2013年11月15日，拜耳（Bayer）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 1100 kBq/mL solution for injection 1. Name of the medicinal product Xofigo 1100 kBq/mL solution for injection 2. Qualitative and quantitative composition Each mL of solution contains 1100 kBq radium Ra 223 dichloride (radium-223 dichloride), corresponding to 0.58 ng radium-223 at the reference date. Radium is present in the solution as a free ion. Each vial contains 6 mL of solution (6.6 MBq radium-223 dichloride at the reference date). Radium-223 is an alpha particle-emitter with a half-life of 11.4 days. The specific activity of radium-223 is 1.9 MBq/ng. The six-stage-decay of radium-223 to lead-207 occurs via short-lived daughters, and is accompanied by a number of alpha, 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 5.0 - 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). Figure 1: Radium-223 decay chain with physical half-lives and mode of decay: Excipients with known effect Each mL of solution contains 0.194 mmol (equivalent to 4.5 mg) of sodium. For the full list of excipients, see section 6.1. 3. Pharmaceutical form Solution for injection. Clear, colourless isotonic solution with pH between 6.0 and 8.0. 4. Clinical particulars 4.1 Therapeutic indications Xofigo is indicated for the treatment of adults with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastases. 4.2 Posology and method of administration Xofigo should be administered only by persons authorised to handle radiopharmaceuticals in designated clinical settings (see section 6.6) and after evaluation of the patient by a qualified physician. Posology The dose regimen of Xofigo is an activity of 55 kBq per kg body weight, given at 4 week intervals for 6 injections. Safety and efficacy beyond 6 injections with Xofigo have not been studied. For details on the calculation of the volume to be administered see section 12. Elderly patients No overall differences in safety or efficacy were observed between elderly (aged ≥ 65 years) and younger patients (aged < 65 years) in the phase III study. No dose adjustment is considered necessary in elderly patients. Patients with hepatic impairment Safety and efficacy of Xofigo have not been studied in patients with hepatic impairment. Since radium-223 is neither metabolised by the liver nor eliminated via the bile, hepatic impairment is not expected to affect the pharmacokinetics of radium-223 dichloride. No dose adjustment is considered necessary in patients with hepatic impairment. Patients with renal impairment In the phase III clinical study, no relevant differences in safety or efficacy were observed between patients with mild renal impairment (creatinine clearance [CLCR]: 50 to 80 mL/min) and normal renal function. Limited data are available on patients with moderate (CLCR: 30 to 50 mL/min) renal impairment. No data are available on patients with severe (CLCR < 30 mL/min) renal impairment or end-stage renal disease. However, since excretion in urine is minimal and the major route of elimination is via the faeces, renal impairment is not expected to affect the pharmacokinetics of radium-223 dichloride. No dose adjustment is considered necessary in patients with renal impairment. Paediatric population The safety and efficacy of Xofigo in children and adolescents below 18 years of age have not been studied. There is no relevant use of this medicinal product in the paediatric population in the indication of prostate cancer. Method of administration Xofigo is for intravenous use. It must be administered by slow injection (generally up to 1 minute). The intravenous access line or cannula must be flushed with isotonic sodium chloride 9 mg/mL (0.9%) solution for injection before and after injection of Xofigo. For additional instructions on the use of the medicinal product, see sections 6.6 and 12. 4.3 Contraindications There are no known contraindications to the use of Xofigo. 4.4 Special warnings and precautions for use Bone marrow suppression Bone marrow suppression, notably thrombocytopenia, neutropenia, leukopenia and pancytopenia, has been reported in patients treated with Xofigo (see section 4.8). Therefore, haematological evaluation of patients must be performed at baseline and prior to every dose of Xofigo. Before the first administration, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/l, the platelet count ≥ 100 x 109/l and haemoglobin ≥ 10.0 g/dl. Before subsequent administrations, the ANC should be ≥ 1.0 x 109/l and the platelet count ≥ 50 x 109/l. In case there is no recovery in these values within 6 weeks after the last administration of Xofigo despite receiving standard of care, further treatment with Xofigo should only be continued after a careful benefit/risk evaluation. Patients