Evaluation of the Reported Rates of Severe Hypersensitivity Reactions Associated with Ferric Carboxymaltose and Iron (III) Isomaltoside 1000 in Europe Based on Data from EudraVigilance and VigiBase™ between 2014 and 2017

Abstract

IntroductionHypersensitivity reactions (HSRs) are among the known adverse events of intravenous (i.v.) iron products. Of these, particularly severe HSRs such as anaphylaxis are of great clinical concern due to their life-threatening potential.MethodsThis was a retrospective pharmacoepidemiological study with a case-population design evaluating the number of reported severe HSRs following administration of the two i.v. iron products—ferric carboxymaltose and iron (III) isomaltoside 1000—in relation to exposure in European countries from January 2014 to December 2017. Exposure to both products was estimated using IQVIA MIDAS sales data in European countries. Information on spontaneously reported severe HSRs was obtained from and analysed separately for the two established safety surveillance databases EudraVigilance and VigiBase™ using the MedDRA® Preferred Terms anaphylactic reaction, anaphylactic shock, anaphylactoid reaction and anaphylactoid shock associated with administration of either product.ResultsBetween 2014 and 2017, the reporting rate of severe HSRs per 100,000 defined daily doses (100 mg dose equivalents of iron) varied from 0.3 to 0.5 for ferric carboxymaltose and from 2.4 to 5.0 for iron (III) isomaltoside 1000. The reporting rate ratio for iron (III) isomaltoside 1000 versus ferric carboxymaltose was between 5.6 (95% CI 3.5–9.0) and 16.2 (95% CI 9.4–27.8).ConclusionsFindings suggest that iron (III) isomaltoside 1000 is associated with a higher reporting rate of severe HSRs related to estimated exposure than ferric carboxymaltose in European countries. Future research investigating the occurrence of severe HSRs associated with i.v. ferric carboxymaltose and iron (III) isomaltoside 1000 is needed to broaden the evidence for benefit-risk assessment.

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

“…In SMQ group A, which most closely matches the HSR definitions adopted by Ehlken et al, the Bayesian inference approach reported a 52% reduction in the odds (i.e. an odds ratio of 0.48) of an event with FDI versus FCM [13].…”

“…Alternative methods of comparison have therefore recently been employed to establish the relative safety of the two formulations of highdose IV iron. For instance, recent studies have relied on spontaneous reporting of adverse reactions and market share data in an attempt to compare hypersensitivity reaction (HSR) rates as recorded in pharmacovigilance (PV) databases [13]. Such studies are fundamentally flawed, with the underreporting and differential reporting of spontaneous adverse reactions resulting in scientifically invalid and potentially misleading conclusions [14].…”

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

“…These same criticisms apply to other real-world database studies that have looked at the incidence of HSRs with IV iron products. Whereas one study of spontaneously reported anaphylactic reactions among IV iron products concluded that relative risk estimates cannot be calculated due to underreporting, possible differential reporting, absence of product brand names, and incomplete usage data [41], other studies have attempted to make comparisons between different IV iron formulations based on spontaneously reported adverse reaction data [13,[28][29][30][31]. Considering ID, a retrospective cohort study of 688,183 IV iron recipients in the US from 2003-2013 (prior to the availability of FCM) showed that the risk of 'anaphylaxis' was higher with ID than with non-dextran IV iron products [42].…”

“…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.…”