Xofigo

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 



 

2 

 This medicinal product is subject to additional monitoring. This will allow quick identification of new 
safety information. Healthcare professionals are asked to report any suspected adverse reactions. See 
section 4.8 for how to report adverse reactions. 
 
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. 
 
 



 

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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 monotherapy or in combination with luteinising hormone releasing hormone (LHRH) analogue is 
indicated for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC), 
symptomatic bone metastases and no known visceral metastases, in progression after at least two prior lines 
of systemic therapy for mCRPC (other than LHRH analogues), or ineligible for any available systemic 
mCRPC treatment (see section 4.4). 
 
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. 
 
Special populations 
 
Elderly 
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. 
 
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. 
 
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 for patients with moderate (CLCR: 30 to 50 mL/min) renal impairment. No data 
are available for 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 
There is no relevant use of Xofigo in the paediatric population in the indication of prostate cancer. 
 



 

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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 
 
Xofigo is contraindicated in combination with abiraterone acetate and prednisone/prednisolone (see 
section 4.4). 
 
4.4 Special warnings and precautions for use 
 
Combination with abiraterone and prednisone/prednisolone or with systemic cancer therapies other than 
LHRH analogues 
 
An interim analysis from a clinical trial in chemotherapy-naïve patients with asymptomatic or mildly 
symptomatic castration resistant prostate cancer and progressive disease with bone metastases showed an 
increased risk of fractures and a trend for increased mortality among patients receiving Xofigo in 
combination with abiraterone acetate and prednisone/prednisolone compared to patients receiving placebo in 
combination with abiraterone acetate and prednisone/prednisolone (see section 5.1).  
Therefore, Xofigo is contraindicated in combination with abiraterone acetate and prednisone/prednisolone 
(see section 4.3).  
 
Safety and efficacy of Xofigo in combination with cancer therapies other than LHRH analogues have not 
been established; an increased risk of mortality and fractures is possible. The combination of radium-223 
with other systemic cancer therapies other than LHRH analogues is therefore not recommended. 
 
Data on a safe period after which Xofigo can be administered following treatment with abiraterone acetate in 
combination with prednisone/prednisolone and vice versa is limited. Based on the elimination half-life of 
Xofigo and abiraterone, it is recommended that subsequent treatment with Xofigo is not initiated for at least 
5 days after the last administration of abiraterone acetate in combination with prednisone/prednisolone. 
Subsequent systemic cancer treatment should not be initiated for at least 30 days after the last administration 
of Xofigo. 
 
Treatment of patients with asymptomatic or mildly symptomatic bone metastases 
 
An increased risk of death and fractures was observed in a clinical study, where Xofigo was added to 
abiraterone acetate and prednisone/prednisolone in patients with asymptomatic or mildly symptomatic 
castration resistant prostate cancer. 
 
Treatment benefit of Xofigo in adults with castration-resistant prostate cancer and only asymptomatic bone 
metastases is not established. The use of Xofigo is therefore not recommended for treatment of adults with 
castration-resistant prostate cancer and only asymptomatic bone metastases. In adults with castration-
resistant prostate cancer and mildly symptomatic bone metastases the benefit of treatment should be 
carefully assessed to outweigh the risks considering that high osteoblastic activity is likely to be required for 
treatment benefit (see section 5.1). 
 



 

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Patients with a low level of osteoblastic bone metastases 
 
In clinical studies, patients with fewer than 6 bone metastases had an increased risk of fractures and did not 
have a statistically significant survival benefit. A pre-specified subgroup analysis also showed that overall 
survival was not significantly improved in patients with a total ALP < 220 U/L. Therefore in patients with a 
low level of osteoblastic bone metastases radium-223 is not recommended (see section 5.1). 
 
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 
 
Xofigo increases the risk of bone fractures. In a clinical study, the addition of Xofigo to abiraterone acetate 
and prednisone/prednisolone, increased the incidence of fractures approximately three-fold in the Xofigo arm 
(see sections 4.8 and 5.1). Increased fracture risk has been found especially in patients with medical history 
of osteoporosis and in patients with less than 6 bone metastases. Xofigo is believed to accumulate at sites of 
high bone turnover such as sites of degenerative bone disease (osteoporosis) or recent (micro-)fracture 
increasing the risk of fractures. Other factors such as concomitant use of steroids may further increase the 
risk of fracture. 
 
