Boxed warning added to ferric carboxymaltose injection labeling

What Is FDA Doing?

The Food and Drug Administration has approved revisions to the labeling for ferric carboxymaltose injection (currently marketed as Injectafer) that adds a boxed warning, the agency’s most prominent safety warning. This boxed warning describes the risk for symptomatic hypophosphatemia (low levels of phosphate in the blood) associated with ferric carboxymaltose injection and recommends phosphate monitoring in patients at risk of hypophosphatemia and in any patient who receives a repeat course of therapy within three months of the prior course.

Clinical manifestations depend on the severity and duration of hypophosphatemia. Symptoms may include muscle weakness or pain, fatigue, tremors, confusion, seizures, and cardiac arrhythmias. Chronic severe hypophosphatemia may lead to osteomalacia (bone softening) and bone fractures.

FDA has previously approved other labeling updates for Injectafer that describe this risk. In 2019, FDA determined that ferric carboxymaltose injection can cause serious symptomatic hypophosphatemia. As a result, in February 2020, FDA approved labeling revisions that, along with other changes, added a warning about this risk. In 2023, the warning was revised to include recommendations for serum phosphate level monitoring in patients at risk for hypophosphatemia and in any patient who receives a repeat course of treatment within three months. The revised warning also included osteomalacia and fractures as potential long-term complications and added inflammatory bowel disease as a possible risk factor for hypophosphatemia. In 2025, the warning was further revised to include additional risk factors for hypophosphatemia.

In 2026, FDA conducted an assessment of hypophosphatemia in association with ferric carboxymaltose injection using multiple data sources, including the FDA Adverse Event Reporting System (FAERS) database (which has been incorporated into the FDA Adverse Event Monitoring System [AEMS] database), literature reports, and FDA’s Sentinel System. FDA found that symptomatic hypophosphatemia continues to be reported with ferric carboxymaltose injection and serum phosphate testing levels are low despite labeling changes in February 2020 and May 2023.

What Is Ferric Carboxymaltose Injection (Injectafer)?

Ferric carboxymaltose injection (Injectafer) is a prescription iron replacement medicine originally approved in 2013 to treat iron deficiency anemia. Ferric carboxymaltose injection is given intravenously (through the vein). Iron deficiency anemia is a common type of anemia that can cause fatigue, weakness, shortness of breath, and other symptoms. Injectafer is approved for patients one year of age and older who cannot tolerate or do not fully respond to oral iron. It is also approved for iron deficiency in adults who have non-dialysis-dependent chronic kidney disease, and for iron deficiency in adults with heart failure and New York Heart Association class II/III to improve exercise capacity. Certain strengths of Injectafer are also approved as ferric carboxymaltose injection generic products. Generic application holders are expected to update their labeling to incorporate this change after this approval.

What Should Patients Do?

Patients should immediately report any new or worsening symptoms of low phosphate levels (e.g., muscle weakness or pain, fatigue, bone and joint pain, confusion) to their health care provider. Some of these symptoms may mimic those of iron deficiency anemia.

What Should Health Care Providers Do?

Health care providers should inform patients of the risk of hypophosphatemia with ferric carboxymaltose injection use. Health care providers should also:

• Check serum phosphate levels prior to a repeat course of treatment if the patient is at risk for low serum phosphate or if the patient will receive a repeat course of therapy within three months of the prior course.

• Correct pre-existing hypophosphatemia prior to administering Injectafer.

• Monitor serum phosphate levels in patients at risk for chronic low serum phosphate.

• Treat hypophosphatemia as medically indicated.

• Consider permanent discontinuation of Injectafer for severe symptomatic hypophosphatemia or persistent hypophosphatemia.

What Did FDA Find?

FDA found that symptomatic hypophosphatemia continues to be reported with ferric carboxymaltose injection, despite labeling changes in February 2020 and May 2023 adding and strengthening the warning about this risk. The FAERS case series included reports of symptomatic hypophosphatemia that occurred after both single and multiple infusions of ferric carboxymaltose injection. Consequences included hospitalization, need for phosphate replacement therapy over weeks to months, and extensive monitoring with regular follow-up medical visits.

Data from the FDA’s Sentinel System indicate that serum phosphate laboratory testing occurs in fewer than 20% of ferric carboxymaltose administration episodes.

Hypophosphatemia associated with ferric carboxymaltose can lead to serious outcomes including hospitalization, a need for prolonged phosphate replacement therapy, osteomalacia, and fractures. This serious adverse reaction can be prevented or reduced in severity through appropriate phosphate level monitoring and early intervention. Therefore, FDA has required a boxed warning be added to the Injectafer labeling describing the risk for symptomatic hypophosphatemia and recommending mitigation strategies. This action highlights the warning already in the Injectafer labeling.

How Do I Report Side Effects from Ferric Carboxymaltose Injection (Injectafer)?

To help FDA track safety issues with medicines, we urge consumers and health care providers to report side effects involving ferric carboxymaltose injection or other medicines to the FDA MedWatch program using the information in the “Contact FDA” box at the bottom of this page.

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