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Background Anthroposophic medicinal products (AMPs) are widely used in Europe and world-wide. Objective To determine the frequency of reported adverse drug reactions (ADRs) from all AMPs on the market, in absolute numbers and relative to the maximum daily administration doses (MDADs). Patients and Methods Retrolective safety analysis of AMP-related ADRs in pharmacovigilance databases of four AMP Marketing Authorisation Holders in Germany. For each ADR, information about the patient, outcome, causality and AMP was retrieved. Primary outcome was the frequency of reported ADRs relative to MDADs sold. Results In the period 2010–2017, a total of 5506 ADRs were reported that had occurred in 2765 different patients, comprising 370 different AMPs. A total of 104 ADRs (1.9%) were classified as serious. The frequency of ADRs for all AMPs was 1.50 per million MDADs. For serious ADRs the frequency was 0.03 per million MDADs. ADRs were more frequently reported with parenteral AMP administration (injections) than with oral or local administration (18.85 vs. 0.59 vs. 1.61 ADRs per million MDADs, respectively; p

The primary care medical practitioners as well as common public must be made aware of the importance and benefits of reporting adverse drug reactions (ADRs). The reporting of ADRs through periodic safety update reports is a regulatory requirement in many countries including India, however, the importance of ADR reporting through spontaneous reporting system cannot be ignored. After the initiation of Programme for International Drug Monitoring, WHO-Uppsala Monitoring Centre (UMC), Sweden, succeeded in establishing a worldwide pharmacovigilance (PV) network in >150 countries. As a full member of this program, India also has developed a robust PV system through Pharmacovigilance Programme of India (PvPI) involving its various ADR Monitoring Centers and after due quality check of Individual Case Safety Reports (ICSRs), submits this information to UMC through a web-based tool VigiFlow®. This information is then stored into VigiBase® which is the repository of worldwide ICSRs. Based on the drug safety information collected, PvPI issues alerts, recommends label change (if any), and identifies signals thereby supporting National Regulatory Authority. At national level, PvPI has developed several tools for reporting of ADRs by the stakeholders. This article provides an overview of adverse events reporting tools in India vis-a-vis selected countries around the world, based on a comparative literature search. This article also throws light upon the regulatory aspects of PV in India, findings of PvPI and its recommendations to Central Drugs Standard Control Organization, collaboration of PvPI with Public Health Programmes, future prospects of reporting ADRs in India and how it will help enhance the quality of ADR-reporting by citizens of India.

Drug use is inherently related to both beneficial effects on health as well as the occurrence of risks. The beneficial effects may be related to efficacy, the treatment range of a product, or even to user-friendliness of a product. However, in addition to the occurrence of adverse drug reactions, a drug can also have an unexpected beneficial effect on a patient's health, not related to the indication for which the drug was used. The aim of this article is to characterize the reports of unexpected beneficial effects of drugs in the Dutch spontaneous reporting system.A descriptive analysis was used to gain insight in number of reports and drug classes responsible for unexpected beneficial effects of drugs. Grouping of positive side effects into classes was done by a conventional qualitative content analysis of the cases.Four hundred nine reports which described unexpected beneficial effects of drugs were included, which mentioned 451 associations between suspected drugs and unexpected beneficial effects. There were 147 drug classes on the 4th ATC level involved. Content analysis of the reports gave rise to 22 categories of unexpected beneficial effects of drugs, including one "other category". DISCUSSION AND CONCLUSION: The analysis showed a diverse spectrum of reported reactions and drugs with some categories of unexpected beneficial effects of drugs mentioned multiple times for certain drug classes on the 4th ATC level. Most of these findings are consistent with the existing literature and knowledge on the pharmacological mechanism of the drugs in question. Coding harmonization would make it possible to study these effects in international databases.

Made available in DSpace on 2021-06-25T10:55:23Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-01-01 Introduction: Considering the need for effective postmarketing surveillance of disease-modifying therapies (DMTs) in multiple sclerosis (MS), we analyzed the potential of the spontaneous reports for safety signal detection, verifying the completeness of the reports in the FDA Adverse Event Reporting System (FAERS). Methods: All reports with DMTs for MS considered the primary suspect cause of ADRs and registered between January 2004 and June 2019 were selected. The vigiGrade completeness score was applied and reports with a score greater than 0.80 were considered well documented. Descriptive statistical analysis and comparisons of well-documented reports by DMTs were performed. Results: A total of 297,926 reports were analyzed. The lowest completeness rates were observed for type of report (13.5%), dose (62.7%), and time from treatment start to the ADR (79.0%). Overall, 80.8% of reports were classified as well documented and those related to natalizumab had the highest proportion (92.4%, p

Objective Direct oral anticoagulants (DOACs) were developed to avoid the limitations of vitamin K antagonists (VKAs). DOACs are associated with a greater incidence of gastrointestinal bleeding and a smaller number of intracranial haemorrhages than VKAs. Therefore, it is important to deepen our knowledge of their safety profiles. The aim of this study was thus to analyse adverse drug reaction (ADR) reports on DOACs and VKAs using the Sicilian Spontaneous Reporting System (SRS) database. Methods All ADR reports with DOACs and VKAs as suspected drugs that were entered into the Sicilian SRS database during the period 2001-2019 were selected. In detail, all reports with the following single active substances were included: dabigatran etexilate, rivaroxaban, apixaban and edoxaban; acenocoumarol and warfarin were included as a comparator group. Descriptive statistical methodology was used to evaluate characteristics of the reported cases with a case-by-case assessment. Results and discussion Out of 521 reports related to anticoagulants, 444 (85.2%) and 77 (14.8%) involved DOACs and VKAs, respectively. DOAC-related reports were mainly of gastrointestinal disorders. In contrast, VKAs were mostly associated with blood and lymphatic system disorders, injury, investigations and vascular disorders. Many more cases of ADRs in the form of gastrointestinal disorders concerned dabigatran etexilate (n = 179, 73.7%) than the other DOACs, while ADRs in the form of blood disorders were mainly associated with acenocoumarol (n = 27, 57.4%). The most commonly reported Preferred Terms for DOACs were dyspepsia (n = 89, 17.1%), upper abdominal pain (n = 41, 9.2%) and pruritus (n = 26, 5.8%), whereas for VKAs, they were anaemia (n = 21, 27.3%) and hypocoagulable state (n = 18, 3.5%). Potentially interacting concomitant medications particularly included antithrombotic agents (n = 19, 4.3%) for DOACs and proton-pump inhibitors (PPIs) (n = 37, 48.1%) and antithrombotic agents (n = 13, 16.9%) for VKAs. Conclusion The ADRs most commonly associated with DOACs, especially dabigatran, were gastrointestinal disorders, particularly gastrointestinal bleeding. Our study also highlights the potential role of drug-drug interactions in the ADRs. The cases of gastrointestinal bleeding highlight the need for careful prescribing of DOACs and use of potentially interacting concomitant drugs.

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.

Background and Objective: Adverse drug reactions (ADRs) are associated with increased economic burden on the society. Monitoring of ADRs can help in decreasing the incidence of preventable adverse reactions. Methods: Under Pharmacovigilance Program of India, collection and reporting of ADRs has been going on at Dayanand Medical College and Hospital since January 2011. Here, we have analyzed the individual case safety reports (ICSRs) reported and uploaded between January 2017 and June 2019 from our centre. The ADR form provided by PvPI was used for collecting information, and the causality assessment was done according to the WHO-UMC scale. Results: A total of 498 ICSRs were uploaded through Vigiflow software during this period. Highest number of ADRs were recorded in the age group of 31-45 years (29.01%) and the least number of ADRs were recorded in the children less than 15 years of age (6.76%). General Medicine ward reported the highest number of ADRs and the antibiotics were most commonly associated with ADRs (26.21%), followed by antipsychotics (13.83%) and NSAIDs (12.14%). More than 90% of ADRs were non-serious (93.17%) and most of the ADRs were skin and soft tissue related (49.20%). Conclusion: Spontaneous reporting among indoor patients shows highest number of ADRs with use of antibiotics and almost all of the ADRs were non-serious in nature. Almost half of the total ADRs were skin and subcutaneous tissue related. Continuous efforts are required for further strengthening of the pharmacovigilance program of India.