Prior to starting radium-223 bone status (e.g. by scintigraphy, bone mineral density measurement) and 
baseline risk of fractures of patients (e.g. osteoporosis, less than 6 bone metastases, medication increasing 
fracture risk, low body mass index) should be carefully assessed, and closely monitored for at least 
24 months. Preventive measures such as the use of bisphosphonates or denosumab should be considered 
before starting or resuming treatment with Xofigo (see section 4.8). In patients with a high baseline risk of 



 

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fracture, the benefit of treatment should be carefully assessed to outweigh the risk. 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. 
 
Gastrointestinal toxicity 
 
Xofigo increases the incidence of diarrhoea, nausea, and vomiting (see section 4.8) which may result in 
dehydration. Oral intake and fluid status of patients should be carefully monitored. Patients should be 
advised to seek medical advice if they experience severe or persistent diarrhoea, nausea, vomiting.  
Patients who display signs or symptoms of dehydration or hypovolemia should be promptly treated. 
 
Excipients with known effect 
 
Depending on the volume administered, this medicinal product can contain up to 2.35 mmol (54 mg) sodium 
per dose, equivalent to 2.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult. 
 
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. 
 



 

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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 
 
Xofigo has no or negligible influence on the ability to drive and 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, thrombocytopenia and bone fracture.  
 
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 

  

Musculoskeletal and 
connective tissue 
disorders  

Bone fracture  Osteoporosis 

General disorders and 
administration site 
conditions 

 Injection site reactions  

 
Description of selected adverse reactions 
 
Bone fractures 
Xofigo increases the risk of bone fractures (see section 5.1). In clinical studies, concurrent use of 
bisphosphonates or denosumab reduced the incidence of fractures in patients treated with radium-223 
monotherapy. Fractures have occurred for up to 24 months after the first dose of radium-223. 
 



 

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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 national reporting system listed in Appendix V. 
 
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: Therapeutic radiopharmaceuticals, other therapeutic radiopharmaceuticals, 
various therapeutic radiopharmaceuticals, ATC code: V10XX03 
 



 

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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/µm) 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 µm (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 / serum C-terminal crosslinked telopeptide of type I collagen 
[S-CTX-I] and type I collagen crosslinked C-telopeptide [ICTP]). 
 
Cardiac electrophysiology / QT prolongation 
No significant QTc prolonging effects were observed after intravenous injection of Xofigo in comparison 
with placebo in a subgroup of 29 patients in the phase III study (ALSYMPCA). 
 
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. Main secondary endpoints included time to symptomatic 
skeletal events (SSE), time to progression of total alkaline phosphatase (ALP), time to progression of 
prostate specific antigen (PSA), response of total ALP and normalisation of total ALP. 
 
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. 
 



 

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During the treatment period, 83% of patients received luteinising hormone-releasing hormone (LHRH) 
agonists and 21% 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) 
 

 
 



 

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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 

 

Sy
m

pt
om

at
ic

 sk
el

et
al

 e
ve

nt
 

(S
SE

) 

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 

SS
E 

co
m

po
ne

nt
s 

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 
use of bisphosphonates at baseline and prior use of docetaxel. 
 
A statistically significant overall survival benefit of treatment could not be demonstrated in the subgroups of 
patients with fewer than 6 metastases (HR for radium-223 to placebo 0.901; 95% CI [0.553 -1.466], 
p=0.674) or a baseline total alkaline phosphatase (ALP) < 220 U/L (HR 0.823; 95% CI [0.633 -1.068], 
p=0.142) in the phase III ALSYMPCA study. Therefore, efficacy may be diminished in patients with a low 
level of osteoblastic activity from their bone metastases. 
 
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. 
 



 

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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 (15.5%) patients in the Xofigo group and 
54 (17.9%) 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. 
 
Combination with abiraterone and prednisone/prednisolone 
The clinical efficacy and safety of concurrent initiation of Xofigo, abiraterone acetate and 
prednisone/prednisolone treatment was assessed in a randomized, placebo-controlled multicenter phase III 
study (ERA-223 trial) in 806 chemotherapy-naïve patients with asymptomatic or mildly symptomatic 
castration resistant prostate cancer with bone metastases. The study was unblinded early based on an 
Independent Data Monitoring Committee Recommendation. At an interim analysis, an increased incidence 
of fractures (28.6% vs 11.4%) and reduced median overall survival (30.7 months versus 33.3 months, 
HR 1.195, 95% CI [0.950 - 1.505], p=0.13) was observed among patients receiving Xofigo in combination 
with abiraterone acetate and prednisone/prednisolone compared to patients receiving placebo in combination 
with abiraterone acetate and prednisone/prednisolone. 
 
