A grade 3 decrease in serum calcium levels was experienced in 2.5% of patients treated with XGEVA and 1.2% of patients treated with zoledronic acid. A grade 4 decrease in serum calcium levels was experienced in 0.6% of patients treated with XGEVA and 0.2% of patients treated with zoledronic acid (see section 4.4).

Osteonecrosis of the jaw (ONJ)

In three phase III active-controlled clinical trials in patients with advanced malignancies involving bone, ONJ was confirmed in 1.8% of patients treated with XGEVA and 1.3% of patients treated with zoledronic acid. Clinical characteristics of these cases were similar between treatment groups. Among subjects with confirmed ONJ, most (81% in both treatment groups) had a history of tooth extraction, poor oral hygiene, and/or use of a dental appliance. In addition most subjects were receiving or had received chemotherapy (see section 4.4). Patients with certain identified risk factors for ONJ were excluded from participation in the pivotal studies (see section 5.1).

Skin infections (predominantly cellulitis) leading to hospitalisation

In three phase III active-controlled clinical trials in patients with advanced malignancies involving bone, skin infections leading to hospitalisation (predominantly cellulitis) were reported more frequently in patients receiving XGEVA (0.9%) compared with zoledronic acid (0.7%).

In postmenopausal women with osteoporosis, skin infections leading to hospitalisation were reported for 0.4% women receiving Prolia® (denosumab 60 mg every 6 months) and for 0.1% women receiving placebo (see section 4.4).

Other special populations

In a clinical study of patients without advanced cancer with severe renal impairment (creatinine clearance < 30 ml/min) or receiving dialysis, there was a greater risk of developing hypocalcaemia in the absence of calcium supplementation.

4.9 Overdose

There is no experience with overdose in clinical studies. XGEVA has been administered in clinical studies using doses up to 180 mg every 4 weeks and 120 mg weekly for 3 weeks.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for the treatment of bone diseases – other drugs affecting bone structure and mineralisation, ATC code: M05BX04

Mechanism of action

RANKL exists as a transmembrane or soluble protein. RANKL is essential for the formation, function and survival of osteoclasts, the sole cell type responsible for bone resorption. Increased osteoclast activity, stimulated by RANKL, is a key mediator of bone destruction in metastatic bone disease and multiple myeloma. Denosumab is a human monoclonal antibody (IgG2) that targets and binds with high affinity and specificity to RANKL, preventing the RANKL/RANK interaction from occurring and resulting in reduced osteoclast numbers and function, thereby decreasing bone resorption and cancer-induced bone destruction.

Pharmacodynamic effects

In phase II clinical studies of patients with advanced malignancies involving bone, subcutaneous (SC) dosing of XGEVA administered either every 4 weeks or every 12 weeks resulted in a rapid reduction in markers of bone resorption (uNTx/Cr, serum CTx), wi