英文药名：Evista（Raloxifene filmcoated tablets） 中文药名：雷洛昔芬薄膜片 生产厂家：礼来 药品介绍 药品英文名 Raloxifene 药品别名 易维特、Evista 药物剂型 雷洛昔芬薄膜衣片剂：60mg/片。避光，30℃以下干燥处保存，不得冷冻。 药理作用 本品是一种苯噻吩类化合物，是新概念抗骨吸收的非激素类药物，属于第二代选择性雌激素受体调节剂(SERM)。SERM能起雌激素激动作用或拮抗作用。本品对骨骼和心血管系统有雌激素激动作用，对乳房和子宫有雌激素拮抗作用，而没有雌激素的诸多不良反应，可使骨矿物质密度增加，防止绝经后骨质丧失；降低总胆固醇、低密度脂蛋白胆固醇(LDL-C)、纤维蛋白原和脂蛋白A水平，不影响甘油三酯、高密度脂蛋白胆固醇(HDL-C)；不会刺激乳腺和子宫内膜，不增加乳腺癌和子宫内膜癌的危险。 药动学 雷洛昔芬口服后迅速吸收，口服剂量的大约60%被吸收，进入循环前被大量葡萄糖醛酸苷化，绝对生物利用度为2%。达到平均最大血浆浓度的时间取决于雷洛昔芬和其葡糖醛酸苷化代谢物全身内转换和肠肝循环。雷洛昔芬在全身广泛分布，分布容积不依赖于剂量，与血浆蛋白紧密结合(98%～99%)。本品大量参与首关代谢成为葡萄糖醛基结合物：雷洛昔芬-4-葡萄糖苷酸，雷洛昔芬-6-葡萄糖苷酸和雷洛昔芬-4，6-葡萄糖苷酸。未检出其他代谢物。雷洛昔芬包含低于其结合浓度的1% 和葡糖苷酸代谢物。通过肠肝循环维持雷洛昔芬的水平，血浆半衰期为27.7h。通过单次用药的结果推测多次用药的药代动力学。增加雷洛昔芬的剂量导致血浆时间浓度曲线下面积（AUC )增加的比例轻度下降。进入体内的雷洛昔芬及其葡萄糖苷酸代谢物的绝大部分在5日内排泄，主要通过粪便，经尿排出的部分少于6%。肾功能不全时少于总剂量的6% 经尿中排出，一项人群的药代动力学研究表明，经净体质量校正的肌酐清除率降低47% 会导致雷洛昔芬的清除降低17% 和雷洛昔芬结合物的清除降低15% 。肝硬化和轻度肝功能不全者（Child-Pugh A 级)，单次使用雷洛昔芬的药代动力学与健康者比较，血浆雷洛昔芬的浓度比对照者约高2.5倍并与胆红素水平相关。 适应证 用于预防和治疗妇女绝经后骨质疏松。能显著地降低椎体骨折发生率，但髋部骨折发生率的降低未被证实。当决定给绝经后妇女选择使用雷洛昔芬或其他治疗（包括雌激素)时，需考虑绝经期症状，对子宫和乳腺组织的作用及对心血管的危险性和有利影响。 禁忌证 1.对本品或片剂中所含的任何赋形剂成分过敏者禁用。 2.正在或既往患有静脉血栓栓塞性疾病者(VTE)，包括深静脉血栓、肺栓塞和视网膜静脉血栓者禁用。 3.肝功能减退包括胆汁淤积、严重肾功能减退者禁用。 4.难以解释的子宫出血以及子宫内膜癌患者禁用。 5. 雷洛昔芬仅用于绝经后妇女。有妊娠可能的妇女禁用。怀孕妇女摄入雷洛昔芬可能引起胎儿损害。如果妊娠妇女误服或在服用该药期间妊娠，应向病人说明对胎儿的可能损害。 6.尚不知雷洛昔芬是否经乳汁分泌，所以哺乳期妇女不推荐使用，雷洛昔芬可能影响婴儿的发育。 7.儿童不适用。 8.雷洛昔芬不宜用于有子宫内膜癌症状和体征者，或难以解释的子宫出血者。因为对这类病人的安全性尚未充分研究。 注意事项 1.绝经2年后的妇女方可使用。 2.本品雷洛昔芬不引起子宫内膜增生。治疗期间的任何子宫出血都属意外并应请专家做全面检查。其最常见的子宫出血的原因是内膜萎缩和良性内膜息肉。绝经后妇女接受雷洛昔芬治疗3年中，报道的良性内膜息肉为 0.7% ，而安慰剂治疗妇女为 0.2%。3.因缺乏与雌激素合用的经验，不推荐同时使用。 4.建议饮食钙摄入量不足的妇女服用钙剂和维生素D。 5.雷洛昔芬可增加静脉血栓栓塞事件的危险性，这点与目前使用的激素替代治疗伴有的危险性相似。对任何原因可能造成静脉血栓事件的病人均需考虑危险－益处的平衡。雷洛昔芬在一些因疾病或其它情况而需要长时间制动的病人应停药。在出现上述情况时立即或在制动之前3 天停药。直到上述情况被解决或病人可以完全活动才能再次开始使用雷洛昔芬。 6.雷洛昔芬主要在肝脏代谢。肝硬化和轻度肝功能不全病人血浆雷洛昔芬的浓度比对照者约高2.5倍，并与总胆红素水平相关。在雷洛昔芬于肝功能不全妇女中的安全性和有效性未得到进一步评价以前，此药不被推荐用于这类病人。如发现血清总胆红素、谷氨酰转肽酶、碱性磷酸酶、丙氨酸氨基转移酶(ALT)和天冬氨酸氨基转移酶(AST)在治疗中升高，应严密监测。 7.在因口服雌激素造成的高甘油三酯血症的病人中，雷洛昔芬可能会引起其血清甘油三酯水平的进一步上升。因此当有此类病史的病人使用雷洛昔芬时，应监测血清甘油三酯水平。 8.雷洛昔芬对减少血管扩张(潮热)无作用，对其他与雌激素有关的绝经期症状也无效。 9. 雷洛昔芬不适用于男性患者。尚不清楚雷洛昔芬对驾驶和机器操作能力的影响。 10.雷洛昔芬在乳腺癌患者中的安全性尚无足够的研究。目前没有关于雷洛昔芬单用或联合治疗早期或晚期乳腺癌的临床资料，因此只有当患者已完成针对其乳腺癌的治疗，包括辅助治疗后再应用雷洛昔芬进行骨质疏松的预防及治疗。因为缺乏与全身雌激素合用的经验，不推荐同时使用。 不良反应 1.常见药物不良反应为潮热和小腿痛性痉挛。 2.少见的为血小板数目轻度减少、恶心、呕吐、腹痛和消化不良、皮疹、血压升高、头痛。 3.最严重的的不良反应为静脉血栓栓塞。有研究资料显示，参加研究的12000 名妇女在治疗期间2～36 月中出现的不良反应，绝大多数通常无需停止治疗。在预防组人群中出现因任何不良反应而中断治疗者：使用雷洛昔芬的病人581名为10.7%，而安慰剂组584名为11.1%。治疗组由于任何不良事件而中断治疗者：雷洛昔芬治疗病人2557名为10.9% ，而安慰剂治疗组2,567名为8.8% 。与使用雷洛昔芬有关的不良反应在雷洛昔芬治疗组和安慰剂组之间有显著不同（p<0.05)。叙述如下：所有安慰剂对照的临床研究中静脉血栓栓塞事件，包括深静脉血栓，肺栓塞和视网膜静脉血栓发生的频率约0.7%或3.25例/每1000 病人年。与安慰剂比较雷洛昔芬治疗的相对危险性为2.32 (CI1.26，4.26)。开始治疗的4个月静脉血栓栓塞事件的危险性最大。浅静脉血栓性静脉炎的发生频率少于1% 。与安慰剂比较使用雷洛昔芬的病人血管扩张（潮热)的发生轻度增加（骨质疏松症的预防研究，绝经后2 至8 年，雷洛昔芬和安慰剂分别为24.3%和18.2% ；骨质疏松症的治疗研究，平均年龄66岁，雷洛昔芬和安慰剂分别为9.7%和6.4%)，不良反应多数出现在开始治疗的6个月，在以后则极少出现。观察到的另一个不良反应为小腿痛性痉挛（预防组 雷洛昔芬和安慰剂分别为5.5% 和1.9% ，治疗组 雷洛昔芬和安慰剂分别为7.0%和3.7% )还观察到的一个不具统计意义的改变（p>0.05)，但有明显的剂量趋势。即外周水肿在预防组雷洛昔芬组和安慰剂组分别为3.1% 和1.9% ，治疗组的发生率分别为5.2% 和4.4% 。有报道在雷洛昔芬治疗期间血小板数目轻度减少（6～10%)。上市后随访中有极少(<1/10,000) 胃肠症状的报告如恶心、呕吐、腹痛和消化不良；皮疹；血压升高及包括偏头痛在内的头痛。有13.5%的雷洛昔芬和11.4%的安慰剂治疗的病人出现流感综合症。 极少病例出现AST和/或ALT 轻度增加，不能排除是雷洛昔芬所致，在安慰剂人群中发生的频率相似。雷洛昔芬（n=317)与持续的联合（n=110)激素替代治疗（HRT)或周期（n=205 )HRT的几个临床研究相比，雷洛昔芬治疗时乳腺症状和子宫出血的发生率显著低于任何一种HRT 治疗方案。 用法用量 口服，每次60mg，每日1次。可以在一天中的任何时候服用且不受进餐的限制。老年人无需调整剂量。由于疾病的自然过程，雷洛昔芬需要长期使用。通常建议饮食钙摄入量不足的妇女服用钙剂和维生素 D 。或遵医嘱。 药物相应作用 1.同时摄入碳酸钙或含铝和氢氧化镁的抗酸剂对全身使用雷洛昔芬不影响。 2.同时服用雷洛昔芬和华法林不改变两种化合物的药代动力学，但发现能轻度减少凝血酶原时间，所以当雷洛昔芬与华法林或其他香豆素类衍生物合用时需监测凝血酶原时间。对已经接受香豆素抗凝的药物在开始雷洛昔芬治疗后几周可能出现对凝血酶原时间的作用。 3.雷洛昔芬不影响对单次使用甲基泼尼松龙的药代动力学。 4.雷洛昔芬不影响地高辛稳态药时曲线下面积(ALJC)，地高辛的药物最大浓度(Cmax)增加少于5%。 5.雷洛昔芬不宜与考来烯胺(或其他阴离子交换树脂)同时服用，后者可显著减低雷洛昔芬的吸收和肠肝循环。 6.与氨苄西林同服会减低雷洛昔芬的峰浓度，但由于不影响整体吸收量和清除率，故可以同服。 7.雷洛昔芬可轻度增加激素结合球蛋白的浓度，包括性激素结合球蛋白(SHBG)、甲状腺素结合球蛋白(TBG)和皮质激素结合球蛋白(CBG)，使相应的总的激素浓度增高，但并不影响游离激素的浓度。 8.因缺乏与全身雌激素合用的经验，不推荐同时使用。 Evista 60mg film-coated tablets 1. Name of the medicinal product EVISTA 60 mg film coated tablets 2. Qualitative and quantitative composition Each film coated tablet contains 60 mg raloxifene hydrochloride, equivalent to 56 mg raloxifene free base. Excipient: each tablet contains lactose (149.40 mg). For a full list of excipients, see section 6.1. 3. Pharmaceutical form Film coated tablet. Elliptically shaped, white tablets imprinted with the code '4165'. 