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 the treatment of all conditions included in the category of malignant 
neoplasms (except central nervous system tumours, haematopoietic and lymphoid tissue neoplasms) and in 
the treatment of multiple myeloma (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. At 4 hours post injection, 
the mean 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. 



 

13 

 
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 



 

14 

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. 
 



 

15 

6.5 Nature and contents of container 
 
Colourless Type I glass vial closed with a grey bromobutyl rubber stopper either with or without foil-clad 
made of Ethylene tetrafluoroethylene (ETFE), both capped with 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 AG 
51368 Leverkusen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/13/873/001 
 
 



 

16 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 13 November 2013 
Date of latest renewal: 21 June 2018 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
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). 
 



 

17 

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 0.04561 0.00085 0.04645 83 
Small intestine wall 0.00319 0.00360 0.00047 0.00726 45 
Stomach wall 0.00000 0.00002 0.00011 0.00014 22 
ULI3 wall 0.00000 0.03149 0.00082 0.03232 50 
Heart wall 0.00161 0.00007 0.00005 0.00173 42 
Kidneys 0.00299 0.00011 0.00011 0.00321 36 
Liver 0.00279 0.00010 0.00008 0.00298 36 
Lungs 0.00109 0.00007 0.00005 0.00121 --4 
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 0.13217 0.00642 0.00020 0.13879 41 
Osteogenic cells 1.13689 0.01487 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 0.02312 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 
4Absorbed dose data to the lung are based on model-derived calculation using pooled blood time-activity data from all 
subjects 
 
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 other solutions. 
 
Each vial is for single use only. 
 



 

18 

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: 
 

Volume to be administered (mL)  = Body weight (kg)  activity (55 kBq/kg body weight) DK factor  1100 kBq/mL 
 
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. 



 

19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 



 

20 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Bayer AS 
Drammensveien 288 
NO-0283 Oslo  
Norway 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  
 
 Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent 
updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE 

OF THE MEDICINAL PRODUCT 
 
 Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and 
interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any 
agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
 At the request of the European Medicines Agency; 
 Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result of an important 
(pharmacovigilance or risk minimisation) milestone being reached.  
 
 



 

21 

 Obligation to conduct post-authorisation measures 
 
The MAH shall complete, within the stated timeframe, the below measures: 
 
Description  Due date 
The MAH shall conduct and submit the results of a phase IV randomised open-label 
multicentre study according to an agreed protocol in order to further characterise the efficacy 
and safety, in particular the risk of fractures, the risk of formation of visceral and nodal 
metastases of radium-223 in the authorized indication.  

The protocol should foresee a stratified randomization of patients according to total ALP levels. 
 

Q3 2025 

The MAH shall conduct and submit the results of a non-interventional post-authorisation safety 
study (PASS) based on the data from the Prostate Cancer Data Base Sweden (PCBaSe) and 
other relevant Scandinavian cancer registers or other suitable data sources, in order to further 
characterise the safety of radium-223 in the authorized indication. 
 

Q2 2021 

The MAH shall conduct and submit the results of a phase I biodistribution study according to an 
agreed protocol in order to further characterize correlation between the extent of the disease, the 
dose and the distribution of radium-223 in bone metastases versus sites of impaired bone health 
(e.g. osteoporosis) versus normal bone structure. 
 

Q1 2023 



 

22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



 

23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 



 

24 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
LEAD POT 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xofigo 1100 kBq/mL solution for injection 
radium Ra 223 dichloride 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
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.  
Each vial contains 6 mL of solution (6.6 MBq radium-223 dichloride at the reference date). 
 
 
3. LIST OF EXCIPIENTS 
 
Water for injections, sodium citrate, sodium chloride, hydrochloric acid. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection 
6 mL 
1100 kBq/mL at 12 h (CET) ref. date: [DD/MM/YYYY] 
6.6 MBq/vial at 12 h (CET) ref. date: [DD/MM/YYYY] 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 

 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



 

25 

9. SPECIAL STORAGE CONDITIONS 
 
Storage should be in accordance with national regulation on radioactive materials. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
[Bayer logo] 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/13/873/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Not applicable. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
Not applicable. 
 
