者 5 肺栓塞 PE 或有其病史者 6 妊娠期妇女或有妊娠可能的妇女 妊娠期妇女用药可能对胎儿造成损害 大鼠使用低于临床暴露量的剂量 胚胎 胎仔因分娩 困难致死或幼仔死亡率增加 家兔使用10倍 以体表面积mg m2单位计 临床暴露量剂量 出 现胚胎 胎仔致死 妊娠期妇女或有妊娠可能的妇女如需用药 应告知其对胎儿潜在风险 5 WARNINGS AND PRECAUTIONS 警告和注意事项警告和注意事项 5 1 Cardiovascular Disorders 心血管疾病心血管疾病 Risk factors for cardiovascular disorders 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 对心血管疾病风险因素 应适当处理 包括动脉血管疾病 如高血压 糖尿病 吸烟 高胆 固醇血症 肥胖 静脉血栓栓塞症 VTE 如有VTE个人或家族病史 肥胖 系统性红斑狼 疮 Stroke 卒中 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 ten thousand women years The increase in risk was demonstrated in year 1 and persisted 在WHI雌激素单药治疗的研究中 有妇女 50 79岁 每日接受CE 0 625mg 单药治疗与相同年 龄组接受安慰剂妇女相比 45相较33 每一万个妇女 一年 卒中风险有统计意义显著增加 的报道 证实在第1年风险增加并持续 In the clinical trials for OSPHENA duration of treatment up to 15 months the incidence rates of thromboembolic and hemorrhagic stroke were 0 72 and 1 45 per thousand women respectively in OSPHENA 60 mg treatment group and 1 04 and 0 per thousand women in placebo 临床试验 治疗时间达15个月 受试者为女性 中 本药60mg治疗组血栓栓塞性卒中和出 血性卒中的发生率分别为0 72 和1 45 安慰剂组为1 04 和0 Should thromboembolic or hemorrhagic stroke occur or be suspected OSPHENA should be discontinued immediately 如出现或疑为血栓栓塞性卒中或出血性卒中 应立即停药 Coronary Heart Disease 冠心病 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 placebo In the OSPHENA clinical trials a single MI occurred in a woman receiving 60 mg of ospemifene 在WHI雌激素单药治疗的研究中 与安慰剂组相比 单独使用雌激素的妇女对冠心病 CHD 无影响 CHD定义为非致死性心肌梗死 无症状心肌梗死 冠心病猝死 临床试验中 本 药60mg治疗组中有一例妇女出现心肌梗死 Venous Thromboembolism 静脉血栓栓塞症 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 ten thousand women years although only the increased risk of DVT reached statistical significance 23 versus 15 per ten thousand women years The increase in VTE risk was demonstrated during the first 2 years 在WHI雌激素单药治疗的研究中 有妇女每日接受CE 0 625mg 单药治疗与接受安慰剂妇 女相比 33相较22 每一万个妇女 一年 静脉血栓栓塞症 VTE DVT或PE 风险增加的报 道 尽管只有DVT风险达到有统计意义显著增加 前2年显示VTE风险增加 In the OSPHENA clinical trials the incidence of DVT was 1 45 per thousand women in OSPHENA 60 mg treatment group and 1 04 per thousand women in placebo Should a VTE occur or be suspected OSPHENA should be discontinued immediately 临床试验中 本药60mg治疗组DVT发生率为1 45 安慰剂组为1 04 如出现或疑为 VTE 应立即停药 If feasible OSPHENA 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 如需进行伴血栓栓塞 或延长固定期间风险增加的外科手术 情况允许 应在手术前停用本 药至少4 6周 5 2 Malignant Neoplasms 恶性肿瘤恶性肿瘤 Endometrial Cancer 子宫内膜癌 OSPHENA is an estrogen agonist antagonist with tissue selective effects In the endometrium OSPHENA has agonistic effects In the OSPHENA clinical trials 60 mg treatment group no cases of endometrial cancer were seen with exposure up to 52 weeks There was a single case of simple hyperplasia without atypia Endometrial thickening equal to 5 mm or greater was seen in the OSPHENA treatment groups at a rate of 60 1 per thousand women vs 21 2 per thousand women for placebo The incidence of any type of proliferative weakly plus active plus