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While antipsychotic-induced weight gain has been widely described in adults, it has yet to be better characterized in children and adolescents.The aim of this study was to assess antipsychotic-induced weight-gain reporting in children and adolescents as compared to adults, and according to the type of antipsychotic.The study is an observational, case-non-case study using individual case safety reports from the WHO global pharmacovigilance database VigiBaseAmong 282,224 antipsychotic-related spontaneous reports included in this analysis, we identified 16,881 (6.0%) weight-gain cases. Disproportionality in weight-gain reporting was found in children (adjusted ROR (aROR) 3.6; 95% CI 3.3-3.8) and in adolescents (aROR 2.3; 95% CI 2.2-2.4) compared to adults. Use of risperidone was associated with the highest increase in weight-gain reporting in children (aROR 4.9; 95% CI 3.9-6.1) and adolescents (aROR 3.6; 95% CI 3.1-4.1).Compared to adults, weight-gain reporting with antipsychotics was disproportionally higher in the pediatric population, especially in children under 12 years of age. Considering the impact of weight gain on global morbidity and mortality, physicians should closely monitor weight gain in young patients, especially children on risperidone.

Aims Adverse drug reactions (ADRs) are important causes of death. However, the main involved drugs are relatively unknown. The present study was performed to characterise death-related drugs recorded in a large pharmacovigilance database during the last 10 years. Methods A retrospective analysis of VigiBase, the World Health Organization pharmacovigilance database, was performed investigating fatal ADRs registered between 1 January 2010 and 31 December 2019 in male and female patients aged ≥18 years and reported by physicians. Analyses were descriptive investigating age, sex and suspected drugs. Differences in reporting according to sex, age and continents were investigated using disproportionality analysis with calculation of reporting odds ratio and its 95% confidence interval. Results Among the 23 millions ADRs recorded in VigiBase, 3 250 967 were included with 43 685 fatal. They were reported mainly in patients older than 75 years. The 3 most frequently involved drug classes were antineoplastic/immunomodulating drugs followed by nervous system and cardiac drugs. The top 3 individual drugs were denosumab, lenalidomide and thalidomide with marked differences according to age, sex, continents and countries. The risk of reporting fatal ADRs was higher in males, in the Americas and in patients ≥65 years. Conclusion Fatal ADRs registered in a large pharmacovigilance database during the last 10 years correspond to just over 1% of the total number of ADRs. They occurred more in males, after 65 years and with antineoplastic/immunomodulating drugs in general. Our study also highlighted, for the first time, important differences in fatal ADRs between continents and countries.

Hearing loss can have a negative impact on communication, with significant vocational, educational, and social consequences. Drugs are one of the causes of hearing loss in children. The objective of our study was to describe drug-induced hearing loss in the pediatric population. Reports of hearing loss from 1985 to December 2019 in the pediatric population (< 18 years) were extracted from the French PharmacoVigilance Database (FPVD). We performed a retrospective and descriptive analysis of adverse drug reaction (ADR) reports. A total of 70 ADR reports were identified among the 51,216 reports registered in the FPVD, 37 involving adolescents (12–17 years, 52.9%), 28 children (2–11 years, 40.0%), and 5 infants (28 days–23 months, 7.1%). Overall, 40 reports (57.1%) involved girls. A total of 56 reports (80.0%) were “serious.” The most frequent hearing disorders were deafness (n = 31, 44.3%) and hypoacusis (n = 22, 31.4%). Suspected drugs (ATC 5th level) were amikacin (n = 11, 15.7%), cisplatin (n = 11, 15.7%), doxorubicin (n = 4, 5.7%), vincristine (n = 4, 5.7%), clarithromycin (n = 4, 5.7%), ceftriaxone (n = 3, 4.3%), isotretinoin (n = 3, 4.3%), and vancomycin (n = 3, 4.3%). This study shows that about three out of four cases of drug-induced hearing loss in the pediatric population were “serious”. It also underlines the under-reporting of these ADRs and the importance of strengthening hearing monitoring in children during and long after drug exposure.