 



 

26 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Xofigo 1100 kBq/mL solution for injection 
radium Ra 223 dichloride 
For intravenous use. 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
6 mL 
6.6 MBq/vial at 12 h (CET) ref. date: [DD/MM/YYYY] 
 
 
6. OTHER 
 

 
 
[Bayer logo] 
 



 

27 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



 

28 

Package leaflet: Information for the patient 
 

Xofigo 1100 kBq/mL solution for injection 
radium Ra 223 dichloride 

 
 

 This medicine is subject to additional monitoring. This will allow quick identification of new safety 
information. You can help by reporting any side effects you may get. See the end of section 4 for how to 
report side effects. 
 
Read all of this leaflet carefully before you are given this medicine because it contains important 
information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor who will supervise the procedure.  
- If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this 

leaflet. See section 4.  
 
What is in this leaflet: 
1. What Xofigo is and what it is used for 
2. What you need to know before Xofigo is used 
3. How Xofigo is used 
4. Possible side effects 
5. How Xofigo is stored 
6. Contents of the pack and other information 
 
 
1. What Xofigo is and what it is used for 
 
This medicine contains the active substance radium Ra 223 dichloride (radium-223 dichloride). 
 
Xofigo is used to treat adults with advanced castration-resistant prostate cancer in progression after at least 
two other cancer treatments apart from treatments to maintain reduced levels of male hormone (hormone 
therapy), or who cannot take any other cancer treatment. Castration-resistant prostate cancer is a cancer of 
the prostate (a gland of the male reproductive system) that does not respond to treatment that reduces male 
hormones. Xofigo is only used when the disease has spread to the bone but is not known to have spread to 
other internal organs, and is causing symptoms (e.g. pain). 
 
Xofigo contains the radioactive substance radium-223 which mimics the calcium found in bones. When 
injected into the patient, radium-223 reaches the bone where the cancer has spread to and emits short-range 
radiation (alpha particles) which kills the surrounding tumour cells. 
 
 
2.  What you need to know before Xofigo is used 
 
Xofigo must not be given 
 in combination with abiraterone and prednisone/prednisolone (which are used together to treat prostate 

cancer). 
 



 

29 

Warnings and precautions 
Talk to your doctor before you are given Xofigo 
- Xofigo must not be given in combination with abiraterone and prednisone/prednisolone due to a possible 

increase in the risk of bone fracture or death. Additionally, there are uncertainties about the effects of 
Xofigo in combination with other medicines used to treat metastatic prostate cancer. If you are already 
taking one of those medicines, please tell your doctor.  

- If you plan to take Xofigo following treatment with abiraterone and prednisone/prednisolone, you must 
wait 5 days before starting treatment with Xofigo. 

- If you plan to take other cancer therapy following treatment with Xofigo, you must wait at least 30 days 
before starting treatment. 

- Xofigo is not recommended if cancer in your bones is not causing symptoms, such as pain.  
- Xofigo can lead to a decrease in the number of your blood cells and blood platelets. Before starting 

treatment and before each subsequent dose your doctor will perform blood tests. Depending on the 
results of these tests your doctor will decide if treatment can be started, can be continued, or needs to be 
postponed or discontinued.  

- If you suffer from decreased blood cell production in the bone marrow, e.g. if you have received 
prior chemotherapy (other medicines used to kill cancer cells) and/or radiation therapy, you may be at 
higher risk and your doctor will give you Xofigo with caution. 

- If your tumour has spread to the bone extensively, you may also be more likely to have decreases in your 
blood cells and platelets, so your doctor will give you Xofigo with caution. 

- The limited data available do not suggest any major differences in the blood cell production of patients 
receiving chemotherapy after treatment with Xofigo compared with those who did not receive Xofigo. 

- There are no data on the use of Xofigo in patients with Crohn’s disease (a long-term inflammatory 
disease of the intestines) and with ulcerative colitis (a long-term inflammation of the colon). As Xofigo 
is excreted in the faeces, it may make acute inflammation of your bowels worse. Therefore, if you suffer 
from these conditions your doctor will carefully consider if you can be treated with Xofigo. 

