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。
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.
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.
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
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.
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.
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.
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
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.
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.
Radium-223 is an isotope which decays and is not metabolised.
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.
The pharmacokinetics of radium-223 dichloride were linear in the activity range investigated (51 to 276 kBq/kg).
Safety and effectiveness of Xofigo have not been studied in children and adolescents below 18 years of age.
5.3 Preclinical safety data
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.
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
Hydrochloric acid, dilute
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
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
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.
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
8. Marketing authorisation number(s)
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 13 November 2013
10. Date of revision of the text
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
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.