ons of Any Severity (Trials 1, 2, and 3)
Body System Xgeva
n = 2841
% Zoledronic Acid
n = 2836 %
GASTROINTESTINAL
Nausea 31 32
Diarrhea 20 19
GENERAL
Fatigue/Asthenia 45 46
INVESTIGATIONS
HypocalcemiaLaboratory-derived and below the central laboratory lower limit of normal [8.3 鈥?8.5 mg/dL (2.075 鈥?2.125聽mmol/L) for calcium and 2.2 鈥?2.8 mg/dL (0.71 鈥?0.9 mmol/L) for phosphorus] 18 9
Hypophosphatemia 32 20
NEUROLOGICAL
Headache 13 14
RESPIRATORY
Dyspnea 21 18
Cough 15 15
As with all therapeutic proteins, there is potential for immunogenicity. 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. 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.
The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of a positive antibody (including neutralizing antibody) test result 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 antibodies to denosumab with the incidence of antibodies to other products may be misleading.
No formal drug-drug interaction trials have been conducted with Xgeva.
In clinical trials in patients with breast cancer metastatic to bone, Xgeva was administered in combination with standard anticancer treatment. Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy.
There was no evidence that various anticancer treatments affected denosumab systemic exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar between patients receiving concomitant chemotherapy and/or hormone therapy [see Clinical Pharmacology (12.2)].
There are no adequate and well-controlled trials of Xgeva in pregnant women. Use Xgeva during pregnancy only if the potential benefit justifies the potential risk to the fetus. Encourage women who become pregnant during Xgeva treatment to enroll in Amgen鈥檚 Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.
In an embryofetal developmental study, cynomolgus monkeys received subcutaneous denosumab weekly during organogenesis at doses up to 6.5-fold higher than the recommended human dose of 120 mg every 4聽weeks, based on body weight (mg/kg). No evidence of maternal toxicity or fetal harm was observed. However, this study only assessed f