- If you suffer from untreated spinal cord compression or if it is thought likely that you are developing 
spinal cord compression (pressure on the spinal cord nerves which can be caused by a tumour or other 
lesion), your doctor will first treat this disease with standard treatment before starting or continuing 
treatment with Xofigo. 

- If you have osteoporosis or a known increased risk for fractures (e.g. recent bone fracture, fragility), 
or take or have been taking steroids (e.g. prednisone/prednisolone), please tell your doctor. You might 
be at a higher risk of bone fractures. Your doctor might prescribe you a drug to prevent bone fractures 
before starting or continuing treatment with Xofigo. 

- If you experience any new or unusual pain or swelling in bone region prior, during or after your 
treatment with Xofigo, you should consult your doctor. 

- If you experience a bone fracture, your doctor will first stabilise the fractured bone before starting or 
continuing treatment with Xofigo. 

- If you take or have taken bisphosphonates or have received chemotherapy prior to treatment with 
Xofigo, please tell your doctor. A risk of osteonecrosis of the jaw (dead tissue in the jaw bone which is 
mainly seen in patients who have been treated with bisphosphonates) cannot be excluded (see section 4). 

- Xofigo contributes to your overall long-term cumulative radiation exposure. Long-term cumulative 
radiation exposure may increase your risk for developing cancer (in particular of bone cancer and 
leukaemia) and hereditary abnormalities. No cases of cancer caused by Xofigo have been reported in 
clinical trials with a follow-up of up to three years. 

 
Your doctor will test your bone health before deciding whether you can be given Xofigo. During treatment 
and for 2 years after starting treatment with Xofigo, your doctor will continuously monitor your bone health. 
 
Children and adolescents 
This medicine is not for use in children and adolescents. 
 
Other medicines and Xofigo 
No interaction studies with other medicines have been done. 
 



 

30 

Xofigo must not be given in combination with abiraterone and prednisone/prednisolone due to a possible 
increase in the risk of bone fracture or death. Additionally, there are uncertainties about the effects of Xofigo 
in combination with other systemic medicines used to treat metastatic prostate cancer. If you are already 
taking one of those medicines, please tell your doctor. 
 
If you take or have taken bisphosphonates or other medicines to protect your bone health or steroids (e.g. 
prednisone/prednisolone) prior to treatment with Xofigo, please tell your doctor. You might be at a higher 
risk for bone fractures. 
 
If you are taking calcium, phosphate and/or Vitamin D, your doctor will carefully consider if you need to 
temporarily stop taking these substances before you start treatment with Xofigo. 
 
There are no data on the use of Xofigo at the same time as chemotherapy (other medicines used to kill 
cancer cells). Xofigo and chemotherapy used together may further decrease the number of your blood cells 
and blood platelets. 
 
Tell your doctor if you are taking, have recently taken or might take any other medicines, including 
medicines obtained without a prescription. 
 
Pregnancy and breast-feeding 
Xofigo is not for use in women and must not be given to women who are, or may be, pregnant or who are 
breast-feeding. 
 
Contraception in males and females 
If you are engaged in sexual activity with a woman who could become pregnant you are advised to use 
effective birth control methods during and up to 6 months after treatment with Xofigo. 
 
Fertility 
There is a potential risk that radiation from Xofigo could affect your fertility. Please ask your doctor how this 
may affect you, especially if you are planning to have children in the future. You may wish to seek advice on 
conservation of sperm before treatment starts. 
 
Driving and using machines 
It is considered unlikely that Xofigo will affect your ability to drive or to use machines. 
 
Xofigo contains sodium 
Depending on the volume administered, this medicine can contain up to 54 mg sodium (main component of 
cooking/table salt) per dose. This is equivalent to 2.7% of the recommended maximum daily dietary intake 
of sodium for an adult. 
 
 
3. How Xofigo is used 
 
There are strict laws on the use, handling and disposal of medicines like Xofigo. It will only be used in 
special controlled areas. This product will only be handled and given to you by people who are trained and 
qualified to use it safely. These persons will take special care for the safe use of this product and will keep 
you informed of their actions. 
 
The dose you receive depends on your body weight. The doctor supervising the procedure will calculate the 
quantity of Xofigo to be used in your case. 
The recommended dose of Xofigo is 55 kBq (Becquerel, the unit used to express radioactivity) per kilogram 
body weight. 
No dose adjustment is necessary if you are 65 years of age or older or if you have reduced kidney or liver 
function. 
 