disordered endometrium was 86 1 per thousand women in OSPHENA vs 13 3 per thousand women for placebo Uterine polyps occurred at an incidence of 5 9 per thousand women vs 1 8 per thousand women for placebo 本药是一种具有组织选择性作用的雌激素激动药和拮抗药 在子宫内膜中 具有雌激素激动 作用 临床试验中 本药60mg治疗组 暴露至52周 未见子宫内膜癌 有一例非异常子宫 内膜增生的病例 本药治疗组60 1 和安慰剂组21 2 患者可见子宫内膜增厚5mm或以上 任何类型增殖的发生率 合并病变性 活动性 无序性增殖 本药治疗组为86 1 安慰剂 组为13 3 本药治疗组5 9 和安慰剂组1 8 患者可见子宫息肉 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 the use of estrogens for less than 1 year The greatest risk appears to be 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 有妇女 有子宫 使用非对抗性雌激素患子宫内膜癌风险增加的报道 其较非使用者风险增 加2 12倍 依赖于治疗时间和雌激素剂量 多数研究显示使用雌激素少于1年风险无显著性 增加 最大风险似乎与长期用药有关 用药5 10年 风险增加15 24倍 停用雌激素后风险 可持续8 15年 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 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 The use of progestins with OSPHENA therapy was not evaluated in the clinical trials 雌激素治疗时合用孕激素可降低子宫内膜增生的风险 而子宫内膜增生可能是子宫内膜癌 的先兆 但雌激素与孕激素合用可能较雌激素单药治疗有风险 包括乳腺癌风险增加 本 药与孕激素合用疗效在临床试验中尚未评估 Clinical surveillance of all women using OSPHENA 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 所有用药女性均应进行临床监测 未经确诊的持续或复发性生殖器异常出血的绝经后妇 女应采取适当的诊断措施以排除恶性肿瘤 包括定向和随机的子宫内膜取样 Breast Cancer 乳腺癌 OSPHENA 60 mg has not been adequately studied in women with breast cancer therefore it should not be used in women with known or suspected breast cancer or with a history of breast cancer 本药尚未在乳腺癌患者中进行充分研究 故已知或疑为乳腺癌 或有乳腺癌病史的患者不得 用药 5 3 Severe Hepatic Impairment 严重肝功能损害严重肝功能损害 OSPHENA should not be used in women with severe hepatic impairment see Use in Specific Populations 8 7 and Clinical Pharmacology 12 3 严重肝功能损害女性不得用药 6 ADVERSE REACTIONS 不良反应不良反应 The following serious adverse reactions are discussed elsewhere in the labeling Cardiovascular Disorders see Boxed Warning Warnings and Precautions 5 1 Malignant Neoplasms see Boxed Warning Warnings and Precautions 5 2 下列不良反应已在说明书其他章节讨论 心血管疾病 恶性肿瘤 6 1 Clinical Trials Experience 临床试验经验临床试验经验 Because clinical trials are conducted under widely varying conditions adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice 由于临床试验是在各种不同条件下进行的 观察到的不良反应发生率不能直接与其他临 床试验中的发生率相比较 可能也不能反应临床实践中观察到的发生率 The safety of OSPHENA has been assessed in nine phase 2 3 trials N 1892 with doses ranging from 5 to 90 mg per day The duration of treatment in these studies ranged from 6 weeks to 15 months Most women N 1370 had a treatment period of at least 12 weeks 409 had at least 52 weeks 1 year of exposure 本药安全性通过9项2 3期试验 N 1892 评估 剂量范围为5 90mg 日 研究持续时间为6周 15个月 大部分妇女 N 1370 接受过至少为期12周的治疗 409名妇女接受过至少52周 1年 的暴露 The incidence rates of thromboembolic and hemorrhagic stroke were 0 72 per thousand women 1 reported case of thromboembolic stroke and 1 45 per thousand women 2 reported cases of hemorrhagic stroke respectively in OSPHENA 60 mg treatment group and 1 04 and 0 per thousand women respectively in placebo The incidence of