In an embryofetal developmental study, cynomolgus monkeys received subcutaneous denosumab weekly during organogenesis at doses up to 13-fold higher than the recommended human dose of 60 mg administered once every 6 months based on body weight (mg/kg). No evidence of maternal toxicity or fetal harm was observed. However, this study only assessed fetal toxicity during a period equivalent to the first trimester and fetal lymph nodes were not examined. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. Potential adverse developmental effects resulting from exposures during the second and third trimesters have not been assessed in animals [see Nonclinical Toxicology (13.2)].

8.3 Nursing Mothers
It is not known whether Prolia 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 Prolia, 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 Prolia 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)].

8.4 Pediatric Use
Prolia is not recommended in pediatric patients. The safety and effectiveness of Prolia in pediatric patients have not been established.

Treatment with Prolia may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Prolia therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent primates dosed with denosumab at 10 and 50 times (10 and 50 mg/kg dose) higher than the recommended human dose of 60 mg administered once every 6 months, based on body weight (mg/kg), had abnormal growth plates [see Nonclinical Toxicology (13.2)].

8.5 Geriatric Use
Of the total number of patients in clinical studies of Prolia, 9943 patients (76%) were ≥ 65 years old, while 3576 (27%) were ≥ 75 years old. No overall differences in safety or efficacy were observed between these patients and younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment
No dose adjustment is necessary in patients with renal impairment.

In clinical studies, patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis were at greater risk of developing hypocalcemia. Consider the benefit-risk profile when administering Prolia to patients with severe renal impairment or receiving dialysis. Clinical monitoring of calcium and mineral levels (phosphorus and magnesium) is highly recommended. Adequate intake of calcium and vitamin D is important in patients with severe renal impairment or receiving dialysis [see Warnings and Precautions (5.1), Adve