Xofigo

/ Bayer

This drug should be administered only by persons authorised to handle radiopharmaceuticals in designated clinical settings, after evaluation of the patient by a qualified physician.
The dose regimen of of this substance is an activity of 55 kBq per kg body weight, given at 4 week intervals for 6 injections.
For calculation of the volume to be administered, please see prescribing information.
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: The safety and efficacy of Xofigo in children and adolescents below 18 years of age have not been studied.
There is no relevant use of this medicinal product in the paediatric population in the indication of prostate cancer.
Method of administration: Xofigo is for intravenous use. It must be administered by slow injection (generally up to 1 minute).
The intravenous access line or cannula must be flushed with isotonic sodium chloride 9 mg/mL (0.9%) solution for injection before and after injection of Xofigo.

Treatment of adults with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastases. 

In combination with abiraterone acetate and prednisone/prednisolone.

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.
Therefore, Xofigo is contraindicated in combination with abiraterone acetate and prednisone/prednisolone.
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.
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.
Bone marrow suppression: Bone marrow suppression, notably thrombocytopenia, neutropenia, leukopenia and pancytopenia, has been
reported in patients treated with Xofigo.
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 10^9/l, the platelet count ≥ 100 x 10^9/l and haemoglobin ≥ 10.0 g/dl. Before subsequent administrations, the ANC should be ≥ 1.0 x 10^9/l and the platelet count ≥ 50 x 10^9/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.
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. 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.
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 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.
See prescribing information for full details.

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 prescribing information for full details.

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. Safety and efficacy of concomitant chemotherapy with Xofigo have not been established.

Xofigo is not indicated in women. Xofigo is not to be used in women who are, or may be, pregnant or breast-feeding.

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.