deep vein thrombosis DVT was 1 45 per thousand women in OSPHENA 60 mg treatment group 2 reported cases of DVT and 1 04 1 case of DVT in placebo 本药60mg治疗组血栓栓塞性卒中和出血性卒中的发生率分别为0 72 1例 和1 45 2例 安慰剂组为1 04 和0 本药60mg治疗组DVT发生率为1 45 2例 安慰剂组为1 04 1 例 Table 1 lists adverse reactions occurring more frequently in the OSPHENA 60 mg treatment group than in placebo and at a frequency 1 本药60mg治疗组和安慰剂组 发生程度 1 的不良反应见表1 Table 1 Adverse Reactions Reported More Common in the OSPHENA Treatment Group 60 mg Once Daily and at Frequency 1 0 in the Double Blind Controlled Clinical Trials with OSPHENA vs Placebo 表表1 双盲 对照临床试验中本药 双盲 对照临床试验中本药60mg剂量组和安慰剂组报道的更为常见发生程度 剂量组和安慰剂组报道的更为常见发生程度 1 的的 不良反应不良反应 Ospemifene 60 mg 本药本药60mg剂量组剂量组 Placebo 安慰剂组安慰剂组 N 1242 N 958 Vascular Disorders 血管疾病 Hot flush 潮热 7 5 2 6 Reproductive System and Breast Disorders 生殖系统和乳腺疾病 Vaginal discharge 阴道分泌物 3 8 0 3 Genital discharge 生殖器排泄物 1 3 0 1 Musculoskeletal and Connective Tissue Disorders 肌肉骨骼和结缔组织疾病 Muscle spasms 肌肉痉挛 3 2 0 9 Skin and Subcutaneous Tissue Disorders 皮肤和皮下组织疾病 Hyperhidrosis 多汗症 1 6 0 6 7 DRUG INTERACTIONS 药物相互作用药物相互作用 OSPHENA is primarily metabolized by CYP3A4 and CYP2C9 CYP2C19 and other pathways contribute to the metabolism of ospemifene 本药主要通过细胞色素P450 CYP 3A4和CYP 2C9 CYP 2C19代谢 7 1 Estrogens and estrogen agonist antagonist 雌激素和雌激素激动药雌激素和雌激素激动药 拮抗药拮抗药 OSPHENA should not be used concomitantly with estrogens and estrogen agonists antagonists The safety of concomitant use of OSPHENA with estrogens and estrogen agonists antagonists has not been studied 本药不得与雌激素和雌激素激动药 拮抗药合用 安全性尚不明确 7 2 Fluconazole 氟康唑氟康唑 Fluconazole a moderate CYP3A strong CYP2C9 moderate CYP2C19 inhibitor should not be used with OSPHENA Fluconazole increases the systemic exposure of ospemifene by 2 7 fold Administration of fluconazole with ospemifene may increase the risk of OSPHENA related adverse reactions see Clinical Pharmacology 12 3 氟康唑是一种中效CYP 3A4 强效CYP 2C9 中度CYP 2C19抑制药 不得与本药合用 氟 康唑可增加本药的系统暴露量2 7倍 合用可使与本药相关的不良反应风险增高 7 3 Rifampin 利福平利福平 Rifampin a strong CYP3A4 moderate CYP2C9 moderate CYP2C19 inducer decreases the systemic exposure of ospemifene by 58 Therefore co administration of OSPHENA with drugs such as rifampin which induce CYP3A4 CYP2C9 and or CYP2C19 activity would be expected to decrease the systemic exposure of ospemifene which may decrease the clinical effect see Clinical Pharmacology 12 3 利福平是一种强效CYP 3A4 中效CYP 2C9 中效CYP 2C19抑制药 可降低本药系统暴露 量58 故本药与利福平或其他诱导CYP 3A4 CYP 2C9 CYP 2C19的药物合用可降低本药 系统暴露量 从而降低本药疗效 7 4 Ketoconazole 酮康唑酮康唑 Ketoconazole a strong CYP3A4 inhibitor increases the systemic exposure of ospemifene by 1 4 fold Administration of ketoconazole chronically with ospemifene may increase the risk of OSPHENA related adverse reactions see Clinical Pharmacology 12 3 酮康唑是一种强效CYP 3A4抑制药 可增加本药系统暴露量1 4倍 长期合用可使与本药相 关的不良反应风险增高 7 5 Warfarin 华法林华法林 Repeated administration of ospemifene