4. Clinical particulars 4.1 Therapeutic indications EVISTA is indicated for the treatment and prevention of osteoporosis in postmenopausal women. A significant reduction in the incidence of vertebral, but not hip fractures has been demonstrated. When determining the choice of EVISTA or other therapies, including oestrogens, for an individual postmenopausal woman, consideration should be given to menopausal symptoms, effects on uterine and breast tissues, and cardiovascular risks and benefits (see section 5.1). 4.2 Posology and method of administration The recommended dose is one tablet daily by oral administration, which may be taken at any time of the day without regard to meals. No dose adjustment is necessary for the elderly. Due to the nature of this disease process, EVISTA is intended for long term use. Generally calcium and vitamin D supplements are advised in women with a low dietary intake. Use in renal impairment: EVISTA should not be used in patients with severe renal impairment (see section 4.3). In patients with moderate and mild renal impairment, EVISTA should be used with caution. Use in hepatic impairment: EVISTA should not be used in patients with hepatic impairment (see section 4.3). 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients. Must not be used in women with child bearing potential. Active or past history of venous thromboembolic events (VTE), including deep vein thrombosis, pulmonary embolism and retinal vein thrombosis. Hepatic impairment including cholestasis. Severe renal impairment. Unexplained uterine bleeding. EVISTA should not be used in patients with signs or symptoms of endometrial cancer as safety in this patient group has not been adequately studied. 4.4 Special warnings and precautions for use Raloxifene is associated with an increased risk for venous thromboembolic events that is similar to the reported risk associated with current use of hormone replacement therapy. The risk-benefit balance should be considered in patients at risk of venous thromboembolic events of any aetiology. EVISTA should be discontinued in the event of an illness or a condition leading to a prolonged period of immobilisation. Discontinuation should happen as soon as possible in case of the illness, or from 3 days before the immobilisation occurs. Therapy should not be restarted until the initiating condition has resolved and the patient is fully mobile. In a study of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, raloxifene did not affect the incidence of myocardial infarction, hospitalized acute coronary syndrome, overall mortality, including overall cardiovascular mortality, or stroke, compared to placebo. However, there was an increase in death due to stroke in women assigned to raloxifene. The incidence of stroke mortality was 1.5 per 1000 women per year for placebo versus 2.2 per 1000 women per year for raloxifene. This finding should be considered when prescribing raloxifene for postmenopausal women with a history of stroke or other significant stroke risk factors, such as transient ischemic attack or atrial fibrillation. There is no evidence of endometrial proliferation. Any uterine bleeding during EVISTA therapy is unexpected and should be fully investigated by a specialist. The two most frequent diagnoses associated with uterine bleeding during raloxifene treatment were endometrial atrophy and benign endometrial polyps. In postmenopausal women who received raloxifene treatment for 4 years, benign endometrial polyps were reported in 0.9 % compared to 0.3 % in women who received placebo treatment. Raloxifene is metabolised primarily in the liver. Single doses of raloxifene given to patients with cirrhosis and mild hepatic impairment (Child-Pugh class A) produced plasma concentrations of raloxifene which were approximately 2.5 times the controls. The increase correlated with total bilirubin concentrations. Until safety and efficacy have been evaluated further in patients with hepatic insufficiency, the use of EVISTA is not recommended in this patient population. Serum total bilirubin, gamma-glutamyl transferase, alkaline phosphatase, ALT and AST should be closely monitored during treatment if elevated values are observed. Limited clinical data suggest that in patients with a history of oral oestrogen-induced hypertriglyceridemia (>5.6 mmol/l), raloxifene