Several papers have described hyponatraemia with tramadol. However, in most reports, several confounding factors can be found. We used the WHO pharmacovigilance database (VigiBase®) to investigate if tramadol alone could be associated with hyponatraemia. All 1992-2019 ICSRs (individual case safety reports) with the preferred term (PT) "hyponatraemia" and tramadol were included. Two disproportionality analyses were performed: (1) after inclusion of all reports, and (2) after exclusion of concomitant hyponatraemic drugs. Results are expressed as reporting odds ratios (ROR; 95% CI) and information component (IC). Of 19 747 604 ICSRs, 225 575 were included. A significant association was found between tramadol use and reports of hyponatraemia (ROR = 1.49 [1.39-1.60], IC = 0.57 [IC025 = 0.47]). After exclusion of hyponatraemic drugs, the previously found association disappeared. The study failed to find any pharmacovigilance signal of hyponatraemia with tramadol alone. We suggest that reports of hyponatraemia with tramadol can be explained principally by other underlying causes of hyponatraemia, especially other concomitant hyponatraemic drugs.

Introduction : La notification spontanee des effets indesirables medicamenteux (EIMs) est un des piliers de la surveillance en post-AMM. Une des principales limites de cette derniere concerne la qualite de l’information de ces notifications.L’objectif principal de cette etude etait d’evaluer l’informativite des observations d’EIMs enregistrees dans la Base Nationale de PharmacoVigilance (BNPV) a partir des declarations des medecins generalistes (MGs). L’objectif secondaire etait d’identifier les facteurs associes a une declaration complete.Methode : Toutes les observations d’EIMs declarees en France, en 2015, par les MGs ont ete extraites. Apres analyse du contenu de ces declarations (EIM, date d’apparition, description clinique, medicament impute, etc.), l’informativite etait analysee a partir de plusieurs criteres obligatoires (âge, genre, EIM et medicament(s) suspecte(s)) et facultatifs (antecedents medicaux, medicaments concomitants, evolution de la symptomatologie et examens complementaires) ; cela a permis de classifier les declarations en « bien renseignee », « moyennement renseignee » et « mal renseignee ».Resultats : Durant l’annee 2015, la BNPV comportait 3 020 declarations realisees par les MGs francais. Seulement 16,4 % des declarations de pharmacovigilance rapportees etaient « bien renseignees ». Les criteres les moins bien documentes etaient les medicaments concomitants (41,4 %) et les examens complementaires (37,4 %). Les observations completes etaient associees a la gravite des cas (OR = 3,02 [IC 95 % 2,44 ; 3,23], p

In adults, statins safety profile is well known. However, literature data on their adverse drug reactions (ADRs) remain scarce in children in real-life setting. In order to better characterize ADRs related to 'real-life' use of statins in children, we reviewed statin-related ADRs recorded in the World Health Organization (WHO) global database of individual case safety reports (ICSRs), VigiBase. Methods. Individual case safety reports (ICSRs) in children (2-11 years) and adolescents (12-17 years) associated with statins from January 1, 1987, to July 18, 2017, were extracted from VigiBase. Characteristics of ICSRs, type of ADRs according to MedDRA classification (SOC and PT), and ICSR seriousness were described using SAS 9.4. A total of 311 ICSRs were identified for 8 statins with 712 ADRs. Musculoskeletal disorders (n = 85, 27.3%) were the first registered ADRs followed by general disorders (n = 67, 21.5%; mainly asthenia and pain). More than 1 out of 5 ADRs were 'injury, poisoning and procedural complications' (n = 67), mainly accidental or intentional exposures (n = 44, 14.1%), overdoses (n = 14, 4.5%), or off-label use (n = 11, 3.5%). Overall, 133 (42.8%) reports were 'serious', including 11 deaths. Deaths mainly involved adolescents with intentional overdose and completed suicide with other associated drugs in 75% of reports. Our study identified rare but serious safety issues (rhabdomyolysis, myalgia, and hepatocellular injury). These ADRs can impact quality of life or lead to life-threatening complications in children. Our results should be supplemented with other data sources. Spontaneous statin ADR reports in children to pharmacovigilance networks must be promoted.

