Hypocalcaemia
In three phase III, active-controlled clinical studies in patients with advanced malignancies involving bone, hypocalcaemia was reported in 9.6% of patients treated with XGEVA® and 5.0% of patients treated with zoledronic acid.[SmPC, p. 7]
A grade 3 decrease in serum calcium levels was experienced in 2.5% of patients treated with XGEVA® and 1.2% of patients treated with zoledronic acid. A grade 4 decrease in serum calcium levels was experienced in 0.6% of patients treated with XGEVA® and 0.2% of patients treated with zoledronic acid.[SmPC, p. 7]
Symptoms of hypocalcaemia in clinical studies included paresthesias or muscle stiffness, twitching, spasms and muscle cramps. [SmPC, p. 7]
In the post-marketing setting, severe symptomatic hypocalcaemia (including fatal cases) has been reported.[SmPC, p. 7]
Osteonecrosis of the jaw (ONJ)
In clinical studies, the incidence of ONJ increased with length of exposure; ONJ has also been diagnosed after stopping treatment with XGEVA®, with the majority of cases occurring within 5 months after the last XGEVA® dose.[SmPC, p. 7]
In the primary treatment phases of three phase III, active-controlled clinical studies in patients with advanced malignancies involving bone, ONJ was confirmed in 1.8% of patients treated with XGEVA® (median exposure of 12.0 months; range 0.1–40.5) and 1.3% of patients treated with zoledronic acid. Clinical characteristics of these cases were similar between treatment groups. Among subjects with confirmed ONJ, most (81% in both treatment groups) had a history of tooth extraction, poor oral hygiene, and/or use of a dental appliance. In addition most subjects were receiving or had received chemotherapy. The studies in patients with breast or prostate cancer included an XGEVA® extension treatment phase (median overall exposure of 14.9 months; range 0.1–67.2). The patient-year adjusted overall incidence of confirmed ONJ was 1.1% during the first year of treatment, 3.7% in the second year and 4.6% per year thereafter. The median time to ONJ was 20.6 months (range: 4–53).[SmPC, p. 8]
In a phase III study in patients with non-metastatic prostate cancer (a patient population for which XGEVA® is not indicated), with longer treatment exposure of up to 7 years, the patient-year adjusted incidence of confirmed ONJ was 1.1% during the first year of treatment, 3.0% in the second year and 7.1% per year thereafter.[SmPC, p. 8]
In two phase II, single-arm clinical studies in patients with giant cell tumour of bone, ONJ occurred in 2.3% (12 of 523) of patients treated with XGEVA® (median overall exposure of 20.3 months; range: 0–83.4). The patient-year adjusted incidence of ONJ was 0.2% during the first year of treatment and 1.7% in the second year. The median time to ONJ was 19.4 months (range: 11–40). Based on duration of exposure, there are insufficient data in giant cell tumour of bone patients to assess risk of ONJ beyond 2 years.[SmPC, p. 8]
Drug-related hypersensitivity
In the post-marketing setting, events of hypersensitivity, including rare events of anaphylactic reactions, have been reported in patients receiving XGEVA®.[SmPC, p. 8]
Atypical fractures of the femur
In the clinical study program, atypical femoral fractures were reported rarely in patients treated with XGEVA®.[SmPC, p. 8]
Other special populations
In a clinical study of patients without advanced cancer with severe renal impairment (creatinine clearance < 30 ml/min) or receiving dialysis, there was a greater risk of developing hypocalcaemia in the absence of calcium supplementation.[SmPC, p. 8]