may be associated with a marked increase in serum triglycerides. Patients with this medical history should have serum triglycerides monitored when taking raloxifene. The safety of EVISTA in patients with breast cancer has not been adequately studied. No data are available on the concomitant use of EVISTA and agents used in the treatment of early or advanced breast cancer. Therefore, EVISTA should be used for osteoporosis treatment and prevention only after the treatment of breast cancer, including adjuvant therapy, has been completed. As safety information regarding co-administration of raloxifene with systemic oestrogens is limited, such use is not recommended. EVISTA is not effective in reducing vasodilatation (hot flushes), or other symptoms of the menopause associated with oestrogen deficiency. EVISTA contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Concurrent administration of either calcium carbonate or aluminium and magnesium-hydroxide containing antacids do not affect the systemic exposure of raloxifene. Co-administration of raloxifene and warfarin does not alter the pharmacokinetics of either compound. However, modest decreases in the prothrombin time have been observed, and if raloxifene is given concurrently with warfarin or other coumarin derivatives, the prothrombin time should be monitored. Effects on prothrombin time may develop over several weeks if EVISTA treatment is started in patients who are already on coumarin anticoagulant therapy. Raloxifene has no effect on the pharmacokinetics of methylprednisolone given as a single dose. Raloxifene does not affect the steady-state AUC of digoxin. The Cmax of digoxin increased by less than 5 %. The influence of concomitant medication on raloxifene plasma concentrations was evaluated in the prevention and treatment trials. Frequently co-administered medicinal products included: paracetamol, non-steroidal anti-inflammatory drugs (such as acetylsalicylic acid, ibuprofen, and naproxen), oral antibiotics, H1 antagonists, H2 antagonists, and benzodiazepines. No clinically relevant effects of the co-administration of the agents on raloxifene plasma concentrations were identified. Concomitant use of vaginal oestrogen preparations was allowed in the clinical trial programme, if necessary to treat atrophic vaginal symptoms. Compared to placebo there was no increased use in EVISTA treated patients. In vitro, raloxifene did not interact with the binding of warfarin, phenytoin, or tamoxifen. Raloxifene should not be co-administered with cholestyramine (or other anion exchange resins), which significantly reduces the absorption and enterohepatic cycling of raloxifene. Peak concentrations of raloxifene are reduced with co-administration with ampicillin. However, since the overall extent of absorption and the elimination rate of raloxifene are not affected, raloxifene can be concurrently administered with ampicillin. Raloxifene modestly increases hormone-binding globulin concentrations, including sex steroid binding globulins (SHBG), thyroxine binding globulin (TBG), and corticosteroid binding globulin (CBG), with corresponding increases in total hormone concentrations. These changes do not affect concentrations of free hormones. 4.6 Pregnancy and lactation EVISTA is only for use in postmenopausal women. EVISTA must not be taken by women of child bearing potential. Raloxifene may cause foetal harm when administered to a pregnant woman. If this medicinal product is used mistakenly during pregnancy or the patient becomes pregnant while taking it, the patient should be informed of the potential hazard to the foetus (see section 5.3). It is not known whether raloxifene is excreted in human milk. Its clinical use, therefore, cannot be recommended in breast-feeding women. EVISTA may affect the development of the baby. 4.7 Effects on ability to drive and use machines Raloxifene has no known influence on the ability to drive and use machines. 