Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

The following adverse reactions are discussed below and also elsewhere in the labeling:

The most common adverse reactions in patients receiving Xgeva (per-patient incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1).

The most common serious adverse reaction in patients receiving Xgeva was dyspnea.

The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia.

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 other clinical trials and may not reflect the rates observed in practice.

The safety of Xgeva was eva luated in three randomized, double-blind, double-dummy trials [see Clinical Trials (14)] 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 Xgeva. In Trials 1, 2, and 3, patients were randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4聽weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5聽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 Xgeva was 12 months (range: 0.1 鈥?41) and median duration on-study was 13 months (range: 0.1 鈥?41). Of patients who received 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 鈥?93). Seventy-five percent of patients who received Xgeva received concomitant chemotherapy.

Severe Mineral/Electrolyte Abnormalities

Osteonecrosis of the Jaw

In the primary treatment phases of Trials 1, 2, and 3, ONJ was confirmed in 1.8% of patients in the Xgeva group and 1.3% of patients in the zoledronic acid group [see Warnings and Precautions (5.2)]. When events occurring during an extended treatment phase of approximately 4 months in each trial are included, the incidence of confirmed ONJ was 2.2% in patients who received Xgeva. The median time to ONJ was 14 months (range: 4 鈥?25).

Table 1. Per-patient Incidence of SelectedAdverse reactions reported in at least 10% of patients receiving Xgeva in Trials 1, 2, and 3, and meeting one of the following criteria:
- At least 1% greater incidence in Xgeva-treated patients, or
- Between-group difference (either direction) of less than 1% and more than 5% greater incidence in patients treated with zoledronic acid compared to placebo (U.S. Prescribing Information for zoledronic acid) Adverse Reacti