Adverse reactions : תופעות לוואי

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                    Very                      Common                   Uncommon (MedDRA)                        common
Blood and lymphatic                                        Neutropenia Thrombocytopenia                                          Lymphopenia system disorders                                           Pancytopenia Leukopenia
Gastrointestinal             Diarrhoea disorders                    Vomiting
Nausea
Musculoskeletal and          Bone fracture
Osteoporosis connective tissue disorders
General disorders and
Injection site reactions administration site conditions


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 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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il/