Background Recombinant human follitropin alfa (r-hFSH) is used for ovarian stimulation as part of medically assisted reproduction. There is a risk for ovarian hyperstimulation syndrome (OHSS) with r-hFSH treatment, and an increased risk for thromboembolic events in the presence of pregnancy with OHSS. Objectives To report the frequency of OHSS and thromboembolism with originator follitropin alfa (GONAL-f) based on the Global Safety Database of Merck KGaA, Darmstadt, Germany and a systematic review of published data. Data Sources Reports of OHSS and thromboembolism were obtained from the Global Safety Database of Merck KGaA, Darmstadt, Germany from 20 October 1995 to 19 October 2018. The systematic review was based on MEDLINE and Embase searches from inception to 19 October 2018. Study Eligibility Criteria Patients receiving GONAL-f for ovulation induction or ART, with a starting dose within the range included in the prescribing information and providing information on the occurrence of OHSS and/or thromboembolism. Study Appraisal and Synthesis Matches In the Global Safety Database of Merck KGaA, Darmstadt, Germany there were an estimated 16,525,975 treatment cycles since 20 October 1995; 1110 reported cases of OHSS and 80 reported cases of thromboembolic events (reporting rates 6.7 and 0.48 per 100,000 treatment cycles, respectively). The systematic review identified 45 studies (5186 patients exposed to GONAL-f; 5240 treatment cycles). There were 272 reports of OHSS (5190 [5.19%] per 100,000 treatment cycles), including 10 cases of severe OHSS (191 [0.19%] per 100,000 treatment cycles). Limitations There may be the potential for under-reporting of safety outcomes in the literature, and under-reporting is a well-known phenomenon in spontaneous reporting databases. Conclusion and Implications of Key Findings Our analyses demonstrate low rates of OHSS and thromboembolism with GONAL-f. Electronic Supplementary Material The online version of this article (10.1007/s12325-020-01512-w) contains supplementary material, which is available to authorized users.

Pharmacovigilance is defined by the World Health Organization as the science and practice related to the detection, assessment, understanding and prevention of adverse drug reactions (ADRs). In a well-functioning pharmacovigilance system, information on possible ADRs is collected from patients, health professionals and marketing authorisation holders. Of all data sources for drug safety monitoring, spontaneous reporting systems provide the highest volume of information at the lowest maintenance cost and have proven their value in the early detection of product-related safety issues. At the beginning of 2018, the Brazilian Health Regulatory Agency (Agencia Nacional de Vigilância Sanitaria—Anvisa) decided to replace the national electronic reporting system in Brazil (Notivisa) with the system provided by Uppsala Monitoring Centre (VigiFlow) for ADR reporting. This paper describes that process and reports on the progress made by Anvisa in terms of making Brazil compliant with international pharmacovigilance standards as well as significantly increasing the number of individual case safety reports collected.

Introduction Concerns over safety profiles of tumor necrosis factor (TNF)-alfa inhibitors have been raised. The purpose of this study was to clarify the adverse events associated with TNF-alfa inhibitors using a spontaneous reporting system database. Materials and methods A retrospective pharmacovigilance disproportionality analysis was conducted using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between 2004 and 2017 were analyzed, and the reporting odds ratio (ROR) and 95% confidence interval (CI) for each adverse event were calculated. Results Among the 34,031 reports of adverse events associated with TNF-alfa inhibitors, 65.8% were women, who were frequently in their 60s (28.2%). Signals were detected for pneumonia (ROR, 5.36; 95% CI, 5.14-5.6), interstitial lung disease (ROR, 2.04; 95% CI, 1.95-2.15), pneumocystis jirovecii pneumonia (ROR, 11.8; 95% CI, 11.1-12.5), and herpes zoster (ROR, 6.4; 95% CI, 5.92-6.91) for TNF-alfa inhibitors as a class. There was variability in their signal strength across individual TNF-alfa inhibitors. Conclusion The strength of the associations of TNF-alfa inhibitors with adverse events is variable, and further studies are required to evaluate the identified signals.

The US Food and Drug Administration (FDA) and other major regulators regularly issue safety advisories about licensed drugs with new adverse effects that have been documented through observational studies, clinical trials, and spontaneously reported adverse drug events. To assess the possible effects of a representative group of FDA Drug Safety Communications on the reporting of the specific adverse effect featured in the advisory on new cases reported to the FDA Adverse Event Reporting System (FAERS). We examined 16 FDA Drug Safety Communications issued from 2010 to 2015 that had not previously been the focus of advisories from regulators in the UK, Canada, or Australia. We compared the reports of the adverse effect in the 8 calendar quarters preceding the advisory and in the 4 quarters following. We measured change in reporting frequency by calculating the event reporting odds ratio (ROR) for the post-warning compared to the pre-warning periods. We defined a credible association of the advisory with increased reporting as a ROR ≥ 2.0 and p value of

Background: Spontaneous reporting systems are essential as they help detect serious unknown adverse drug reaction (ADR). However, underreporting of ADR is a commonly associated problem. This research work aims to assess knowledge, barriers, and factors that encourage the reporting of ADR among physicians. Methods: A total of 600 physicians working at a tertiary referral hospital in Riyadh, Saudi Arabia, were included in this cross-sectional study. A pretested questionnaire was used. Results: Out of the 600 physicians, 240 (40%) completed the questionnaire. Most of the participants (85.4%) could correctly define ADR; nearly 75% physicians were unaware of the spontaneous reporting of ADR in Saudi Arabia. A total of 175 (72.9%) physicians had not reported any ADR among their patients in the last year; 40% of the physicians said that they did not report ADR because they were unaware of the online reporting of ADR. Providing guidelines and regular bulletins on the reporting of ADR is a critical aspect that encourages physicians to report ADR (51%). Education and training are the most recognized measures for improving the reporting of ADR. Conclusion: Physicians were adequately aware of ADR but inadequately aware of the reporting system and reporting authorities. Continuing medical education, training, and integration of the reporting of ADR into physicians’ various clinical activities may improve ADR reporting.

Background: Allopurinol can induce severe cutaneous adverse reactions (SCARs), including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Aims and Methods: We analyzed the Individual Case Safety Reports (ICSRs) sent from January 2001 until April 2019 to the Campania regional Center of Pharmacovigilance (Southern Italy) that reported allopurinol as suspected, with a focus on those reporting at least one serious cutaneous adverse drug reaction (ADR). This study was aimed to describe the main characteristics of all ADRs associated with allopurinol, analyze the proportion of serious cutaneous ADRs of total ICSRs related to allopurinol and to compare the main features (age, sex, seriousness and outcome) of ICSRs that reported serious cutaneous ADRs with those that did not. Results: The Campania regional Center of Pharmacovigilance received 108 ICSRs that reported allopurinol as suspected. ADRs occurred more frequently in the elderly (median age: 71years) and female patients (53.7%). Fifty-seven percent of all ADRs were classified as serious and 58% had a favorable outcome. Fifty-six ICSRs reported at least one serious cutaneous ADR; among these ICSRs, 37 cases of SCARs were found [DRESS syndrome (n = 3; 5.4%), SJS (n = 8; 14.3%) and TEN (n = 26; 46.4%)]. Serious cutaneous ADRs commonly occurred in the elderly (median age: 73years) and female patients (62.5%). They frequently required hospitalization (75%) and had an unfavorable outcome (46%). No statistically significant differences were found between ICSRs that reported serious cutaneous ADRs and ICSRs that did not report serious cutaneous ADRs except for the seriousness degree “Hospitalization or its prolongation” and the outcome degrees “Unfavorable” and “Favorable”. Conclusion: This study found that 52% (56/108) of all ICSRs having allopurinol as a suspected drug were serious cutaneous ADRs. Serious cutaneous ADRs associated with allopurinol frequently required hospitalization or prolonged hospitalization, and almost half had an unfavorable outcome.

