Amgen’s Prolia Gets FDA Boxed Warning for Risk of Severe Hypocalcemia

Amgen’s Prolia Gets FDA Boxed Warning for Risk of Severe Hypocalcemia

Prolia was first approved in 2010 for treating bone loss in postmenopausal women, and later, also in men.

The US Food and Drug Administration (FDA) has added a boxed warning to the safety information of Amgen’s osteoporosis drug Prolia (denosumab) for the increased risk of severe hypocalcemia in patients with advanced chronic kidney disease (CKD).

Hypocalcemia refers to an abnormally low level of calcium in the blood.

The FDA said that CKD patients on dialysis or who have mineral and bone disorders (CKD-MBD) are at the greatest risk of the condition.

The agency made the decision to add the warning after conducting a review of available information, which found that Prolia increased the risk of very low calcium levels in the blood (hypocalcemia) in patients with advanced CKD, particularly patients on dialysis. The review found that patients with advanced CKD who were taking Prolia experienced severe hypocalcemia that led to “serious harm,” including hospitalization, life-threatening events and death. Severe hypocalcemia appears to be more common in patients with CKD who also have CKD-MBD.

“As a result, we are revising the Prolia prescribing information to include a new Boxed Warning, FDA’s most prominent warning, communicating this increased risk,” the FDA announced.

Hypocalcemia is a serious condition that can be asymptomatic or lead to symptoms including confusion, seizures, irregular heart rhythm, fainting, face twitching, uncontrolled muscle spasms, tingling or numbness. The condition is serious but treatable and can potentially lead to life-threatening neurological or psychological complications.

Prolia was first approved in 2010 for treating bone loss in postmenopausal women and two years later, for men as well. Its US patent is due to expire next year in February.

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Prolia is a monoclonal antibody against receptor activator of nuclear factor kappa-B ligand (RANKL), which is involved in the formation, function and survival of osteoclasts, the cells responsible for bone resorption (breaking down bone tissue). By inhibiting RANKL, Prolia decreases the activity of osteoclasts, thereby reducing bone loss and increasing bone mass and strength. It is injected every six months.

Prolia has been a growing blockbuster for Amgen, hitting $3.6 billion in 2022 and for the first time, $1 billion in the second quarter of last year.

The FDA’s boxed warning comes after the agency issued a safety alert in November 2022, outlining a “substantial risk” of hypocalcemia for people on dialysis based on interim study data.

The FDA’s latest analysis was based on data from the Centers for Medicare and Medicaid Services (CMC). It also evaluated 25 case submissions that it received — reported to the FDA Adverse Event Report System (FAERS) database — between July 2010 and May 2021 involving patients with CKD, some of whom were on dialysis, who experienced complications of severe hypocalcemia after initiating Prolia treatment, including arrhythmias and other symptoms associated with severe hypocalcemia.

The evaluation revealed a significant increase in the development of hypocalcemia among patients taking Prolia compared to those taking more widely used oral bisphosphonates such as Merck’s Fosamax (alendronate).

According to the results, during the first 12 weeks of treatment, 41 percent of patients taking Prolia developed hypocalcemia compared with two percent of those on bisphosphonates. Patients developed severe hypocalcemia two to ten weeks following each Prolia injection, with the greatest risk occurring within two to five weeks.

Other bone loss drugs, including Amgen’s Xgeva (denosumab) and Evenity (romosozumab-aqqg) and Merck’s Fosamax, already have warnings in their safety information about prescribing the drugs to patients with kidney disease. In addition to osteoporosis and despite being the same drug as Prolia, Xgeva is also used to treat multiple myeloma treatment-induced bone loss, metastases to bone and giant cell tumor of bone. Xgeva is given as a 120 mg injection once every four weeks while Prolia is given as a 60 mg injection once every six months.

With the boxed warning, the FDA has advised healthcare providers to check kidney function and consider other treatments before prescribing Prolia to patients with kidney disease.

The agency said patients should also be monitored closely, particularly in weeks two to ten after each injection. They may also need calcium and vitamin D supplements.

Amgen’s osteoporosis trio of Prolia, Xgeva and Evenity amounted to $2.8 billion in sales in 2022.

In May 2023, Amgen shared real-world data from a study with half a million patients that showed Prolia reduced fracture risk in postmenopausal women with osteoporosis compared to Fosamax. Additionally, the company said longer treatment with Prolia was associated with higher improvements in fracture risk reduction.