with evidence of compromised bone marrow reserve e.g. following prior cytotoxic chemotherapy and/or radiation treatment (EBRT) or prostate cancer patients with advanced diffuse infiltration of the bone (EOD4; “superscan”) should be treated with caution. An increased incidence of haematological adverse reactions such as neutropenia and thrombocytopenia was observed in these patients during the phase III study (see section 4.8). The efficacy and safety of cytotoxic chemotherapy performed after treatment with Xofigo has not been established. The limited available data indicates that patients receiving chemotherapy after Xofigo had a similar haematological profile compared to patients receiving chemotherapy after placebo (see also section 5.1). Crohn's disease and ulcerative colitis Safety and efficacy of Xofigo in patients with Crohn's disease and with ulcerative colitis have not been studied. Due to the faecal excretion of Xofigo, radiation may lead to aggravation of acute inflammatory bowel disease. Xofigo should only be administered after a careful benefit-risk assessment in patients with acute inflammatory bowel disease. Spinal cord compression In patients with untreated imminent or established spinal cord compression, treatment with standard of care, as clinically indicated, should be completed before starting or resuming treatment with Xofigo. Bone fractures In patients with bone fractures, orthopaedic stabilisation of fractures should be performed before starting or resuming treatment with Xofigo. Osteonecrosis of the jaw In patients treated with bisphosphonates and Xofigo, an increased risk of development of osteonecrosis of the jaw (ONJ) cannot be excluded. In the phase III study, cases of ONJ have been reported in 0.67% patients (4/600) in the Xofigo arm compared to 0.33% patients (1/301) in the placebo arm. However, all patients with ONJ were also exposed to prior or concomitant bisphosphonates (e.g. zoledronic acid) and prior chemotherapy (e.g. docetaxel). Secondary malignant neoplasms Xofigo contributes to a patient's overall long-term cumulative radiation exposure. Therefore, long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. In particular, the risk for osteosarcoma, myelodysplastic syndrome and leukaemias may be increased. No cases of Xofigo-induced cancer have been reported in clinical trials in follow-up of up to three years. Excipients with known effect Depending on the volume administered, this medicinal product can contain up to 2.35 mmol (54 mg) sodium per dose. To be taken into consideration by patients on a controlled sodium diet. 4.5 Interaction with other medicinal products and other forms of interaction No clinical interaction studies have been performed. As interactions with calcium and phosphate cannot be excluded, pausing supplementation with these substances and/or Vitamin D should be considered some days before starting with Xofigo treatment. Concomitant chemotherapy with Xofigo may have additive effects on bone marrow suppression (see section 4.4). Safety and efficacy of concomitant chemotherapy with Xofigo have not been established. 4.6 Fertility, pregnancy and lactation Contraception in males Animal reproduction studies have not been conducted with Xofigo. Because of potential effects on spermatogenesis associated with radiation, men should be advised to use effective contraceptive methods during and up to 6 months after treatment with Xofigo. Pregnancy and breast-feeding Xofigo is not indicated in women. Xofigo is not to be used in women who are, or may be, pregnant or breast-feeding. Fertility There are no human data on the effect of Xofigo on fertility. Based on studies in animals, there is a potential risk that radiation from Xofigo could cause adverse effects on fertility (see section 5.3). Male patients should seek advice on conservation of sperm prior to treatment. 4.7 Effects on ability to drive and use machines There is neither evidence nor is it expected that Xofigo will affect the ability to drive or use machines. 4.8 Undesirable effects Summary of the safety profile The overall safety profile of Xofigo is based on data from 600 patients treated with Xofigo in the phase III study. The most frequently observed adverse reactions (≥ 10%) in patients receiving Xofigo were diarrhoea, nausea, vomiting and thrombocytopenia. The most serious adverse reactions were thrombocytopenia and neutropenia (see section 4.4 and 'Description of selected adverse reactions' below). Tabulated list of adverse reactions The adverse reactions observed with Xofigo are represented in the table below (see Table 1). They are classified according to System Organ Class. The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions. Adverse reactions from clinical trials are classified according to their frequencies. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1: Adverse reactions reported in clinical trials in patients treated with Xofigo System Organ Class (MedDRA) Very common Common Uncommon Blood and lymphatic system disorders Thrombocytopenia Neutropenia, Pancytopenia, Leukopenia Lymphopenia Gastrointestinal disorders Diarrhoea, Vomiting, Nausea     General disorders and administration site conditions   Injection site reactions Description of selected adverse reactions Thrombocytopenia and Neutropenia Thrombocytopenia (all grades) occurred in 11.5% of patients treated with Xofigo and 5.6% of patients receiving placebo. Grade 3 and 4 thrombocytopenia was observed in 6.3% of patients treated with Xofigo and in 2% of patients receiving placebo (see section 4.4). Overall, the frequency of grade 3 and 4 thrombocytopenia was lower in patients that did not previously receive docetaxel (2.8% in patients treated with Xofigo versus 0.8% in patients receiving placebo) compared to patients that previously received docetaxel (8.9% in patients treated with Xofigo versus 2.9% in patients receiving placebo). In EOD4 (“superscan”) patients, thrombocytopenia (all grades) was reported in 19.6% of patients treated with Xofigo and in 6.7% of patients receiving placebo. Grade 3 and 4 thrombocytopenia was observed in 5.9% of patients treated with Xofigo and in 6.7% of patients receiving placebo (see section 4.4). Neutropenia (all grades) was reported in 5% of patients treated with Xofigo and in 1% of patients receiving placebo. Grade 3 and 4 neutropenia was observed in 2.2% of patients treated with Xofigo and in 0.7% of patients receiving placebo. Overall, the frequency of grade 3 and 4 neutropenia was lower in patients that did not previously receive docetaxel (0.8% in patients treated with Xofigo versus 0.8% in patients receiving placebo) compared to patients that previously received docetaxel (3.2% in patients treated with Xofigo versus 0.6% in patients receiving placebo). In a phase I study, neutrophil and platelet count nadirs occurred at 2 to 3 weeks after intravenous administration of a single dose of Xofigo. Injection site reactions Grade 1 and 2 injection site reactions, such as erythema, pain and swelling, were reported in 1.2% of patients treated with Xofigo and in 0% of patients receiving placebo. 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. In particular, the risk for osteosarcoma, myelodysplastic syndrome and leukaemias may be increased. No cases of Xofigo-induced cancer have been reported in clinical trials in follow-up of up to three years. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. 4.9 Overdose 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, general supportive measures, including monitoring for potential haematological and gastrointestinal toxicity should be undertaken. Single Xofigo doses containing an activity of up to 276 kBq per kg body weight were evaluated in a phase I clinical trial and no dose-limiting toxicities were observed. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Various therapeutic radiopharmaceuticals, ATC code: V10XX03 Mechanism of action Xofigo is a therapeutic alpha particle-emitting pharmaceutical. Its active moiety radium-223 (as radium-223 dichloride) mimics calcium and selectively targets bone, specifically areas of bone metastases, by forming complexes with the bone mineral hydroxyapatite. The high linear energy transfer of alpha emitters (80 keV/micrometer) leads to a high frequency of double-strand DNA breaks in adjacent tumour cells, resulting in a potent cytotoxic effect. Additional effects on the tumour microenvironment including osteoblasts and osteoclasts also contribute to the in vivo efficacy. The alpha particle range from radium-223 is less than 100 micrometers (less than 10 cell diameters) which minimises damage to the surrounding normal tissue. Pharmacodynamic effects Compared with placebo, there was a significant difference in favour of Xofigo for all five serum biomarkers for bone turnover studied in a phase II randomised 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]). Clinical efficacy and safety The clinical safety and efficacy of Xofigo have been evaluated in a double-blind, randomised, multiple dose, phase III, multicentre study (ALSYMPCA; EudraCT 2007-006195-1)) in castration-resistant prostate cancer patients with symptomatic bone metastases. Patients with visceral metastases and malignant lymphadenopathy exceeding 3 cm were excluded. The primary efficacy endpoint was overall survival. Secondary endpoints included time to symptomatic skeletal events (SSE), ALP, and PSA progression. At the cut-off date of the pre-planned interim analysis (confirmatory analysis), a total