PURPOSE: The aim of the study is to characterise safety signals based on the Dutch spontaneous reporting system (SRS) and to investigate the association between signal characteristics and Product Information (PI) update stratified by approval type: centrally authorised products (CAPs) versus nationally and decentralised authorised products (NAPs). METHODS: This study evaluates the full cohort of signals disseminated from the Dutch SRS in the period from 2008 to 2017. Each retrieved signal was characterised on a number of aspects. The signal management process from signal generation to a potential PI update was analysed in four steps: (1) signal characterisation; (2) proposed actions by the Dutch national competent authority (NCA) for the signals; (3) presence of PI update (yes/no) and association with signal characteristics; (4) timing from the moment the signal was issued to PI update. For step 1-3 we stratified products in CAPs and NAPs. RESULTS: Of all signals, 88.7% led to a proposed regulatory action by the NCA. Signals from the Dutch SRS for CAPs versus NAPs more often concerned biologicals, important medical events, class effects and shorter periods since marketing authorization. We detected PI updates for 26.2% of CAP signals and 61.3% of NAP signals. CONCLUSIONS: The Dutch SRSs remains an important source of signals. There are some notable differences in the characteristics of signals for CAPs versus NAPs. Signals for NAPs more frequently led to PI updates.

Introduction It is generally acknowledged that the ocular safety profile of intravitreal anti-VEGF drugs is acceptable, while the burden of systemic safety of these intravitreal agents is still being debated. The evaluation of the systemic safety of these drugs using real-world data (RWD), such as spontaneous reporting systems (SRS), electronic medical records (EMRs) and claims databases has several advantages, including the capture of outcomes among real-world populations over long observation periods. Nevertheless, there is a relatively small body of research exploring the post-marketing safety of these drugs. Areas covered The aim of this scoping review is to outline and discuss some of the methodological challenges to be faced when investigating the systemic safety of intravitreal anti-VEGF drugs using different sources of RWD. Expert opinion Such challenges include the selection of the most suitable data source, taking into account how well drug utilization is captured and whether the outcomes and covariates of interest can be captured. The strengths and limitations of some analytic methods that can be used to quantify risk, such as the intention-to-treat approach and the as-treated approach, complement each other, and using these together provides a more balanced analysis.

Background Age is one of the most important risk factors in the development of diabetes mellitus and certain drug classes indicated for this condition may be associated with clinically important adverse drug reactions (ADRs). The aim of this study was to analyse the suspected ADRs in older patients with diabetes mellitus, reported to the Portuguese Pharmacovigilance System from 2008 to 2018. Research design and methods A retrospective analysis of suspected ADRs reports was performed, involving patients aged ≥65 years. Results : Of a total of 751 reports collected, 439 were considered serious, 199 led to hospitalization and in 19 of them occurred a fatal outcome. Most of them were observed in females (n=393) and involved patients belonging mainly to the age group 65-74 years (n=405). Taking into account a total of 2134 suspected ADRs, the most frequent were hypoglycaemia (2.67%) and lactic acidosis (2.62%). The drugs specifically indicated for glycaemic control were the most frequently involved in ADRs. Conclusions Most of the ADRs were reported as serious and were mainly associated to drugs used in diabetes mellitus. In addition, the majority of them, such as hypoglycaemia, are preventable, highlighting the importance to identify possible factors that determine this occurrence, especially in the elderly.

BackgroundAdverse drug reaction (ADR) reporting practices by health care professionals remain poor. Over-the-counter (OTC) drugs are perceived as safe; however, they can also cause ADRs. The objective of this study was to analyze ADR reporting for OTC drugs in a 10-year period, in order to evaluate frequency of ADRs, population that ADRs most affect and reporters of ADRs of OTC drugs in Croatia.MethodsSpontaneously reported ADRs of non-analgesic OTC drugs, collected from January 2008 to December 2017 were analyzed. Data was obtained from Agency for Medicinal Products and Medical Devices of Croatia (HALMED).ResultsThere were 547 ADRs of OTC drugs reported in total and an increase in number of reports through the years was observed. Pharmacists reported 45.4% of all ADRs, and were most frequent reporters (p ConclusionsPharmacists most frequently reported ADRs of OTC drugs and consumers’ awareness of ADR reporting has risen. Other health care professionals (e.g., nurses and dentists) must be offered proper education in order to improve reporting practice of ADRs. Health care professionals should address concerns about OTC drug safety in elderly and children.

Background Infliximab (IFX) has changed the management of many life-threatening immune-mediated diseases. The high cost of IFX and its patent expiry have led to pharmaceutical companies developing a biosimilar; however, its safety profile remains unknown in the real world. The purpose of this study was to clarify the adverse events associated with IFX originator and its biosimilar using the Japanese Adverse Drug Event Report (JADER) database. Methods Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between the third quarter of 2014 and the fourth quarter of 2018. We calculated the reporting odds ratio and 95% confidence interval for each adverse event. Results We obtained 2771 reports of adverse events associated with IFX originator and 402 reports with IFX biosimilar. Signals were detected for pneumonia, interstitial lung disease, tuberculosis, and sepsis with both IFX originator and its biosimilar, whereas there was no signal for infection with the biosimilar. Conclusions The strength of the association between IFX originator and its biosimilar with adverse events is partly different, but reports were quite limited for the biosimilar compared with originator. It is recommended that research be continued in order to accumulate a wide variety of information, and that newly reported data be placed in the multifaceted viewpoints for improvement of care levels.

Objectives: Human papillomavirus (HPV) vaccines have proved to be effective in preventing cervical carcinoma. Although their safety profile resembled those of any other vaccine, few clinical studies showed that HPV vaccines might also induce severe adverse events. Methods: The authors aimed to investigate the safety profile of HPV vaccines, by analyzing the individual case safety reports (ICSRs) of a suspected adverse event following immunization (AEFI) concerning HPV vaccines that were sent to the Italian Pharmacovigilance Spontaneous Reporting System (RNF) in the Campania Region from January 2007 to September 2018. Results: During the study period, 82 ICSRs, covering 181 AEFIs, related to HPV vaccines were sent to the RNF in the Campania Region. The mean age of patients who experienced an AEFI after HPV vaccinations was 13 ± 4.5 years. The majority of ICSRs reported AEFIs that were considered as not serious (82%) and that had a favorable outcome (93%). Conclusion: The overall results of the study demonstrated that, except for a few cases, AEFIs related to HPV vaccines reflect those already reported in the summary of product characteristics. The authors did not identify any new safety issues or serious, rare or unexpected AEFIs that were medically confirmed to be related to HPV vaccines.

