2013年11月15日拜耳（Bayer）宣布，抗癌药物Xofigo（radium 223 dichloride，镭223二氯）已获欧盟委员会（EC）批准，用于有症状骨转移（symptomatic bone metastases ）及无已知内脏转移（no known visceral metastatic disease）的阉割性前列腺癌（CRPC）患者的治疗。 Xofigo的获批，是基于关键性III期ALSYMPCA研究的数据，该项研究中，与安慰剂相比，Xofigo显着改善了整体存活率（OS），同时延迟了首次有症状骨骼事件（SSE）的发生时间。 此前，Xofigo已于今年5月获得了FDA的批准，是首个α-粒子辐射放射性治疗药物。拜耳拥有Xofigo的全球独家销售权。在美国，拜耳与Algeta US公司共同推广该药。 临床试验中，Xofigo表现出了良好的安全性，该药以一种完全新颖的方式改善患者的预后。镭233发射的α粒子能够作用于骨转移的癌细胞，能够帮助改善患者的生存。 骨骼是体内转移性癌症影响的最常见部位，前列腺癌的骨转移尤其普遍。转移性前列腺癌中有约90%的患者发生骨转移。骨转移能够导致增加骨骼事件的发生频率，并已被证明是CRPC患者发病和致死的主要病因. 关于Xofigo： Xofigo（radium 223 dichloride，镭223二氯）是一种α-粒子辐射放射性治疗药物，其活性部分（active moiety）模拟了钙离子（calcium），通过与骨骼中的羟基磷灰石（HAP）形成复合物，选择性地靶向骨骼，尤其是骨转移区域。镭233【α-发射器（80千电子伏/微米）】发射的高LET （linear energy transfer, 线性能量转移）射线，能够在邻近肿瘤细胞中引发高频率的双链DNA断裂，从而产生强效的细胞毒效应。对肿瘤微环境（包括骨细胞和破骨细胞）的额外效应，也有助于体内（in vivo）的疗效。 来自Xofigo的α粒子量程小于100微米（不到10个细胞直径），能够最大限度地减少对周围正常组织的伤害. Xofigo(二氯化镭233[radium Ra 223 dichloride])注射剂，为静脉使用 美国初次批准：2013 1 适应证和用途 Xofigo是适用为有去势耐受前列腺癌，症状性骨转移和无已知内脏转移疾病患者的治疗。 2 剂型和给药方法 2.1 推荐剂量 Xofigo的给药方案是50 kBq(1.35微居里)每kg体重，在4周间隔给予共6次注射。尚未研究用Xofigo超过6次注射的安全性和疗效。 给予给定患者的体积应用以下计算： ●患者的体重(kg) ●剂量水平50 kBq/kg体重或1.35微居里/kg体重 ●在参比日期产品的放射性浓度(1,000 kBq/mL；27微居里/mL) ●用衰减校正系数对镭-223物理衰变校正 对将被给予患者的总体积计算如下： 衰减校正系数表是校正至中午中央标准时间(CST)。为测定衰变校正系数，计数参比日期前和后天数。衰变校正系数表包括校正占12欧洲中部时间中午(CET)在制造地点和12美国中部中午CST间7小时差值，比CET 较早7小时。 给予前和后立即，在一台适当放射性同位素剂量校正仪测量应确定患者给予Xofigo的净剂量曾用一个美国国家标准和技术研究所(NIST)可追踪的镭-223标准校正(从Bayer要求得到)和用日期和时间校正衰变。剂量校正仪必须用国家认可标准校正，在任何可能影响剂量学和不超过1年的间期的维持步骤后进行调试。 2.2 给药 在跨越1分钟缓慢静脉注射给予Xofigo。 注射Xofigo前和后用等张盐水冲洗静脉注取线或插管。 2.3对使用/处置指导 一般警告 Xofigo(一种α粒子-发射药)在指定临床情况中应只被授权人们接收，使用和给药。收据，贮存，使用，转移和遗弃Xofigo要遵守条例和/或官方机构适当许可。 Xofigo应由用户以辐射安全性和药学质量要求两方面满意方式处置。应采用适当无菌注意事项。 辐射保护 Xofigo的给予伴随对其他人的潜在危险(如，医护人员，照顾者和患者的家庭成员)从体液泄漏来自辐射或污染例如尿，粪，或呕吐物。因此，辐射保护注意事项必须按照国家和当地条例。 对药物处置 对放射性药物处置遵守正常工作步骤和用通用注意事项处置和给药例如手套和隔离袍当处置血液和体液避免污染。接触皮肤或眼睛情况中，被影响区域应被立即用水冲洗。在溢出Xofigo事件中，应立即联系当地辐射安全官员开始必要测量和要求步骤对区域去污染。建议用一种复合剂例如0.01 M乙二胺四乙酸(EDTA)溶液去除污染。 对患者护理 任何时间可能，患者应使用厕所和厕所每次使用后应冲洗几次。当处置体液，简单地待手套和洗手将保护照顾者。沾有Xofigo或患者粪物质或尿衣服应立即和与其他衣服分开洗涤。 镭-223主要是一种α发射体，有95.3%能量发射的分量为α-粒子。β-粒子的发射分量为3.6%，而γ-辐射分量发射为1.1%。伴处置患者外辐射暴露剂量预计是低，因为典型处理活性将低于 8,000 kBq(216微居里)。符合达到合理的尽可能低(ALARA)原则对辐射暴露最小化，建议在辐射区花费时间最小化，与辐射源距离的最大化，和使用适当屏蔽。与制备或给药有联系的任何未使用产品或材料都按放射性废物处理和应按照当地条例遗弃。 伴镭-223及其子体的衰减的γ辐射允许对Xofigo放射性测量和用标准仪器检测污染。 为制备的指导 非肠道药物产品给药前应被肉眼观测颗粒物质和变色，无论何时溶液和容器允许。 Xofigo是备用溶液和不应被稀释或与任何溶液混合。每个小瓶只为单次使用。 剂量学 根据5例有去势耐受前列腺癌患者中临床生物分布数据计算主要器官中吸收的辐射剂量。用OLINDA/EXM(器官内剂量评估/指数模型分析[Organ Level INternal Dose Assessment/EXponential Modeling])，根据医用内辐射剂量(MIRD)算法的一种软件程序，被广泛使用为确定β和γ发射同位核素进行吸收辐射剂量的计算。对镭-223，主要是一种α 粒子-发射体，对小肠，红骨髓和骨/骨细胞作假设提供对Xofigo最佳可能的吸收辐射剂量计算，考虑其观察到的生物分布和特异性特征。 表2中列出对不同器官计算的吸收辐射剂量。有最高吸收辐射剂量器官为骨(骨细胞)，红骨髓，上大肠壁，和下大肠壁。对其他器官的计算吸收剂量是较低。 3 剂型和规格 可得到Xofigo(二氯化镭223注射剂)在单次使用小瓶在参比日期含6 mL溶液，浓度1,000 kBq/mL(27微居里/mL)有总放射性6,000 kBq/小瓶(162 微居里/小瓶)在参比日期。 4 禁忌证 在妊娠中禁忌Xofigo。 Xofigo当给予妊娠妇女根据其作用机制可致胎儿危害。Xofigo不适用妊娠或可能成为妊娠妇女禁忌Xofigo。如妊娠期间使用药物，或如患者当服用药物成为妊娠，忠告患者对胎儿潜在危害[见特殊人群中使用(8.1)]。 5 警告和注意事项 5.1 骨髓抑制 在随机试验中，用Xofigo组2%患者经受骨髓衰竭或进行性全血细胞减少与之比较用安慰剂治疗患者没有。有2例由于骨髓衰竭死亡和对7/13例用Xofigo治疗患者，在死亡时正在骨髓衰竭。13例经历骨髓衰竭患者中，54%需要输血。用Xofigo组4%患者和安慰剂组2%由于骨髓抑制永远终止治疗。 在随机试验中，观察到Xofigo-治疗患者与血管出血伴骨髓抑制相关死亡1%，与之比较用安慰剂治疗患者为0.3%。对用Xofigo和安慰剂治疗患者染相关死亡(2%)，严重感染(10%)，和发热性中性粒细胞减少(<1%)的发生率相似。在用Xofigo治疗患者中曾报道骨髓抑制；显著的血小板减少，中性粒细胞减少，全细胞减少，和白细胞减少。在随机试验中，在每次剂量前，每4周得到完全血液计数(CBCs)和CBCs最低值而恢复时间特征未充分确定。在一项Xofigo分开的单剂量1期研究中，嗜中性和血小板计数最低值发生在Xofigo剂量至推荐剂量1至5倍给药后2至3周，和给药后接近6至8周大多数患者恢复[见不良反应(6)]。 在基线时和每剂Xofigo前患者必须进行血液学评价。首次给予Xofigo前，绝对嗜中性计数(ANC) 应是 ≥ 1.5 × 109/L，血小板计数 ≥ 100 × 109/L和血红蛋白 ≥ 10 g/dL。随后给予Xofigo前， ANC应是 ≥ 1 × 109/L和血小板计数 ≥ 50 × 109/L。尽管接受支持性医护，末次给予Xofigo后6至8周内这些值没有恢复，应终止进一步用Xofigo治疗。有骨髓保留受损的证据患者应密切监视和当临床指示提供支持措施。尽管对骨髓衰竭直至医护经受危及生命并发症患者终止Xofigo。 尚未确定同时化疗与Xofigo的安全性和疗效。由于对骨髓抑制相加的潜能不建议临床试验外，与化疗同时使用。如果在治疗期间给予化疗，其他全身放射性同位素或半身由外放疗，应终止Xofigo。 6 不良反应 在使用说明书另外节这更详细讨论以下严重不良反应： ●骨髓抑制[见警告和注意事项(5.1)] 6.1 临床试验经验 因为临床试验是在广泛不同情况下进行的，临床试验观察到不良反应率不能与另一种药临床试验发生率直接比较而且可能不反映实践中观察到的发生率。 在随机化临床试验中，在有转移去势耐受骨转移前列腺癌患者中，600例患者接受静脉注射50 kBq/kg(1.35微居里/kg)Xofigo和最佳标准医护和301例患者接受安慰剂和最佳标准医护一旦每4周直至6剂注射。随机化前，在Xofigo和安慰剂组中分别58%和57%的患者已接受多西紫杉醇。对Xofigo中位治疗时间为20周(6个疗程)和对安慰剂为18周(5个疗程)。 接受Xofigo患者中最常见不良反应(≥ 10%)为恶心，腹泻，呕吐，和周围水肿(表3)。