EU reassesses the safety of injectable iron treatments following severe cases of bone complications

The European Medicines Agency (EMA) has launched a safety review of all injectable iron medicines available in the European Union. The measure was taken following reports of severe cases of hypophosphataemia (a drop in blood phosphate levels), some of them associated with osteomalacia, a condition in which bones fail to mineralise properly.

The EMA will determine whether existing safety measures are sufficient or whether the marketing authorisations for these medicines need to be amended.

When injectable iron treatments are used

These treatments are used when oral iron cannot be administered or is ineffective, or when the body needs to replenish its iron stores rapidly. They are used, for example, in patients with renal failure undergoing dialysis, before or after certain surgical procedures, in people with heart failure, and in women with severe iron deficiency during or after pregnancy. They are also prescribed for certain conditions that affect the absorption of nutrients in the intestine.

The review covers several types of preparations: ferric carboxymaltose, ferric derisomaltose, ferric gluconate, iron hydroxide polymaltose complex, iron dextran, and iron sucrose. Depending on the medicine, administration is via injection, intravenous infusion, intramuscular injection, or through the dialysis machine.

Orally administered iron medicines are not included in this procedure, as the EMA notes that they deliver considerably smaller amounts of iron over a given period of time, and therefore carry a lower risk of causing hypophosphataemia.

What a drop in blood phosphate means

Phosphate plays an essential role in the formation and maintenance of bone structure. An excessive drop in blood phosphate levels (hypophosphataemia) can cause fatigue and muscle or bone pain. If the deficiency is severe or prolonged, it can impair bone mineralisation, leading to osteomalacia, which manifests as bone pain and, in some cases, fractures.

Hypophosphataemia and associated osteomalacia are already listed as adverse reactions for injectable ferric carboxymaltose preparations. The EMA notes that hypophosphataemia is a common adverse reaction, potentially affecting up to one in ten patients treated. For the associated osteomalacia, the available data do not allow an exact frequency to be established.

Severe cases arising after just a few doses

The signals that prompted this review related in particular to ferric carboxymaltose preparations. The EMA received reports of severe cases of hypophosphataemia, some progressing to osteomalacia, occurring after as few as one or two doses in patients with no known risk factors. In other instances, the drop in phosphate was identified only after a delay.

One reason the problem may go unnoticed is the similarity of its symptoms to those of iron deficiency: fatigue and muscle or bone pain may be attributed to anaemia, and the changes characteristic of osteomalacia are not always visible on X-ray.

Although the initial signals related principally to ferric carboxymaltose, the EMA extended the review to cover the entire category of injectable iron medicines after similar cases emerged with other preparations as well.

The FDA introduced its most severe possible warning in the United States

The EMA review began shortly after a similar decision was taken in the United States. On 1 September, the Food and Drug Administration (FDA) added a Boxed Warning — the agency's strongest safety warning — to the prescribing information for injectable ferric carboxymaltose, in relation to the risk of symptomatic hypophosphataemia.

The risk had been known for several years: the FDA first introduced a warning regarding symptomatic hypophosphataemia as far back as 2020. In 2023, the guidance was updated to include monitoring of phosphate levels in patients with risk factors and in those starting a new treatment course within less than three months, and osteomalacia and fractures were added as potential long-term complications. The warning was updated again in 2025, with the addition of further risk factors.

Nevertheless, an FDA review conducted in 2026, drawing on multiple data sources, found that cases of symptomatic hypophosphataemia had continued to occur, with some patients requiring hospitalisation and treatment to correct their phosphate levels for weeks or even months.

What the EMA will examine next

The review is being carried out by the EMA's Pharmacovigilance Risk Assessment Committee (PRAC), at the request of the Austrian medicines authority. The Committee brings together representatives of EU member states, as well as Iceland, Liechtenstein, and Norway.

The PRAC will assess the risk of hypophosphataemia and bone complications for all injectable iron preparations included in the procedure, as well as the effectiveness of existing safety measures. The Committee will determine whether the new data alter the benefit–risk balance for these treatments and whether changes to the marketing authorisations are required.

The opening of this review does not, at this stage, mean that recommendations on the use or safety of these medicines have changed. Once the analysis is complete, the PRAC will issue recommendations, which will be forwarded to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), as the medicines in question are authorised at national level in European countries.