 

31 

Administration of Xofigo and conduct of the procedure 
Xofigo will be injected slowly via a needle into one of your veins (intravenously). The healthcare 
professional will flush the intravenous access line or cannula before and after injection with a saline solution. 
 
Duration of the procedure 
- Xofigo is given once every 4 weeks for a total of 6 injections. 
- There are no data available on the safety and efficacy of treatment with more than 6 injections of 

Xofigo. 
 
After administration of Xofigo 
- Care should be taken when handling materials, such as bed linen, that come into contact with body 

fluids (such as spill of urine, faeces, vomiting etc.). Xofigo is excreted mainly via the faeces. The doctor 
will tell you if you need to take any special precautions after receiving this medicine. Contact your 
doctor if you have any questions. 

 
If you have been given more Xofigo than you should 
An overdose is unlikely. 
However, in the case of an accidental overdose, your doctor will start appropriate supportive treatment and 
will check you for changes in the number of blood cells, and for gastrointestinal symptoms (e.g. diarrhoea, 
nausea [feeling sick], vomiting). 
 
If you have any further questions on the use of Xofigo, please ask the doctor who supervises the procedure. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
The most serious side effects in patients receiving Xofigo are 
- decrease in the number of blood platelets (thrombocytopenia), 
- decrease in the number of neutrophils, a type of white blood cells (neutropenia, which may lead to 

an increased risk of infection). 
 
Contact your doctor immediately if you notice the following symptoms as they may be signs of 
thrombocytopenia or neutropenia (see above): 
- any unusual bruising, 
- more bleeding than usual after injury, 
- fever, 
- or if you seem to be catching a lot of infections. 
 
Your doctor will perform blood tests before starting treatment and before each injection to check your 
number of blood cells and platelets (see also section 2). 
 
 
The most frequent side effects in patients receiving Xofigo (very common [may affect more than 
1 in 10 people]) are: 
- diarrhoea, nausea (feeling sick), vomiting, thrombocytopenia (decrease in the number of blood 

platelets) and bone fracture. 
 
Risk of dehydration: tell your doctor if you have any of the following symptoms: dizziness, increased thirst, 
decreased urination or dry skin as these can all be symptoms of dehydration. It is important to avoid 
dehydration by drinking plenty of fluids. 
 



 

32 

Other possible side effects are listed below by how likely they are: 
 
Common (may affect up to 1 in 10 people) 
- decrease in the number of white blood cells (leukopenia) 
- decrease in the number of neutrophils, a type of white blood cells (neutropenia, which may lead to an 

increased risk of infection) 
- decrease in the number of red and white blood cells and blood platelets (pancytopenia) 
- injection site reactions (e.g. redness of the skin [erythema], pain and swelling) 
 
Uncommon (may affect up to 1 in 100 people) 
- decrease in the number of lymphocytes, a type of white blood cells (lymphopenia) 
- weakened bones (osteoporosis) 
 
Xofigo contributes to your overall long-term cumulative radiation exposure. Long-term cumulative radiation 
exposure may increase your risk of developing cancer (in particular of bone cancer and leukaemia) and 
hereditary abnormalities. No cases of cancer caused by Xofigo have been reported in clinical trials with a 
follow-up of up to three years. 
 
If you have symptoms of pain, swelling or numbness of the jaw, a “heavy jaw feeling” or loosening of a 
tooth, please contact your doctor. Cases of osteonecrosis of the jaw (dead tissue in the jaw bone which is 
mainly seen in patients who have been treated with bisphosphonates) have occurred in patients treated with 
Xofigo. All these cases were only seen in patients receiving bisphosphonates prior to or at the same time of 
treatment with Xofigo and chemotherapy prior to treatment with Xofigo. 
 
Reporting of side effects 
If you get any side effects talk to your doctor. This includes any possible side effects not listed in this leaflet. 
You can also report side effects directly via the national reporting system listed in Appendix V. By reporting 
side effects, you can help provide more information on the safety of this medicine. 
 
 
5. How Xofigo is stored 
 
You will not have to store this medicine. This medicine is stored under the responsibility of the specialist in 
appropriate premises. Storage of radiopharmaceuticals will be in accordance with national regulations on 
radioactive materials. 
 
