On September 1, 2026, the FDA approved a labeling change to ferric carboxymaltose (FCM) that adds a boxed warning describing the risk for severe symptomatic hypophosphatemia. The warning recommends phosphate monitoring for patients at risk for hypophosphatemia and for any patient who receives a repeat course of therapy within 3 months. 

The development of hypophosphatemia has been associated with all IV iron products that employ a carbohydrate iron shell, including iron dextran, ferumoxytol, FCM and ferric derisomaltose, and is attributed to the phosphaturic effects of fibroblast growth factor-23 (FGF-23), the synthesis of which is induced by the carbohydrate moiety. Iron sucrose and sodium ferric gluconate, which do not employ a carbohydrate shell, are not associated with hypophosphatemia.

The incidence of hypophosphatemia with FCM is significantly higher than that with other agents, averaging around 40% in clinical trials and observational studies depending on the patient population, dosing and definitions utilized. The majority of serum phosphorus reductions with FCM are small and transient. More severe and prolonged hypophosphatemia may lead to the “6-H syndrome” with high FGF-23 level, hypophosphatemia, hyperphosphaturia, hypovitaminosis D, hypocalcemia and secondary hyperthyroidism. Deteriorating mobility and multiple fractures, akin to tumor-induced osteomalacia, have been reported.

In patients with nondialysis-dependent CKD and iron deficiency who have failed oral iron therapy or have more severe iron deficiency, IV FCM is an attractive therapeutic option since 1,000 mg can be administered in 15 minutes, unlike iron dextran, which requires a 2 to 4-hour infusion to administer 1,000 mg, or iron sucrose, sodium ferric gluconate or ferumoxytol, which require multiple infusions to deliver 1,000 mg. A single, shorter visit is more patient-friendly and preserves veins for future hemodialysis vascular access.

FCM has a lower rate of severe allergic reactions than iron dextran, ferumoxytol or ferric derisomaltose. In patients with nondialysis-dependent CKD who receive FCM, risk factors for the development of hypophosphatemia include pre-existing secondary hyperparathyroidism, significant residual renal function and concomitant therapy with bisphosphonates or diuretics. The recently published Kidney Disease Outcomes Quality Initiative commentary on the Kidney Disease: Improving Global Outcomes 2026 anemia guideline recommends prompt assessment of serum phosphate levels for patients presenting with progressive fatigue, bone pain or muscular weakness during FCM therapy to minimize complications associated with hypophosphatemia (Jalal DI, et al. Am J Kidney Dis. 2026;doi:10.1053/j.ajkd.2026.03.036). If hypophosphatemia is present, it should be repleted as indicated and additional IV iron, if needed, should be switched to a formulation other than FCM.

The most severe cases of FCM-induced symptomatic hypophosphatemia have been reported in patients requiring multiple, repeated doses of FCM for bleeding due to gynecologic and gastrointestinal disorders, not nondialysis-dependent CKD patients who may require occasional doses of FCM once or twice per year. According to the consensus statement of a multispecialty expert panel, routine serum phosphate level measurement is not recommended for low-risk patients before or after treatment with FCM, and prophylactic oral phosphorus after FCM is unlikely to effectively elevate phosphate and is not recommended for routine clinical practice (Rosano G, et al. J Clin Med. 2025;doi:10.3390/jcm14144861).

Because of its ease of administration and low rate of severe allergic reactions, FCM remains an attractive IV iron supplement despite the new boxed warning from the FDA regarding severe symptomatic hypophosphatemia, which is rare in patients with nondialysis-dependent CKD with occasional use.

Disclosures: Wish reports no relevant financial disclosures.