57%的Xofigo-治疗患者报道3和4级不良事件和安慰剂-治疗患者为63%。Xofigo-治疗患者最常见实验室异常(≥ 10%)为贫血，淋巴细胞减少，白细胞减少，血小板减少，和中性粒细胞减(表4)。 接受Xofigo患者17%发生由于不良事件终止治疗和接受安慰剂患者为21%。最常见实验室异常导致终止Xofigo为贫血(2%)和血小板减少(2%)。 表3 显示≥ 2%患者中发生不良反应和其中对Xofigo发生率超过安慰剂的发生率。 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use XOFIGO safely and effectively. See full prescribing information for XOFIGO. Xofigo (radium Ra 223 dichloride) Injection, for intravenous use Initial U.S. Approval: 2013 INDICATIONS AND USAGE Xofigo is an alpha particle-emitting radioactive therapeutic agent indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease. (1) DOSAGE AND ADMINISTRATION The dose regimen of Xofigo is 50 kBq (1.35 microcurie) per kg body weight, given at 4 week intervals for 6 injections. (2.1) DOSAGE FORMS AND STRENGTHS Single-use vial at a concentration of 1,000 kBq/mL (27 microcurie/mL) at the reference date with a total radioactivity of 6,000 kBq/vial (162 microcurie/vial) at the reference date (3) CONTRAINDICATIONS Pregnancy (4, 8.1) WARNINGS AND PRECAUTIONS Bone Marrow Suppression: Measure blood counts prior to treatment initiation and before every dose of Xofigo. Discontinue Xofigo if hematologic values do not recover within 6 to 8 weeks after treatment. Monitor patients with compromised bone marrow reserve closely. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care measures. (5.1) ADVERSE REACTIONS The most common adverse drug reactions (≥ 10%) in patients receiving Xofigo were nausea, diarrhea, vomiting, and peripheral edema. The most common hematologic laboratory abnormalities (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION. Revised: 05/2013 * Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Xofigo is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage The dose regimen of Xofigo is 50 kBq (1.35 microcurie) per kg body weight, given at 4 week intervals for 6 injections. Safety and efficacy beyond 6 injections with Xofigo have not been studied. The volume to be administered to a given patient should be calculated using the: • Patient’s body weight (kg) • Dosage level 50 kBq/kg body weight or 1.35 microcurie/kg body weight • Radioactivity concentration of the product (1,000 kBq/mL; 27 microcurie/mL) at the reference date • Decay correction factor to correct for physical decay of radium-223. The total volume to be administered to a patient is calculated as follows: Volume to be administered (mL) = Body weight in kg × 50 kBq/kg body weight Decay factor × 1,000 kBq/mL or Volume to be administered (mL) = Body weight in kg × 1.35 microcurie/kg body weight Decay factor × 27 microcurie/mL Table 1: Decay Correction Factor Table Days from Reference Date Decay Factor Days from Reference Date Decay Factor -14 2.296 0 0.982 -13 2.161 1 0.925 -12 2.034 2 0.870 -11 1.914 3 0.819 -10 1.802 4 0.771 -9 1.696 5 0.725 -8 1.596 6 0.683 -7 1.502 7 0.643 -6 1.414 8 0.605 -5 1.330 9 0.569 -4 1.252 10 0.536 -3 1.178 11 0.504 -2 1.109 12 0.475 -1 1.044 13 0.447     14 0.420 The Decay Correction Factor Table is corrected to 12 noon Central Standard Time (CST). To determine the decay correction factor, count the number of days before or after the reference date. The Decay Correction Factor Table includes a correction to account for the 7 hour time difference between 12 noon Central European Time (CET) at the site of manufacture and 12 noon US CST, which is 7 hours earlier than CET. Immediately before and after administration, the net patient dose of administered Xofigo should be determined by measurement in an appropriate radioisotope dose calibrator that has been calibrated with a National Institute of Standards and Technology (NIST) traceable radium-223 standard (available upon request from Bayer) and corrected for decay using the date and time of calibration. The dose calibrator must be calibrated with nationally recognized standards, carried out at the time of commissioning, after any maintenance procedure that could affect the dosimetry and at intervals not to exceed one year. 2.2 Administration Administer Xofigo by slow intravenous injection over 1 minute. Flush the intravenous access line or cannula with isotonic saline before and after injection of Xofigo. 