4.8 Undesirable effects In osteoporosis treatment and prevention studies involving over 13,000 postmenopausal women all adverse reactions were recorded. The duration of treatment in these studies ranged from 6 to 60 months. The majority of adverse reactions have not usually required cessation of therapy. In the prevention population discontinuations of therapy due to any adverse reaction occurred in 10.7 % of 581 EVISTA treated patients and 11.1 % of 584 placebo-treated patients. In the treatment population discontinuations of therapy due to any clinical adverse event occurred in 12.8 % of 2,557 EVISTA treated patients and 11.1 % of 2,576 placebo treated patients. The adverse reactions associated with the use of raloxifene in osteoporosis clinical trials are summarised in the table below. The following convention has been used for the classification of the adverse reactions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) very rare (<1/10,000), not known (cannot be estimated from the available data). Vascular disorders Very common: Vasodilation (hot flushes) Uncommon: Venous thromboembolic events, including deep vein thrombosis, pulmonary embolism, retinal vein thrombosis Superficial vein thrombophlebitis Musculoskeletal and connective tissue disorders Common: Leg cramps General disorders and administration site conditions Very common: Flu syndrome Common: Peripheral oedema Compared with placebo-treated patients the occurrence of vasodilatation (hot flushes) was modestly increased in EVISTA patients (clinical trials for the prevention of osteoporosis, 2 to 8 years postmenopausal, 24.3 % EVISTA and 18.2 % placebo; clinical trials for the treatment of osteoporosis, mean age 66, 10.6 % for EVISTA and 7.1 % placebo). This adverse reaction was most common in the first 6 months of treatment, and seldom occurred de novo after that time. In a study of 10,101 postmenopausal women with documented coronary heart disease or at increased risk for coronary events (RUTH), the occurrence of vasodilatation (hot flushes) was 7.8 % in the raloxifene-treated patients and 4.7 % in the placebo-treated patients. Across all placebo-controlled clinical trials of raloxifene in osteoporosis, venous thromboembolic events, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis occurred at a frequency of approximately 0.8 % or 3.22 cases per 1,000 patient years. A relative risk of 1.60 (CI 0.95, 2.71) was observed in EVISTA treated patients compared to placebo. The risk of a thromboembolic event was greatest in the first four months of therapy. Superficial vein thrombophlebitis occurred in a frequency of less than 1 %. In the RUTH study, venous thromboembolic events occurred at a frequency of approximately 2.0 % or 3.88 cases per 1000 patient-years in the raloxifene group and 1.4 % or 2.70 cases per 1000 patient-years in the placebo group. The hazard ratio for all VTE events in the RUTH study was HR = 1.44 (1.06 – 1.95). Superficial vein thrombophlebitis occurred in a frequency of 1 % in the raloxifene group and 0.6 % in the placebo group. Another adverse reaction observed was leg cramps (5.5 % for EVISTA, 1.9 % for placebo in the prevention population and 9.2 % for EVISTA, 6.0 % for placebo in the treatment population). In the RUTH study, leg cramps were observed in 12.1 % of raloxifene-treated patients and 8.3 % of placebo-treated patients. Flu syndrome was reported by 16.2 % of EVISTA treated patients and 14.0 % of placebo treated patients. One further change was seen which was not statistically significant (p > 0.05), but which did show a significant dose trend. This was peripheral oedema, which occurred in the prevention population at an incidence of 3.1 % for EVISTA and 1.9 % for placebo; and in the treatment population occurred at an incidence of 7.1 % for EVISTA and 6.1 % for placebo. In the RUTH study, peripheral oedema occurred in 14.1 % of the raloxifene-treated patients and 11.7 % of the placebo-treated patients, which was statistically significant. Slightly decreased (6-10 %) platelet counts have been reported during raloxifene treatment in placebo-controlled clinical trials of raloxifene in osteoporosis. Rare cases of moderate increases in AST and/or ALT have been reported where a causal relationship to raloxifene can not be excluded. A similar frequency of increases was noted among placebo patients. In a study (RUTH) of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, an additional adverse reaction of cholelithiasis occurred in 3.3 % of patients treated with raloxifene and 2.6 % of patients treated with placebo. Cholecystectomy rates for raloxifene (2.3 %) were not statistically significantly different from placebo (2.0 %). EVISTA (n = 317) was compared with continuous combined (n = 110) hormone replacement therapy (HRT) or cyclic (n = 205) HRT patients in some clinical trials. The incidence of breast symptoms and uterine bleeding in raloxifene treated women was significantly lower than in women treated with either form of HRT. The adverse reactions reported in post-marketing experience and are presented in the table below. Blood and lymphatic system disorders Very rare: thrombocytopenia Gastrointestinal disorders Very rare: Gastrointestinal symptoms such as nausea, vomiting, abdominal pain, dyspepsia General disorders and administration site conditions Rare: peripheral oedema Investigations Very rare: Increased blood pressure Nervous system disorders Very rare: Headache, including migraine Skin and subcutaneous tissue disorders Very rare: Rash Reproductive system and breast disorders Very rare: Mild breast symptoms such as pain, enlargement and tenderness Vascular disorders Rare: venous thromboembolic reaction Very rare: arterial thromboembolic reaction 4.9 Overdose In some clinical trials, daily doses were given up to 600 mg for 8 weeks and 120 mg, for 3 years. No cases of raloxifene overdose were reported during clinical trials. In adults, symptoms of leg cramps and dizziness have been reported in patients who took more than 120 mg as a single ingestion. In accidental overdose in children younger than 2 years of age, the maximum reported dose has been 180 mg. In children, symptoms of accidental overdose included ataxia, dizziness, vomiting, rash, diarrhea, tremor, and flushing, and elevation in alkaline phosphatase. The highest overdose has been approximately 1.5 grams. No fatalities associated with overdose have been reported. There is no specific antidote for raloxifene hydrochloride. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmaco-therapeutic group: Selective Oestrogen Receptor Modulator, ATC code: G03XC01. As a selective oestrogen receptor modulator (SERM), raloxifene has selective agonist or antagonist activities on tissues responsive to oestrogen. It acts as an agonist on bone and partially on cholesterol metabolism (decrease in total and LDL-cholesterol), but not in the hypothalamus or in the uterine or breast tissues. Raloxifene's biological actions, like those of oestrogen, are mediated through high affinity binding to oestrogen receptors and regulation of gene expression. This binding results in differential expression of multiple oestrogen-regulated genes in different tissues. Recent data suggests that the oestrogen receptor can regulate gene expression by at least two distinct pathways which are ligand-, tissue-, and/or gene-specific. a) Skeletal Effects The decrease in oestrogen availability which occurs at menopause, leads to marked increases in bone resorption, bone loss and risk of fracture. Bone loss is particularly rapid for the first 10 years after menopause when the compensatory increase in bone formation is inadequate to keep up with resorptive losses. Other risk factors which may lead to the development of osteoporosis include early menopause; osteopenia (at least 1 SD below peak bone mass); thin body build; Caucasian or Asian ethnic origin; and a family history of osteoporosis. Replacement therapies generally reverse the excessive resorption of bone. In postmenopausal women with osteoporosis, EVISTA reduces the incidence of vertebral fractures, preserves bone mass and increases bone mineral density (BMD). Based on these risk factors, prevention of osteoporosis with EVISTA is indicated for women within ten years of menopause, with BMD of the spine between 1.0 and 2.5 SD below the mean value of a normal young population, taking into account their high lifetime risk for osteoporotic fractures. Likewise, EVISTA is indicated for the treatment of osteoporosis or established osteoporosis in women with BMD of the spine 2.5 SD below the mean value of a normal young population and/or with vertebral fractures, irrespective of BMD. i) Incidence of fractures. In a study of 7,705 postmenopausal women with a mean age of 66 years and with osteoporosis or osteoporosis with an existing fracture, EVISTA treatment for 3 years reduced the incidence of