Cases of severe symptomatic hypocalcaemia have occurred in patients receiving Denosumab 120 mg ( Xgeva ) or 60 mg ( Prolia ); some of these cases were fatal in those receiving the 120 mg dose.

Denosumab 120 mg solution for injection ( Xgeva ) is given once every 4 weeks for the prevention of skeletal related events ( pathological fracture, radiation to bone, spinal cord compression or surgery to bone ) in adults with bone metastases from solid tumours.
Denosumab 60 mg solution for injection ( Prolia ) is given once every 6 months for the treatment of osteoporosis in postmenopausal women at increased risk of fractures, and for the treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk.

Possible risk of fatal hypocalcaemia

Hypocalcaemia is a known risk with Denosumab use, especially in patients with severe renal impairment ( creatinine clearance less than 30 mL/min; estimated glomerular filtration rate [ eGFR ] 15-29 mL/min/1.73m2 ) or receiving dialysis. Severe symptomatic hypocalcaemia, including three fatal cases, has been reported in patients receiving Denosumab 120 mg. Severe symptomatic hypocalcaemia has also been reported in patients at increased risk of hypocalcemia receiving Denosumab 60 mg.

Signs and symptoms of hypocalcaemia include altered mental status, tetany, seizures and QTc prolongation. Hypocalcaemia with Denosumab most commonly occurs within the first 6 months of dosing, but it can occur at any time during treatment.

Periodic monitoring of calcium levels ( at the discretion of the prescriber ) is recommended after use of Denosumab in patients predisposed to hypocalcaemia, including those with severe renal impairment. In patients receiving 120 mg Denosumab, supplementation of calcium and vitamin D is required unless hypercalcaemia is present; if hypocalcaemia occurs, additional calcium supplementation may be necessary.

Advice for healthcare professionals

The following precautions should be followed to minimise the risk of hypocalcaemia with Denosumab:

• Denosumab 120 mg ( for cancer indications ) should not be used in patients with severe, untreated hypocalcaemia;

• Denosumab 60 mg ( for osteoporosis indications ) should not be used in patients with hypocalcaemia, regardless of severity.

Warnings and recommendations:

• Pre-existing hypocalcaemia must be corrected prior to initiating Denosumab, and supplementation of calcium and vitamin D is required in all patients receiving 120 mg Denosumab unless hypercalcaemia is present;

• Adequate intake of calcium and vitamin D is important in all patients receiving 60 mg Denosumab;

• Patients with severe renal impairment ( creatinine clearance less than 30 mL; eGFR 15-29 mL/min/1.73m ) or receiving dialysis are at greater risk of developing hypocalcaemia, and monitoring of calcium levels in these patients is recommended.

Source: Drug Safety Update, 2012