Spontaneous Reports of Serious Adverse Drug Reactions Resulting From Drug-Drug Interactions: An Analysis From the French Pharmacovigilance Database.

Marina Babin,Ghada Miremont-Salamé,Antoine Pariente,On Behalf Of The French Network Of Pharmacovigilance Centres ,Alexandre Marceron,Amandine Ferreira,Joëlle Micallef,Louis Létinier

doi:10.3389/fphar.2020.624562

Abstract

Few data are available on the clinical impact of drug–drug interactions (DDIs). Most of the studies are limited to the analysis of exposure to potential DDI or the targeted impact of the combination of a few drugs or therapeutic classes. The analysis of adverse drug reaction (ADR) reports could be a mean to study generally the adverse effects identified due to a DDI. Our objective was to describe the characteristics of ADRs resulting from DDIs reported to the French Pharmacovigilance system and to identify the drugs most often implicated in these ADRs. Considering all ADR reports from January 01, 2012, to December 31, 2016, we identified all cases of ADR resulting from a DDI (DDI-ADRs). We then described these in terms of patients’ characteristics, ADR seriousness, drugs involved (two or more per case), and ADR type. Of the 4,027 reports relating to DDI-ADRs, 3,303 were related to serious ADRs. Patients with serious DDI-ADRs had a median age of 76 years (interquartile range: 63–84); 53% were male. Of all serious DDI-ADRs, 11% were life-threatening and 8% fatal. In 36% of cases, the DDI causing the ADR involved at least three drugs. Overall, 8,424 different drugs were mentioned in the 3,303 serious DDI-ADRs considered. Altogether, drugs from the “antithrombotic agents” subgroup were incriminated in 34% of serious DDI-ADRs. Antidepressants were the second most represented therapeutic/pharmacological subgroup (5% of serious DDI-ADRs). Among the 3,843 ADR types reported in the 3,303 serious DDI-ADRs considered, the most frequently represented were hemorrhage (40% clinical hemorrhage; 6% biological hemorrhage), renal failure (8%), pharmacokinetic alteration (5%), and cardiac arrhythmias (4%). Hemorrhagic accidents are still an important part of serious ADRs resulting from DDIs reported in France. The other clinical consequences of DDIs seem less well identified by pharmacovigilance. Moreover, more than one-third of serious DDI-ADRs involved at least three drugs.

Highlights

Exposure to drug–drug interactions (DDIs) is a well-known public health issue (Becker et al, 2008; Létinier et al, 2019)
Most of the recent publications in the field have not focused on such description but instead on the detection of safety signals regarding unknown DDIs (Jiang et al, 2015; Vilar et al, 2017); in terms of general prescription, we could identify only one study performed in a French region that has shown the reported adverse drug reaction (ADR) related to DDI mainly concerning renal failure and hemorrhages (Duval, 2017)
These proportions of severity are higher for DDIs than for all 190,261 ADRs reported to the BNPV during the study period (63% of serious cases and 3% of deaths)

Summary

Introduction

Exposure to drug–drug interactions (DDIs) is a well-known public health issue (Becker et al, 2008; Létinier et al, 2019). Some pharmacoepidemiological studies have tried to estimate the clinical impact of these DDIs, but it remains difficult given the multiplicity of the drugs involved and the diversity of potential adverse events (Magro et al, 2012; Hennessy et al, 2016). Pharmacovigilance databases of spontaneous reporting can provide complementary information to investigate this impact, as they can allow describing the adverse drug reactions (ADRs) as DDI induced. The other existing publications were mainly investigating some targeted drugs (Montastruc et al, 2012; Suzuki et al, 2015; Schlit et al, 2017), and none was identified that considered more than two drugs when exploring the consequences of DDIs in terms of ADRs, this could frequently occur in patients

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