The reporting of hypersensitivity reactions (HSRs) among non-steroidal anti-inflammatory drugs (NSAIDs) according to cyclooxygenase (COX) selectivity and chemical groups has not been published yet in one study. This study assessed the reporting frequency of HSRs for NSAIDs based on their relative inhibitory potency towards COX enzymes and chemical groups, including the presence/absence of a functional sulfonamide group, in strata of 5 years after market authorization. A case/non-case study was performed among Individual Case Safety Reports (ICSRs) with NSAIDs as suspected drugs in VigiBase, the WHO spontaneous reporting database. Cases were ICSRs mentioning angioedema and anaphylactic/anaphylactoid shock conditions, while non-cases were ICSRs without HSRs. NSAIDs were categorized into (i) NSAIDs with highly COX-2 selectivity (coxibs), (ii) Non-coxib NSAIDs with COX-2 preference, (iii) NSAIDs with poor selectivity, or (iv) NSAIDs with unknown selectivity. Chemical groups were defined based on the Anatomical Therapeutic Chemical classification system and the presence/absence of a functional sulfonamide group. Reporting odds ratios (RORs) and 95% confidence intervals (95% CIs) were calculated using logistic regression analysis. We identified 13,229 cases and 106,444 non-cases. In the first 5 years after marketing, poor selectivity NSAIDs and acetic acid derivatives were associated with the highest ROR of HSRs (age- and sex-adjusted ROR 2.12, 95%CI: 1.98-2.28 and ROR 2.21, 95%CI: 1.83-2.66, respectively), all compared to coxibs, and also sulfonamide NSAIDs compared to non-sulfonamide NSAIDs (age- and sex-adjusted ROR 1.38, 95%CI: 1.29-1.47). After the first 5 years of marketing, most of the RORs returned to approximately 1. This article is protected by copyright. All rights reserved.

High-quality adverse drug reaction (ADR) reports are essential for conducting drug safety monitoring in pharmacovigilance. The study aim was to assess the current quality of ADR reports in western China, and to identify problems with ADR report quality.A sample of 1139 reports received by the Shaanxi ADR Monitoring Center from January 2015 to December 2017 was selected. ADR report quality was evaluated using an ADR report quality evaluation system.None of the reports were rated as excellent and 1.40% (n = 16) as good. Report quality was better for new and serious reports than for general reports. Medical institutions generated higher quality reports than pharmaceutical manufacturers. Nurses generated higher quality reports than doctors, pharmacists, and other professionals. Reporters of different occupations showed significant differences in the quality of the indicators Reporting time limit, Intervention ADR time, ADR termination time, ADR intervention measures, Original disease, and Cause of medication (P = 0.000).The ADR data quality was poor in western China, and of lower quality than reported data from previous research in other regions. Improvements in the quality and availability of ADR reports are urgently needed.

WHAT IS KNOWN AND OBJECTIVE Pregabalin is used for neuropathic and postherpetic pain and generalized anxiety. The aim of this study was to obtain the onset profiles of adverse events (AE) related to falls (AEFs) such as "somnolence," "dizziness," "loss of consciousness" and "fall" onset and several clinical factor combinations such as age and administered dose, using spontaneous reporting system (SRS) analysis such as the US Food and Drug Administration Adverse Event Reporting System (FAERS) database and the Japanese Adverse Drug Event Report (JADER) database. METHODS We used the reporting odds ratio (ROR) to analyse the association between pregabalin and AEFs. Additionally, we used the time-to-onset analysis. RESULTS AND DISCUSSION The crude RORs of AEFs such as somnolence and dizziness were higher than one for both the databases. The adjusted RORs for AEFs in the ≥60 years age group compared to those in the

Neonates experience adverse drug reactions (ADRs), but under-reporting of suspected ADRs to national spontaneous reporting schemes in this population is particularly high. A prospective observational study collected suspected neonatal ADRs at a tertiary neonatal unit. Cases were analysed for causality by six assessors using three existing methods. Sixty-three suspected ADR cases were identified in 35/193 neonates (18.1%). The proportion of suspected ADRs where the drug was prescribed "off-label" was 30/68 (44.1%). When 34 cases were assessed for causality using three methods, global kappa scores of less than 0.3 for each tool suggested only "fair" inter-rater reliability. Neonatal ADRs can be captured and occur from a variety of drugs affecting many organ systems. The current tools for assessing causality need to be adapted before they can reliably assess neonatal ADRs.

Introduction: Various methods have been implemented to detect adverse drug reaction (ADR) signals. However, the applicability of machine learning methods has not yet been fully evaluated.Objective: To evaluate the feasibility of machine learning algorithms in detecting ADR signals of nivolumab and docetaxel, new and old anticancer agents.Methods: We conducted a safety surveillance study of nivolumab and docetaxel using the Korea national spontaneous reporting database from 2009 to 2018. We constructed a novel input dataset for each study drug comprised of known ADRs that were listed in the drug labels and unknown ADRs. Given the known ADRs, we trained machine learning algorithms and evaluated predictive performance in generating safety signals of machine learning algorithms (gradient boosting machine [GBM] and random forest [RF]) compared with traditional disproportionality analysis methods (reporting odds ratio [ROR] and information component [IC]) by using the area under the curve (AUC). Each method then was implemented to detect new safety signals from the unknown ADR datasets.Results: Of all methods implemented, GBM achieved the best average predictive performance (AUC: 0.97 and 0.93 for nivolumab and docetaxel). The AUC achieved by each method was 0.95 and 0.92 (RF), 0.55 and 0.51 (ROR), and 0.49 and 0.48 (IC) for respective drug. GBM detected additional 24 and nine signals for nivolumab and 82 and 76 for docetaxel compared to ROR and IC, respectively, from the unknown ADR datasets.Conclusion: Machine learning algorithm based on GBM performed better and detected more new ADR signals than traditional disproportionality analysis methods.

Background: Drug-drug interactions (DDIs) are an important cause of adverse drug reactions (ADRs). In literature most of studies focus only on potential DDIs, while detailed data on serious ADRs associated with DDIs are limited. Our aim is to identify and characterize serious ADRs caused by DDIs using a spontaneous reporting database.Methods: All serious ADR reports, not related to vaccines and with a “definite”, “probable” or “possible” causality assessment, inserted into the National Pharmacovigilance database from Veneto Region (January 1, 2015 to May 31, 2020) were analyzed. A list of drug pairs was created by selecting the reports containing at least two suspected or concomitant drugs. We verified which drug pairs potentially interacted according to the online version of DRUGDEX® system. For each potential DDI we controlled whether the ADR description in the report corresponded to the interaction effect as described in Micromedex. A detailed characterization of all serious reports containing an occurring DDI was performed.Results: In the study period a total of 31,604 reports of suspected ADRs from the Veneto Region were identified, of which 2,195 serious reports (6.9% of all ADR reports) containing at least two suspected or concomitant drugs were analyzed. We identified 1,208 ADR reports with at least one potential DDI (55.0% of 2,195) and 381 reports (17.4% of 2,195 reports) with an occurring ADR associated with a DDI. The median age of patients and the number of contraindicated or major DDIs were significantly higher in reports with an occurring DDI. Warfarin was the most frequently reported interacting drug and the most common ADRs were gastrointestinal or cerebral hemorrhagic events. The proton pump inhibitors/warfarin, followed by platelet aggregation inhibitors/warfarin were the drug-drug combinations most frequently involved in ADRs caused by DDIs. The highest proportion of fatal reports was observed with platelet aggregation inhibitors/warfarin and antidepressants/warfarin.Conclusion: Our findings showed that about one-third of patients exposed to a potential DDI actually experienced a serious ADR. Furthermore, our study confirms that a spontaneous reporting database could be a valuable resource for identifying and characterizing ADRs caused by DDIs and the drugs leading to serious ADRs and deaths.