Summary Introduction In France since 2011, report of adverse drug reactions (ADRs) has been extended to patients (and patients’ associations) who can declare directly ADRs to their regional pharmacovigilance centre. In pharmacovigilance, informativeness of ADRs reports is important to improve signal's detection. The present study was performed to compare the quality of patients’, physicians and community pharmacists’ reports. Methods We performed a retrospective study investigating the quality of patients’, physicians and community pharmacies’ ADRs reported to Toulouse University PharmacoVigilance Centre (TUPVC) from January 2014 to June 2017. We used mandatory and non-mandatory criteria, as defined by European Medicines Agency. Reports’ quality was defined as “satisfactory” when more than 90% of items were completed. We also compared reports’ quality according to ADRs seriousness and the used reporting tools (email or the mobile app VigiBip®). Results The number of reports to TUPVC increased between 2014 and 2016 (+51%) for patients and remained stable for pharmacists and physicians. According to the mandatory criteria, quality of the investigated reports was “satisfactory” (more than 90% of the items filled) whatever the reporter and without significant differences between reporters. For the non-mandatory criteria, clinical description of ADRs and ADRs’ outcome were only filled over 90%. Significant differences were observed between the different reporters: community pharmacists informed better clinical description, ADR outcome and concomitant drugs versus both patients and physicians. Physicians informed better medical history and biological data whereas patients informed medical history and other aetiologies better than pharmacists and clinical description of ADRs better than physicians. Conclusion The present study failed to show differences between pharmacies’, physicians’ and patients’ ADRs reports, for the mandatory criteria. However, significant differences were found for non-mandatory criteria with drug data more filled by pharmacists and medical ones more by physicians and patients.

Some reports have raised concerns regarding a potential risk of cataracts associated with statins. However, clinical and observational studies evaluating the risk led to conflicting results. We assessed whether lipid-lowering drugs (LLD) use is associated with an increased risk of cataract using the WHO's Individual Case Safety Reports database, VigiBase® . We performed a disproportionality analysis with all reports between 1/1/1988 and 12/31/2018 to measure the reporting risk of 'cataract' in patients ≥45 years. Primary analysis compared LLD users to non-users. To mitigate some potential confounding bias, we performed several sensitivity analyses excluding reports (i) with an association of at least two LLD, (ii) with antidiabetic and glucocorticoids and (iii) with lovastatin. We also analyzed the data according to the different classes of age limiting the period of study to years 2002-2012. We identified 14 664 reports of cataract (3 049 in LLD users, 66% women, 66 ± 20 years). Statins (84%, atorvastatin, simvastatin, rosuvastatin and lovastatin) were mostly reported, followed by fibrates (5.7%), nicotinic acid (3%), bile acid sequestrants (2%), herbal cholesterol and triglyceride reducers (2%) and others (ezetimibe, PCSK9 inhibitors, 15%). LLD users were associated with a greater risk of reports than non-users (ROR 2.47, 95% CI 2.37-2.57). This association was also found for statins in general, fibrates, bile sequestrants, nicotinic acid, herbal drugs and others. Similar trends were observed in sensitivity analyses (except for fibrates and nicotinic acid after exclusion of reports with at least two LLD or in older patients ≥75 years). Using a large real-life database (>18.5 million reports), we found a signal of cataract for LLD as a whole and statins, bile sequestrants and herbal drugs in particular. The signal disappeared for fibrates and nicotinic acid in older patients. No definite conclusions can be made for ezetimibe or PCSK9 inhibitors (evolocumab and alirocumab). This suggests that a decrease in cholesterol could be important in the pathophysiology of cataract in patients exposed to the main LLD.

