Reported Severe Hypersensitivity Reactions after Intravenous Iron Administration in the European Economic Area (EEA) Before and After Implementation of Risk Minimization Measures

Abstract

Introduction Severe hypersensitivity reactions (HSRs) such as anaphylaxis are of great clinical concern because of their life-threatening potential. The adverse events attributable to intravenous iron products include HSRs. An investigation by the European Medicines Agency presented in late 2013 resulted in the implementation of risk minimization measures (RMMs). Objective This study evaluated the number of severe HSRs reported for intravenous iron substances related to exposure for the 4-year periods before and after this implementation. Methods This was a retrospective pharmacoepidemiologic study with a case-population design. We obtained information from the safety surveillance database EudraVigilance on spontaneously reported severe HSRs using the Medical Dictionary for Regulatory Activities preferred terms "anaphylactic reaction/shock" and "anaphylactoid reaction/shock". Exposure was estimated using IQVIA MIDAS sales data in European economic area countries. Results Reporting rates for individual products were heterogenous, and the implementation of RMMs appeared to have no clear impact. Reporting rates remained low for the full study period for iron sucrose (0.03-0.20) and ferric gluconate (0.02-0.14) and were higher at the beginning and lower at the end of the study period for ferric carboxymaltose (1.47-0.18). No clear trend was detected for iron dextran (range 0.22-2.80) and iron (III) isomaltoside 1000 (range 0-7.94). Conclusions Future research is needed to investigate whether the wide variability in reporting rates for severe HSRs associated with these intravenous iron products are due to potential differences in the safety profiles of these substances.

Indirect methods of comparison of the safety of ferric derisomaltose, iron sucrose and ferric carboxymaltose in the treatment of iron deficiency anemia

“…Given this pooling, the Bayesian and naïve approaches to pooling were conducted by applying a lower requirement for the standard of evidence (namely the inclusion of non-comparative studies) in order to increase the sample sizes across all arms analyzed. Despite the inclusion of non-comparative studies, the present analysis still represents a marked improvement on approaches that rely on combining data from PV and market share data, where agreement between events and exposure is extremely tenuous, doubly so when relying on proprietary market share data, which is not subject to any external scrutiny from peer reviewers, clinicians or marketing authorization holders [13,42]. Even in the case where exposure estimates could be derived from a source congruent with the event incidence data, previous analyses of HSR incidence after IV iron administration have also been confounded by highly selective use of preferred terms for HSRs and misaligned reporting periods, thereby conflating heightened post-launch vigilance and genuinely elevated incidence of HSRs [13,14,43].…”

Iron Sucrose: A Wealth of Experience in Treating Iron Deficiency

“…Hypersensitivity reactions with IV iron therapy are generally very rare, but findings have varied among different IV iron treatments. In a recent retrospective pharmacoepidemiological study comparing all available IV iron products, iron sucrose showed one of the lowest reporting rates for severe hypersensitivity, although the limitations of such analyses of pharmacovigilance data are well recognized [148]. Similarly, among patients in a study in the US Medicare non-dialysis population to compare the risk of anaphylaxis among marketed IV iron products, anaphylaxis risk was lowest for iron sucrose [149].…”

Evaluation of the reported rates of hypersensitivity reactions associated with iron dextran and ferric carboxymaltose based on global data from VigiBase™ and IQVIA™ MIDAS® over a ten-year period from 2008 to 2017

“…Coverage varied by country. Sales data were normalized to 100 mg dose equivalents, termed 1 defined daily dose (DDD) of iron, as has been done in similar studies of this nature [13,[28][29][30][31][32].…”

“…iii) Anaphylactic/anaphylactoid reaction terms (anaphylactic reaction, anaphylactic shock, anaphylactoid reaction, and anaphylactoid shock), as used in two prior studies of spontaneously reported adverse reactions [31,32]. iv) Cases with a fatal outcome.…”