Purpose The COVID-19 pandemic was widely reported to present a stress to medical systems globally and disrupted the lives of patients and health care practitioners. Since spontaneous reporting heavily relies on both health care professionals and patients, an understandable question is whether the stress of the pandemic diminished spontaneous reporting. Herein we assess the hypothesis that the COVD-19 pandemic negatively impacted spontaneous reporting of adverse drug events. Methods We analyzed 119 weeks of spontaneous report counts from the Pfizer Safety database (January 1, 2018 to April 12, 2020). We fitted autoregressive integrated moving average models to aggregated and disaggregated time series and charted the model residuals on Individual value-moving range and exponentially weighted moving average charts to identify statistically unexpected changes associated with the pandemic. Results Overall reporting of serious adverse events showed no unexpected decline, Total global reporting declined, driven by health care professional reporting (both serious and non-serious), starting after week 8, 2020, exceeding model expectations by week 15, 2020, suggesting the pandemic as an assignable cause. However, reporting remained within longer term historic ranges. The Japan time series was the one individual country time series showing a significant decline, and unusual periodicity related to national holidays. A few countries, notably Taiwan, showed statistically unexpected reporting increases associated with the pandemic commencing as early as week 3, 2020. Literature reporting of adverse drug events was stable. Ancillary findings included prevalent year-end/beginning reporting minima, more with health professional than consumer reports. Implications In a large and diverse pharmaceutical company database we did detect a significant global decline in total reporting, driven by healthcare professionals, not consumers, and non-serious reports, consistent with the pandemic as an assignable cause, but the reporting remained within long term ranges. suggesting a relative durability. Importantly, our analyses found no unexpected decline in overall serious reporting. Future avenues for research include assessing whether these effects impaired signal detection, performing the same analysis on large public spontaneous reporting system data to assess generalizability of our findings, and follow-up analysis to assess if impacts on spontaneous reporting abate., Highlights • The COVID-19 pandemic is a historic event that presented a shock to health care systems. • Time series modelling and statistical process control charts were used to assess the impact of the pandemic on spontaneous adverse drug reaction reporting. • Spontaneous adverse drug reaction reporting significantly declined by week 15, 2020, suggesting the pandemic as an assignable cause.

One post-marketing surveillance challenge for many regulatory authorities is access to information regarding the safety of over-the-counter (OTC) medicines. National spontaneous adverse drug reaction (ADR) report data represent a rich potential data source for the detection of safety signals associated with OTC medicines, yet little is known regarding the possibility of detecting safety signals for OTC medicines within these datasets. The aim of this study was to evaluate the potential for detecting safety signals for OTC medicines in National ADR spontaneous reporting data, using OTC non-steroidal anti-inflammatory drugs (NSAIDs) and gastrointestinal bleeding as an example. Data from the Australian Adverse Drug Reactions System (ADRS) dataset (1971&ndash, 2008) and the Canadian Vigilance Adverse Reaction Online Database (VAROD) (1965&ndash, 2013) were used to explore the feasibility of using spontaneous reporting data, exploring the association between gastrointestinal bleeding and the use of OTC NSAIDs. Safety signals were examined using disproportionality analyses and reporting odds ratios calculated. After adjusting for age, gender, medications known to increase the risk of bleeding, and medications used for the management of conditions associated with an increased risk of bleeding, a two-fold increase in the risk of gastrointestinal (GI) bleeding with OTC NSAID was observed within each dataset. This study demonstrates that spontaneous ADR reporting data can be used in pharmacovigilance to monitor the safety of OTC medicines.

Background: To highlight the importance of spontaneous reporting programs in post marketing surveillance of medicines. Authors also aimed at providing various dimensions of spontaneous programs, including the strengths and weakness, and providing an insight on the future prospects of pharmacovigilance systems. Methods: Various literature related to post marketing surveillance and spontaneous reporting programs were reviewed and the relevant ones highlighting the strengths and weaknesses are summarized. A balance of information on strengths and weaknesses is listed. The health professionals’ awareness regarding existing spontaneous reporting programs is highlighted. Future prospects of pharmacovigilance are discussed. Results: Though beneficial, spontaneous reporting programs encounter several limitations and difficulties in diagnosing adverse drug reaction. Under-reporting and bias are major challenges. Online signal detection tools and innovative methods are needed to strengthen the spontaneous reporting programs. We provide the various issues to be considered while depending on spontaneous reporting programs as a method of post marketing surveillance. Conclusion: To strengthen the spontaneous reporting programs as an effective post marketing surveillance method, more awareness among health professionals and innovative strategies is needed. Integrating pharmacogenetic data can be a potential aspect of future pharmacovigilance. Plain language summary Monitoring adverse effects of marketed medicines through reporting by healthcare professionals and its challenges and way forward Introduction: This article highlights the importance of safety monitoring of medicines after they are launched in the market, mainly through reporting by healthcare professionals. We also highlight the strengths and weaknesses, and provide an insight on the future prospects of pharmacovigilance systems. Methods: Various literature related to the topic were reviewed and the relevant ones highlighting the strengths and weaknesses are summarized. A balance of information on strengths and weaknesses is listed. Health professionals’ awareness regarding existing programs on reporting safety of medicines is highlighted. Results: Though beneficial, reporting of adverse effects by healthcare professionals who deal with patient lacks clarity in diagnosing the adverse effects. Under-reporting and bias are the major challenges. Online software is needed to strengthen reporting by healthcare professionals. We list the various issues to be considered while depending on healthcare professionals’ reporting of adverse effects as a method of post marketing surveillance. Conclusion: To strengthen medicine safety monitoring and reporting by healthcare professionals, more awareness among health professionals and innovative strategies are needed. Integrating the genetic data of patients can be beneficial in predicting adverse effects, therefore avoiding them and enhancing safe prescribing and dispensing by healthcare professionals.

PURPOSE Spontaneous reporting constitutes one of the most fundamental and important systems for pharmacovigilance. In Japan, important regulation changes in the vaccine spontaneous reporting were implemented between 2009 and 2013; however, no studies had yet assessed the impact of the changes. The objective of this study was to assess the impact on the reporting trends in vaccine reports and on signal detection for vaccines. METHODS For assessment of the impact on the reporting trends, we performed the joinpoint trend analysis and descriptively considered number of vaccine reports grouped by the timing of the regulation change. For assessment of the impact on signal detection, we performed signal detection using dataset during the pre or postperiod of the regulation changes, and compared their agreement rates, which was calculated with a reference set for vaccines, created by the Global Research in Paediatrics project. RESULTS We retrieved 467 635 spontaneous reports, including 12 287 vaccine reports from April 2004 to March 2019. The average number of vaccine reports per year increased from 231 reports during the preperiod to 1227 during the postperiod. The joinpoint trend analysis found two joinpoints and differentiated three trends, significant increased trend of which was observed when regulations had changed. For signal detection, the agreement rate was improved when using data during the postperiod. CONCLUSION We concluded that the regulation changes increased the number of vaccine reports, and could have improved signal detection performance for vaccines by accelerating accumulation of reports, while more spontaneous reports are necessary to optimize signal detection.

Wei He, Difei Yao, Yangmin Hu, Haibin Dai Department of Pharmacy, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China Background: Spontaneous reporting of adverse drug events (ADEs) has long been the cornerstone of pharmacovigilance. Medical institutions in China have been a major source of ADE case reports, but the proportion of reports from tertiary hospitals is low due to the serious underreporting of case reports. The same problem existed in the Second Affiliated Hospital of Zhejiang University School of Medicine (SAHZU).Objective: In order to increase the number of ADE reports and promote hospital pharmacovigilance, SAHZU’s clinical pharmacists established a pharmacist-led ADE management model. The aim of this paper is to introduce this management model and explore the advantages and disadvantages of the model.Methods: Pharmacist-led ADE management model was gradually formed from 2015 to 2017 in the SAHZU. This “pharmacist-led” model is reflected not only in the fact that clinical pharmacists are the main reporters of SAHZU’s ADEs but also in that they are the main groups to analyze and manage ADE and drug errors. The sources of ADEs reported by clinical pharmacists mainly include pharmacy rounds, ADE-related pharmacist consultations, centralized monitoring, ADE warning signal analysis, newly introduced drug evaluations, and drug safety research.Results: A total of 533 ADEs were reported by SAHZU to China’s spontaneous reporting system (SRS) in 2017, while the data in 2012 was 177, with an increase by 201%. In 2012, the proportion of “new” and “serious” reports was 16.4%. The proportions during the period from 2015 to 2017 were 41.4%, 60.8%, and 52.2%, respectively, which were statistically significant compared with the proportion in 2012. The proportion of ADEs reported by clinical pharmacists during the period from 2014 to 2017 were 51.5%, 57.3%, 68.8%, and 90.8%, respectively, which were statistically significant compared with the proportion in 2013 (P

