Reports of severe hypophosphatemia linked to injectable iron medicines — including cases of osteomalacia after just one or two doses and in patients with no recognized risk factors — have prompted a European safety review. 

The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) has launched the review across all injectable iron formulations, not only ferric carboxymaltose, amid concerns that current risk-minimization measures may not be sufficient.

Clinical Context and Risk Factors 

Injectable iron is used to treat iron deficiency and iron-deficiency anemia when oral supplements are inadequate, not tolerated, or too slow, including in patients on dialysis, those undergoing surgery, people with heart failure, women with severe deficiency during or after pregnancy, and patients with malabsorption disorders.

Hypophosphatemia is a recognized adverse effect of ferric carboxymaltose and is classified as common, affecting up to 1 in 10 patients. However, the frequency of hypophosphatemia-related osteomalacia remains unknown because of insufficient data. Current product information recommends phosphate monitoring in patients receiving high doses or long-term treatment and those with existing risk factors.

Clinicians should also be alert to a diagnostic challenge: symptoms of low phosphate, including fatigue, muscle pain, and bone pain, can overlap with those of the underlying iron deficiency, potentially delaying diagnosis. Osteomalacia may also not be visible on standard x-rays, further complicating timely diagnosis.

Supporting Evidence and Regulatory Scope 

A systematic review and meta-analysis covering 42 clinical trials found that hypophosphatemia occurred significantly more often with ferric carboxymaltose than with iron isomaltoside (47% vs 4%). Greater reductions in serum phosphate were also observed with ferric carboxymaltose. Preserved kidney function and markers of more severe iron deficiency, including low baseline ferritin and transferrin saturation, were identified as significant predictors.

Hypophosphatemia persisted through study end points in up to 45% of patients treated with ferric carboxymaltose, with follow-up extending to 3 months. The findings suggested that hypophosphatemia may be more strongly associated with ferric carboxymaltose than with some other intravenous iron formulations, rather than representing a uniform class effect across all intravenous iron preparations.

The PRAC evaluation includes injectable medicines containing ferric carboxymaltose, ferric derisomaltose, iron dextran, ferric gluconate, ferric hydroxide polymaltose complex, and iron sucrose. Oral iron supplements are excluded because they provide considerably lower iron amounts over time and carry a lower risk for hypophosphatemia.

However, PRAC said similar cases have also been reported with other injectable iron medicines, which is why the current review covers the whole class rather than a single product.

Regulatory Next Steps 

The committee will assess the risk for hypophosphatemia and related bone disorders, as well as the effectiveness of existing risk-reduction measures. It will determine whether the risks affect the medicines’ overall benefit-risk balance and whether changes to their marketing authorizations are needed.

PRAC’s final recommendations will be forwarded to the Coordination Group for Mutual Recognition and Decentralised Procedures – Human, which will adopt a position across EU member states, Iceland, Liechtenstein, and Norway. 

Potential regulatory outcomes could include enhanced monitoring, updated prescribing information, or additional risk-minimization measures for healthcare professionals using injectable iron formulations.