of 809 patients were randomised 2:1 to receive Xofigo 55 kBq/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 e.g. local external beam radiotherapy, bisphosphonates, corticosteroids, antiandrogens, oestrogens, estramustine or ketoconazole. An updated descriptive analysis of safety and of overall survival was performed in 921 randomised patients prior to implementing crossover (i.e. offering patients in the placebo group to receive Xofigo treatment). Demographic and baseline disease characteristics (interim analysis population) were similar between the Xofigo and placebo groups and are shown below for Xofigo: • the mean age of patients was 70 years (range 49 to 90 years). • 87% of patients enrolled had an ECOG performance status score of 0-1. • 41% received bisphosphonates. • 42% of patients did not receive prior docetaxel because they were deemed ineligible or refused to receive docetaxel. • 46% of patients had no pain or WHO scale 1 (asymptomatic or mildly symptomatic) and 54% had pain WHO scale 2-3. • 16% of patients had <6 bone metastases, 44% of patients had between 6 and 20 bone metastases, 40% of patients had more than 20 bone metastases or superscan. During the treatment period, 83% of patients received luteinising hormone-releasing hormone (LHRH) agonists and 26% of patients received anti-androgens concomitantly. The results of both the interim and updated analysis revealed that overall survival was significantly longer in patients treated with Xofigo plus best standard of care compared to patients treated with placebo plus best standard of care (see Table 2 and Figure 2). A higher rate of non-prostate cancer related deaths was observed in the placebo group (26/541, 4.8% in the Xofigo arm compared to 23/268, 8.6% in the placebo arm). Table 2: Survival results from the phase III ALSYMPCA study Xofigo Placebo Interim analysis N = 541 N = 268 Number (%) of deaths 191 (35.3%) 123 (45.9%) Median overall survival (months) (95% CI) 14.0 (12.1 – 15.8) 11.2 (9.0 – 13.2) Hazard ratiob (95% CI) 0.695 (0.552 – 0.875) p-valuea (2-sided) 0.00185 Updated analysis N = 614 N = 307 Number (%) of deaths 333 (54.2%) 195 (63.5%) Median overall survival (months) (95% CI) 14.9 (13.9 – 16.1) 11.3 (10.4 – 12.8) Hazard ratiob (95% CI) 0.695 (0.581 – 0.832) CI = confidence interval a The Phase 3 study ALSYMPCA was stopped for efficacy after the interim analysis. As the updated analysis is provided for descriptive purposes only, a p-value is not provided. b Hazard ratio (Xofigo over placebo) < 1 favours Xofigo. Figure 2: Kaplan-Meier overall survival curves (updated analysis) The results of the interim analysis and the updated analysis also showed a significant improvement in all main secondary endpoints in the Xofigo arm compared to the placebo arm (see Table 3). Time to event data on ALP progression were supported by statistically significant advantage with respect to ALP normalisation and ALP responses at week 12. Table 3: Secondary efficacy endpoints from the phase III ALSYMPCA study (interim analysis) Incidence Time-to-event analysis (95% CI) [no. (%) of patients] [median no. of months] Hazard ratio < 1 favours Xofigo p-value Xofigo N = 541 Placebo N = 268 Xofigo N = 541 Placebo N = 268 Symptomatic skeletal event (SSE) SSE composite endpoint a 132 (24.4%) 82 (30.6%) 13.5 (12.2 – 19.6) 8.4 (7.2 – NE)b 0.610 (0.461 – 0.807) 0.00046 SSE components External beam radiation for pain relief 122 (22.6%) 72 (26.9%) 17.0 (12.9 – NE) 10.8 (7.9 – NE) 0.649 (0.483 – 0.871) 0.00375 Spinal cord compression 17 (3.1%) 16 (6.0%) NE NE 0.443 (0.223 – 0.877) 0.01647 Surgical intervention 9 (1.7%) 5 (1.9%) NE NE 0.801 (0.267 – 2.398) 0.69041 Bone fractures 20 (3.7%) 18 (6.7%) NE NE 0.450 (0.236 – 0.856) 0.01255 Total ALP progression c 79 (14.6%) 116 (43.3%) NE 3.7 (3.5 – 4.1) 0.162 (0.120 – 0.220) < 0.00001 PSA progression d 288 (53.2%) 141 (52.6%) 3.6 (3.5 – 3.7) 3.4 (3.3 – 3.5) 0.671 (0.546 – 0.826) 0.00015 ALP = alkaline phosphatase; CI = confidence interval; NE = not estimable; PSA = prostate-specific antigen; SSE = symptomatic skeletal event a Defined as occurrence of any of the following: external beam radiotherapy to relieve pain, or pathologic fracture, or spinal cord compression, or tumor-related orthopedic surgical intervention. b not estimable owing to insufficient events after the median c Defined as ≥ 25% increase compared to baseline/nadir. d Defined as a ≥ 25% increase and an increase in absolute value of ≥ 2 ng/mL compared to baseline/nadir. Subgroup survival analysis Subgroup survival analysis showed a consistent survival benefit for treatment with Xofigo, independent of total alkaline phosphatase (ALP), use of bisphosphonates at baseline and prior use of docetaxel. Quality of life Health Related Quality