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.

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 study 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).

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 were 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, treatment 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 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 studies 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.

Contraception in males

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 (see section 4.6).

Excipients

Depending on the volume administered, this medicinal product contains up to 54 mg (2.35 mmol) 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.

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 may potentially have toxic effects on male gonads and spermatogenesis (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 studies 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), rare (≥1/10 000 to <1/1 000); very rare (<1/10 000).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse reactions reported in clinical studies 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.

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 studies 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 www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 study and no dose-limiting toxicities were observed.