Introduction La fasciite a eosinophiles (FE) est une connectivite fibrosante rare dont les etiologies et la physiopathologie sont peu connues. De nombreuses associations medicamenteuses imputables ont ete decrites. Nous rapportons ici une etude de pharmacovigilance dont l’objectif etait d’etudier la disproportionnalite de rapports et de preciser les caracteristiques des FE induites par des medicaments. Materiel et methodes Cette etude est une analyse des cas de FE de la base de donnees de l’OMS, Vigibase et du reseau Francais de pharmacovigilance. Nous avons realise une premiere etude observationnelle retrospective avec analyse de disproportionnalite dans Vigibase pour identifier les associations medicamenteuses significatives et une seconde dans la base de donnees de pharmacovigilance francaise pour caracteriser les FE induites par des medicaments. Resultats Cent-une FE ont ete identifiees dans Vigibase et incluses dans l’analyse. Sur les 85 medicaments imputables rapportes, 10 l’etaient dans au moins 3 cas differents et ont ete inclus. Les resultats complets sont presentes en Figure 1. L’analyse a identifie 9 medicaments presentant une disproportionnalite significative: le nivolumab (ROR = 104,25 ; 95 % IC [61,0–175,6]), le pembrolizumab (ROR = 39,80 ; 95 % IC [14,64–108,19]), l’ipilimumab (ROR = 35,12 ; 95 % IC [11,13–110,78]), l’atorvastatine (ROR= 9,84 ; 95 % IC [4,0–24,18]), la simvastatine (ROR = 9,47 ; 95 % IC [3,0–29,86]), les vaccins anti-HPV (ROR = 8,41 ; 95 % CI [3,09–22,85]), l’esomeprazole (ROR = 9,62 ; 95 % IC [3,54–26,16]), l’acide zoledronique (ROR = 12,89 ; 95 % IC [4,09–40,67] et le carbidopa;levodopa (ROR = 22,11 ; 95 % IC [7,01–69,73]). L’analyse par classe medicamenteuse a confirme une association significative pour 6 d’entre elles: les inhibiteurs de checkpoint (22 cas, ROR = 75,32 ; 95 % IC [46,95–120,81]), les statines (12 cas, ROR = 10,83 ; 95 % IC [5,93-19,78]), les vaccins (ROR = 3.40 ; 95 % CI [1.49–7.75]), les biphosphonates (ROR = 11,71 ; 95 % IC [4,31–31,84]), les inhibiteurs de pompe a proton (ROR = 5,72 ; 95 % IC [2,33–14,06]), et les agonistes dopaminergiques (ROR = 16,25 ; 95 % IC [5,15–51,27]). Les anti-TNF alpha, bien que rapportes dans 9 cas, ne montraient pas de disproportionnalite significative (ROR = 1,7 ; 95 % IC [0,8–3,3]). Au sein de la base de donnee francaise de pharmacovigilance, 13 cas ont ete identifies, associes a 16 medicaments imputables. Ces cas presentaient une bonne reponse aux corticoides, une hypereosinophilie importante (mediane 1627/mm3 IIQ [1305–2174]) et une proportion inhabituelle (30,8 %) en comparaison d’autres series d’atteinte de la tete et du cou. Discussion Cette etude permet d’identifier des medicaments possiblement imputables dans la survenue d’une fasciite a eosinophiles, notamment les inhibiteurs de checkpoint et les statines. Les cas pharmaco-induits semblent se presenter avec une proportion plus importante d’atteinte de la tete et du cou et une hypereosinophilie importante.

Resume Objectif L’objectif etait d’evaluer la satisfaction des MG ayant participe a un reseau d’aide a la declaration des effets indesirables medicamenteux (EIM), nomme PharmacoMIP-MG via un assistant de recherche clinique (ARC) se deplacant a leur cabinet, en region Midi-Pyrenees. Methode Un questionnaire a ete adresse aux 59 MG du reseau PharmacoMIP-MG ayant declare un EIM, sur 117, en novembre 2016. Resultats Au total, 44 MG ont repondu au questionnaire (moyenne d’âge 44 ans ± 11 ans ; 48 % de femmes). La note de satisfaction etait en moyenne de 9 sur 10 (ET ± 1,06). L’aide personnalisee d’un ARC etait tres appreciee (n = 39 ; 89 %) et permettait un gain de temps (n = 35 ; 90 %). Parmi les 95 % (n = 42) des MG affirmant vouloir continuer a declarer les EIM a l’avenir, 83 % (n = 35) pensaient continuer a declarer par l’intermediaire de l’ARC, les autres affirmaient declarer directement au centre regional de pharmacovigilance, principalement via des outils numeriques en ligne. Conclusion Les MG repondants etaient nombreux et globalement tres satisfaits du reseau et de son fonctionnement, corroborant l’augmentation observee du nombre de declaration d’EIM sur la region depuis sa mise en œuvre.

Drug monitoring and safety is a daily challenge for clinicians. Pharmacovigilance is the study of adverse-drug reactions and iatrogenic diseases. If not always life-threatening, these reactions can impair patient’s overall and oral well-being and quality of life. Methods for quantifying the risk of drug use are numerous, ranging from experimental pharmacology and toxicology observations to the results of clinical trials and pharmacoepidemiology data. This chapter also underlines the importance of pharmacogenetics and pharmacogenomics approaches.

Summary Introduction Since 2015, Toulouse University PharmacoVigilance Center (TUPVC) set up a pharmacovigilance (PV) general practitioner (GP) network, called PharmacoMIP-MG. A clinical research assistant (CRA) moves to the office of GPs included in the PharmacoMIP-MG network (PMIP-GPs). There, he collects the adverse drug reaction (ADR) reports and drug-related questions. This additional support is not available to GPs not included in the PV network (NoPMIP-GPs) who have to ask drug questions spontaneously to the TUPVC. Objective The objective of this study was to compare the number and characteristics of drug questions between PMIP-GPs and NoPMIP-GPs. Methods All questions asked by GPs to the TUPVC from 01 Jan 2015 to 31 Dec 2017 were reviewed. Questions were classified into two groups: “general” and “related to a patient”. The “related to a patient” category was divided in three subgroups: “ADRs”, Drug-Drug Interactions and “Drug Management”. Drugs were classified according to anatomical therapeutic chemical (ATC) classification. For comparisons, Wilcoxon test, Chi2 test or Fisher test were used. Results During the study period, the CRA collected 293 questions from the 165 PMIP-GPs. TUPVC received 333 questions asked spontaneously by the 3400 NoPMIP-GPs. PMIP-GPs asked significantly 3 times more questions than NoPMIP-GPs. Most of the GP questions were classified in the “related to a patient” category (74.9%). When we compared the proportion of “related to a patient” to “general” questions, there was no statistically significant difference between PMIP-GPs and NoPMIP-GPs. PMIP-GPs asked more questions about “ADRs”, but less on “Drug Management” and or “Drug-Drug Interactions”. The drugs most frequently involved were amiodarone, rivaroxaban and levothyroxine. Conclusion This is the first study about GPs’ drug-related questions asked to a PV center. We found that an organization, such as a CRA-GP “face to face” visit, increased the number of drug questions. This kind of organization should be developed in order to improve independent drug information outreach.

Remdesivir is a nucleotide analog prodrug with antiviral activity against a broad spectrum of human coronavirus in cell cultures and mouse models including severe acute respiratory syndrome-associated coronavirus 2. Recently, the Food and Drug Agency (FDA) and the European Medicines Agency (EMA) recommended remdesivir for the treatment of patients hospitalized with severe coronavirus disease 2019 (COVID-19) infection.1,2 In the remdesivir clinical development program, some cases have raised concerns regarding potential hepatobiliary disorders associated with remdesivir, including in healthy volunteers and patients with COVID-19.3 In cohort studies of patients hospitalized for severe COVID-19 who were treated with compassionate-use remdesivir, elevated hepatic enzymes were the most frequent adverse drug reaction reported.4,5 In the first randomized, double-blind, placebo-controlled clinical trial assessing the effect of intravenous remdesivir in adults admitted to hospital with severe COVID-19 (n = 237), a higher proportion of remdesivir recipients than placebo recipients had dosing prematurely stopped by the investigators because of adverse events including aminotransferase or bilirubin increases (3 versus 0).6 Although there is no signal from the available data of severe hepatotoxicity or drug-induced liver injury in clinical trials, the number of patients exposed to remdesivir was too limited. Therefore, there is an urgent need to investigate the hepatic safety profile associated with remdesivir in COVID-19 patients.

Ivermectin Toxicity and Nonsense Mutations Encephalopathy and coma developed in a 13-year-old boy shortly after he received a single dose of ivermectin to prevent scabies infection. ABCB1 sequencin...

Objectives Neurological adverse effects (NAEs) induced by biotherapies have been reported in the literature mainly in adult patients with inflammatory bowel disease (IBD), rheumatic diseases, or psoriasis. There are scant data in children. Aims of this study are to report and describe noninfective NAE associated with anti-TNFα antibodies in pediatric IBD, and to evaluate their incidence. Methods We retrospectively collected all reports of NAE in pediatric IBD treated with anti-TNFα antibodies recorded in the French Pharmacovigilance Database. To estimate the national incidence of NAEs, we extrapolated data from the French regional inception population-based cohort EPIMAD. Results Between 2000 and 2018, 231 adverse events in pediatric IBD exposed to anti-TNFα antibodies were reported to this Database. Seventeen NAEs (7.36%) were collected: 8 severe NAE (1 demyelinating neuropathy, 1 optic neuritis, 1 acute transverse myelitis, 1 polyradiculoneuritis, 1 sensorineural hearing loss, 1 seizure, 1 stroke, and 1 glioma), 7 moderate NAE (headaches), and 2 neuropsychic events. The median delay between anti-TNFα start and NAE occurrence was 6 months (range: 13 days to 26 months). In 10 of 17 patients, anti-TNFα antibodies were stopped. Nine of 17 patients had a complete resolution (including 2 severe NAE) and 8 of 17 a partial resolution (including 6 severe NAE). We estimate the incidence of severe NAE in pediatric IBD treated with anti-TNFα antibodies at 1 case for 10,000 patients-year in France. Conclusions NAE associated with anti-TNFα antibodies in pediatric IBD are rare. In severe NAE, we recommend to discontinue anti-TNFα therapy and to consider alternative treatment.

Spontaneous reporting remains one of the cornerstones of post-marketing drug safety surveillance. One of its main limitations is a lack of completeness.The main aim of this study was to assess the completeness of pharmacovigilance reports sent by general practitioners (GPs) to regional pharmacovigilance centers (RPC) reported in the French pharmacovigilance database (FPVD). Secondary aim was to identify factors associated with complete reports.All adverse drugs reactions (ADRs) sent by GPs in France in 2015 were analyzed. According to information provided in ADR reports (ADR, date of occurrence, clinical description, drugs suspected, etc.), completeness was analyzed from#8220;mandatory#8221; criteria (age, gender, ADR#160;and suspected drug(s)) and#8220;non-mandatory#8221; criteria (medical history, concomitant drugs, symptoms evolution and complementary exams) and classified#160;as#160;#8220;well-documented#8221;,#8220;slightly-documented#8221; or#8220;poorly-documented#8221;.In 2015, the FPVD contained 3,020 ADR reports realized by GPs. Only 16.4% of these reports were classified as#8220;well-documented#8221;, in accordance with study criteria. The most poorly documented items were concomitant drugs (41.4%) and complementary exams (37.4%). An association between a#8220;well-documented#8221; ADR report and its#8220;seriousness#8221; (OR = 3,02 [95%#160;CI#160;2,44; 3,23], P#160;lt;#160;10#8211;3) and elderly compared to adults (OR#160;=#160;1,76 [95% CI 1,42; 2,18], P#160;lt;#160;10#8211;3) or children (OR = 4,59 [95% CI 2,51; 8,39], P#160;lt;#160;10#8211;3).Our study shows that only one out of six ADR reports was#8220;well-documented#8221;. It appears to be important to promote pharmacovigilance to improve completeness of ADR reports.

Three studies have suggested a potential positive association between the use of tamoxifen in breast cancer and Parkinsonism, mainly after long-term exposure. To explore this potential signal, we performed a case/non-case study using the World Health Organization Global Individual Case Safety Reports (ICSRs) database, VigiBase® between 1979 and 2018. Among women ≥ 55 years, we measured the risk of reporting “Parkinsonism” compared with all other adverse drug reactions [as a reporting odds ratio (ROR 95% CI)] for tamoxifen compared to all other drugs or aromatase inhibitors. During the study period, 356 ICSRs of Parkinsonism reported with tamoxifen were identified. We failed to find a positive association between tamoxifen exposure and Parkinsonism in comparison with exposure to other drugs (ROR = 0.79; 95% CI 0.71–0.88) or aromatase inhibitors (ROR = 0.39; 95% CI 0.33–0.46). This study did not find evidence for Parkinsonism associated with tamoxifen.

The characteristics of pharmacology and drug evaluation in the pediatric age group highlight the necessity for the pharmacovigilance community to adjust to the specific features of children. At the time of marketing a medicinal product intended for children, the product's safety profile is sometimes less well known than for adults due to fewer or small sample clinical trials. Furthermore, the frequent off-labeled drug use, the use of unsuitable dosage forms and the need for continuous dose adjustments increase the risk of medication errors and thus lead to avoidable adverse drug reactions (ADRs). The occurrence of child-specific ADRs (such as growth disorders) or ADRs more commonly occurring in children than in adults make it necessary to monitor the safety of child-specific drugs. Pediatric pharmacovigilance includes also the consequences of in utero exposure, whether manifestations are present from birth or occur in early childhood (such as neurodevelopmental disorders). The incidence of ADRs varies with age, setting of medical care (in- or out-patients, pediatric specialties) and by country in which the study was carried out. The drugs most frequently reported with ADRs are those most commonly used in the pediatric age group, i.e. antibiotics and vaccines. The ADRs most often reported are skin, neurological and general disorders. As in adults, spontaneous notification is essential to generate alerts and child-specific pharmacoepidemiological studies are necessary and should be developed.

Objectives To examine and compare the experiences and attitudes of primary care physicians in three different regulatory environments (United States, Canada, and France) towards interactions with pharmaceutical sales representatives, particularly their perspectives on safety information provision and self-reported influences on prescribing. Methods We recruited primary care physicians for 12 focus groups in Montreal, Sacramento, Toulouse and Vancouver. A thematic analysis of the interview data followed a five-stage framework analysis approach. Results Fifty-seven family physicians (19 women, 38 men) participated. Physicians expected a commercial bias and generally considered themselves to be immune from influence. They also appreciated the exchange and the information on new drugs. Across all sites, physicians expressed concern about missing harm information; however, attitudes to increased regulation of sales visits in France and the US were generally negative. A common solution to inadequate harm information was to seek further commercially sourced information. Physicians at all sites also expressed sensitivity to critiques from medical students and residents about promotional interactions. Conclusions Physicians have contradictory views on the inadequate harm information received from sales representatives, linked to their lack of awareness of the drugs’ safety profiles. Commonly used strategies to mitigate information bias are unlikely to be effective. Alternate information sources to inform prescribing decisions, and changes in the way that physicians and sales representatives interact are needed.

The use of mobile apps is increasing in medicine. In pharmacovigilance, mobile apps may help to increase adverse drug reaction reporting and improve the communication of safety issues. The Toulouse University Pharmacovigilance Center has developed VigiBIP®, a free smartphone app available on Android and Apple stores, for reporting adverse drug reactions and requesting drug safety information. The present study was performed to compare the main characteristics of spontaneous adverse drug reaction reports received through VigiBIP® with classical methods of reporting (phone, e-mail, fax, letter, website) during 25 months (2015–17). Using the Chi squared test, we compared the type of reporter, adverse drug reaction seriousness, drugs involved and reported ADRs using VigiBIP® and classical methods of reporting A total of 4102 reports were received by the Toulouse University Pharmacovigilance Center, including 4.7% through VigiBip®. Patients’ reports were significantly more frequent with VigiBip® (6.7%) than with classical methods (3.4%) [p = 0.01]. Reported adverse drug reactions and involved drugs differed according to the method of reporting used. Our study shows that a mobile app is an additional tool used in pharmacovigilance. Types of reporters and adverse drug reactions in VigiBIP were different to those seen in classical methods of reporting.