2.3 Instructions for Use / Handling General warning Xofigo (an alpha particle-emitting pharmaceutical) should be received, used and administered only by authorized persons in designated clinical settings. The receipt, storage, use, transfer and disposal Xofigo are subject to the regulations and/or appropriate licenses of the competent official organization. Xofigo should be handled by the user in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken. Radiation protection The administration of Xofigo is associated with potential risks to other persons (e.g., medical staff, caregivers and patient’s household members) from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations. For drug handling Follow the normal working procedures for the handling of radiopharmaceuticals and use universal precautions for handling and administration such as gloves and barrier gowns when handling blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the affected area should be flushed immediately with water. In the event of spillage of Xofigo, the local radiation safety officer should be contacted immediately to initiate the necessary measurements and required procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diamine-tetraacetic acid (EDTA) solution is recommended to remove contamination. For patient care Whenever possible, patients should use a toilet and the toilet should be flushed several times after each use. When handling bodily fluids, simply wearing gloves and hand washing will protect caregivers. Clothing soiled with Xofigo or patient fecal matter or urine should be washed promptly and separately from other clothing. Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-particles. The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 1.1%. The external radiation exposure associated with handling of patient doses is expected to be low, because the typical treatment activity will be below 8,000 kBq (216 microcurie). In keeping with the As Low As Reasonably Achievable (ALARA) principle for minimization of radiation exposure, it is recommended to minimize the time spent in radiation areas, to maximize the distance to radiation sources, and to use adequate shielding. Any unused product or materials used in connection with the preparation or administration are to be treated as radioactive waste and should be disposed of in accordance with local regulations. The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement of Xofigo and the detection of contamination with standard instruments. Instructions for preparation Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Xofigo is a ready-to-use solution and should not be diluted or mixed with any solutions. Each vial is for single use only. Dosimetry The absorbed radiation doses in major organs were calculated based on clinical biodistribution data in five patients with castration-resistant prostate cancer. Calculations of absorbed radiation doses were performed using OLINDA/EXM (Organ Level INternal Dose Assessment/EXponential Modeling), a software program based on the Medical Internal Radiation Dose (MIRD) algorithm, which is widely used for established beta and gamma emitting radionuclides. For radium-223, which is primarily an alpha particle-emitter, assumptions were made for intestine, red marrow and bone/osteogenic cells to provide the best possible absorbed radiation dose calculations for Xofigo, considering its observed biodistribution and specific characteristics. The calculated absorbed radiation doses to different organs are listed in Table 2. The organs with highest absorbed radiation doses were bone (osteogenic cells), red marrow, upper large intestine wall, and lower large intestine wall. The calculated absorbed doses to other organs are lower. 3 DOSAGE FORMS AND STRENGTHS Xofigo (radium Ra 223 dichloride injection) is available in single-use vials containing 6 mL of solution at a concentration of 1,000 kBq/mL (27 microcurie/mL) at the reference date with a total radioactivity of 6,000 kBq/vial (162 microcurie/vial) at the reference date. 4 CONTRAINDICATIONS Xofigo is contraindicated in pregnancy. Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Xofigo is not indicated for use in women. Xofigo is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Bone Marrow Suppression In the randomized trial, 2% of patients on the Xofigo arm experienced bone marrow failure or ongoing pancytopenia compared to no patients treated with placebo. There were two deaths due to bone marrow failure and for 7 of 13 patients treated with Xofigo, bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients on the Xofigo arm and 2% on the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) were similar for patients treated with Xofigo and placebo. Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; has been reported in patients treated with Xofigo. In the randomized trial, complete blood counts (CBCs) were obtained every 4 weeks prior to each dose and the nadir CBCs and times of recovery were not well characterized. In a separate single-dose phase 1 study of Xofigo, neutrophil and platelet count nadirs occurred 2 to 3 weeks after Xofigo administration at doses that were up to 1 to 5 times the recommended dose, and most patients recovered approximately 6 to 8 weeks after administration [see Adverse Reactions (6)]. Hematologic eva luation of patients must be performed at baseline and prior to every dose of Xofigo. Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. Before subsequent administrations of Xofigo, the ANC should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. If there is no recovery to these values within 6 to 8 weeks after the last administration of Xofigo, despite receiving supportive care, further treatment with Xofigo should be discontinued. Patients with evidence of compromised bone marrow reserve should be monitored closely and provided with supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure. The safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label: • Bone Marrow Suppression [see Warnings and Precautions (5.1)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer with bone metastases, 600 patients received intravenous injections of 50 kBq/kg (1.35 microcurie/kg) of Xofigo and best standard of care and 301 patients received placebo and best standard of care once every 4 weeks for up to 6 injections. Prior to randomization, 58% and 57% of patients had received docetaxel in the Xofigo and placebo arms, respectively. The median duration of treatment was 20 weeks (6 cycles) for Xofigo and 18 weeks (5 cycles) for placebo. The most common adverse reactions (≥ 10%) in patients receiving Xofigo were nausea, diarrhea, vomiting, and peripheral edema (Table 3). Grade 3 and 4 adverse events were reported among 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in Xofigo-treated patients (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (Table 4). Treatment discontinuations due to adverse events occurred in 17% of patients who received Xofigo and 21% of patients who received placebo. The most common hematologic laboratory abnormalities leading to discontinuation for Xofigo were anemia (2%) and thrombocytopenia (2%). Table 3 shows adverse reactions occurring in ≥ 2% of patients and for which the incidence for Xofigo exceeds the incidence for placebo. Table 3: Adverse Reactions in the Randomized Trial System/Organ Class Preferred Term Xofigo (n=600) Placebo (n=301) Grades 1-4 % Grades 3-4 % Grades 1-4 % Grades 3-4 % Blood and lymphatic system disorders Pancytopenia 2 1 0 0 Gastrointestinal disorders Nausea 36 2 35 2 Diarrhea 25 2 15 2 Vomiting 19 2 14 2 General disorders and administration site conditions Peripheral edema 13 2 10 1 Renal and urinary disorders Renal failure and impairment 3 1 1 1 Laboratory Abnormalities Table 4 shows hematologic laboratory abnormalities occurring in > 10% of patients and for which the incidence for Xofigo exceeds the incidence for placebo. Table 4: Hematologic Laboratory Abnormalities Hematologic Laboratory Abnormalities Xofigo (n=600) Placebo (n=301) Grades 1-4 % Grades 3-4 % Grades 1-4 % Grades 3-4 % Anemia 93 6 88 6 Lymphocytopenia 72 20 53 7 Leukopenia 35 3 10 <1 Thrombocytopenia 31 3 22 <1 Neutropenia 18 2 5 <1 Laboratory values were obtained at baseline and prior to each 4-week cycle. As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of patients on Xofigo and in 2% of patients on placebo. Among patients who received Xofigo, the laboratory abnormality grade 3-4 thrombocytopenia occurred in 1% of docetaxel naïve patients and in 4% of patients who had received prior docetaxel. Grade 3-4 neutropenia occurred in 1% of docetaxel naïve patients and in 3% of patients who have received prior docetaxel. Fluid Status Dehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia. Injection Site Reactions Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo. Secondary Malignant Neoplasms Xofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms [see Nonclinical Toxicology (13.1)]. However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs. 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow up for patients on the trial. Subsequent Treatment with Cytotoxic Chemotherapy In the randomized clinical trial, 16% patients in the Xofigo group and 18% patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy. 7 DRUG INTERACTIONS No formal clinical drug interaction studies have been performed. Subgroup analyses indicated that the concurrent use of bisphosphonates or calcium channel blockers did not affect the safety and efficacy of Xofigo in the randomized clinical trial. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category X [see Contraindications (4)] Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of Xofigo in pregnancy and Xofigo is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. Xofigo is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with Xofigo. 8.3 Nursing Mothers Xofigo is not indicated for use in women. It is not known whether radium-223 dichloride is excreted in human milk. Because many drugs are excreted in human milk, and because of potential for serious adverse reactions in nursing infants from Xofigo, a decision should be made whether to discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and efficacy of Xofigo in pediatric patients have not been established. In single- and repeat-dose toxicity studies in rats, findings in the bones (depletion of osteocytes, osteoblasts, osteoclasts, fibro-osseous lesions, disruption/disorganization of the physis/growth line) and teeth (missing, irregular growth, fibro-osseous lesions in bone socket) correlated with a reduction of osteogenesis that occurred at clinically relevant doses beginning in the range of 20 – 80 kBq (0.541 - 2.16 microcurie) per kg body weight. 8.5 Geriatric Use Of the 600 patients treated with Xofigo in the randomized trial, 75% were 65 years of age and over and while 33% were 75 years of age and over. No dosage adjustment is considered necessary in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Patients with Hepatic Impairment No dedicated hepatic impairment trial for Xofigo has been conducted. Since radium-223 is neither metabolized by the liver nor eliminated via the bile, hepatic impairment is unlikely to affect the pharmacokinetics of radium-223 dichloride [see Clinical Pharmacology (12.3)]. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with mild hepatic impairment. No dose adjustments can be recommended for patients with moderate or severe hepatic impairment due to lack of clinical data. 8.7 Patients with Renal Impairment No dedicated renal impairment trial for Xofigo has been conducted. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with existing mild (creatinine clearance [CrCl] 60 to 89 mL/min) or moderate (CrCl 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CrCl less than 30 mL/min) due to limited data available (n = 2) [see Clinical Pharmacology (12.3)]. 