A Pooled Analysis of Serum Phosphate Measurements and Potential Hypophosphataemia Events in 45 Interventional Trials with Ferric Carboxymaltose

Abstract

Ferric carboxymaltose (FCM) has been shown to achieve rapid replenishment of iron stores and correction of anaemia in various populations with iron deficiency. A decrease in serum phosphate (PO43−) levels, which in most cases is asymptomatic, has been reported with IV iron preparations. Hypophosphataemia (HP) is a known adverse drug reaction with FCM. This post hoc pooled analysis investigates the frequency, duration, risk factors, and clinical signs of HP as reported in interventional clinical trials with FCM. Pooled data from subjects enrolled across 45 clinical trials in different therapy areas were included. A three-step adjudication process was utilised to identify adverse events of HP. Stratified analyses by therapy group and stepwise logistic regression analysis were used to identify predictors of HP. This pooled analysis confirms that FCM is associated with increased rates of serum PO43− lowering, but mean serum PO43− values were seen to recover at Week 4 and further recover at Week 8. Among all subjects receiving FCM therapy (n = 6879), 41.4% (n = 2847) reached a PO43− nadir value <2.5 mg/dL at any point on study and 0.7% (n = 49) reached a nadir <1 mg/dL. Although gastroenterology and women’s health subjects were identified to be at higher risk, occurrence of severe HP (<1 mg/dL [0.3 mmol/L]) following FCM administration was not observed to be common among subjects in these studies. Furthermore, there was no correlation between laboratory serum PO43− values and the occurrence of reported adverse events related to low PO43− levels.

Cost-effectiveness analysis of ferric carboxymaltose versus iron sucrose for the treatment of iron deficiency anemia in patients with inflammatory bowel disease in Spain

“… 37 A few post-marketing reports have identified some patients with symptomatic hypophosphatemia requiring clinical intervention following administration of FCM, in those with risk factors for developing low serum phosphate levels. 38 , 39 IBD patients may have absorption disorders, vitamin deficiency (such as vitamin D), be receiving co-medications, and experience recurrent bleeding episodes, all of which may prompt them to have lower phosphate baseline values, independent of intravenous iron treatment. 40 , 41 In patients at risk for hypophosphatemia, repeated parenteral iron treatment, especially with FCM, needs to be adapted to reflect the underlying disease and its inherent risk for hypophosphatemia, other hypophosphatemia-inducing drugs, and the time necessary to restitute iron stores.…”

Hypophosphataemia, fibroblast growth factor 23 and third-generation intravenous iron compounds: a narrative review

“… 33 A further pooled analysis of 45 interventional trials including FCM ( n =15,080) confirmed the association between FCM and hypophosphataemia incidence as 41.4% of participants displaying mild hypophosphataemia at any point of the trials included ( n =2847, PO 4 3− concentration <0.8 mmol/L) and 0.7% ( n =49) suffering from severe hypophosphataemia (PO 4 3− concentration <0.3 mmol/L). 34 Such results highlight that hypophosphataemia is possibly a drug-specific side-effect that is not necessarily exhibited uniformly by all other i.v. iron compounds.…”

Questions and answers on iron deficiency treatment selection and the use of intravenous iron in routine clinical practice

“…Hypophosphataemia: One potential consequence of intravenous iron recognized recently is a fall in serum phosphate with several formulations, particularly ferric carboxymaltose [81]. Concentrations fall below the normal range in up to 40% of cases and relate to release of a hormone, fibroblast growth factor-23 (FGF-23), from osteocytes [81][82][83]. This prompts receptor-mediated renal phosphate excretion, a reduction in circulating parathyroid hormone levels, and indirectly reduces gut phosphate absorption through an FGF-23mediated reduction in 1,25-di-OH vitamin D [83].…”

“…The effect is usually asymptomatic and reaches a nadir between 1 and 2 weeks [ 81 ]. In most cases, phosphate concentrations have returned to baseline by 12 weeks [ 82 , 84 ]. Isolated case reports, often in the setting of other metabolic disorders and mostly in patients receiving multiple infusions, have shown a potential association between longer periods of hypophosphataemia and osteomalacia and fractures [ 83 , 85 ].…”

“…Isolated case reports, often in the setting of other metabolic disorders and mostly in patients receiving multiple infusions, have shown a potential association between longer periods of hypophosphataemia and osteomalacia and fractures [ 83 , 85 ]. These events are extremely rare and there are currently no intravenous iron-related clinical trial data that report an association between clinical adverse events and low phosphate levels [ 82 , 86 ].…”