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We used the HealthWise Wales (HWW) platform to explore public knowledge about the UK Yellow Card scheme (YCS), the spontaneous reporting scheme for suspected adverse drug reactions (ADRs) and whether a short information video could improve awareness. Members of the public in Wales (n= 1,606) completed a questionnaire about the YCS, watched the information video and then completed a follow‐up questionnaire.\ud \ud Almost half (46.5%) of respondents said they had previously experienced an ADR (over 90% of the ADRs involving prescribed medicines). Before the video, 18% of respondents knew how to report an ADR via the YCS and of these, 34% were from allied‐health professions. Immediately after watching it, 71% participants reported knowing how to report and 82% reported being confident to report. If this awareness were maintained, such an approach could contribute to improved reporting of suspected ADRs by the public.

Aims: Retroperitoneal fibrosis (RPF) is a rare chronic fibro-inflammatory disorder that may be secondary to certain drugs, including β-blocking agents (BBAs). However, their causative role is unclear. We aimed to investigate this association. Methods: Disproportionality analysis was carried out on cases from 1985 to 4 October 2020 in VigiBase, the World Health Organization pharmacovigilance database. The Bayesian-based IC 025 metric and reporting odds ratio were used in order to assess the adverse event signal. We also analysed all published case reports from the literature regarding BBA-associated RPF to assess the value of suggested supportive clinical evidence. Results: In total, 1599 individual case safety reports of RPF were reported to VigiBase, of which 132 (32%) concerned 16 different single BBA. For 12 of these agents (75%), reporting of RPF was disproportionate, indicating a potential safety signal. Line listing analysis of individual case safety reports showed no consistent time interval from start of BBA to RPF diagnosis (range 0.7–264 mo). Dechallenge was negative or unknown in the majority of cases (74%). In 18 published cases from the literature, time from start of BBA to RPF diagnosis varied widely (range 3–156 mo). BBA were discontinued 6 months before (n = 1) or at the time of RPF diagnosis (n = 17). Most patients (84%) also received RPF specific treatment. Follow-up duration was short (median 5 mo [range 1–24 mo]) and in most cases (83%) relevant follow-up data were lacking. Conclusion: Although disproportionality analysis indicated a potential safety signal for RPF associated with BBAs, clinical evidence did not support a cause-and-effect relationship.

Aim Statins are used in the treatment of hyperlipidaemia. They are among the most commonly prescribed drugs worldwide. Statins have been linked to musculoskeletal adverse drug reactions. However muscle rupture has not been discussed as an adverse drug reaction to statins so far. The aim of this article is to give an overview of cases of muscle rupture associated with the use of statins. Method We analyzed the cases of muscle rupture associated with the use of statins that were collected by the Netherlands Pharmacovigilance Centre Lareb complemented with the review of cases from the EudraVigilance database. Results Fifteen cases of muscle rupture associated with statin use have been identified in the database of the Netherlands Pharmacovigilance Centre. Overall, there was a plausible temporal association of events in most cases. In addition, the EudraVigilance database contained 165 reports of muscle rupture reported in patients using statins. Muscle rupture was disproportionally associated with statin use in both databases. The reporting odds ratio was 23.4 (95% CI 11.9, 46.0) and 14.6 (95% CI 12.3, 17.2), respectively. Conclusion Data from spontaneous reporting systems suggest that use of statins is associated with muscle rupture. Physicians and patients should be aware that this can occur.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Several factors are known to influence spontaneous reporting of adverse drug reactions (ADRs). Among them, ‘seriousness’ of the reaction is one of the most important. • However, evolution in the reporting of ‘serious’vs.‘non-serious’ ADRs over time for the same drug remains unknown. WHAT THIS STUDY ADDS • Spontaneous reports mainly involve ‘non-serious’ ADRs during the first years of marketing and ‘serious’ ADRs later, particularly for drugs with non-hospital use. AIM To investigate trends in spontaneous reporting to the French Pharmacovigilance system of ‘serious’ (SADRs) and ‘non-serious’ (NSADRs) adverse drug reactions over time. METHODS Annual SADR : NSADR ratios were calculated for each drug and their evolution tested with linear trend tests. RESULTS Among the 39 new active substances commercialized in France in 2000, 16 had sufficient data to perform linear trend tests. An increasing linear relation was found for five widely prescribed drugs, a non-significant increasing trend for eight others, i.e. drugs mostly used in hospitals. CONCLUSION ADR reports mainly concern NSADRs during first years of marketing. Reports of SADRs are proportionally more frequent later.