The following information is intended for the specialist only: 
Xofigo must not be used after the expiry date which is stated on the vial and the lead pot. 
This medicine does not require any special temperature storage conditions. 
Xofigo must not be used if discolouration, the occurrence of particulate matter or a defective container is 
noticed. 
 
 
6. Contents of the pack and other information 
 
What Xofigo contains 
 
- The active substance is: radium Ra 223 dichloride (radium-223 dichloride). 

 
Each mL of solution contains 1100 kBq radium-223 dichloride, corresponding to 0.58 ng radium-223 
at the reference date. 

 
Each vial contains 6 mL of solution (6600 kBq radium-223 dichloride at the reference date). 

 
- The other ingredients are: water for injections, sodium citrate, sodium chloride and hydrochloric acid 

(see end of Section 2 for further information on sodium). 
 



 

33 

What Xofigo looks like and contents of the pack 
 
Xofigo is a clear and colourless solution for injection. It is supplied in a colourless glass vial closed with a 
grey rubber stopper and aluminium seal. The vial contains 6 mL of solution. It is stored in a lead pot. 
 
 
Marketing Authorisation Holder 
Bayer AG 
51368 Leverkusen 
Germany 
 
Manufacturer 
Bayer AS 
Drammensveien 288  
NO-0283 Oslo 
Norway 
 
 



 

34 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België / Belgique / Belgien 
Bayer SA-NV 
Tél/Tel: +32-(0)2-535 63 11 

Lietuva 
UAB Bayer 
Tel. +37 05 23 36 868 

България 
Байер България ЕООД 
Тел. +359 (0)2-424 72 80  

Luxembourg / Luxemburg 
Bayer SA-NV 
Tél/Tel: +32-(0)2-535 63 11 

Česká republika 
Bayer s.r.o. 
Tel: +420 266 101 111 

Magyarország 
Bayer Hungária KFT 
Tel.:+36 14 87-41 00 

Danmark 
Bayer A/S 
Tlf: +45-45 23 50 00 

Malta 
Alfred Gera and Sons Ltd. 
Tel: +35 621 44 62 05 

Deutschland 
Bayer Vital GmbH 
Tel: +49 (0)214-30 513 48 

Nederland 
Bayer B.V. 
Tel: +31-(0)297-28 06 66 

Eesti 
Bayer OÜ 
Tel: +372 655 8565 

Norge 
Bayer AS 
Tlf. +47-23 13 05 00 

Ελλάδα 
Bayer Ελλάς ΑΒΕΕ 
Τηλ: +30 210 61 87 500 

Österreich 
Bayer Austria Ges. m. b. H. 
Tel: +43-(0)1-711 46-0 

España 
Bayer Hispania S.L. 
Tel: +34-93-495 65 00 

Polska 
Bayer Sp. z o.o. 
Tel.: +48 22 572 35 00 

France 
Bayer HealthCare 
Tél(N° vert): +33-(0)800 87 54 54 

Portugal 
Bayer Portugal, Lda. 
Tel: +351 21 416 42 00 

Hrvatska 
Bayer d.o.o. 
Tel: + 385-(0)1-6599 900 

România 
SC Bayer SRL 
Tel: +40 21 529 59 00 

Ireland 
Bayer Limited 
Tel: +353 1 216 3300 

Slovenija 
Bayer d. o. o. 
Tel.: +386 (0)1 58 14 400 

Ísland 
Icepharma hf. 
Sími: +354 540 8000 

Slovenská republika 
Bayer, spol. s r.o. 
Tel: +421 2 59 21 31 11 

Italia 
Bayer S.p.A. 
Tel: +39 02 397 81 

Suomi/Finland 
Bayer Oy 
Puh/Tel: +358 20 785 21 

Κύπρος 
NOVAGEM Limited 
Τηλ: +357 22 48 38 58 

Sverige 
Bayer AB 
Tel: +46 (0) 8 580 223 00 

Latvija 
SIA Bayer 
Tel: +371 67 84 55 63 

United Kingdom 
Bayer plc 
Tel: +44 (0) 118 206 3000 

 
This booklet was last revised in {MM/YYYY}. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
----------------------------------------------------------------------------------------------------------------------------- 



 

35 

The following information is intended for healthcare professionals only 
 
The complete SmPC of Xofigo is provided as a tear-off section at the end of the printed leaflet in the product 
package, with the objective to provide healthcare professionals with other additional scientific and practical 
information about the administration and use of this radiopharmaceutical. 
 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET