WHO Global Individual Case Safety Research Articles

The opioid epidemic: A worldwide exploratory study using the WHO pharmacovigilance database.

The current opioid epidemic in the United States began 20 years ago and has become the leading cause of accidental deaths in the country. This crisis prompted us to explore trends in opioid abuse and dependence worldwide. We sought to identify other countries at high-risk of opioid use disorders, using the World Health Organization's (WHO) pharmacovigilance database. We performed a disproportionality analysis using VigiBase, the WHO Global Individual Case Safety Report (ICSR) database. Five opioids used worldwide were included: oxycodone, fentanyl, morphine, tramadol, and codeine. We extracted all ICSRs associated with the drugs of interest, considered as suspect medication and recorded up until 5 June 2021, using the narrow Standardised MedDRA Query (SMQ) for drug abuse and dependence. Countries with at least one ICSR for each of the five opioids were retained. The relationship between the use of a drug (i.e. an opioid) and the occurrence of an adverse drug reaction (i.e. drug abuse and dependence) for each country was assessed by calculating the information component (IC) and its 99.9% CI [IC0005 ; IC9995 ], using a quasi-Bayesian confidence propagation neural network (BCPNN). A hierarchical cluster analysis (Ward's method) of the IC0005 value for each of the five opioids was performed to identify subgroups of countries with similar reported risks of opioid abuse and dependence. Among 21 countries, the optimal number of clusters was calculated to be four, each with a Jaccard index >0.5 (0.95, 0.78, 0.65 and 0.75, respectively). Six countries with the highest signals of drug abuse and dependence were identified in cluster 1, with significant CIs for the five opioids of interest (IC0005 > 0), ranging from 0.9 to 5.8 for the lower endpoint. There appear to be four distinct clusters of countries with similar opioid abuse and dependence profiles. The group with the highest reported risk for the opioids oxycodone, fentanyl, morphine, tramadol and codeine includes Australia, Canada, France, Germans, the United Kingdom and the United States.

Diarrhoea with the angiotensin receptor neprilysin inhibitor sacubitril + valsartan: A pharmacovigilance study.

Diarrhoea is an adverse drug reaction of the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril + valsartan. It was also described with olmesartan and more recently with other angiotensin receptor blockers. The study was performed to compare diarrhoea reports in pharmacovigilance databases with sacubitril + valsartan and valsartan. The study used reports of diarrhoea with the ARNI sacubitril + valsartan registered: first in the French PharmacoVigilance Database (FPVD) and second in Vigibase®, the WHO Global Individual Case Safety Report database. After description of the main characteristics, disproportionality analyses were performed. Results are reported as reporting odds ratios (ROR) with 95% confidence interval. We found 29 reports of diarrhoea with sacubitril + valsartan in the FPVD and 686 in Vigibase®. With sacubitril + valsartan, diarrhoea occurred more frequently in males around 70 years with a median delay of 3 days. With valsartan, diarrhoea occurred more frequently in females around 68 years with a median delay of 0.5days. In the FPVD, a significant association was found with sacubitril + valsartan in comparison with valsartan alone before (ROR = 8.78 [5.19-14.85]) and after (ROR = 11.19 [5.89-21.25]) exclusion of concomitant drugs known to be associated with diarrhoea. A significant association was also found in Vigibase® after adjustment on age, sex, reporter and its location (ROR = 1.31 [1.14-1.50]). Diarrhoea reported with sacubitril + valsartan has marked differences in gender, delay of occurrence and frequency of reporting in comparison with diarrhoea with valsartan. From a pharmacodynamic point of view, these results suggest a specific role of sacubitril in diarrhoea.

Drug-induced IgA vasculitis in children and adults: Revisiting drug causality using a dual pharmacovigilance-based approach.

IgA vasculitis (IgAV) is an immune complex small-vessel vasculitis. Drug-induced IgAV cases were rarely reported in the literature. Drug causality assessment is challenging as many other etiological factors can be involved. We performed a pharmacovigilance study to identify the main drugs reported to induce IgAV. We used the French pharmacovigilance database (FPVD) and the WHO global individual case safety reports database (VigiBase) to retrieve IgAV cases. Cases from the FPVD were reviewed by two investigators using predefined criteria. Disproportionality analyses (case - non-case approach) were conducted in VigiBase to identify drugs significantly associated with IgAV reporting. Of the 467 IgAV cases retrieved from the FPVD, 115 (47 children and 68 adults) have been assessed as definite or probable, reported with 178 suspected drugs. Overall IgAV cases were mainly male (58%), with a median age of 33.5 (8.0-63.3) years. No death was reported. Besides, we identified 1558 possible IgAV cases in VigiBase. Among them, 40 were associated with a disproportionality in IgAV reporting. Drugs were mainly vaccines, antibiotics and TNF-α blockers, these finding being consistent in both databases. IgAV reporting with TNF-α blockers was significantly associated with their use in inflammatory bowel diseases, psoriasis or ankylosing spondylitis compared to other indications. Our systematic study enables the identification of culprit drugs in drug-induced IgAV. These results strengthen the immune pathophysiology of IgAV and the role of underlying disease. The list of suspected drugs may be useful for physicians to manage patients with IgAV and consider appropriate drug discontinuation. What is already known about this subject? IgA vasculitis has multifactorial etiology. To date, possible culprit drugs have been reported only in case reports. What does this study add? Using a dual pharmacovigilance-based approach, we identified drugs associated with the occurrence of IgA vasculitis, such as all types of vaccines, major antibiotics and immunomodulatory agents, mainly TNF-α blockers. How might this impact on clinical practice or future developments? Physicians should be aware of drug-induced IgA vasculitis and we provide evidence on the most frequent implicated drugs.

The association between receptor binding affinity and metabolic side effect profile of antipsychotics and major cardio- and cerebrovascular events: A case/non-case study using VigiBase

Antipsychotics (APs) have been associated with major adverse cardio- and cerebrovascular events (MACCE), but the underlying mechanisms are unclear. Our aim was to elucidate the association between APs, stratified for receptor affinity and metabolic side effects (MSE), in the reporting of MACCE. A case/non-case study was conducted using data from the WHO global Individual Case Safety Report (ICSR) database, VigiBase, among all reports associated with an AP. Cases were ICSRs of MACCE, while non-cases were all other adverse drug reactions (ADRs). APs were classified by AP group, the degree of receptor affinity for adrenergic, dopaminergic, muscarinic, histaminic, and serotoninergic receptors and by MSE profile. The strength of the association was estimated with logistic regression and expressed as crude and adjusted reporting odds ratios (RORadj.) with corresponding 95% confidence intervals (95%CIs). We identified 4987 reports of MACCE and 328,907 reports of other ADRs. Atypical APs (RORadj. 2.46; 95%CI 2.20–2.74) were significantly associated with the reporting of MACCE compared to typical ones. APs with high affinity for Adrenergic alfa-1 (RORadj. 2.98; 95%CI 1.93–4.59), Histaminic H1 (RORadj. 2.31; 95%CI 1.98–2.68), Muscarinic M1 (RORadj. 1.87; 95%CI 1.74–2.01), and Serotoninergic 5-HT2A (RORadj. 3.19; 95%CI 2.07–4.92) were associated with a higher risk of reporting of MACCE compared to low affinity. APs with higher-risk of MSE were associated with higher risk of reporting of MACCE (RORadj. 1.88; 95%CI 1.73–2.05) compared to the lower-risk. APs with high affinity for Adrenergic alfa-1, Histaminic H1, Muscarinic M1, and Serotoninergic 5-HT2A receptors and with high-risk of MSE may explain the occurrence of those events.

Cardiac failure in patients treated with azacitidine, a pyrimidine analogue: Case reports and disproportionality analyses in Vigibase

Azacitidine (AZA), a pyrimidine analogue, is validated for high-risk myelodysplastic syndrome or low-blast acute myeloid leukaemia in unfit patients for more intensive treatment. This study assessed the putative link between cardiac failure (CF) and AZA exposure. Cases of CF in patients treated with AZA were retrospectively collected and described from several centres of the Groupe Francophone des Myélodysplasies. A description analysis and a disproportionality analysis using Vigibase, the WHO Global Individual Case Safety Reports (ICSRs) database, were conducted on ICSRs by the Standardized MedDRA Queries (SMQ broad) cardiac failure and by preferred terms cardiac failure and cardiac failure acute. The reported odds ratio (ROR) and its 95% 2-sided confidence interval was computed by comparing the proportion of CF reports with the suspected drug (AZA) and the proportion of reports of the same adverse drug reaction with all other suspected drugs in the database during the same period. In the 4 case reports, all patients presented a cardiovascular history. In 1 patient, CF recurred after AZA re-challenge. The pharmacovigilance analysis in Vigibase retrieved 307 ICSRs of CF (SMQ) with AZA. Significant disproportionality signals associated with AZA were identified by using the SMQ cardiac failure (ROR 1.3) and the preferred terms cardiac failure (ROR 5.1) and cardiac failure acute (ROR 23.2). This study points to the potential role of AZA in the occurrence of CF. Cardiac evaluation before AZA initiation and regular monitoring of cardiac function during AZA treatment should be performed in patients with a history of cardiovascular disease.

Late cardiac adverse events in patients with cancer treated with immune checkpoint inhibitors

BackgroundImmune checkpoint inhibitor (ICI)-associated early cardiac adverse events (CAEs), mostly acute and fulminant myocarditis, have been well characterized and mainly occur during the first 90 days after ICI therapy initiation....

P: 65 Drug-induced Hyperammonaemia: Data From VigiBase, the WHO Database

BACKGROUND: Altered consciousness secondary to metabolic encephalopathies represents a major cause of ICU admission with favorable outcome when diagnosed and treated rapidly. Ammonia dosage is thus recommended in most textbooks in the absence of any diagnosis after etiological work-up encompassing biological sampling, cerebral imaging and EEG. Despite hyperammonaemia is most commonly secondary to liver diseases, portosystemic shunts, inborn errors of metabolism, mostly urea cycle defects, microbial pullulation or drug-induced hyperammonaemia (DIH) are other possible causes. DIH is poorly described but is mainly recognized as the consequence of valproic acid. Some antineoplastic agents, fluorouracile or asparaginase, have been implicated but this class is evolving rapidly. To describe the drugs associated with DIH. METHODS: We used VigiBase, the WHO global Individual Case Safety Report (ICSR) database, which contains reports of suspected adverse drug reactions (ADRs) collected by national drug authorities in over 130 countries between 1967 and 8 May 2019. This observational retrospective study included all ADRs reported as "hyperammonaemia" according to the Medical Dictionary for Drug Regulatory Activities (MedDRAv21.1) term (Prefered term [PT] level). The drugs considered in the analysis were those notified as suspected treatments. Drugs used to treat hyperammonaemia or hepatic encephalopathy were excluded as were drugs reported less than 3 times. Drugs with a positive lower end of the 95% credibility interval for the information component (IC025) ≥0, an indicator value for disproportionate Bayesian reporting, was considered as causative of hyperammonaemia. RESULTS: Among 19 438 165 ICSRs, 576 drugs were identified for the term "hyperammonaemia [PT]". Six were excluded because they were used to treat hyperammonaemia or hepatic encephalopathy. Thus, 73 drugs had a an IC025 ≥0 and represented 2759 cases (0.014%). Twelve drugs were reported more than thirty times (Table 1). CONCLUSION: Besides commonly involved drugs, some other commonly used drugs seem associated in DIH. These data could help in the etiological work-up of hyperammonemia.

Comparative study of hypoglycaemia induced by opioids. Is it a class effect?

ABSTRACTObjective: Drug-induced hypoglycaemia has been described with the use of tramadol and methadone. The authors aimed to determine if drug-induced hypoglycaemia could be a class effect for opioids.Methods: The authors performed a disproportionality analysis in VigiBase®, the WHO global individual case safety report database with nine opioids (codeine, fentanyl, hydromorphone, methadone, morphine, oxycodone, tramadol, buprenorphine and nalbuphine) using the broad Standardised MedDRA Query for hypoglycaemia. The authors also carried out a descriptive study of opioid-induced hypoglycaemia in the French PharmacoVigilance DataBase (FPVDB) using the MedDRA Preferred Term ‘hypoglycaemia’.Results: The global adjusted Reporting Odds Ratio (aROR) value for the 9 opioids was 1.53 (95% CI 1.52–1.54). The aROR ranged from 1.09 to 1.97 depending on the opioid, but all were statistically significant. A sex ratio of 0.74 was found for the reports of opioid-induced hypoglycaemia in Vigibase®. The authors also found 133 reports of hypoglycaemia in the FPVDB related to opioids. Among the reports, 55 were glycaemic imbalances in diabetics occurring shortly after the start of opioid treatment.Conclusion: This work highlighted a significant association between all opioids and hypoglycaemia, thereby indicating that opioid-induced hypoglycaemia is probably a class effect. Women and/or diabetics seem to be more at risk for developing opioid-induced hypoglycaemia.

Drug-induced systemic lupus: revisiting the ever-changing spectrum of the disease using the WHO pharmacovigilance database

ObjectiveDrug-induced lupus (DIL) is an idiosyncratic side effect of treatments in which symptoms overlap with those of systemic lupus erythematosus (SLE). The spectrum of DIL constantly evolves with that of...

Statins and diabetes: Are all statins at risk? A pharmacoepidemiological study

Association between diabetes (D) and statins (S) is well demonstrated. However, results are conflicting according to the different S with for example association with atorvastatin or rosuvastatin but not with others in the Takker's meta-analysis. Little is known about the risk in real world. We investigated this safety signal in a pharmacovigilance database. Using Vigibase ® , the WHO Global Individual Case Safety Report (ICSR) database with over 14 million reports, we performed a disproportionality analysis including ICSRs until March 2017 only with age (≥ 18 years) and gender known. Cases were ICSRs with D (defined as reports registered under the HLT MedDRA terms “D mellitus” or “hyperglycemic conditions”) and non-cases all other ICSRs. Drug exposure to S (atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin) was identified using the ATC code C10AA, i.e. HMG CoA reductase inhibitors defined as “suspected” or “concomitant”. Strength of the link was quantified by crude Reporting Odds-Ratio (ROR) with 95% CI. P threshold was 0.05. Among the 9,372,588 ICSRs, 13,071 involved S plus D. Most of the patients were women (69.3%) with age mainly between 45 and 64 years (57.0%). The 3 most frequently involved S were atorvastatin (62.4%) followed by simvastatin (20.4%) and rosuvastatin (11.7%). A signal was found between D and S in general [ROR = 4.29 (4.21–4.38)] and all other S in particular. The higher ROR value was found with atorvastatin [7.27 (7.10–7.45)] followed by rosuvastatin [3.02 (2.86–3.17)] and the lowest with cerivastatin [1.38 (1.07–1.78)]. Sensibility analyses investigating ROR with one S after exclusion of cases registered with the other S show similar results. The present study found a clear signal of S for all S showing that the diabetogenic risk of S is a class property. This is the first study investigating the risk of D according to the different S in the context of real world.

Allergy-like immediate reactions with herbal medicines in children: A retrospective study using data from VigiBase®.

The use of herbal medicines in children and the general population is continually on the rise with an overall herbal lifetime and current use ranging between 0.8%-85.5% and 2.2%-8.9%, respectively. Although acute hypersensitivity reactions are generally considered to be rare, little knowledge exists on the frequency and type of these reactions especially in specific populations like children. To assess the patterns of acute hypersensitivity reactions to herbal medicines reported to the WHO global individual case safety report (ICSR) database VigiBase® in children. From the original VigiBase® extract for the time between 1968 and 2014, we included all reports with adverse drug reactions (ADR) associated with herbal medicines in children where WHO-ART reaction terms were indicative of acute hypersensitivity reactions. VigiBase® contained 2646 ICSRs with 14860 distinct adverse reactions reported in association with herbal medicine in children. Among those, 79 cases with 107 allergy-like reactions met our inclusion criteria. The most commonly reported WHO-ART terms were urticaria or rash/rash erythematous (59.8%), and allergic reaction (8.4%). The most frequently reported suspected herbal medicines were mixed herbal products (51.4%), Hedera helix (15.0%), and Echinacea purpurea (5.6%). Most frequent routes of administration were oral (75.9%), topical (8.9%), and rectal (3.8%). Over 30% of cases were reported in the age group from 7 to 12years. The majority of reports were received from Germany (29.1%), Thailand (21.5%), and Australia (11.4%). VigiBase® contains a considerable number of acute hypersensitivity reactions in children associated with herbal medicines, including life-threatening reactions such as anaphylactic shock.

Adverse drug reactions in Nigerian children: a retrospective review of reports submitted to the Nigerian Pharmacovigilance Centre from 2005 to 2012

Background: Adverse drug reactions (ADRs) in children recorded in national pharmacovigilance databases in high-income countries have been analysed. Nigeria has a population of 31 million children and became a member of the WHO Programme for International Drug Monitoring in 2004 since when it has been submitting reports of suspected ADRs to the WHO Global Individual Case Safety Report database, VigiBase.Objective: To gain information on reported ADRs in Nigerian children aged 0–17 years in VigiBase from 2005 to 2012.Methods: The data were analysed for annual reports, age and sex of patients, type of reporters, suspected drugs and adverse reactions. The most commonly reported ADRs and suspected drugs were ranked, and drugs associated with the fatalities were evaluated.Results: A total of 297 reports of 473 ADRs in 297 children were received from doctors, pharmacists, other health-care professionals and consumers during the period. ADRs were most frequently reported for anti-retrovirals (74, 24%), antibiotics (71, 23%) and anti-malarials (60, 20%). The most frequently reported ADRs were rash (15.2%), fever (10.3%) and pruritus (6.8%). Anti-infective agents were responsible for more than half of the reports. Twenty-one children (7%) died, eight from acute renal failure. Seven of the cases of acute renal failure were associated with contaminated paracetamol/diphenhydramine hydrochloride and herbal medicines used for teething problems. In the majority of cases, the products were contaminated with diethylene glycol. There were 14 cases of Stevens–Johnson syndrome, three of which were fatal.Conclusion: Anti-infective agents (antibiotics, anti-malarials and anti-retrovirals) were associated with a majority of the ADRs. Stevens–Johnson syndrome was the most frequent severe ADR. Some of the fatalities were associated with sub-standard and herbal medications.

Performance of Probabilistic Method to Detect Duplicate Individual Case Safety Reports

Individual case reports of suspected harm from medicines are fundamental for signal detection in postmarketing surveillance. Their effective analysis requires reliable data and one challenge is report duplication. These are multiple unlinked records describing the same suspected adverse drug reaction (ADR) in a particular patient. They distort statistical screening and can mislead clinical assessment. Many organisations rely on rule-based detection, but probabilistic record matching is an alternative. The aim of this study was to evaluate probabilistic record matching for duplicate detection, and to characterise the main sources of duplicate reports within each data set. vigiMatch™, a published probabilistic record matching algorithm, was applied to the WHO global individual case safety reports database, VigiBase(®), for reports submitted between 2000 and 2010. Reported drugs, ADRs, patient age, sex, country of origin, and date of onset were considered in the matching. Suspected duplicates for the UK, Denmark, and Spain were reviewed and classified by the respective national centre. This included evaluation to determine whether confirmed duplicates had already been identified by in-house, rule-based screening. Furthermore, each confirmed duplicate was classified with respect to the likely source of duplication. For each country, the proportions of suspected duplicates classified as confirmed duplicates, likely duplicates, otherwise related, and unrelated were obtained. The proportions of confirmed or likely duplicates that were not previously known by the national organisation were determined, and variations in the rates of suspected duplicates across subsets of reports were characterised. Overall, 2.5 % of the reports with sufficient information to be evaluated by vigiMatch were classified as suspected duplicates. The rates for the three countries considered in this study were 1.4 % (UK), 1.0 % (Denmark), and 0.7 % (Spain). Higher rates of suspected duplicates were observed for literature reports (11 %) and reports with fatal outcome (5 %), whereas a lower rate was observed for reports from consumers and non-health professionals (0.5 %). The predictive value for confirmed or likely duplicates among reports flagged as suspected duplicates by vigiMatch ranged from 86 % for the UK, to 64 % for Denmark and 33 % for Spain. The proportions of confirmed duplicates that were previously unknown to national centres ranged from 89 % for Spain, to 60 % for the UK and 38 % for Denmark, despite in-house duplicate detection processes in routine use. The proportion of unrelated cases among suspected duplicates were below 10 % for each national centre in the study. Probabilistic record matching, as implemented in vigiMatch, achieved good predictive value for confirmed or likely duplicates in each data source. Most of the false positives corresponded to otherwise related reports; less than 10 % were altogether unrelated. A substantial proportion of the correctly identified duplicates had not previously been detected by national centre activity. On one hand, vigiMatch highlighted duplicates that had been missed by rule-based methods, and on the other hand its lower total number of suspected duplicates to review improved the accuracy of manual review.

