High-Dose Intravenous Iron with Either Ferric Carboxymaltose or Ferric Derisomaltose: A Benefit-Risk Assessment

Abstract

The intravenous iron formulations ferric carboxymaltose (FCM) and ferric derisomaltose (FDI) offer the possibility of administering a large amount of iron in one infusion. This results in faster correction of anemia and the formulations being better tolerated than oral iron formulations. This triad of logistic advantages, improved patient convenience, and fast correction of anemia explains the fact that intravenous iron formulations nowadays are frequently prescribed worldwide in the treatment of iron deficiency anemia. However, these formulations may result in hypophosphatemia by inducing a strong increase in active fibroblast growth factor-23 (FGF-23), a hormone that stimulates renal phosphate excretion. This effect is much more pronounced with FCM than with FDI, and therefore the risk of developing hypophosphatemia is remarkably higher with FCM than with FDI. Repeated use of FCM may result in severe osteomalacia, which is characterized by bone pain, Looser zones (pseudofractures), and low-trauma fractures. Intravenous iron preparations are also associated with other adverse effects, of which hypersensitivity reactions are the most important and are usually the result of a non-allergic complement activation on nanoparticles of free labile iron—Complement Activation-Related Pseudo-Allergy (CARPA). The risk on these hypersensitivity reactions can be reduced by choosing a slow infusion rate. Severe hypersensitivity reactions were reported in < 1% of prospective trials and the incidence seems comparable between the two formulations. A practical guideline has been developed based on baseline serum phosphate concentrations and predisposing risk factors, derived from published cases and risk factor analyses from trials, in order to establish the safe use of these formulations.

Incidence of Hypophosphatemia After Intravenous Administration of Iron: A Matching-Adjusted Indirect Comparison of Data from Japanese Randomized Controlled Trials

“…The increased transcription is accompanied by increased proteolytic cleavage of iFGF23 resulting in maintenance of normal phosphate levels [ 11 , 24 ]. As had been observed previously in patients with autosomal dominant hypophosphatemic rickets, phosphaturia and hypophosphatemia occur when iFGF23 levels are high, with phosphaturia mediated by iFGF23-associated reductions in expression of the sodium-dependent phosphate cotransporter 2A (NPT2A) and 2C (NPT2C) in the proximal tubule in the kidney [ 25 , 26 ]. The current hypothesis regarding the mechanism underpinning the incidence of iatrogenic hypophosphatemia after administration of FCM posits that iFGF23 protein cleavage is inhibited causing high levels of iFGF23 and hypophosphatemia.…”

Intravenous iron-induced hypophosphatemia and kidney stone disease

“…Ideally, IV iron formulations with a low risk of hypophosphatemia should have preference for the treatment of iron deficiency and calcitriol should be used with caution in patients with IV iron-induced hypophosphatemia. Such low-risk IV iron formulations, that can also be used in CKD stage 4/5 patients include ferric derisomaltose, low-molecular weight iron dextran, and ferrumoxytol, which is not available in Europe ( Boots and Quax, 2022 ).

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Efficacy and safety of intravenous iron repletion in patients with heart failure: a systematic review and meta-analysis

“…iron replacement has been induced by increased secretion of fibroblast growth factor (FGF) 23 that leads to increased urinary phosphate excretion and decreased concentration of active vitamin D [ 28 , 29 ]. Dose, repetitive iron infusions, severity of ID, increasing age and vitamin D deficiency among others have been identified as predisposing factors for development of this side-effect [ 30 ]. Nevertheless, it remains unclear whether and at what extent this might have negative long-term effects on HF patients.…”