of Life (HRQOL) was assessed in the phase III ALSYMPCA study using specific questionnaires: the EQ-5D (generic instrument) and the FACT-P (prostate cancer specific instrument). Both groups experience a loss of quality of life. Relative to placebo, the decline in quality of life was slower for Xofigo during the on-treatment period as measured by EQ-5D utility index score (-0.040 versus – 0.109; p=0.001), EQ-5D self-reported Visual Analogue health status scores (VAS) (-2.661 versus -5.860; p=0.018) and the FACT P total score (-3.880 versus -7.651, p=0.006) but did not reach published minimally important differences. There is limited evidence that the delay in loss of HRQOL extends beyond the treatment period. Pain relief The results from the phase III ALSYPMCA study regarding time to external beam radiation therapy (EBRT) for pain relief and fewer patients reporting bone pain as an adverse event in the Xofigo group indicate a positive effect on bone pain. Subsequent treatment with cytotoxic substances In the course of the 2:1 randomised ALSYMPCA study, 93 (17%) patients in the Xofigo group and 54 (16.8%) patients in the placebo group received cytotoxic chemotherapy at varying times after the last treatment. No differences in haematological laboratory values were apparent between the two groups. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Xofigo in all subsets of the paediatric population in prostate carcinoma (excluding rhabdomyosarcoma) (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties General introduction Pharmacokinetic, biodistribution and dosimetry data have been obtained from 3 phase I studies. Pharmacokinetic data were obtained in 25 patients at activities ranging from 51 to 276 kBq/kg. Pharmacokinetic, biodistribution and dosimetry data were obtained in 6 patients at an activity of 110 kBq/kg given twice, 6 weeks apart, and in 10 patients at an activity of 55, 110 or 221 kBq/kg. Absorption Xofigo is administered as an intravenous injection and is thus 100% bioavailable. Distribution and organ uptake After intravenous injection, radium-223 is rapidly cleared from the blood and is incorporated primarily into bone and bone metastases, or is excreted into the intestine. Fifteen minutes post injection, about 20% of the injected activity remained in the blood. At 4 hours, about 4% of the injected activity remained in the blood, decreasing to less than 1% at 24 hours after the injection. The volume of distribution was higher than the blood volume indicating distribution to peripheral compartments. At 10 minutes post injection, activity was observed in the bone and in the intestine. The level of activity in the bone was in the range of 44% to 77% at 4 hours post injection. No significant uptake was seen in other organs such as heart, liver, kidneys, urinary bladder and spleen at 4 hours post injection. Biotransformation Radium-223 is an isotope which decays and is not metabolised. Elimination Faecal excretion is the major route of elimination from the body. About 5% is excreted in the urine and there is no evidence of hepatobiliary excretion. The whole body measurements at 7 days after injection (after correcting for decay) indicate that a median of 76% of administered activity was excreted from the body. The rate of elimination of radium-223 dichloride from the gastrointestinal tract is influenced by the high variability in intestinal transit rates across the population, with the normal range from once daily to once weekly bowel evacuation. Linearity/non-linearity The pharmacokinetics of radium-223 dichloride were linear in the activity range investigated (51 to 276 kBq/kg). Paediatric population Safety and effectiveness of Xofigo have not been studied in children and adolescents below 18 years of age. 5.3 Preclinical safety data Systemic toxicity In single and repeated dose toxicity studies in rats, the main findings were reduced body weight gain, haematological changes, reduced serum alkaline phosphatase and microscopic findings in the bone marrow (depletion of haematopoietic cells, fibrosis), spleen (secondary extra-medullary haematopoiesis) and bone (depletion of osteocytes, osteoblasts, osteoclasts, fibro-osseous lesions, disruption/disorganisation of the physis/growth line). These findings were related to radiation-induced impairment of haematopoiesis and a reduction of osteogenesis and started at the lowest activity of 22 kBq per kg body weight (0.4 times the clinically recommended dose). In dogs, haematological changes were observed starting at the lowest activity of 55 kBq/kg, the clinically recommended dose. Dose-limiting myelotoxicity was seen in dogs after single administration of 497 kBq radium-223 dichloride per kg body weight (9 times the clinically recommended