Xgeva Adverse Reactions

The following adverse reactions are discussed as follows and elsewhere in the labeling: Hypersensitivity [see Hypersensitivity under Precautions].
Hypocalcemia [see Hypocalcemia, Renal Impairment under Precautions].
Osteonecrosis of the Jaw [see Osteonecrosis of the Jaw (ONJ) under Precautions].
Atypical Subtrochanteric and Diaphyseal Femoral Fracture [see Atypical Subtrochanteric and Diaphyseal Femoral Fracture under Precautions].
Hypercalcemia Following Treatment Discontinuation in Patients with Giant Cell Tumor of Bone and in Patients with Growing Skeletons [see Hypercalcemia Following Treatment Discontinuation in Patients with Giant Cell Tumor of Bone and in Patients with Growing Skeletons and Use in Children under Precautions].
Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation [see Precautions].
Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Bone Metastasis from Solid Tumors: The safety of denosumab (XGEVA) was evaluated in three randomized, double-blind, double-dummy trials [see Pharmacology: Pharmacodynamics: Clinical Trials: Bone Metastasis from Solid Tumors under Actions] in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of denosumab (XGEVA). In Studies 20050136, 20050244, and 20050103, patients were randomized to receive either 120 mg of denosumab (XGEVA) every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required.
The median duration of exposure to denosumab (XGEVA) was 12 months (range: 0.1-41) and median duration on-study was 13 months (range: 0.1-41). Of patients who received denosumab (XGEVA), 46% were female. Eighty-five percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18-93). Seventy-five percent of patients who received denosumab (XGEVA) received concomitant chemotherapy.
The most common adverse reactions in patients (incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 4). The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation of denosumab (XGEVA) were osteonecrosis and hypocalcemia. (See Table 4.)