A Review of Safety Data from Spontaneous Reports on Marketed Products Containing Tramadol and Celecoxib: A Vigibase Descriptive Analysis

Background: The concomitant administration of opioids and non-steroidal anti-inflammatory drugs is used to manage pain in clinical practice, given their synergistic analgesic effect. Among their possible combinations, tramadol and celecoxib are routinely used. The aim of this study was to explore the safety profile of tramadol and celecoxib administered individually compared to their concomitant administration in clinical practice. Methods: Retrospective analysis of adverse-drug-reactions from the safety database Vigibase, The WHO global individual case safety report database system. A case was defined as an adverse-drug-reaction included in a report of Vigibase between January 2000 and March 2012. Three groups were studied: ‘tramadol-no-celecoxib’ (tramadol was only reported as suspected or interacting drug), ‘celecoxib-no-tramadol’ (celecoxib was only reported as suspected or interacting drug) and ‘celecoxib+tramadol’ (both drugs co-administered and reported as suspected or interacting drug). MedDRA dictionary was used to code adverse-drug-reactions. Reporting proportions were calculated as the number of adverse-drug reactions of a given type divided by the overall total number of reported adverse-drug-reaction in each drug-group. Results: Reporting proportions for global profile, and for each studied group of adverse-drug-reaction, were lower for the concomitant administration than for each individual drug, specifically for the drug (either tramadol or celecoxib) primary involved in the particular adverse-drug-reaction. Therefore, no safety signals were found for ‘gastrointestinal bleeding’ and ‘gastrointestinal signs and symptoms’; ‘cardiovascular’ and ‘cerebrovascular events’ (related to ‘ischemic and embolic-thrombotic events’); ‘renal’ and ‘renovascular’ events (including cardiac failure related events); neither for ‘central nervous system’ effects; neither for ‘respiratory depression’; ‘development of tolerance with repeated administration’ (including abuse/dependence/withdrawal reported events); ‘hepatic disorders (drug-related)’; ‘skin events’; and neither for the most frequent preferred terms: ‘nausea’, ‘vomiting’, ‘constipation’, ‘myocardial infarction’ and ‘hypertension’. Conclusion: Based on reporting proportions, no trend was observed to an increased risk for any specific potential safety concern when both tramadol and celecoxib, are administered concomitantly.

VigiGrade: A Tool to Identify Well-Documented Individual Case Reports and Highlight Systematic Data Quality Issues

BackgroundIndividual case safety reports of suspected harm from medicines are fundamental to post-marketing surveillance. Their value is directly proportional to the amount of clinically relevant information they include. To improve the quality of the data, communication between stakeholders is essential and can be facilitated by a simple score and visualisation of the results.ObjectiveThe objective of this study was to propose a measure of completeness and identify predictors of well-documented reports, globally.MethodsThe Uppsala Monitoring Centre has developed the vigiGrade completeness score to measure the amount of clinically relevant information in structured format, without reflecting whether the information establishes causality between the drug and adverse event. The vigiGrade completeness score (C) starts at 1 for reports with information on time-to-onset, age, sex, indication, outcome, report type, dose, country, primary reporter and comments. For each missing dimension, a penalty is detracted which varies with clinical relevance. We classified reports with C > 0.8 as well-documented and identified all such reports in the WHO global individual case safety report database, VigiBase, from 2007 to January 2012. We utilised odds ratios with statistical shrinkage to identify subgroups with unexpectedly high proportions of well-documented reports.ResultsAltogether, 430,000 (13 %) of the studied reports achieved C > 0.8 in VigiBase. For VigiBase as a whole, the median completeness was 0.41 with an interquartile range of 0.26–0.63. Two out of three well-documented reports come from Europe, and two out of three from physicians. Among the countries with more than 1,000 reports in total, the highest rate of well-documented reports is 65 % in Italy. Tunisia, Spain, Portugal, Croatia and Denmark each have rates above 50 %, and another 20 countries have rates above 30 %. On the whole, 24 % of the reports from physicians are well-documented compared with only 4 % for consumers/non-health professionals. Notably, Denmark and Norway have more than 50 % well-documented reports from consumers/non-health professionals and higher rates than for physicians. The rate of well-documented reports for the E2B format is 11 % compared with 22 % for the older INTDIS (International Drug Information System) format. However, for E2B reports entered via the WHO programme’s e-reporting system VigiFlow, the rate is 29 %.ConclusionOverall, only one report in eight provides the desired level of information, but much higher proportions are observed for individual countries. Physicians and e-reporting tools also generate greater proportions of well-documented reports overall. Reports from consumers/non-health professionals in specific regions have excellent quality, which illustrates their potential for the future. vigiGrade has already provided valuable information by highlighting data quality issues both in Italy and the USA.Electronic supplementary materialThe online version of this article (doi:10.1007/s40264-013-0131-x) contains supplementary material, which is available to authorized users.