Adverse events (AEs) caused by polypharmacy have recently become a clinical problem, and it is important to monitor the safety profile of drug-drug interactions (DDIs). Mining signals using the spontaneous reporting systems is a very effective method for single drug-induced AE monitoring as well as early detection of DDIs. The objective of this study was to compare signal detection algorithms for DDIs based on frequency statistical models. Five frequency statistical models: the Ω shrinkage measure, additive (risk difference), multiplicative (risk ratio), combination risk ratio, and chi-square statistics models were compared using the Japanese Adverse Drug Event Report (JADER) database as the spontaneous reporting system in Japan. The drugs targeted for the survey are all registered and classified as “suspect drugs” in JADER, and the AEs targeted for this study were the same as those in a previous study on Stevens-Johnson syndrome (SJS). Of 3924 pairs that reported SJS, the number of signals detected by the Ω shrinkage measure, additive, multiplicative, combination risk ratio, and chi-square statistics models was 712, 3298, 2252, 739, and 1289 pairs, respectively. Among the five models, the Ω shrinkage measure model showed the most conservative signal detection tendency. Specifically, caution should be exercised when the number of reports is low because results differ depending on the statistical models. This study will contribute to the selection of appropriate statistical models to detect signals of potential DDIs.

Summary The French Addictovigilance Network aims to monitor all psychoactive substances with abuse potential including prescription drugs and other legal and illegal substances such as new psychoactive substances (NPS) and its consequences in humans. Created in 1990 through a network of regional addictovigilance centres covering the entire country, these pharmacologists with expertise in addictovigilance have developed interface with different partners (physicians, toxicologists, network of community pharmacies, addictology care centers…) and implemented several original tools of pharmacosurveillance (such as DRAMES [death related to the abuse of medicines] in strong collaboration with toxicologists or such OPPIDUM [observation of illegal products and misuse of psychotropic medications]), complementary to the spontaneous reporting. A such multidimensional approach including proactive surveillance by these tools and also among several heterogenous data sources (such as data from hospitals or claims database) is able to detect early addictovigilance signals and warnings as illustrated with three following examples: cannabis use and acute serious cardiovascular disorders, new synthetic opioids (ocfentanil, carfentanil) and severe opiate overdose or deaths, the diverted use of psychoactive drugs (codeine analgesics or sedative H1 antihistamines called purple drank) by adolescents and young adults. The choice of a broad strategy and the multifaceted system implemented by the French Addictovigilance Network using elements of pharmacology (fundamental, clinical, pharmacoepidemiology) expertise is an innovative method to detect early addictovigilance signals, and to describe its characteristics in order to increase awareness of psychoactive substances by patients, users and health professionals.

Consumers are more inclined than healthcare professionals (HCPs) to submit adverse drug reaction (ADR) reports, usually because of first-hand experience with an ADR. As consumer ADR reporting has led to important findings in other countries, the Turkish Pharmacovigilance Center (TUFAM) started accepting ADR reports directly from consumers. The purpose of this study was to, for the first time in Turkey, review and compare ADR reports from consumers and HCPs. We identified and evaluated all ADR reports that were submitted by TUFAM to VigiBase between 1 January 2014 and 31 December 2016 and fulfilled minimum reporting criteria. Minimum reporting criteria required an identifiable reporter, an identifiable patient, at least one suspected active substance/drug and at least one suspected adverse reaction. We compared ADRs submitted by either consumers or HCPs with respect to the reported sex of patients, the Medical Dictionary for Regulatory Activities preferred terms (PTs) used, designated medical event (DME) terms, the seriousness of the ADRs and the suspect drugs. We analyzed 9150 spontaneous ADR reports that fulfilled the minimum reporting criteria. Of these, 3141 were submitted by consumers and 6009 were submitted by HCPs. Annual reporting rates (RRs) and the number of consumer ADR reports showed an increasing trend over time. The male:female ratio was 0.85 for consumer reports and 0.76 for HCP reports. In total, 12 of the 20 most frequently used PTs were identical for both consumers and HCPs. For ADRs classified as serious, consumers submitted 33.3% and HCPs submitted 52.2%. Consumers used only ten Designated Medical Event (DME) terms while HCPs used 35 DME terms out of a total of 62 DME terms at least once. Consumers most frequently reported ADRs to nervous system drugs, whereas HCPs most frequently reported ADRs to anti-infective drugs for systemic use. Consumers most frequently reported ADRs linked to gastrointestinal disorders, whereas HCPs most frequently reported ADRs linked to skin and subcutaneous tissue disorders. This is the first study to compare spontaneous ADR reports from consumers and HCPs in Turkey. Our analysis indicates the reporting of ADRs by both consumers and HCPs is increasing. We found not only similarities in the two groups regarding suspect drugs and classification terms used, but also prominent differences. Consumers and HCPs had 12 of the 20 most frequently used PTs in common, but the remaining eight PTs used by consumers differed from those used by HCPs. This probably reflects the effect an ADR can have on a consumer’s daily life. HCPs also reported more serious ADRs than did consumers. Consumer reports have a secondary contribution to ADR reporting, which might then be used to improve existing pharmacovigilance systems with the consumer’s perspective in mind.

Spontaneous reporting is the primary method used in pharmacovigilance (PV) to detect drug safety signal. Specific criteria used in pharmacovigilance to prove accountability of a drug are rarely present in rare disease. The low number of alerts also makes it challenging. The aim of this commentary is to raise awareness among pharmacists on issues and opportunities for pharmacovigilance in rare diseases, taking pulmonary arterial hypertension (PAH) as example, from which a subset of cases are drug-induced. It is demonstrated how a dedicated program named VIGIAPATH created to reinforce pharmacovigilance of drug-induced pulmonary arterial hypertension at a national level, led to increase self-reporting and confirm safety signals. Thanks to a specific program such as VIGIAPATH, pharmacists can play an important role in communication with clinicians, patients and regulatory agencies, facilitating the detection of potential safety signals at an early stage in rare disease.

The effectiveness of active pharmacovigilance depends on the specific methods adopted and the work patterns put into place. Over the past few years, much attention has been paid to the importance of implementing such systems in China. However, less has been done to evaluate the state of implementation and future needs of such systems. This paper reviews China’s recent approaches to active pharmacovigilance by examining: (1) information collected from scientific articles and the websites of the China Food and Drug Administration and the China National Center for Adverse Drug Reaction Monitoring, (2) information available on China’s spontaneous reporting systems (SRS) and active pharmacovigilance system, and (3) annual reports and internal reports on this subject. Areas that improved most meaningfully for China’s active pharmacovigilance in recent years appear to include: (1) quicker reporting and more intelligent scanning methods for adverse drug reactions (ADRs), (2) the use of pharmacovigilance approaches to mine electronic hospital records, and (3) the development of integrated systems including the China Hospital Pharmacovigilance System and China Sentinel Hospital Alliance Program. Not only has the national online SRS system provided a platform for passive pharmacovigilance, it has also become an important platform for various explorations of active pharmacovigilance in China. Quick reporting and intelligent scanning of ADRs, facilitated by automated ADR detection based on electronic hospital records, have accelerated to capabilities for active pharmacovigilance. The outcomes of the programs, such as the China Hospital Pharmacovigilance System and China Sentinel Hospital Alliance Program, usher in a new era for China’s active pharmacovigilance. These are particularly important to bridge the information system of sentinel hospitals and ADR research centers, but gaps remain. Thus, much work needs to be done before a high-level active pharmacovigilance system is sufficiently mature to ensure drug safety in the country.