vertebral fractures by 47 % (RR 0.53, CI 0.35, 0.79; p < 0.001) and 31 % (RR 0.69, CI 0.56, 0.86; p < 0.001) respectively. Forty five women with osteoporosis or 15 women with osteoporosis with an existing fracture would need to be treated with EVISTA for 3 years to prevent one or more vertebral fractures. EVISTA treatment for 4 years reduced the incidence of vertebral fractures by 46 % (RR 0.54, CI 0.38, 0.75) and 32 % (RR 0.68, CI 0.56, 0.83) in patients with osteoporosis or osteoporosis with an existing fracture respectively. In the 4th year alone, EVISTA reduced the new vertebral fracture risk by 39 % (RR 0.61, CI 0.43, 0.88). An effect on non-vertebral fractures has not been demonstrated. From the 4th to the 8th year, patients were permitted the concomitant use of bisphosphonates, calcitonin and fluorides and all patients in this study received calcium and vitamin D supplementation. In the RUTH study overall clinical fractures were collected as a secondary endpoint. EVISTA reduced the incidence of clinical vertebral fractures by 35% compared with placebo (HR 0.65, CI 0.47 0.89). These results may have been confounded by baseline differences in BMD and vertebral fractures. There was no difference between treatment groups in the incidence of new nonvertebral fractures. During the whole length of the study concomitant use of other bone-active medications was permitted. ii) Bone Mineral Density (BMD): The efficacy of EVISTA once daily in postmenopausal women aged up to 60 years and with or without a uterus was established over a two-year treatment period. The women were 2 to 8 years postmenopausal. Three trials included 1,764 postmenopausal women who were treated with EVISTA and calcium or calcium supplemented placebo. In one of these trials the women had previously undergone hysterectomy. EVISTA produced significant increases in bone density of hip and spine as well as total body mineral mass compared to placebo. This increase was generally a 2 % increase in BMD compared to placebo. A similar increase in BMD was seen in the treatment population who received EVISTA for up to 7 years. In the prevention trials, the percentage of subjects experiencing an increase or decrease in BMD during raloxifene therapy was: for the spine 37 % decreased and 63 % increased; and for the total hip 29 % decreased and 71 % increased. iii) Calcium kinetics. EVISTA and oestrogen affect bone remodelling and calcium metabolism similarly. EVISTA was associated with reduced bone resorption and a mean positive shift in calcium balance of 60 mg per day, due primarily to decreased urinary calcium losses. iv) Histomorphometry (bone quality). In a study comparing EVISTA with oestrogen, bone from patients treated with either medicinal product was histologically normal, with no evidence of mineralisation defects, woven bone or marrow fibrosis. Raloxifene decreases resorption of bone; this effect on bone is manifested as reductions in the serum and urine levels of bone turnover markers, decreases in bone resorption based on radiocalcium kinetics studies, increases in BMD and decreases in the incidence of fractures. b) Effects on lipid metabolism and cardiovascular risk Clinical trials showed that a 60 mg daily dose of EVISTA significantly decreased total cholesterol (3 to 6 %), and LDL cholesterol (4 to 10 %). Women with the highest baseline cholesterol levels had the greatest decreases. HDL cholesterol and triglyceride concentrations did not change significantly. After 3 years therapy EVISTA decreased fibrinogen (6.71 %). In the osteoporosis treatment study, significantly fewer EVISTA-treated patients required initiation of hypolipidaemic therapy compared to placebo. EVISTA therapy for 8 years did not significantly affect the risk of cardiovascular events in patients enrolled in the osteoporosis treatment study. Similarly, in the RUTH study, raloxifene did not affect the incidence of myocardial infarction, hospitalized acute coronary syndrome, stroke or overall mortality, including overall cardiovascular mortality, compared to placebo (for the increase in risk of fatal stroke see section 4.4). The relative risk of venous thromboembolic events observed during raloxifene treatment was 1.60 (CI 0.95, 2.71) when compared to placebo, and was 1.0 (CI 0.3, 