had no effect on the pharmacokinetics of a single 10 mg dose of warfarin No study was conducted with multiple doses of warfarin The effect of ospemifene on clotting time such as the International Normalized Ratio INR or prothrombin time PT was not studied see Clinical Pharmacology 12 3 重复给予本药 对单次给予华法林10mg剂量的药代动力学无影响 尚无进行华法林多次给 药的研究 本药对凝血时间 CT 如国际标准化比值 INR 或凝血酶原时间 PT 的作用尚不 明确 7 6 Highly Protein Bound Drugs 高蛋白结合药物高蛋白结合药物 Ospemifene is more than 99 bound to serum proteins and might affect the protein binding of other drugs Use of OSPHENA with other drug products that are highly protein bound may lead to increased exposure of either that drug or ospemifene see Clinical Pharmacology 12 3 本药可与血浆蛋白高度结合 99 可能影响其他药物与蛋白的结合 本药与其他高蛋白结 合药物合用 可能互相增加彼此的暴露量 7 7 Multiple Enzyme Inhibition 多酶抑制多酶抑制 Co administration of OSPHENA with a drug known to inhibit CYP3A4 and CYP2C9 isoenzymes may increase the risk of OSPHENA related adverse reactions 合用已知抑制CYP 3A4 CYO 2C9同工酶的药物可使与本药相关的不良反应风险增高 8 USE IN SPECIFIC POPULATIONS 特殊人群用药特殊人群用药 8 1 Pregnancy 妊娠期妇女妊娠期妇女 Teratogenic effects 致畸作用致畸作用 Pregnancy Category X see Contraindications 4 妊娠分级 X级 Risk Summary 风险概述风险概述 Based on animal data OSPHENA is likely to increase the risk of adverse outcomes during pregnancy and labor Adverse findings at maternally toxic doses included embryofetal lethality in rats and rabbits and neonatal mortality and difficult labor in rats The reproductive effects observed are consistent with and are considered to be related to estrogen receptor activity of OSPHENA 依据动物试验数据 妊娠期妇女和分娩妇女用药可能增加不良事件 大鼠和家兔使用母体毒 性剂量 不良发现包括胚胎 胎仔致死 幼仔死亡以及大鼠分娩困难 观察到的生殖作用与 本药的雌激素受体活动有关 Animal Data 动物数据动物数据 The effects of OSPHENA on embryo fetal development were studied in rats 0 1 1 or 4 mg kg day and rabbits 3 10 or 30 mg kg day when treated from implantation through organogenesis In rabbits there was an increase in the incidence of total resorptions at 30 mg kg day 10 times the human exposure based on surface area mg m 2 Drug induced malformations were not observed in either rats or rabbits 本药胚胎 胎儿毒性通过大鼠 一日0 1mg kg 1mg kg 4mg kg 家兔 一日3mg kg 10mg kg 30mg kg 胚胎着床至器官形成期试验得以研究 家兔一日30mg kg 以体表面积mg m2计 为 人类暴露量10倍 剂量组总再吸收发生率增加 大鼠和家兔中未观察到药物诱发的畸形 The effects of OSPHENA on pre and postnatal development were studied in pregnant rats 0 01 0 05 and 0 25 mg kg day treated from implantation through lactation Pregnant rats given 0 05 or 0 25 mg kg day OSPHENA 0 8 to 4 the human exposure based on surface area mg m 2 had a significantly prolonged and difficult gestation increased post implantation loss increased number of dead pups at birth and an increased incidence of postnatal loss OSPHENA did not induce adverse effects in the surviving offspring of pregnant rats at drug exposures up to 4 the human exposure 本药产前和产后毒性通过妊娠大鼠 一日0 01mg kg 0 05mg kg 0 25mg kg 胚胎着床至哺乳 期试验得以研究 妊娠大鼠一日0 05mg kg 0 25mg kg 以体表面积mg m2计 为人类暴露量 的0 8 4 剂