FDA Slaps Boxed Warning on Osteoporosis Drug

The FDA added a boxed warning to the label of the osteoporosis drug denosumab (Prolia) over the risk of severe hypocalcemia in patients with advanced chronic kidney disease (CKD), the agency announced Friday.

After a review of the evidence, including new data published in JAMA, the FDA determined that denosumab can increase the risk for severe hypocalcemia compared with bisphosphonates in patients with advanced CKD, especially those on dialysis. Patients on dialysis or with mineral and bone disorder (MBD) have the highest risk of very low blood calcium levels.

The new data, which involved women on dialysis, showed that 41% developed severe hypocalcemia during the first 12 weeks of denosumab treatment, compared with 2.0% of those taking oral bisphosphonates.

The FDA’s “most prominent” warning, the boxed warning lists the potential for serious harm from severe hypocalcemia. This could include hospitalization, life-threatening events, and death in patients with advanced CKD taking denosumab. Severe hypocalcemia can also be asymptomatic or can present with symptoms like confusion, seizures, irregular heart rhythm, fainting, face twitching, uncontrolled muscle spasms, or weakness, tingling, or numbness in parts of the body.

As part of its new drug safety communication, the FDA advised clinicians to carefully select appropriate patients for this treatment and increase monitoring of blood calcium levels, particularly for the first 2 to 10 weeks after each injection. Calcium and vitamin D supplements may also be required.

Prior to prescribing denosumab, clinicians should assess their patients’ kidney function and consider the risk of severe hypocalcemia with denosumab in the context of other available treatments for osteoporosis for patients with advanced CKD — especially those on dialysis.

“If Prolia is still being considered for these patients, for initial or continued use, check their calcium blood levels and assess them for evidence of CKD-MBD,” the FDA advised.

Patients taking denosumab shouldn’t stop their medication without first consulting with their healthcare provider.

The label update comes after the FDA initially issued a safety alert in November 2022 about denosumab’s potential hypocalcemia risk in dialysis-dependent women. The safety alert was prompted after interim results from maker Amgen’s ongoing safety study — required upon approval — that indicated an increased risk of hypocalcemia in patients with advanced kidney disease.

The drug was first approved in 2010 for postmenopausal women with osteoporosis at high risk for bone fracture and later picked up indications to treat men with osteoporosis, glucocorticoid-induced osteoporosis, and bone loss in those receiving androgen-deprivation therapy for prostate cancer and for women receiving aromatase inhibitor therapy for breast cancer. (Denosumab is also approved under the trade name Xgeva to reduce the risk of bone-related events in certain cancer patients.)

Administered via injection every 6 months, the treatment works by blocking the protein receptor activator of nuclear factor kappa beta (RANK) and prevents osteoclasts from breaking down bone in the body.

The FDA asked patients and healthcare professionals to report side effects involving denosumab to the agency’s MedWatch program.

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