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FDA Adds Black Box to Prolia PI Warning of Severe Hypocalcemia Risk in CKD


The Boxed Warning reflects FDA research into severe adverse events including hospitalization and death in persons with CKD treated with denosumab.

Treatment with denosumab (Prolia) in patients with advanced chronic kidney disease (CKD), is associated with an increase in the risk of severe hypocalcemia, according to an updated Food and Drug Administration (FDA) safety alert issued on January 19, 2024.

In response to its investigations the agency announced the addition of a Boxed Warning to the denosumab prescribing information and amendments to the patient Medication Guide and the medication’s Risk Evaluation and Mitigation Strategy (REMS) program.

The current alert follows a November 2022, safety communication announcing the agency’s investigation of the potential for severe outcomes in persons with advanced CKD on dialysis receiving subcutaneous denosumab, which is administered every 6 months. The Agency assessed the risk in 2 studies conducted by the Centers for Medicare and Medicaid Services (CMS).

The study compared treatment with denosumab and the class of bisphosphonates and found the risk of developing severe hypocalcemia was significantly increased with denosumab, particularly among study participants with advanced CKD. Severe hypocalcemia typically developed 2 to 10 weeks after each denosumab injection with the greatest risk observed between week 2 and 5.

FDA also reviewed 77 cases submitted to the Agency through the Adverse
Event Report System (AERS) between July 2010 and May 2021, 25 of which described complications of severe hypocalcemia among individuals with CKD. Symptoms reported included arrhythmias, confusion, seizures, face twitching, muscle spasms or weakness following denosumab treatment.

The Boxed Warning now included in denosumab labeling alerts prescribers to the risk of severe hypocalcemia in patients with advanced CKD and particularly those receiving dialysis or who have mineral and bone disorder (MBD). The same information is included in the denosumab Patient Medication Guide and the REMS.

FDA guidance to health care professionals includes the recommendation to screen patients for renal health before prescribing denosumab and to weigh the risk of severe hypocalcemia in patients with advanced CKD with the potential benefits of treatment. If still considering denosumab treatment, a health care professional with expertise in the diagnosis and management of CKD-MBD should be involved in the final decision-making. FDA recommends regular blood calcium monitoring in anyone with severe renal compromise being treated with denosumab and regular assessment for signs and symptoms of CKD-MBD.

Clinicians also should advise individuals at high risk for hypocalcemia to maintain adequate intake of calcium and vitamin D supplementation.

Source: FDA adds Boxed Warning for increased risk of severe hypocalcemia in patients with advanced chronic kidney disease taking osteoporosis medicine Prolia (denosumab). News release. US Food and Drug Administration. January 19, 2024. Accessed January 23, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-increased-risk-severe-hypocalcemia-patients-advanced-chronic-kidney-disease.

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