activity). After repeated administration of the clinically recommended activity of 55 kBq per kg body weight once every 4 weeks for 6 months, two dogs developed non-displaced pelvic fractures. Due to the presence of osteolysis of trabecular bone in other bone locations of treated animals in varying degree, a spontaneous fracture in the context of osteolysis cannot be excluded. The clinical relevance of these findings is unknown. Retinal detachment was seen in dogs after a single injection of activities of 166 and 497 kBq per kg body weight (3 and 9 times the clinically recommended dose), but not after repeated administration of the clinically recommended activity of 55 kBq per kg body weight once every 4 weeks for 6 months. The exact mechanism for induction of retinal detachment is unknown, but literature data suggests that radium is specifically taken up in the tapetum lucidum of the canine eye. Since humans do not have a tapetum lucidum, the clinical relevance of these findings for humans is uncertain. No case of retinal detachment has been reported in clinical trials. No histological changes were observed in organs involved in the excretion of radium-223 dichloride. Osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clinically relevant doses in rats 7 – 12 months after start of treatment. Osteosarcomas were not observed in dog studies. No case of osteosarcoma has been reported in clinical studies with Xofigo. The risk for patients to develop osteosarcomas with exposure to radium-223 is unknown at present. The presence of neoplastic changes, other than osteosarcomas, was also reported in the longer term (12 to 15 months) rat toxicity studies (see section 4.8). Embryotoxicity / Reproduction toxicity Studies on reproductive and developmental toxicity have not been performed. In general, radionuclides induce reproductive and developmental effects. A minimal number of abnormal spermatocytes were seen in a few seminiferous tubules in the testes of male rats after a single administration of ≥ 2270 kBq/kg body weight radium-223 dichloride (≥ 41 times the clinically recommended activity). The testes seemed to otherwise be functioning normally and the epididymides revealed a normal content of spermatocytes. Uterine polyps (endometrial stroma) were observed in female rats after single or repeated administration of ≥ 359 kBq/kg body weight radium-223 dichloride (≥ 6.5 times the clinically recommended activity). Since radium-223 distributes mainly to bone, the potential risk for adverse effects in the male gonads in cancer patients with castration-resistant prostate cancer is very low, but cannot be excluded (see section 4.6). Genotoxicity / Carcinogenicity Studies on the mutagenic and carcinogenic potential of Xofigo have not been performed. In general, radionuclides are considered to be genotoxic and carcinogenic. Safety pharmacology No significant effects were seen on vital organ systems, i.e. cardiovascular (dog), respiratory or central nervous systems (rat), after single dose administration of activities from 497 to 1100 kBq per kg body weight (9 [dog] to 20 [rat] times the clinically recommended activity). 6. Pharmaceutical particulars 6.1 List of excipients Water for injections Sodium citrate Sodium chloride Hydrochloric acid, dilute 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 28 days. 6.4 Special precautions for storage This medicinal product does not require any special temperature storage conditions. Storage of Xofigo should be in accordance with national regulation on radioactive materials. 6.5 Nature and contents of container Colourless Type I glass vial closed with a grey bromobutyl rubber stopper with foil-clad made of Ethylene tetrafluoroethylene (ETFE) and aluminium seal, containing 6 mL of solution for injection. The vial is stored in a lead pot. 6.6 Special precautions for disposal and other handling General warnings Radiopharmaceuticals should be received, used and administered only by authorised persons in designated clinical settings. Their receipt, storage, use, transfer and disposal are subject to the regulations and/or appropriate licenses of the competent official organisation. Xofigo should be handled in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken. Radiation protection The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement of Xofigo and the detection of contaminations with standard instruments. The administration of radiopharmaceuticals creates risks for other persons from external radiation or contamination from spill of urine, faeces, vomiting etc. Radiation protection precautions in accordance with national regulations must therefore be taken. Care should be used when handling materials, such as bed linen, that come into contact with