EMA’s PRAC is reviewing injectable iron medicines over hypophosphataemia, osteomalacia and fracture risks, including concerns with ferric carboxymaltose.
Written By: Anshu Gupta, PharmD
Reviewed By: Pharmacally Editorial Team
The European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has launched a review of injectable iron-containing medicines after reports of serious hypophosphataemia, including cases progressing to hypophosphataemic osteomalacia and fractures. The assessment will determine whether existing risk-minimisation measures are effective and whether regulatory changes are needed.
Safety Concern Extends Beyond Ferric Carboxymaltose
Hypophosphataemia is a recognised adverse effect of injectable iron medicines containing ferric carboxymaltose. EMA product information lists it as a common adverse reaction, affecting up to 1 in 10 patients, while the frequency of hypophosphataemic osteomalacia remains unknown. Current product information recommends phosphate monitoring in patients receiving high doses or long-term treatment and those with recognised risk factors.
The review followed reports that raised concerns about whether these measures adequately control the risk. Serious cases have included hypophosphataemia progressing to osteomalacia in patients who had received only one or two doses of ferric carboxymaltose, including some without recognised risk factors. The EMA source does not specify the doses or cumulative exposure involved in these cases, so the reports should not be interpreted as evidence that they followed a particular high-dose regimen.
FGF23 Provides the Biological Link to Phosphate Loss
The clinical concern has a defined biological basis. Ferric carboxymaltose can increase circulating intact fibroblast growth factor 23 (iFGF23), a hormone that promotes renal phosphate excretion. Greater iFGF23 activity can drive phosphate wasting and reduce active vitamin D, disrupting bone and mineral metabolism. Clinical studies have linked more severe or persistent hypophosphataemia after ferric carboxymaltose with greater changes in iFGF23, parathyroid hormone and vitamin D-related markers.
The risk is not uniform across intravenous iron formulations. Clinical evidence has found substantially higher rates of hypophosphataemia with ferric carboxymaltose than with ferric derisomaltose, supporting the importance of iron formulation in the biological response. However, PRAC has expanded its current regulatory review because similar cases have been reported with other injectable iron products.
Symptoms Can Mimic Iron Deficiency
Hypophosphataemia can be difficult to recognise because fatigue, muscle pain and bone pain may overlap with symptoms of iron deficiency itself. Delayed diagnosis is therefore a concern, particularly when patients continue to experience symptoms after iron replacement.
The potential consequences become more serious when phosphate depletion is severe or persistent. Osteomalacia reflects impaired bone mineralisation and can cause bone pain and, in some cases, fractures. EMA also notes that osteomalacia may not always be visible on conventional X-rays.
Risk Assessment Remains Important
The current EMA communication does not define a new list of risk factors or introduce interim monitoring requirements while the review is underway. Existing product information remains the relevant regulatory framework.
Clinical consensus recommends assessing patients for their risk of symptomatic or severe hypophosphataemia before ferric carboxymaltose treatment. Factors associated with greater risk include repeated infusions, higher cumulative exposure, prolonged treatment and underlying clinical risk factors. Phosphate monitoring is recommended for patients considered at increased risk or those requiring repeated higher-dose courses, rather than routinely for every low-risk patient.
This distinction is important because PRAC is evaluating whether current safeguards are sufficient; it has not yet concluded that they are inadequate.
FDA Adds Boxed Warning for Injectafer
The EMA review follows a September 1, 2026, FDA safety action on ferric carboxymaltose injection (Injectafer), which added a boxed warning for symptomatic hypophosphataemia. FDA reported cases after both single and multiple infusions and now recommends serum phosphate testing before repeat treatment in at-risk patients or when another course is given within three months. The agency also advises correcting pre-existing hypophosphataemia and monitoring patients at risk for chronic phosphate depletion.
PRAC to Reassess Class-Wide Benefit-Risk Balance
The review covers ferric carboxymaltose, ferric derisomaltose, iron dextran, ferric gluconate, ferric hydroxide polymaltose complex and iron sucrose. These medicines are used when oral iron cannot be used or does not provide adequate treatment, or when iron stores need to be restored rapidly.
Oral iron products are excluded because they deliver substantially lower amounts of iron over time and are therefore considered less likely to cause hypophosphataemia.
The Article 31 procedure was initiated at the request of the Austrian medicines agency. PRAC will assess the risk of hypophosphataemia and related bone disorders, together with the effectiveness of existing risk-minimisation measures, before determining whether the overall benefit-risk balance has changed. Any recommendations will proceed to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), which will adopt a position for nationally authorised medicines.
For clinicians, the review reinforces the need to recognise persistent fatigue, muscle pain or bone pain after injectable iron as potentially requiring evaluation beyond iron status alone. For manufacturers, the assessment could ultimately affect phosphate-monitoring recommendations and other risk-minimisation measures across the injectable iron class.
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About the Writer
Anshu Gupta (LinkedIn) is a PharmD professional and healthcare writer with interests in clinical research, pharmacovigilance, regulatory affairs, and medical writing. She has presented research at academic conferences and completed certifications in Good Clinical Practice (GCP), ICH-GCP, and drug safety. Passionate about clinical trials and evidence-based medicine, she is committed to translating scientific evidence into accurate, reliable, and accessible healthcare content.
