Post-marketing Drug Surveillance

ADVERSE DRUG REACTION MONITORING: DOING IT THE FRENCH WAY

Current nonspecific causality assessment tools lack the assessment of drug-induced acute kidney injury (DIAKI). We recently published an editorial letter for developing a specific causality assessment tool for DIAKI. The purpose of the present review was to suggest the possible required parameters and outline the path to developing a kidney-specific causality assessment tool (KSCAT).

A stepwise approach for developing a KSCAT is important as this will be first version of this new tool. Thus, as a first step, we performed a screening of previously published articles on nonspecific and liver-specific causality assessment tools to define possible parameters. The suggested parameters for KSCAT fall into 3 categories: (1) drug-related; (2) kidney-related; and (3) terminology. A tri-polar method was then created that consists of definitive adverse drug reactions (ADRS), terminology, and without ADRS to suggest that the new KSCAT be efficient, specific, user friendly, and less time-consuming. Finally, a pyramid model is suggested to offer the perspectives of experts in the fields of pharmacovigilance, pharmacoepidemiology, and nephrology, as well as decision makers, while developing a KSCAT.

Causality assessment tools, either nonspecific or organ-specific, fall into 3 categories: (1) expert judgment; (2) algorithms; and (3) probabilistic methods. None of the current causality assessment tools is sufficient for assessing the causality of kidney-related ADRs and for screening the expanded definition of ADR included in European Union Directive 2010/84/EU.

The causal relationship between drug(s) and DIAKI may be difficult and may not be assessed appropriately with the use of nonspecific tools or approaches. The aim of this article was to reiterate the need for KSCAT development and to propose the associated steps by stating the main principles: namely, the definition of ADR, suggested parameters to be included in the KSCAT, and integration of technology. Our ultimate desire is to invite experts to develop this new tool using an interdisciplinary approach and to benefit from our review in pursuing the next steps. The development of a KSCAT should start with regular and interdisciplinary consortium meetings of experts; the tool should then be tested for its usability, specificity, and practicality; and, finally, it should be used in real-life pharmacovigilance practices, as well as in research by health authorities, regulators, decision-makers, scientists, and clinicians. A KSCAT would support the provision of reliable and reproducible measures of the relationship likelihood in suspected cases of ADR to overcome uncertainty and provide a standardized approach.

The discovery and quantification of adverse drug reactions has long relied on the careful analysis of spontaneously reported cases. Causality assessment (imputation) was a fundamental feature of individual case report analysis. This was complemented by analysis of aggregated cases, and of disproportionality analyses in spontaneous reports databases. In the absence of more specific information sources, these have resulted in the discovery of many new adverse reactions, altering drug information. It has led to the withdrawal from the market of many drugs, but its use for risk quantification remains fraught with uncertainty. The recent access to population-wide claims or electronic health records databases have confirmed for spontaneous reporting a predominant role in hypothesis generation for serious adverse drug reactions, notably those that result in hospital admission or death. In these cases, the events are identifiable at the population level, and can be quantified precisely using the tools of modern pharmacoepidemiology, to generate specific benefit-risk analyses. Spontaneous reporting remains irreplaceable in signal and alert generation in drug safety, despite its inherent limitations. For signal strengthening and assessment, more systematic and quantitative methods should be sought, such as claims databases for reactions resulting in hospital admissions.

Nalmefene, an opioid antagonist, causes withdrawal syndromes in patients exposed to an opioid agonist. Despite its contraindication, this illogical drug association persists, especially with opioid substitution drugs (ODS). We measured the benefits of the modification in the summary of product characteristics (SPC) in March 2015 and the package leaflet of Selincro^® in September 2016 on this misuse.

We analyzed the observations regarding a use of nalmefene with an opioid between September 2014 and August 2017 in the French pharmacovigilance database and the laboratory.

The combination nalmefene and methadone was reported in about half of the cases (46/90). Observations were highest between October 2015 and March 2016 (29/90) and then decreased. Those with self-medication have increased. From October 2016, declarations become rarer.

The effect of modifications in the SPC and the package leaflet on the use of nalmefene with ODS was real and progressive.

Le nalméfène, antagoniste opiacé, provoque un syndrome de sevrage chez le patient exposé à un agoniste opiacé. Malgré sa contre-indication, cette association médicamenteuse illogique persiste, surtout avec les médicaments de substitution des opiacés (MSO). Nous avons mesuré le retentissement des modifications du résumé des caractéristiques du produit (RCP) en mars 2015 et notice de Selincro^® en septembre 2016 sur ce mésusage.

Nous avons analysé les observations concernant une utilisation de nalméfène avec un opioïde dans la base nationale de pharmacovigilance et du laboratoire exploitant entre septembre 2014 et août 2017.

L’association nalméfène et méthadone était rapportée dans environ la moitié des cas (46/90). Les observations étaient les plus nombreuses entre octobre 2015 et mars 2016 (29/90) puis ont diminué. Celles avec automédication ont augmenté. À partir d’octobre 2016, elles deviennent plus rares.

L’effet des modifications des RCP et notice sur l’utilisation de nalméfène avec les MSO a été réel et progressif.