Click on icon to see table/diagram/image

Severe Mineral/Electrolyte Abnormalities: Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) occurred in 3.1% of patients treated with denosumab (XGEVA) and 1.3% of patients treated with zoledronic acid. Of patients who experienced severe hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes [see Hypocalcemia, Renal Impairment under Precautions].
Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 0.6 mmol/L) occurred in 15.4% of patients treated with denosumab (XGEVA) and 7.4% of patients treated with zoledronic acid.
Osteonecrosis of the Jaw (ONJ): In the primary treatment phases of Studies 20050136, 20050244, and 20050103, ONJ was confirmed in 1.8% of patients in the denosumab (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 (Study 20050136) or prostate (Study 20050103) cancer included an denosumab (XGEVA) open-label extension treatment phase where patients were offered denosumab (XGEVA) 120 mg once every 4 weeks (median overall exposure of 14.9 months; range: 0.1-67.2). 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) [see Osteonecrosis of the Jaw (ONJ) under Precautions].
In a placebo-controlled clinical trial with an extension treatment phase evaluating denosumab (XGEVA) for the prevention of bone metastases in patients with non-metastatic prostate cancer (a patient population for which denosumab (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 Subtrochanteric and Diaphyseal Fracture: In the clinical trial program, atypical femoral fracture has been reported in patients treated with denosumab (XGEVA) and the risk increased with longer duration of treatment. Events have occurred during treatment and after treatment was discontinued [see Atypical Subtrochanteric and Diaphyseal Femoral Fracture under Precautions].
Multiple Myeloma: The safety of denosumab (XGEVA) was evaluated in an international, randomized (1:1), double-blind, active-controlled trial of patients with newly diagnosed multiple myeloma with treatment through disease progression [see Pharmacology: Pharmacodynamics: Clinical Trials: Multiple Myeloma under Actions]. In this trial, patients received 120 mg denosumab (XGEVA) every 4 weeks as a subcutaneous injection (n = 850) or 4 mg (dose adjusted for renal function) of zoledronic acid intravenously (IV) every 4 weeks by IV infusion (n = 852). Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required.
The median duration of exposure to denosumab (XGEVA) was 16 months (range: 1-50) and median duration on-study was 17 months (range: 0.0-49). Of patients who received denosumab (XGEVA), 46% were female, 83% percent were White, 13% Asian, 3% Black or African American, and 4% Hispanic/Latino. The median age of the patients randomized to denosumab (XGEVA) was 63 years (range: 29-91) and all patients who received denosumab (XGEVA) received concomitant anti-myeloma chemotherapy.
The adverse reaction profile of denosumab (XGEVA) in patients with multiple myeloma, Study 20090482, was similar to that observed in Studies 20050136, 20050244, and 20050103. The most common adverse reactions (incidence ≥10%) were diarrhea (34%), nausea (32%), anemia (22%), back pain (21%), thrombocytopenia (19%), peripheral edema (17%), hypocalcemia (16%), upper respiratory tract infection (15%), rash (14%), and headache (11%). The most common serious adverse reaction (incidence ≥5%) was pneumonia (8%). The most common adverse reaction resulting in discontinuation of denosumab (XGEVA) (≥1.0%) was osteonecrosis of the jaw.
Hypocalcemia and Hypophosphatemia: Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) and severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 0.6 mmol/L) occurred in 2% and 21% patients treated with denosumab (XGEVA), respectively.
Osteonecrosis of the Jaw (ONJ): In the primary treatment phase of Study 20090482, ONJ was confirmed in 4.1% of patients in the denosumab (XGEVA) group (median exposure of 16 months; range: 1-50) and 2.8% of patients in the zoledronic acid group (median 15 months; range: 1-45 months). At the completion of the double-blind treatment phase of Study 20090482, the patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ in the denosumab (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) [see Osteonecrosis of the Jaw under Precautions].
Giant Cell Tumor of Bone: The safety of denosumab (XGEVA) was evaluated in two single arm trials (Study 20062004 and Study 20040215) [see Pharmacology: Pharmacodynamics: Clinical Trials: Giant Cell Tumor in Bone under Actions] in which a total of 304 adult or skeletally mature adolescent patients with giant cell tumor of bone received at least 1 dose of denosumab (XGEVA). Patients received 120 mg denosumab (XGEVA) subcutaneously every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Patients receiving concurrent bisphosphonate therapy were excluded from enrollment in both studies. Patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure were excluded from enrollment in Study 20040215. During the trial, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required.
Of the 304 patients who received denosumab (XGEVA), 145 patients were treated with denosumab (XGEVA) for ≥1 year, 44 patients for ≥2 years, and 15 patients for ≥3 years. The median number of doses received was 14 (range: 1-60 doses) and the median number of months on study was 11 (range: 0-54 months). Fifty-eight percent of the enrolled patients were women and 80% were White. The median age was 33 years (range: 13-83 years); a total of 10 patients were skeletally mature adolescents (13 to 17 years of age).
The adverse reaction profile of denosumab (XGEVA) in patients with giant cell tumor of bone was similar to that reported in Studies 20050136, 20050244, and 20050103. The most common adverse reactions in patients (incidence ≥10%) were arthralgia, headache, nausea, back pain, fatigue, and pain in extremity. The most common serious adverse reactions were osteonecrosis of the jaw and osteomyelitis (incidence of 0.7%). The most common adverse reactions resulting in discontinuation of denosumab (XGEVA) were osteonecrosis of the jaw (incidence of 0.7%), and tooth abscess or tooth infection (incidence of 0.7%). The adverse reaction profile appeared similar in skeletally mature adolescents and adults.
Hypocalcemia and Hypophosphatemia: Moderate hypocalcemia (corrected serum calcium less than 8 to 7 mg/dL or less than 2 to 1.75 mmol/L) occurred in 2.6% of patients treated with denosumab (XGEVA).
Severe hypophosphatemia (serum phosphorus less than 2 to 1 mg/dL or less than 0.6 to 0.3 mmol/L) occurred in 29 patients (9.5%).
Osteonecrosis of the Jaw (ONJ): In Study 20062004 and Study 20040215, ONJ was confirmed in 4 of 304 (1.3%) patients who received denosumab (XGEVA). The median time to ONJ was 16 months (range: 13-20 months) [see Osteonecrosis of the Jaw (ONJ) under Precautions].
Hypercalcemia of Malignancy: Denosumab (XGEVA) was evaluated in an open-label, single-arm trial (Study 20070315) in which 33 patients with hypercalcemia of malignancy (with or without bone metastases) refractory to treatment with intravenous bisphosphonate therapy were enrolled [see Pharmacology: Pharmacodynamics: Clinical Trials: Hypercalcemia of Malignancy under Actions].
The adverse reaction profile of denosumab (XGEVA) in patients with hypercalcemia of malignancy was similar to that reported in Studies 20050136, 20050244, 20050103, 20062004, and 20040215. Adverse reactions occurring in greater than 20% of patients were nausea (30%), dyspnea (27%), decreased appetite (24%), headache (24%), peripheral edema (24%), vomiting (24%), anemia (21%), constipation (21%), and diarrhea (21%). The following adverse reactions of Grade 3 or greater severity related to study therapy were reported on study: fatigue (3%) and infection (6%). Grade 3 laboratory abnormalities included hypomagnesemia (3%), hypokalemia (3%), and hypophosphatemia (76%) of patients. No deaths on study were related to denosumab (XGEVA) therapy.
Postmarketing Experience: The following adverse reactions have been identified during post approval use of denosumab (XGEVA). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases [see Contraindications and Precautions].
Hypercalcemia: Severe symptomatic hypercalcemia following treatment discontinuation can occur [see Hypercalcemia Following Treatment Discontinuation in Patients with Giant Cell Tumor of Bone and in Patients with Growing Skeletons under Precautions and Adverse Reactions].
Hypersensitivity, including anaphylactic reactions [see Contraindications and Precautions].
Musculoskeletal pain, including severe musculoskeletal pain. Positive rechallenge has been reported.
Lichenoid drug eruptions (e.g., lichen planus-like reactions).
Alopecia.
Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to denosumab in the studies described as follows with the incidence of antibodies to other studies or to other products may be misleading.
Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of patients with osseous metastases treated with denosumab doses ranging from 30-180 mg every 4 weeks or every 12 weeks for up to 3 years tested positive for binding antibodies. None of the 304 patients with giant cell tumor of bone in Study 20062004 and Study 20040215 tested positive for binding antibodies. In multiple myeloma patients in Study 20090482, 1 out of 199 patients with a post baseline result, tested positive for binding antibodies. No patient with positive binding antibodies tested positive for neutralizing antibodies as assessed using a chemiluminescent cell-based in vitro biological assay. There was no evidence of altered pharmacokinetic profile, toxicity profile, or clinical response associated with binding antibody development.