WHAT IS ALREADY KNOWN ABOUT THE SUBJECT • Concomitant use of different drugs may yield excessive risk for adverse drug reactions and it is a challenging task to do surveillance on the safety profile of the interaction between different drugs. • Currently, several methods are used by pharmacoepidemiologists and statisticians to detect possible drug–drug interactions in spontaneous reporting systems. • However, with the increasing number of reports in the system, there is a growing need for a computerized system that could facilitate the process of data arrangement and detection of drug interaction. WHAT THIS STUDY ADDS • We had already developed a computerized system to detect adverse drug reaction signals due to single drugs. • After the development of this system, interaction between different drugs could also be detected automatically and intelligently. AIMS In spontaneous reporting systems (SRS), there is a growing need for the automated detection of adverse drug reactions (ADRs) resulting from drug–drug interactions. In addition, special attention is also needed for systems facilitating automated data preprocessing. In our study, we set up a computerized system to signal possible drug–drug interactions by which data acquisition and signal detection could be carried out automatically and the process of data preprocessing could also be facilitated. METHODS This system was developed with Microsoft Visual Basic 6.0 and Microsoft Access was used as the database. Crude ADR reports submitted to Shanghai SRS from January 2007 to December 2008 were included in this study. The logistic regression method, the Ω shrinkage measure method, an additive model and a multiplicative model were used for automatic detection of drug–drug interactions where two drugs were used concomitantly. RESULTS A total of 33 897 crude ADR reports were acquired from the SRS automatically. The 10 drug combinations most frequently reported were found and the 10 most suspicious drug–drug ADR combinations for each method were detected automatically after the performance of the system. CONCLUSIONS Since the detection of drug–drug interaction depends upon the skills and memory of the professionals involved, is time consuming and the number of reports is increasing, this system might be a promising tool for the automated detection of possible drug–drug interactions in SRS.

Aims Detection of new adverse drug reactions (ADR) after marketing is often based on a manual review of reports sent to a Spontaneous Reporting System (SRS). Among the many potential signals that are identified, only a limited number are important enough to require further attention. The goal of this study is to gain insight into factors contributing to the selection and dissemination of possible signals originating from the SRS maintained by the Netherlands Pharmacovigilance Foundation.

Aims Voluntary adverse drug reaction (ADR) reporting schemes have operated since the early sixties in many Western countries. It is generally recognized, however, that only a small proportion of ADRs is actually reported. The current survey was conducted to assess attitudes towards reporting of ADRs, and to study which types of ADRs are reported. Methods A questionnaire seeking reasons for nonreporting was sent to a random sample of 10% of medical practitioners in The Netherlands in October 1997. After 6 weeks, a reminder was sent to those who had not responded. Results One thousand four hundred and forty-two (73%) questionnaires were returned, of which 94% were complete. The percentage of GPs (51%) which had ever reported an ADR to the national reporting centre was significantly higher than the percentage of specialists (35%), who reported more often to the pharmaceutical industry (34%vs 48%). 86% of GPs, 72% of surgical specialists and 81% of medical specialists had ever diagnosed an ADR, which they had not reported. Uncertainty as to whether the reaction was caused by a drug (72%), the ADR being trivial (75%) or too well known (93%) were the most important reasons for not reporting. 18% were not aware of the need to report ADRs, 22% did not know how to report ADRs, 38% did not have enough time, 36% thought that reporting was too bureaucratic and only 26% of Dutch physicians knew which ADRs to report. A serious ADR, an unlabelled ADR, an ADR to a new drug, history of reporting of one or more ADRs, and specialty were all independently associated with reporting of 16 hypothetical ADRs. Surgical and medical specialists tended to report less often than GPs. Conclusions There is a considerable degree of underreporting, which might partly be explained by lack of knowledge and misconceptions about spontaneous reporting of adverse drug reactions.

causality attribution are the common criticisms ofSystematic spontaneous reporting of possible drug caused spontaneous reporting systems [2–5]. However, severaladverse eVects began with the ‘Yellow card system’ in studies show that workload, doubt about causal relation-the UK in 1964. It was a medium for doctors to report ship, and doubt about whether it is worth reporting, aretheir concerns on marketed drugs, thereby enhancing the the common reasons for under-reporting [7, 8].limited premarketing clinical data on safety. Now 54 It follows that the attribution of causality is at least ascountries around the world have similar systems, and good as any other careful clinical diagnosis, often aftermany warnings of adverse drug reactions and some the exclusion of other disease (because doctors are lessdeletions from the market have been made on the basis likely to report where there is doubt over causality); ifof such reports [1, 2]. under-reporting is due to workload, then there must beThere has been controversy about actions based on a real motivation to send a report.spontaneous reports. This relates to regulatory actions, In a response to an open ended question [7] on whythought by some to be disproportionate to an extremely doctors report, the following were given as the mainsmall increased risk identified by a few spontaneous reasons, in order of frequency:reports, or where causality has been thought to have motivation to contribute to medical knowledge;been due to confounding and/or biases. Mostly, obser- reaction previously unknown to reporter;vational studies (case-control and cohort studies) have reaction to new drug;been the new ‘gold standard’ by which spontaneous all significant reactions reported;reports are judged. known association between drug and reaction;Recent papers have looked at some of the characteristics severity of reaction.of spontaneous reporting systems, emphasizing the limi- So, spontaneous reports are reports of genuine, generaltations [3–5]. The need to rejuvenate ‘spontaneous clinical concerns about a drug and suspected reaction. Allreporting’ systems of adverse reactions has been expressed, must be treated as ‘valid’, in fact they should be labelledparticularly in response to a fall in reporting rates in ‘clinical concerns’ rather than ‘spontaneous reports’Britain [6]. So far few suggestions have been made in the because the label is descriptively more explicit. Otherpublished literature as to how it could be done. reasons for reporting such as medico-legal considerationsThis article looks again at what so-called ‘spontaneous and current awareness of a particular drug problem werereports’ are and what we can and should do with them. identified [7], but were of much less frequent concern tothe international reporters surveyed.

