etal toxicity during the first trimester, and fetal lymph nodes were not examined. Potential adverse developmental effects resulting from exposures during the second and third trimesters have not been assessed in animals [see Nonclinical Toxicology (13.2)].
In genetically engineered mice in which the gene for RANK ligand (RANKL) has been deleted (a 鈥渒nockout mouse鈥?, the absence of RANKL caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice also showed altered maturation of the maternal mammary gland, leading to impaired lactation postpartum [see Use in Specific Populations (8.3)].
It is not known whether Xgeva is excreted into human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xgeva, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Maternal exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL signaling pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation postpartum [see Nonclinical Toxicology (13.2)].
The safety and effectiveness of Xgeva in pediatric patients have not been established. Treatment with Xgeva may impair bone growth in children with open growth plates and may inhibit eruption of dentition.
In neonatal rats, inhibition of RANKL with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses less than or equal to 10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent monkeys dosed with denosumab at 5 and 25 times (10 and 50 mg/kg dose) higher than the recommended human dose of 120 mg subcutaneously every 4 weeks (based on body weight mg/kg) had abnormal growth plates [see Nonclinical Toxicology (13.2)].
Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.
In a trial of 55 patients without cancer and with varying degrees of renal function who received a single dose of 60 mg denosumab, patients with a creatinine clearance of less than 30 mL/min or receiving dialysis were at greater risk of severe hypocalcemia with denosumab compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been eva luated in patients with a creatinine clearance of less than 30 mL/min or receiving dialysis [see Warnings and Precautions (5.1), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)].
There is no experience with overdosage of Xgeva.
Xgeva (denosumab) is a human IgG2 monoclonal antibody that binds to human RANKL. Denosumab has an approximate molecular weight of 147 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells.
Xgeva is a sterile, preservative-free, clear, colorless to pale yellow solution.
Each single-use vial of Xgeva contains 120 mg denosumab, 4.6% sorbitol, 18 mM acetate, Water for Injection (USP), and sodium hydroxide to a pH of 5.2.
Xgeva binds to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. Xgeva prevents RANKL from
