Severe Hypocalcemia in Patients with Advanced Kidney Disease

Severe Hypocalcemia and Mineral Metabolism Changes

Denosumab products can cause severe hypocalcemia and fatal cases have been reported. Pre-existing hypocalcemia must be corrected prior to initiating therapy with denosumab. Adequately supplement all patients with calcium and vitamin D [see Dosage and Administration (2.1), Contraindications (4), and Adverse Reactions (6.1)].

In patients without advanced chronic kidney disease who are predisposed to hypocalcemia and disturbances of mineral metabolism (e.g. history of hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine, treatment with other calcium-lowering drugs), assess serum calcium and mineral levels (phosphorus and magnesium) 10 to 14 days after denosumab injection. In some postmarketing cases, hypocalcemia persisted for weeks or months and required frequent monitoring and intravenous and/or oral calcium replacement, with or without vitamin D.

Patients with Advanced Chronic Kidney Disease:
Patients with advanced chronic kidney disease [i.e., eGFR <30 mL/min/1.73 m2] including dialysis-dependent patients are at greater risk for severe hypocalcemia following denosumab products administration. Severe hypocalcemia resulting in hospitalization, life-threatening events and fatal cases have been reported. The presence of underlying chronic kidney disease-mineral bone disorder (CKD-MBD, renal osteodystrophy) markedly increases the risk of hypocalcemia. Concomitant use of calcimimetic drugs may also worsen hypocalcemia risk.

To minimize the risk of hypocalcemia in patients with advanced chronic kidney disease, evaluate for the presence of chronic kidney disease mineral and bone disorder with intact parathyroid hormone (iPTH), serum calcium, 25(OH) vitamin D, and 1,25(OH)2 vitamin D prior to decisions regarding denosumab treatment.

Consider also assessing bone turnover status (serum markers of bone turnover or bone biopsy) to evaluate the underlying bone disease that may be present. Monitor serum calcium weekly for the first month after denosumab administration and monthly thereafter. Instruct all patients with advanced chronic kidney disease, including those who are dialysis-dependent, about the symptoms of hypocalcemia and the importance of maintaining serum calcium levels with adequate calcium and activated vitamin D supplementation. Treatment with denosumab in these patients should be supervised by a healthcare provider who is experienced in diagnosis and management of CKD-MBD.