Disease-related adverse events following non-live vaccines: Investigation of a newly described reporting bias through the analysis of the WHO Global ICSR Database, VigiBase

Due to a vaccine-specific reporting bias, it has been recently suggested that some non-live vaccines may be preferentially reported as the suspected cause of the disease or symptoms/signs related to the disease they should prevent.The aim of this study was to analyse the WHO Global Individual Case Safety Report (ICSR) Database, VigiBase, in order to explore this newly described reporting bias in greater detail and to verify whether it can generate potentially misleading signals of disproportionate reporting (SDRs).Vaccines reports entered into VigiBase between 1990 and 2011 were extracted. Twelve non-combined non-live vaccines were chosen for analysis. Two distinct groups of MedDRA preferred terms (PTs) per vaccine were selected on the basis of the disease-specificity. Twenty-four vaccine-events pairs were obtained and referred as “misleading combinations”. A descriptive analysis of the reports retrieved was performed. To verify whether a specific group of selected PTs was disproportionally reported in association with the vaccine representing the respective “misleading combination”, the reporting odds ratio (ROR) was calculated for each of the 24 vaccine-event pairs retrieved considering all the other vaccines as the background.A total of 627,165 reports were analysed. Among ICSRs containing a “misleading combination”, healthcare professionals were the most frequently noted (17%), though reporter type was unknown in 72% of the remaining reports. The reporting rate distribution of the 24 groups of PTs per vaccine included in the study showed that in 16 cases the highest rate was reached by the vaccine representing the respective “misleading combination”. The application of the ROR yielded 21 SDRs out of 24 combinations tested.Findings from this study support the existence of a vaccine-specific reporting bias. Since this phenomenon may result in potentially misleading SDRs, professionals involved in vaccine safety surveillance should also consider this bias during the validation of such disproportional associations.

Outlier removal to uncover patterns in adverse drug reaction surveillance – a simple unmasking strategy

This study aimed to develop an algorithm for uncovering associations masked by extreme reporting rates, characterize the occurrence of masking by influential outliers in two spontaneous reporting databases and evaluate the impact of outlier removal on disproportionality analysis. We propose an algorithm that identifies influential outliers and carries out parallel analysis after their omission. It considers masking of drugs as well as of adverse drug reactions (ADRs), uses a direct measure of the masking effect and makes no assumptions regarding the number of outliers per drug or ADR. The occurrence of masking is characterized in the WHO Global Individual Case Safety Report database, VigiBase and a regional collection of reports from Shanghai, China. For WHO-ART critical terms such as myocardial infarction, rhabdomyolysis and hypoglycaemia outlier removal led to a 25-50% increase in the number of Statistics of Disproportionate Reporting (SDR) and gains in time to detection of 1-2 years, while keeping the rate of spurious SDRs from the parallel analysis at 1%. Twenty-three per cent of VigiBase and 18% of Shanghai SRS reports listed an influential outlier. Twenty-seven per cent of the ADRs and 5% of the drugs in VigiBase, and 2% of the ADRs and 3% of the drugs in Shanghai SRS were involved in an outlier. The overall increase in the number of SDRs for both datasets was 3%. Masking by outliers has substantial impact on specific ADRs including, in VigiBase, rhabdomyolysis, myocardial infarction and hypoglycaemia. It is a local phenomenon involving a fair number of reports but yielding a limited number of additional SDRs.

Possible occurrence of paraesthesia in patients taking norethisterone: an analysis on the WHO Global Individual Case Reports database (VigiBase)

Objective: Progestogens are widely used to treat a large number of common conditions. We aimed to investigate a potential signal concerning progestogens and paraesthesia.Methods: Data were obtained from the VigiBase, the WHO Global Individual Case Safety Reports (ICSR) database, which is maintained by the Uppsala Monitoring Centre. We collected all suspected reports of paraesthesia associated with oral progestogens, reported between January 1972 and June 2012 and classified in VigiBase according to WHO-Adverse Reaction Terminology critical term ‘paraesthesia’. A disproportionality analysis was conducted using the Information Component (IC) and the standard deviation (IC025) as a measure.Results: Out of the total number of reports collected in the VigiBase (7,332,991), paraesthesia was associated with progestogen therapy in 920 reports, coming from 22 countries. Progestogens had the highest number of suspected reports (n = 864) than the other Anatomical Therapeutic Chemical (ATC) considered. Only norethisterone was associated with paraesthesia with positive IC (0.47) and IC025 (0.02).Conclusions: Norethisterone-associated paraesthesia appears to be a rare outcome. However, the widespread use of progestogens in medical practice suggests that it is a complaint that can affect a large number of women. Since paraesthesia can be caused by several drugs, clinicians should consider that it may be also caused by norethisterone.