6.2) when compared to oestrogen or hormonal replacement therapy. The risk of a thromboembolic event was greatest in the first four months of therapy. c) Effects on the endometrium and on the pelvic floor In clinical trials, EVISTA did not stimulate the postmenopausal uterine endometrium. Compared to placebo, raloxifene was not associated with spotting or bleeding or endometrial hyperplasia. Nearly 3,000 transvaginal ultrasound (TVUs) examinations were evaluated from 831 women in all dose groups. Raloxifene treated women consistently had an endometrial thickness which was indistinguishable from placebo. After 3 years of treatment, at least a 5 mm increase in endometrial thickness, assessed with transvaginal ultrasound, was observed in 1.9 % of the 211 women treated with raloxifene 60 mg/day compared to 1.8 % of the 219 women who received placebo. There were no differences between the raloxifene and placebo groups with respect to the incidence of reported uterine bleeding. Endometrial biopsies taken after six months therapy with EVISTA 60 mg daily demonstrated non-proliferative endometrium in all patients. In addition, in a study with 2.5 x the recommended daily dose of EVISTA there was no evidence of endometrial proliferation and no increase in uterine volume. In the osteoporosis treatment trial, endometrial thickness was evaluated annually in a subset of the study population (1,644 patients) for 4 years. Endometrial thickness measurements in EVISTA treated women were not different from baseline after 4 years of therapy. There was no difference between EVISTA and placebo treated women in the incidences of vaginal bleeding (spotting) or vaginal discharge. Fewer EVISTA treated women than placebo treated women required surgical intervention for uterine prolapse. Safety information following 3 years of raloxifene treatment suggests that raloxifene treatment does not increase pelvic floor relaxation and pelvic floor surgery. After 4 years, raloxifene did not increase the risk of endometrial or ovarian cancer. In postmenopausal women who received raloxifene treatment for 4 years, benign endometrial polyps were reported in 0.9 % compared to 0.3 % in women who received placebo treatment. d) Effects on breast tissue EVISTA does not stimulate breast tissue. Across all placebo-controlled trials, EVISTA was indistinguishable from placebo with regard to frequency and severity of breast symptoms (no swelling, tenderness and breast pain). Over the 4 years of the osteoporosis treatment trial (involving 7705 patients), EVISTA treatment compared to placebo reduced the risk of total breast cancer by 62 % (RR 0.38; CI 0.21, 0.69), the risk of invasive breast cancer by 71 % (RR 0.29, CI 0.13, 0.58) and the risk of invasive oestrogen receptor (ER) positive breast cancer by 79 % (RR 0.21, CI 0.07, 0.50). EVISTA has no effect on the risk of ER negative breast cancers. These observations support the conclusion that raloxifene has no intrinsic oestrogen agonist activity in breast tissue. e) Effects on cognitive function No adverse effects on cognitive function have been seen. 5.2 Pharmacokinetic properties Absorption Raloxifene is absorbed rapidly after oral administration. Approximately 60 % of an oral dose is absorbed. Presystemic glucuronidation is extensive. Absolute bioavailability of raloxifene is 2 %. The time to reach average maximum plasma concentration and bioavailability are functions of systemic interconversion and enterohepatic cycling of raloxifene and its glucuronide metabolites. Distribution Raloxifene is distributed extensively in the body. The volume of distribution is not dose dependent. Raloxifene is strongly bound to plasma proteins (98-99 %). Metabolism Raloxifene undergoes extensive first pass metabolism to the glucuronide conjugates: raloxifene-4'-glucuronide, raloxifene-6-glucuronide, and raloxifene-6, 4′-diglucuronide. No other metabolites have been detected. Raloxifene comprises less than 1 % of the combined concentrations of raloxifene and the glucuronide metabolites. Raloxifene levels are maintained by enterohepatic recycling, giving a plasma half-life of 27.7 hours. Results from single oral doses of raloxifene predict multiple dose pharmacokinetics. Increasing doses of raloxifene result in slightly less than