Background: Statin treatment is often associated with poor adherence, which may be due to the onset of adverse drug reactions (ADRs). We investigated on potential risk factors related to preventable cases of statin-induced ADRs and to the discontinuation of statin therapy. Methods: We performed a study using the database of Italian spontaneous reporting. The target population for the preventability assessment was all patients with suspected statin-induced ADRs deriving from Campania Region (a territory of Southern Italy) between 2012 and 2017. Additionally, a local sentinel surveillance site involving General Practitioners was selected to countercheck in routine clinical practice the role of ADRs for statin discontinuation. Results: In total, 34 of 655 (5.19%) regional cases were preventable and among detected risk factors 90.0% was related to healthcare professionals’ practices and 10.0% to patient behaviour. In 81.4% (533/655) of cases, statin therapy was discontinued due to ADRs, mainly classified as not serious and associated with a positive prognosis. These results were also confirmed in the active sentinel site. Conclusions: Our findings suggest an inappropriate use of statins among the identified preventable cases and a potential inappropriate statin discontinuation due to ADRs. These factors may be useful for targeting interventions to improve statin adherence.

Direct patient reporting (DPR) is a system where patients report suspected adverse drug reactions (ADRs) directly to competent bodies. Studies have shown the added advantages of DPR of ADRs. In August 2012, the National Pharmacovigilance Centre (NPC) commenced implementation of a Pharmacovigilance Rapid Alert System for Consumer Reporting (PRASCOR) under the spontaneous reporting system, with the aim of facilitating direct consumer reporting of suspected ADRs to the drug regulatory authority. This study aims to examine the performance of PRASCOR by determining its quantitative contribution to spontaneous reporting of ADRs in Nigeria from inception in August 2012 to February 2017. In the PRASCOR system, consumers of medicines who experience an untoward effect are encouraged to send a prepaid short text message with the name of the medicine and the reaction to a short code (20543). This message with the consumer’s phone number is forwarded as an email alert to the National Agency for Food and Drug Administration and Control (NAFDAC) for follow-up. Logs of text messages from the PRASCOR system obtained from the service provider were reviewed to determine the number of consumer alerts and ‘reportable alerts’ received during the review period. Furthermore, the NPC local database was reviewed to determine the number of individual case safety reports (ICSRs) from PRASCOR and characterize them. A total of 47,071 hits were logged by the PRASCOR server. There were 3594 ‘consumer complaints’, of which 94% were ‘reportable alerts’. Fifty-two per cent (n = 1758) of ‘reportable alerts’ contained information on both a medicine and a suspected ADR. A total of 353 ICSRs in the local database were attributed to PRASCOR, but only 247 (70%) of these were successfully matched to the originating PRASCOR alert. For the period under review, PRASCOR contributed 3.9% of reports in the NPC local database. We conclude that, quantitatively, PRASCOR contributed minimally to the number of ADR reports received under the spontaneous reporting system, but has potential for performing better and adding value to the reporting of ADRs and pharmacovigilance in Nigeria.

BACKGROUND: Safety data is continuously evaluated throughout the life cycle of a medical product to accurately assess and characterize the risks associated with the product. The knowledge about a medical product’s safety profile continually evolves as safety data accumulate. METHODS: This paper discusses data sources and analysis considerations for safety signal detection after a medical product is approved for marketing. This manuscript is the second in a series of papers from the American Statistical Association Biopharmaceutical Section Safety Working Group. RESULTS: We share our recommendations for the statistical and graphical methodologies necessary to appropriately analyze, report, and interpret safety outcomes, and we discuss the advantages and disadvantages of safety data obtained from passive post-marketing surveillance systems compared to other sources. CONCLUSIONS: Signal detection has traditionally relied on spontaneous reporting databases which have been available worldwide for decades. However, current regulatory guidelines and ease of reporting have increased the size of these databases exponentially over the last few years. With such large databases, data mining tools using disproportionality analysis and helpful graphics are often used to detect potential signals. Although the data sources have many limitations, analyses of these data have been successful at identifying safety signals post-marketing. Experience analyzing these dynamic data is useful in understanding the potential and limitations of analyses with new data sources such as social media, claims or electronic medical records data.

Ankur Arora,1,2 Rajinder K Jalali,1,2 Divya Vohora1 1School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India; 2Medical Affairs and Clinical Research, Sun Pharmaceutical Industries Limited, Gurgaon, Haryana, India Background: Numerous reporting biases have been known to affect spontaneous reporting databases. The Weber effect, which constitutes a peak in adverse event (AE) reporting of a drug at the end of second year after regulatory approval followed by a continuous decline thereafter, has been considered an important bias for a long time. The existence of this bias in AE reporting of oncology drugs remains an underevaluated area, prompting a targeted examination.Methods: The US Food and Drug Administration (USFDA) Adverse Event Reporting System (FAERS) was studied for AE reporting patterns of 5 years of 15 new molecular entities (NMEs) and biologics used in oncology. This 5-year period started from the USFDA date of approval for the NMEs and biologics. The number of AEs reported for each of the drugs was plotted against time (years). The AE reporting patterns were specifically examined for the existence of the Weber effect. In addition, AE reporting rate patterns of 5 years of seven NMEs and biologics used in oncology were examined.Results: A total of 50,630 AE reports were logged in to the FAERS for all 15 drugs examined for AE reporting patterns. We observed five distinct AE reporting patterns for 15 drugs; however, none of the AE patterns were identical to the Weber effect. We did not observe a consistent AE reporting rate pattern for the seven drugs examined for AE reporting rates. With the exception of one drug (cetuximab), none of the drugs exhibited a second-year peak in AE reporting rates. This peak was not followed by continuous decline in AE reporting rate thereafter.Conclusion: This study does not support the existence of the Weber effect in AE reporting of oncology drugs. The contemporary AE reporting of oncology drugs does not exhibit a consistent pattern. Keywords: Weber effect, adverse event reporting patterns, oncology drugs, USFDA, FAERS&nbsp

We proposed a statistical criterion to detect drug-drug interactions causing adverse drug reactions in spontaneous reporting systems. The used criterion quantitatively measures the discrepancy between the observed and expected number of adverse events via chi-square statistics. We compared the performance of our method with that of Noren et al. (Stat Med 2008; 27 (16): 3057–3070) through a simulation study. When the number of events for a combination of two drugs was equal to or lower than two, the false positive rate for our method ranged from 0.01 to 0.08, whereas the rate for Noren’s method ranged from 0.01 to 0.06. The sensitivity for our method ranged from 0.09 to 0.29, whereas the sensitivity for Noren’s method ranged from 0.03 to 0.24. The area-under-the-receiver operating characteristic curve for our method was significantly larger than that for Noren’s methods regardless of simulation settings. The proposed method was also applied to the Food and Drug Administration Adverse Event Reporting System database, and a recognized drug-drug interaction was detected. The proposed criterion controlled false positives at an acceptable level and had higher sensitivity than that of Noren’s method had when events were rare.

