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Key Elements in Adverse Drug Interaction Safety Signals

An Assessment of Individual Case Safety Reports



A large proportion of potential drug interactions are known from pre-authorization studies, but adverse drug reactions (ADRs) due to interactions (adverse drug interactions) are often first detected through astute observation in clinical practice. Individual case safety reports (ICSRs) are collected from broad patient populations and allow for the identification of groups of similar reports. Systematic screening for adverse drug interactions in ICSRs will require an understanding of which information on these reports can be suggestive of adverse drug interactions.


The aim of the study was to identify what reported information may support the identification of drug interaction safety signals in collections of ICSRs.


Three previously published safety signals of suspected adverse drug interactions were re-evaluated. To this end, 137 reports related to these signals were retrieved from the WHO Global ICSR Database, VigiBase™, and corresponding original reports were obtained from national pharmacovigilance centres. Criteria from an operational score for causality analysis of drug interactions of clinical cases, the Drug Interaction Probability Scale (DIPS), were applied to each of these reports with the aim of identifying what supportive information tends to be available in ICSRs. For three DIPS elements (plausible time course, resolution of the ADR after terminating the drug inducing the interaction without changes in affected drug therapy (positive dechallenge) and alternative causes of the reaction) we also compared the amount of information in VigiBase™ and in original reports, and in free text and structured data.


Commonly fulfilled DIPS elements on reports supporting an adverse drug interaction signal were plausible time course (50 reports; 36 %) and positive dechallenge (8 reports; 6 %). Alternative causes for the observed adverse reaction were observed in 72 (53 %) reports. We found limited differences between VigiBase™ and original reports for the structured data, although a substantial amount of additional information was available in free text in original reports.


Information on plausible time courses and resolution of the adverse reaction upon withdrawal of the drug suspected to have induced the interaction may be a useful element in identifying suspected adverse drug interactions from ICSRs. Of these, plausible time course is by far the most commonly reported element in the three signals studied here. Our analysis also demonstrated the importance of sharing and analysing information available in free text where relevant clinical details are often available, such as those mentioned above, along with severity and dosage changes.

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The authors are indebted to the National Centres that contribute data to the WHO Programme for International Drug Monitoring. The opinions and conclusions in this study are not necessarily those of the various centres, nor of the WHO. No sources of funding were used to assist in the preparation of this study. The authors have no conflicts of interest that are directly relevant to the content of this study.

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Correspondence to Johanna Strandell.

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Strandell, J., Norén, G.N. & Hägg, S. Key Elements in Adverse Drug Interaction Safety Signals. Drug Saf 36, 63–70 (2013).

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  • Omeprazole
  • International Normalize Ratio
  • Azithromycin
  • Glucosamine
  • Free Text