Research Article: Choice of High-Dose Intravenous Iron Preparation Determines Hypophosphatemia Risk

Date Published: December 1, 2016

Publisher: Public Library of Science

Author(s): Benedikt Schaefer, Philipp Würtinger, Armin Finkenstedt, Vickie Braithwaite, André Viveiros, Maria Effenberger, Irene Sulzbacher, Alexander Moschen, Andrea Griesmacher, Herbert Tilg, Wolfgang Vogel, Heinz Zoller, Kostas Pantopoulos.


Ferric carboxymaltose (FCM) and iron isomaltoside 1000 (IIM) are increasingly used because they allow correction of severe iron deficiency in a single infusion. A transient decrease in serum phosphate concentrations is a frequent side effect of FCM.

To characterize this adverse event and search for its predictors in a gastroenterology clinic patient cohort.

Electronic medical records of patients attending the University Hospital of Innsbruck were searched for the keywords ferric carboxymaltose or iron isomaltoside. Eighty-one patients with documented administration of FCM or IIM with plasma phosphate concentrations before and after treatment were included.

The prevalence of hypophosphatemia (<0.8 mmol/L) increased from 11% to 32.1% after treatment with i.v. iron. The hypophosphatemia risk was greater after FCM (45.5%) compared with IIM (4%). Severe hypophosphatemia (<0.6 mmol/L) occurred exclusively after FCM (32.7%). The odds for hypophosphatemia after i.v. iron treatment were independently determined by baseline phosphate and the choice of i.v. iron preparation (FCM vs. IIM—OR = 20.8; 95% CI, 2.6–166; p = 0.004). The median time with hypophosphatemia was 41 days, but prolonged hypophosphatemia of ≥ 2 months was documented in 13 of 17 patients in whom follow-up was available. A significant increase in the phosphaturic hormone intact FGF-23 in hypophosphatemic patients shows that this adverse event is caused by FCM-induced hormone dysregulation. Treatment with FCM is associated with a high risk of developing severe and prolonged hypophosphatemia and should therefore be monitored. Hypophosphatemia risk appears to be substantially lower with IIM.

Partial Text

Ferric carboxymaltose and iron isomaltoside are iron-carbohydrate complexes, which have shown high efficacy and a low risk of allergic reactions in clinical trials. Even in severely iron deficient patients total iron deficit can be readily corrected in 1–2 infusions. Therefore, the introduction of these iron preparations has prompted the development of new treatment guidelines for patients with iron deficiency anemia due to inflammatory bowel disease, cancer-related anemia and in pregnant women[1–4].

The prevalence of hypophosphatemia (<0.8 mmol/L or <2.5 mg/dL) after treatment with high dose intravenous (i.v.) iron in this group of patients was 32.1% (26 of 81). When 9 patients with a priori hypophosphatemia were excluded, the incidence of de novo hypophosphatemia after iron therapy was 26.4% (19 of 72). The Common Terminology Criteria for Adverse Events (CTCAE, version 4.0)[21] defines severe hypophosphatemia as 0.3–0.59 mmol/L and life threatening hypophosphatemia as < 0.3 mmol/L. Severe and life-threatening hypophosphatemia occurred exclusively after infusion of FCM with an incidence of 29.1% and 3.6%, respectively (Figs 1 and 2). A transient decrease in phosphate concentrations after administration of FCM and less so IIM was documented in phase 3 trials. Although mean phosphate concentration or incidence of hypophosphatemia was reported, the severity and duration of this treatment-related adverse event for individual patients are unknown[5, 10]. Severe short-term and moderate long-term hypophosphatemia caused by i.v. iron has been associated with muscle weakness, pain and osteomalacia in case reports and small case series[11–18]. The present study confirms that hypophosphatemia has a high prevalence of 32.1% after treatment of iron deficiency with high dose i.v. iron in a real life patient population with gastrointestinal disorders. The single most important risk factor for the development of this complication appears to be the choice of the i.v. iron preparation, where FCM was associated with a 20-fold higher risk than IIM and all 18 cases of severe and life-threatening hypophosphatemia (< 0.6 mmol/L) developed after administration of FCM. The true prevalence of transient hypophosphatemia could be even higher because in some patients the longer time interval between i.v. iron treatment and phosphate measurement could have allowed for spontaneous resolution of low phosphate concentration. The median time to resolution of hypophosphatemia was 84 days. Taken together, this retrospective study shows that after FCM treatment a high proportion of gastroenterology patients experience hypophosphatemia of clinically significant severity and/or duration, whereas only one patient developed mild hypophosphatemia after IIM. These findings should be confirmed in prospective clinical studies with head-to-head comparison of FCM and IIM in patients with different underlying diseases.   Source:


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