8.8 Males of Reproductive Potential Contraception Because of potential effects on spermatogenesis associated with radiation, advise men who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective contraceptive method during and for 6 months after completing treatment with Xofigo. Infertility There are no data on the effects of Xofigo on human fertility. There is a potential risk that radiation by Xofigo could impair human fertility [see Nonclinical Toxicology (13.1)]. 10 OVERDOSAGE There have been no reports of inadvertent overdosing of Xofigo during clinical studies. There is no specific antidote. In the event of an inadvertent overdose of Xofigo, utilize general supportive measures, including monitoring for potential hematological and gastrointestinal toxicity, and consider using medical countermeasures such as aluminum hydroxide, barium sulfate, calcium carbonate, calcium gluconate, calcium phosphate, or sodium alginate.1 Single Xofigo doses up to 250 kBq (6.76 microcurie) per kg body weight were eva luated in a phase 1 clinical trial and no dose-limiting toxicities were observed. 11 DESCRIPTION Radium Ra 223 dichloride, an alpha particle-emitting pharmaceutical, is a radiotherapeutic drug. Xofigo is supplied as a clear, colorless, isotonic, and sterile solution to be administered intravenously with pH between 6 and 8. Each milliliter of solution contains 1,000 kBq radium-223 dichloride (27 microcurie), corresponding to 0.53 ng radium-223, at the reference date. Radium is present in the solution as a free divalent cation. Each vial contains 6 mL of solution (6,000 kBq (162 microcurie) radium-223 dichloride at the reference date). The inactive ingredients are 6.3 mg/mL sodium chloride USP (tonicity agent), 7.2 mg/mL sodium citrate USP (for pH adjustment), 0.2 mg/mL hydrochloric acid USP (for pH adjustment), and water for injection USP. The molecular weight of radium-223 dichloride, 223RaCl2, is 293.9 g/mol. Radium-223 has a half-life of 11.4 days. The specific activity of radium-223 is 1.9 MBq (51.4 microcurie)/ng. The six-stage-decay of radium-223 to stable lead-207 occurs via short-lived daughters, and is accompanied predominantly by alpha emissions. There are also beta and gamma emissions with different energies and emission probabilities. The fraction of energy emitted from radium-223 and its daughters as alpha-particles is 95.3% (energy range of 5 - 7.5 MeV). The fraction emitted as beta-particles is 3.6% (average energies are 0.445 MeV and 0.492 MeV), and the fraction emitted as gamma-radiation is 1.1% (energy range of 0.01 - 1.27 MeV). 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The active moiety of Xofigo is the alpha particle-emitting isotope radium-223 (as radium Ra 223 dichloride), which mimics calcium and forms complexes with the bone mineral hydroxyapatite at areas of increased bone turnover, such as bone metastases (see Table 2). The high linear energy transfer of alpha emitters (80 keV/micrometer) leads to a high frequency of double-strand DNA breaks in adjacent cells, resulting in an anti-tumor effect on bone metastases. The alpha particle range from radium-223 dichloride is less than 100 micrometers (less than 10 cell diameters) which limits damage to the surrounding normal tissue. 12.2 Pharmacodynamics Compared with placebo, there was a significant difference in favor of Xofigo for all five serum biomarkers for bone turnover studied in a phase 2 randomized study (bone formation markers: bone alkaline phosphatase [ALP], total ALP and procollagen I N propeptide [PINP], bone resorption markers: C-terminal crosslinking telopeptide of type I collagen [S-CTX-I] and type I collagen crosslinked C-telopeptide [ICTP]). 