Aims There is evidence that different methods used to identify and quantify adverse drug reactions (ADR) in hospitals are not exhaustive (spontaneous reporting or computerized medical databases). The combination of these different sources of data could improve knowledge about ADR frequency in hospitals. The aim of this study was to estimate the incidence of serious ADRs handled in medical wards of a French university hospital using data from the Programme de Medicalization des Systemes d’Information (PMSI) and spontaneous reports recorded in the French Pharmacovigilance Database. Methods The study period was the first semester of 2001. From PMSI, all hospitalization summaries including an ICD-10th code related to a potential ADR were selected. From the French Pharmacovigilance Database, all serious ADRs which occurred during the study period and were reported by physicians working in the University Hospital were collected. After identification of common cases, the capture–recapture method was applied in order to estimate the real number of ADRs occurring during the first semester of 2001. Results From PMSI, we identified 274 different hospital stays related to an ADR. Out of 241 reports selected from the French Pharmacovigilance Database, we retained 151 ADRs for analysis. Fifty-two ADRs were common in the two databases, giving an estimated number of serious ADRs of 796 [95% confidence interval (CI) 638, 954], corresponding to 2.9% of inpatients (95% CI 2.3, 3.5). Conclusions This study shows the lack of exhaustiveness of ADR reporting whatever the sources of data and underlines the interest of merging data from different databases to identify fully the real impact of ADR in hospitals.

Aims To compare information on drug–drug interactions (DDIs) reported on two standard drug-related information sources (Summary of Product Characteristics and Drugdex system by Micromedex), by assessing the prevalence and predictors of potential DDI with proton pump inhibitors (PPIs) in general practice. Methods From the ‘Caserta-1’ Local Health-Service database, 156 general practitioners (GPs) were recruited. From more than 180 000 individuals registered on their lists, we selected patients receiving co-prescription of PPI and medications at interaction risk, according to the Italian Summary of Product Characteristics (SPC) of PPI and Drugdex information, during the year 2003. Thereafter, we carried out a regression analysis to identify the predictors of co-prescription at interaction risk with PPI, on the basis of the two information sources. A number of analyses were performed to evaluate agreement on DDI information between the SPC of PPI and Drugdex. Results According to SPC and Drugdex, 324 (3.0%) and 958 (9.0%) patients, respectively, received co-prescriptions of PPI and potentially interacting medications during the study period. PPI users’ age, type of medication and number of other drug prescriptions per month were independent predictors of receiving co-prescriptions at interaction risk, when considering only Drugdex. With regard to potential DDIs with PPI, a significant disagreement (P

Aims Trends in spontaneous reporting during the first years on the market were analyzed from a sample of selected drugs, with special attention to unlabelled effects. Methods Ten drugs were selected giving rise to approximately 100 spontaneous reports each during the first 4 years of marketing. Case reports were identified from the national pharmacovigilance database. A bibliographical score assigned at the time of reporting was used to identify unlabelled effects. Results were expressed as reporting rates. Results The average reporting rate peaked during the first year of marketing (54.6 per million treatment-months; s.d.:62.8), then progressively decreased during the following years. Unlabelled effects represented 63% of all the spontaneous reports during the first year. Conclusions Unlabelled adverse effects represent a high proportion of spontaneous reports during the early years of marketing.

Spontaneous reporting remains the most used and, undoubtedly, the most cost-effective approach for the identification of adverse drug reactions (ADRs). Most of the limitations of this method are well recognised but the possibility of receiving false-positive reports of coincidental drug-event associations has received little attention. In this paper we propose a method based on the Poisson distribution for computing the maximum number of reports of an ADR that could be expected to be reported coincidentally. Three parameters are required: (i) the background risk of the event in the reference population, (ii) the total number of patients treated with the drug considered and, (iii) the proportion of cases that have been reported to the pharmacovigilance system. For most empirical situations occurring in the post-marketing surveillance setting, the expected number remains low and only a maximum of one to three cases could be accepted as possibly coincidental. For rare adverse events such as agranulocytosis or toxic epidermal necrolysis, coincidental associations are so unlikely that a number of reports greater than three constitutes a strong warning and requires further investigation. These findings suggest that for rare events, reports of coincidental drug-event associations are too unlikely to be considered as an important limitation of spontaneous reporting.

A statistical method is proposed to aid decisions on the recognition of new adverse drug reactions on the basis of spontaneous reports. The maximal number of associations between drug exposure and event is calculated from an independence test between drug and event, taking into account the expected incidence of that particular event in the general population. An example is given which illustrates the method.