proportional increase in the area under the plasma time concentration curve (AUC). Excretion The majority of a dose of raloxifene and glucuronide metabolites are excreted within 5 days and are found primarily in the faeces, with less than 6 % excreted in urine. Special populations Renal insufficiency - Less than 6 % of the total dose is eliminated in urine. In a population pharmacokinetic study, a 47 % decrease in lean body mass adjusted creatinine clearance resulted in a 17 % decrease in raloxifene clearance and a 15 % decrease in the clearance of raloxifene conjugates. Hepatic insufficiency - The pharmacokinetics of a single dose of raloxifene in patients with cirrhosis and mild hepatic impairment (Child-Pugh class A) have been compared to that in healthy individuals. Plasma raloxifene concentrations were approximately 2.5-fold higher than in controls and correlated with bilirubin concentrations. 5.3 Preclinical safety data In a 2-year carcinogenicity study in rats, an increase in ovarian tumors of granulosa/theca cell origin was observed in high-dose females (279 mg/kg/day). Systemic exposure (AUC) of raloxifene in this group was approximately 400 times that in postmenopausal women administered a 60 mg dose. In a 21-month carcinogenicity study in mice, there was an increased incidence of testicular interstitial cell tumours and prostatic adenomas and adenocarcinomas in males given 41 or 210 mg/kg, and prostatic leiomyoblastoma in males given 210 mg/kg. In female mice, an increased incidence of ovarian tumours in animals given 9 to 242 mg/kg (0.3 to 32 times the AUC in humans) included benign and malignant tumours of granulosa/theca cell origin and benign tumours of epithelial cell origin. The female rodents in these studies were treated during their reproductive lives, when their ovaries were functional and highly responsive to hormonal stimulation. In contrast to the highly responsive ovaries in this rodent model, the human ovary after menopause is relatively unresponsive to reproductive hormonal stimulation. Raloxifene was not genotoxic in any of the extensive battery of test systems applied. The reproductive and developmental effects observed in animals are consistent with the known pharmacological profile of raloxifene. At doses of 0.1 to 10 mg/kg/day in female rats, raloxifene disrupted estrous cycles of female rats during treatment, but did not delay fertile matings after treatment termination and only marginally reduced litter size, increased gestation length, and altered the timing of events in neonatal development. When given during the preimplantation period, raloxifene delayed and disrupted embryo implantation resulting in prolonged gestation and reduced litter size but development of offspring to weaning was not affected. Teratology studies were conducted in rabbits and rats. In rabbits, abortion and a low rate of ventricular septal defects (≥ 0.1 mg/kg) and hydrocephaly (≥ 10 mg/kg) were seen. In rats retardation of foetal development, wavy ribs and kidney cavitation occurred (≥ 1 mg/kg). Raloxifene is a potent antioestrogen in the rat uterus and prevented growth of oestrogen-dependent mammary tumours in rats and mice. 6. Pharmaceutical particulars 6.1 List of excipients Tablet core: Povidone Polysorbate 80 Anhydrous lactose Lactose monohydrate Crospovidone Magnesium stearate Tablet coating: Titanium dioxide (E 171) Polysorbate 80 Hypromellose Macrogol 400 Carnauba wax Ink: Shellac Propylene glycol Indigo carmine (E 132) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage Store in the original package. Do not freeze. 6.5 Nature and contents of container EVISTA tablets are packed either in PVC/PE/PCTFE blisters or in high density polyethylene bottles. Blister boxes contain 14, 28, or 84 tablets. Bottles contain 100 tablets. Not all pack sizes may be marketed in all countries. 6.6 Special precautions for disposal and other handling No special requirements. 7. Marketing authorisation holder Daiichi Sankyo Europe GmbH Zielstattstrasse 48 D-81379 Munich Germany 8. Marketing authorisation number(s) EU/1/98/073/001 EU/1/98/073/002 EU/1/98/073/003 EU/1/98/073/004 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 5 August 1998 Date of last renewal: 8 August 2008 10. Date of revision of the text 30 August 2012