such body fluids. Although radium-223 is predominantly an alpha emitter, gamma and beta radiation is associated with the decay of radium-223 and its radioactive daughter isotopes. The external radiation exposure associated with handling of patient doses is considerably lower in comparison to other radiopharmaceuticals for therapeutic purposes as the administered radioactivity will usually be below 8 MBq. However, in keeping with the ALARA (“As Low As Reasonably Achievable”) principle, for minimisation of radiation exposure, it is recommended to minimise the time spent in radiation areas, to maximise the distance to radiation sources, and to use adequate shielding. Any unused product or waste materials should be disposed of in accordance with local regulations. Any materials used in connection with the preparation or administration of Xofigo are to be treated as radioactive waste. 7. Marketing authorisation holder Bayer Pharma AG 13342 Berlin Germany 8. Marketing authorisation number(s) EU/1/13/873/001 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 13 November 2013 10. Date of revision of the text 09/2015 11. Dosimetry The absorbed radiation dose calculation was performed based on clinical biodistribution data. Calculations of absorbed doses were performed using OLINDA/EXM (Organ Level INternal Dose Assessment/EXponential Modeling), a software based on the Medical Internal Radiation Dose (MIRD) algorithm, which is widely used for established beta and gamma emitting radionuclides. For radium-223, as primarily an alpha emitter, additional assumptions were made for the intestine, red marrow and bone/osteogenic cells, to provide the best possible absorbed dose calculations for Xofigo, considering its observed biodistribution and specific characteristics (see Table 4). Table 4: Calculated absorbed radiation doses to organs Target Organ Alpha1 emission (Gy/MBq) Beta emission (Gy/MBq) Gamma emission (Gy/MBq) Total dose (Gy/MBq) Coefficient of variation (%) Adrenals 0.00000 0.00002 0.00009 0.00012 56 Brain 0.00000 0.00002 0.00008 0.00010 80 Breasts 0.00000 0.00002 0.00003 0.00005 120 Gallbladder wall 0.00000 0.00002 0.00021 0.00023 14 LLI2 Wall 0.00000 0.04560 0.00085 0.04645 83 Small intestine wall 0.00319 0.00360 0.00047 0.00726 45 Stomach wall 0.00000 0.00002 0.00012 0.00014 22 ULI3 wall 0.00000 0.03150 0.00082 0.03232 50 Heart wall 0.00161 0.00007 0.00005 0.00173 42 Kidneys 0.00299 0.00011 0.00011 0.00320 36 Liver 0.00279 0.00010 0.00008 0.00298 36 Lungs 0.00000 0.00002 0.00005 0.00007 90 Muscle 0.00000 0.00002 0.00010 0.00012 41 Ovaries 0.00000 0.00002 0.00046 0.00049 40 Pancreas 0.00000 0.00002 0.00009 0.00011 43 Red marrow 0.13200 0.00642 0.00020 0.13879 41 Osteogenic cells 1.14000 0.01490 0.00030 1.15206 41 Skin 0.00000 0.00002 0.00005 0.00007 79 Spleen 0.00000 0.00002 0.00007 0.00009 54 Testes 0.00000 0.00002 0.00006 0.00008 59 Thymus 0.00000 0.00002 0.00003 0.00006 109 Thyroid 0.00000 0.00002 0.00005 0.00007 96 Urinary bladder wall 0.00371 0.00016 0.00016 0.00403 63 Uterus 0.00000 0.00002 0.00023 0.00026 28 Whole body 0.02220 0.00081 0.00012 0.02311 16 1As there was no uptake of radium-223 in most of the soft tissues observed, the alpha contribution to the total organ dose was set to zero for these organs. 2LLI: lower large intestine 3ULI: upper large intestine The haematological adverse reactions observed in the clinical studies with Xofigo are much lower in frequency and severity than what could be expected from the calculated absorbed doses to the red marrow. This may be related to spatial distribution of alpha particle radiation resulting in non-uniform radiation dose to the red marrow. 12. Instruction for preparation of radiopharmaceuticals This medicinal product should be visually inspected before use. Xofigo is a clear, colourless solution and should not be used in case of discolouration, the occurrence of particulate matter or a defective container. Xofigo is a ready-to-use solution and should not be diluted or mixed with any solutions. Each vial is for single use only. The volume to be administered to a given patient should be calculated using the: - Patient's body weight (kg) - Dosage level (55 kBq/kg body weight) - Radioactivity concentration of the product (1100 kBq/mL) at reference date. The reference date is stated on the vial and lead pot label. - Decay correction (DK) factor to correct for physical decay of radium-223. A table of DK factors is provided with each vial as part of the booklet (preceding the package leaflet). The amount of radioactivity in the dispensed volume shall be confirmed by measurement in a properly calibrated activimeter. The total volume to be administered to a patient is calculated as follows: Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.