335P - Dysphonia as a Previously Unreported Side Effect of Bevacizumab Treatment in Patients With Metastatic Breast Cancer

ABSTRACT Introduction Bevacizumab is a humanized monoclonal antibody directed against vascular endothelial growth factor A and has been approved for the treatment of several metastatic tumours. There is considerable heterogeneity in the response to treatment with bevacizumab, both in effectiveness and in toxicity. Here we describe a previously unreported adverse drug reaction (adr) in pts with MBC treated with bevacizumab. Methods In a teaching hospital in the Netherlands (from Sep 2009 to Jul 2011), 32 consecutive pts with MBC treated with chemotherapy and bevacizumab were registered in a retrospective database. TNM stage, comorbidities, concomitant medication, prior treatment for the primary tumour, date of metastatic disease, prior treatment for metastatic disease and toxicities were recorded. The WHO global individual case safety report database, VigiBase, contains summaries of suspected spontaneous case reports summated by health care professionals and pts to national pharmacovigilance centres. As of May 2010, VigiBase contained >5 million case reports. We searched the VigiBase extraction of Dec 2011 for dysphonia. Reporting odds ratios (ROR) were calculated for the occurrence of dysphonia compared with other adr for bevacizumab and paclitaxel. Results In total, 9/32 pts (28%) reported dysphonia during treatment with bevacizumab and 5/9 pts underwent ENT examination. In several pts marked oedema of the vocal cords and/or chronic laryngitis were found. As of Dec 2011, 6,880,361 reports were available in VigiBase, of which16,239 were related to dysphonia. For bevacizumab there were 51 reports for dysphonia and 46,041 reports for other adr. Corresponding figures for all other drugs were 22,108 reports for dysphonia and 25,151,628 reports for other adverse effects: ROR of 1.26 (95% CI: 0.95-1.66). For paclitaxel there were 45 reports for dysphonia and 85,988 reports for other adr. Corresponding figures for all other drugs were 22,114 reports for dysphonia and 25,111,681 reports for other adverse effects: ROR of 0.59 (95% CI: 0.44-0.80)meaning that the risk of angiooedema is significantly higher in bevacizumab users compared to paclitaxel users. Conclusion Dysphonia is a previously unreported side-effect in pts with MBC treated with bevacizumab and paclitaxel. Disclosure S.A. Radema: I am member of an advisory board for Roche. All other authors have declared no conflicts of interest.

Severe muscle symptoms with lipid-lowering agents may be confused with neurogenic claudication associated with spinal canal stenosis

Screening of the WHO global individual case safety report database (VigiBase) has recently identified case reports with HMG CoA reductase inhibitors and muscle symptoms co-reported with spinal stenosis. In some reports spinal stenosis appears to have been listed as a coincidental finding. To assess reports with sufficient information to ascertain if they suggested that there may have been diagnostic confusion between muscle symptoms attributable to HMG CoA reductase inhibitors with or without ezetimibe and symptoms of spinal stenosis. Reports were examined for patient demographics, past history, clinical and investigational findings, co-prescribed medicines and outcomes. Three case histories recorded details suggestive of diagnostic confusion between severe and disabling muscle symptoms affecting the lower limbs attributable to an HMG CoA reductase inhibitor with and without ezetimbe and symptoms of neurogenic claudication due to spinal stenosis. The statins were not discontinued promptly leading to prolonged morbidity. Serum creatine kinase levels (CK) were normal in two patients and not recorded for the third. The reports include two safety issues, firstly the need to consider HMG CoA reductase inhibitors as a cause of severe lower limb muscle symptoms even in the presence of spinal stenosis and normal CK levels and the second, the need to measure serum creatine kinase when these symptoms occur to detect progression of myopathy and potentially serious outcomes.