Purpose To investigate how reporting of adverse drug reactions (ADRs) among adults in Sweden is associated to age and sex, in addition to seriousness of the reaction and drug utilisation. Methods Individual case safety reports (ICSRs) reported by healthcare professionals to the national pharmacovigilance database 2008–2011 were related to defined daily dose (DDD) in the Swedish Prescribed Drug Register (SPDR) for individual's ≥20 years. Data were stratified into five age groups. Crude and adjusted (by age standardisation of prescribed drugs) reporting rate (RR) and reporting rate ratio was evaluated as well as impact of sex-dependent drugs. Results Based on 9898 included ICSRs, the crude results show that overall RR was almost similar for both serious and non-serious reports and indicates highest RR in the youngest age group. Women had higher rates than men, with predominance for non-serious reports, contrary to men who had a higher RR of serious ones. Standardisation led partly to the same result, but age-related distribution was adjusted, with highest overall RR in the oldest age groups. Sex-dependent drugs had marginal impact on the results. Conclusion Age and sex have impact on spontaneous reporting of ADRs. After adjusting for dispensed drugs and by standardisation of age-related differences in prescribed drugs, results indicate that healthcare professionals more frequently reported ADRs for the oldest individuals and for women. Serious reports were more frequently reported for men. Copyright © 2017 John Wiley & Sons, Ltd.

Background: Severe cutaneous adverse reactions (SCARs) are prominent in pharmacovigilance (PhV). They have some commonalities such as nonimmediate nature and T-cell mediation and rare overlap syndromes have been documented, most commonly involving acute generalized exanthematous pustulosis (AGEP) and drug rash with eosinophilia and systemic symptoms (DRESS), and DRESS and toxic epidermal necrolysis (TEN). However, they display diverse clinical phenotypes and variations in specific T-cell immune response profiles, plus some specific genotype–phenotype associations. A question is whether causation of a given SCAR by a given drug supports causality of the same drug for other SCARs. If so, we might expect significant intercorrelations between SCARs with respect to overall drug-reporting patterns. SCARs with significant intercorrelations may reflect a unified underlying concept. Methods: We used exploratory factor analysis (EFA) on data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS) to assess reporting intercorrelations between six SCARs [AGEP, DRESS, erythema multiforme (EM), Stevens–Johnson syndrome (SJS), TEN, exfoliative dermatitis (ExfolDerm)]. We screened the data using visual inspection of scatterplot matrices for problematic data patterns. We assessed factorability via Bartlett’s test of sphericity, Kaiser-Myer-Olkin (KMO) statistic, initial estimates of communality and the anti-image correlation matrix. We extracted factors via principle axis factoring (PAF). The number of factors was determined by scree plot/Kaiser’s rule. We also examined solutions with an additional factor. We applied various oblique rotations. We assessed the strength of the solution by percentage of variance explained, minimum number of factors loading per major factor, the magnitude of the communalities, loadings and crossloadings, and reproduced- and residual correlations. Results: The data were generally adequate for factor analysis but the amount of variance explained, shared variance, and communalities were low, suggesting caution in general against extrapolating causality between SCARs. SJS and TEN displayed most shared variance. AGEP and DRESS, the other SCAR pair most often observed in overlap syndromes, demonstrated modest shared variance, along with maculopapular rash (MPR). DRESS and TEN, another of the more commonly diagnosed pairs in overlap syndromes, did not. EM was uncorrelated with SJS and TEN. Conclusions: The notion that causality of a drug for one SCAR bolsters support for causality of the same drug with other SCARs was generally not supported.

Background: Today, there is a poor knowledge about gender differences in adverse drug reactions (ADRs) to cardiovascular drugs such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). Therefore, the aim of this study was to analyze spontaneous reports of suspected ADRs induced by ACE-inhibitors and ARBs, between January 2001 and June 2015, recorded in a Region of Southern Italy (Campania Region). Methods: We performed a descriptive gender-related analysis of regional safety data, obtained from the spontaneous reporting system. Results: In the considered period, 772 suspected ADRs to ACE inhibitors and ARBs (in monotherapy or in combination) were reported with a slightly higher frequency in men compared with women. In both genders, the most involved category was ARBs in combination, whereas the most prescribed active substance was ramipril. General and administration site conditions, vascular disorders and modification of laboratory parameters were more common in men, while respiratory disorders were most common in women. In 88.2% of cases, not serious ADRs were described more by men than women. Conclusions: This analysis suggested no substantial gender differences. Further studies such as randomized population studies or meta-analysis of ACE inhibitors and ARBs randomized studies are needed to clarify whether gender differences exist in the safety profile of these drugs.

Objective: The current study aims to assess the preventability of the contrast media adverse drug reactions reported through the Campania spontaneous reporting system, identifying the possible limitations emerged in this type of evaluation. Method: All the individual case safety reports validated by the Campania Pharmacovigilance Regional Centre from July 2012 to September 2015 were screened to select those that reported contrast media as suspected drug. Campania Preventability Assessment Committee, in collaboration with clinicians specialized in Radiology, assessed the preventability according to the P-Method, through a case-by-case approach. Results: From July 2012 to September 2015, 13798 cases were inserted by pharmacovigilance managers in the Italian Pharmacovigilance Network database (in the geographical contest of the Campania Region), of which 67 reported contrast media as suspected drug. Five preventable cases were found. The most reported causes for preventability were the inappropriate drug use for the case clinical conditions and the absence of the preventive measure administrated prior to the contrast media administration. Several limitations were found in the evaluation of the critical criteria for the preventability assessment. Conclusions: Educational initiatives will be organized directly to the healthcare professionals involved in the contrast media administration, to promote an appropriate use of the contrast media.

Recombinant drug products successfully treat many life-threatening and chronic diseases. The high cost of these drugs makes them inaccessible to the patients particularly in developing countries. Patent expiration of innovator recombinant drug products has led to the development of biosimilars or similar biologics by several manufacturers. Unlike generics, these are not identical to their innovator products because of the differences in the manufacturing process; however, they are similar in quality characteristics, biological activity, safety, and efficacy. The regulatory procedures used for generic drugs cannot be applied for biosimilars as they are large complex structures produced from living cells and can produce potential risk of immune-based adverse reactions. Out of several safety issues related to biosimilars, two main safety concerns are variable potency and immunogenicity, for which a robust long-term pharmacovigilance system is needed. Various guidelines have been issued for the regulatory approval and pharmacovigilance of biosimilars by USFDA, EU, and pharma-emerging countries like China and India. The article includes the pharmacovigilance plan of biosimilars in these countries, discusses the challenges and opportunities in pharmacovigilance through spontaneous reporting systems, and suggests amendments in the existing suspected adverse event reporting form of the Pharmacovigilance Programme of India.

International audience; INTRODUCTION: In 2017, concerns regarding Adverse Events (AEs) associated with levonorgestrel Intra-Uterine Device Mirena(R) were largely echoed in medias in France. This resulted in a tremendous reporting of AEs to Pharmacovigilance Centres. OBJECTIVES: The aim of this study was to describe the reporting of AEs regarding Mirena(R) in France and to study the impact of media coverage on this reporting. METHODS: All cases reports involving Mirena(R) recorded in the French national pharmacovigilance database from marketing (21/07/1995) until 04/08/2017 were extracted. To allow studying the influence of mediatisation, reports were described separately for the periods preceding and following the observed media coverage peak (15/05/2017). RESULTS: Overall, 3,224 reports were considered, 510 (15.8%) recorded before the media coverage peak, and 2,714 (84.2%) after. Before the peak, 76.5% of reports originated from health professionals; median time-to-report was of 5.5 months (IQR: 1.7-18.6), and median number of AEs per report of 1 (min-max: 1-17). After the peak, 98.6% originated from patients; median time-to-report was 21 months (IQR: 8.1-45.5), and median number of AEs per report was 6 (min-max: 1-37). After the peak, most reports mentioned anxio-depressive disorders (38.8% vs 10.6% before) or sexual disorders (47.3% vs 6.9%). Other emphasized AEs were weight increase (42.3% vs 10.2%) and pain (gastrointestinal, 19.1% vs 3.5%; musculoskeletal, 22.2% vs 4.5%). CONCLUSION: This study highlighted the importance of mediatisation impact on spontaneous reporting with changes concerning amounts of reports, type of reporter, and type of reported AEs. For Mirena(R), this led to generate signals regarding anxio-depressive and sexual disorders.