Xgeva Adverse Reactions

The adverse reactions identified in the clinical trials and from post-marketing experience with XGEVA are presented in table as follows.
Frequency is provided by CIOMS category [e.g., Very common (≥ 10%), common (≥ 1% and < 10%), uncommon (≥ 0.1% and < 1%), rare (≥ 0.01% and < 0.1%), and very rare (< 0.01%)]. (See Table 6.)

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Description of selected adverse reactions: Drug Hypersensitivity Events: In clinical trials in patients with advanced malignancies involving bone, drug hypersensitivity events were reported rarely in subjects treated with XGEVA. In the post-marketing setting, hypersensitivity, including anaphylactic reactions has been reported.
Hypocalcemia: In the post-marketing setting, severe symptomatic hypocalcemia (including fatal cases) has been reported.
Musculoskeletal Pain: In the post-marketing setting, musculoskeletal pain, including severe cases has been reported.
Osteonecrosis of the Jaw (ONJ): In three phase 3 active-controlled clinical trials in patients with advanced malignancies involving bone, ONJ was confirmed in 1.8% of patients in the XGEVA group (median exposure of 12.0 months; range 0.1-40.5) and 1.3% of patients in the zoledronic acid group. The trials 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) (see Pharmacology: Pharmacodynamics: Clinical Data under Actions). The patient-year adjusted incidence (number of events per 100 patient years) 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).
In a phase 3 double-blind, active-controlled clinical trial in patients with newly diagnosed multiple myeloma, ONJ was confirmed in 4.1% of patients in the XGEVA group (median exposure of 15.8 months; range 1-49.8) and 2.8% of patients in the zoledronic acid group. At the completion of the double-blind treatment phase of this trial, the patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ in the XGEVA group (median exposure of 19.4 months; range 1-52), was 2.0% during the first year of treatment, 5.0% in the second year, and 4.5% per year thereafter. The median time to ONJ was 18.7 months (range: 1-44).
In a phase 3 placebo-controlled clinical trial with an extension treatment phase evaluating XGEVA for the prevention of bone metastases 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 (number of events per 100 patient years) of confirmed ONJ was 1.1% during the first year of treatment, 3.0% in the second year, and 7.1% per year thereafter.
Atypical Femoral Fracture: In the clinical trial program, atypical femoral fracture has been reported uncommonly in patients treated with XGEVA 120 mg and the risk increased with longer duration of treatment. Events have occurred during treatment and up to 9 months after treatment was discontinued.
Lichenoid Drug Eruptions: In the post-marketing experience, lichenoid drug eruptions (e.g., lichen planus-like reactions) have been observed.
Immunogenicity: In clinical studies, neutralizing antibodies have not been observed for XGEVA. Using a sensitive immunoassay, < 1% of patients treated with denosumab tested positive for non-neutralizing binding antibodies, with no evidence of altered pharmacokinetics, pharmacodynamic response or toxicity.