12.3 Pharmacokinetics The pharmacokinetics of radium-223 dichloride in blood was linear in terms of dose proportionality and time independence in the dose range investigated (46 to 250 kBq [1.24 to 6.76 microcurie] per kg body weight). Distribution After intravenous injection, radium-223 is rapidly cleared from the blood and is distributed primarily into bone or is excreted into intestine. Fifteen minutes post-injection, about 20% of the injected radioactivity remained in blood. At 4 hours, about 4% of the injected radioactivity remained in blood, decreasing to less than 1% at 24 hours after the injection. At 10 minutes post-injection, radioactivity was observed in bone and in intestine. At 4 hours post-injection, the percentage of the radioactive dose present in bone and intestine was approximately 61% and 49%, respectively. No significant uptake was seen in other organs such as heart, liver, kidneys, urinary bladder, and spleen at 4 hours post-injection [see Dosage and Administration (2.3)]. Metabolism Radium-223 is an isotope that decays and is not metabolized. Elimination Special Populations Pediatric patients Safety and effectiveness of Xofigo have not been established in children and adolescents below 18 years of age. Patients with hepatic impairment No dedicated pharmacokinetic study in patients with hepatic impairment has been conducted. However, since radium-223 is not metabolized and there is no evidence of hepato-biliary excretion based on imaging data, hepatic impairment is not expected to affect the pharmacokinetics of radium-223 dichloride. Patients with renal impairment No dedicated pharmacokinetic study in patients with renal impairment has been conducted. However, since excretion in urine is minimal and the major route of elimination is via the feces, renal impairment is not expected to affect the pharmacokinetics of radium-223 dichloride. 12.6 Cardiac Electrophysiology The effect of a single dose of 50 kBq/kg of radium-223 dichloride on the QTc interval was eva luated in a subgroup of 29 patients (21 received Xofigo and 8 received placebo) in the randomized clinical trial. No large changes in the mean QTc interval (i.e., greater than 20 ms) were detected up to 6 hours post-dose. The potential for delayed effects on the QT interval after 6 hours was not eva luated. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted to eva luate the carcinogenic potential of radium-223 dichloride. However, in repeat-dose toxicity studies in rats, osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clinically relevant doses 7 to 12 months after the start of treatment. The presence of other neoplastic changes, including lymphoma and mammary gland carcinoma, was also reported in 12- to 15-month repeat-dose toxicity studies in rats. Genetic toxicology studies have not been conducted with radium-223 dichloride. However, the mechanism of action of radium-223 dichloride involves induction of double-strand DNA breaks, which is a known effect of radiation. Animal studies have not been conducted to eva luate the effects of radium-223 dichloride on male or female fertility or reproductive function. Xofigo may impair fertility and reproductive function in humans based on its mechanism of action. 14 CLINICAL STUDIES The efficacy and safety of Xofigo were eva luated in a double-blind, randomized, placebo-controlled phase 3 clinical trial of patients with castration-resistant prostate cancer with symptomatic bone metastases. Patients with visceral metastases and malignant lymphadenopathy exceeding 3 cm were excluded. The primary efficacy endpoint was overall survival. A key secondary efficacy endpoint was time to first symptomatic skeletal event (SSE) defined as external beam radiation therapy (EBRT) to relieve skeletal symptoms, new symptomatic pathologic bone fracture, occurrence of spinal cord compression, or tumor-related orthopedic surgical intervention. There were no scheduled radiographic assessments performed on study. All patients were to continue androgen deprivation therapy. At the cut-off date of the pre-planned interim analysis, a total of 809 patients had been randomized 2:1 to receive Xofigo 50 kBq (1.35 microcurie)/kg intravenously every 4 weeks for 6 cycles (n = 541) plus best standard of care or matching placebo plus best standard of care (n = 268). Best standard of care included local EBRT, corticosteroids, antiandrogens, estrogens, estramustine or ketoconazole. Therapy was continued until unacceptable toxicity or initiation of cytotoxic chemotherapy, other systemic radioisotope, hemi-body EBRT or other investigational drug. Patients with Crohn’s disease, ulcerative colitis, prior hemibody radiation or untreated imminent spinal cord compression were excluded from the study. In patients with bone fractures, orthopedic stabilization was performed before starting or resuming treatment with Xofigo. The following patient demographics and baseline disease characteristics were balanced between the arms. The median age was 71 (range 44-94) with a racial distribution of 94% Caucasian, 4% Asian, 2% Black and <1% Other. Patients were enrolled predominantly from Europe (85%) with 4% of patients enrolled from North America. ECOG performance status was 0-1 in 86% of patients. Eighty-five percent of patients had 6 or more bone scan lesions and of those 40% had > 20 lesions or a superscan. Opiate pain medications were used for cancer-related pain in 54% of patients, non-opiate pain medications in 44% of patients and no pain medications in 2% of patients. Patients were stratified by baseline ALP, bisphosphonate use, and prior docetaxel exposure. Prior bisphosphonates were used by 41% of patients and 58% had received prior docetaxel. During the treatment period, 83% of Xofigo patients and 82% of placebo patients received gonadotropin-releasing hormone agonists and 21% of Xofigo patients and 34% of placebo patients received concomitant antiandrogens. Use of systemic steroids (41%) and bisphosphonates (40%) was balanced between the arms. The pre-specified interim analysis of overall survival revealed a statistically significant improvement in patients receiving XOFIGO plus best standard of care compared with patients receiving placebo plus best standard of care. An exploratory updated overall survival analysis performed before patient crossover with an additional 214 events resulted in findings consistent with the interim analysis (Table 5). Table 5: Overall Survival Results from the Phase 3 Clinical Trial * Survival time is calculated as months from date of randomization to date of death from any cause. Subjects who are not deceased at time of analysis are censored on the last date subject was known to be alive or lost to follow-up. † p-value is from a log-rank test stratified by total ALP, current use of bisphosphonates, and prior use of docetaxel. ‡ Hazard ratio is from a Cox proportional hazards model adjusted for total ALP, current use of bisphosphonates, and prior use of docetaxel. Hazard ratio < 1 favors radium-223 dichloride.   Xofigo Placebo Interim Analysis     Subjects randomized 541 268 Number of deaths 191 (35.3%) 123 (45.9%) Censored 350 (64.7%) 145 (54.1%) Median survival (months)* (95% CI) 14.0 (12.1, 15.8) 11.2 ( 9.0, 13.2) p-value† 0.00185 Hazard ratio (95% CI)‡ 0.695 (0.552, 0.875)     Updated Analysis   Subjects randomized 614 307 Number of deaths 333 (54.2%) 195 (63.5%) Censored 281 (45.8%) 112 (36.5%) Median survival (months)* (95% CI) 14.9 (13.9, 16.1) 11.3 (10.4, 12.8) Hazard ratio (95% CI)‡ 0.695 (0.581, 0.832) The Kaplan-Meier curves for overall survival based on the updated survival results are shown in Figure 1. Figure 1: Kaplan-Meier Overall Survival Curves from the Phase 3 Clinical Trial  The survival results were supported by a delay in the time to first SSE favoring the Xofigo arm. The majority of events consisted of external beam radiotherapy to bone metastases. 15 REFERENCES 1. Radiation Emergency Medical Management. [REMM/National Library of Medicine Website.] http://www.remm.nlm.gov/int_contamination.htm#blockingagents 16 HOW SUPPLIED/STORAGE AND HANDLING Xofigo (radium Ra 223 dichloride injection) is supplied in single-use vials containing 6 mL of solution at a concentration of 1,000 kBq/mL (27 microcurie/mL) with a total radioactivity of 6,000 kBq/vial (162 microcurie/vial) at the reference date (NDC 50419-208-01). Store at room temperature, below 40° C (104° F). Store Xofigo in the original container or equivalent radiation shielding. This preparation is approved for use by persons under license by the Nuclear Regulatory Commission or the relevant regulatory authority of an Agreement State. Follow procedures for proper handling and disposal of radioactive pharmaceuticals [see Dosage and Administration (2.3)].