Objectives In recent clinical trials some cardiac arrhythmias were reported with use of remdesivir for COVID-19. To address this safety concern, we investigated whether use of remdesivir for COVID-19 is associated with an increased risk of bradycardia. Methods Using VigiBase®, the World Health Organization Global Individual Case Safety Reports database, we compared the cases of bradycardia reported in COVID-19 patients exposed to remdesivir with those reported in COVID-19 patients exposed to hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids. All reports of patients with COVID-19 registered up to the 23th of September 2020 were included. We conducted disproportionality analyses allowing the estimation of reporting odds ratios (RORs) with 95% Confident Intervals (95% CI). Results We found 302 cardiac effects including 94 bradycardia (31%) among the 2,603 reports with remdesivir prescribed in COVID-19 patients. Most of reports were serious (75, 80%) and in 16 reports (17%) evolution was fatal. Compared with hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids, the use of remdesivir was associated with an increased risk of reporting bradycardia (ROR 1.65; 95% CI 1.23, 2.22). Consistent results were observed in other sensitivity analyses. Conclusions This post-marketing study in a real-world setting suggests that the use of remdesivir is significantly associated with an increased risk of reporting bradycardia and serious bradycardia when compared with the use of with hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids. This result is in line with pharmacodynamic properties of the remdesivir.

Antipsychotic drugs possess side atropinic (anticholinergic) properties that may induce several adverse drug reactions (ADRs), such as memory loss or cognitive impairment. The aim of the present study was investigating anticholinergic burden in patients treated with antipsychotic drugs. All ADR reports including at least one antipsychotic and registered between 2000 and 2015 in the Midi-Pyrenees PharmacoVigilance Database were extracted and analyzed using the Anticholinergic Duran's list. The primary objective of this cross-sectional study was to calculate anticholinergic burden in antipsychotic-treated patients; the secondary one was to investigate associated factors. Among the 1,948 reports, the average number of atropinic drugs per report was 2.4 +/- 1.4. At least one atropinic drug was found in 59.4% of reports (1,158), in addition to antipsychotic drugs. The mean anticholinergic burden per report was 3.9 +/- 2.9. A value >/= 3 was found in 61.7% of the reports. A significant association between anticholinergic burden, age and male gender of patients was found. The mean value of anticholinergic burden remained stable during the study period. This study showed high values of anticholinergic burden in patients receiving antipsychotics. Thus, considering the potential noxious clinical impact of atropinic properties on cognitive functions, an appropriate approach should be to reduce prescription of antipsychotics with a high anticholinergic burden but also coprescription of other frequently associated atropinic drugs, like antiparkinsonians, H1 antihistamines or imipraminic antidepressants in these patients.

Studies that evaluate the safety of non-prescription drugs in children remain scarce. The aim of the present study was to compare adverse drug reactions (ADRs) due to prescription versus non-prescription drugs in children. We conducted a retrospective analysis of ADR notifications for a pediatric population (aged

The potential favorizing role of drugs in sleep apnea syndrome (SAS) is unknown. This study investigates drugs associated with SAS in a pharmacovigilance database. SAS recorded as adverse drug reactions (ADRs) in VigiBase® , the WHO pharmacovigilance database (more than 11 million reports), from 1978 to 2015 was selected. The risk of SAS reports was estimated using the case-noncase method, with cases being SAS and noncases all other recorded ADRs. During this 37-year period, 3325 ADRs including the word SAS were registered (0.05% of the database). Mean age was 51.2 ± 16.9 years with 52% men. ADRs were 'serious' in around 82% of cases. The case-noncase study found an association between SAS and exposition with sodium oxybate, rofecoxib, quetiapine, and clozapine for individual drugs and coxibs, antipsychotics, benzodiazepines, and opium alkaloids for drug classes. The potential role of other drugs is discussed. This study suggests that SAS can be associated with some drugs (mainly psychotropics) that are able to reveal or aggravate such a disease. Physicians should take into account the role of drugs in the etiological appraisal and management of SAS.

International audience; BACKGROUND:Several clusters of encephalopathy occurred after the market change from Holoxan® (ifosfamide lyophilized powder) to Ifosfamide EG® (liquid formulation) and justified a formal survey in 2015. In June 2016, the regulatory authority decided to apply a precautionary measure in reducing the shelf life of Ifosfamide EG® at 7 months. One-year study from spontaneous reports lead to suspect a potential residual risk. Due to the many limitations associated with spontaneous notifications, we performed a multicentric observational study, aiming to better explore this pharmacovigilance signal.METHODS:We performed a case-control study in pediatric oncology Departments of 25 university hospitals between July 1st, 2016 and July 1st, 2018. All children (

International audience; Purpose: Hepatotoxicity associated with methylprednisolone (MP) is rarely reported in the literature. The aim of the present study was to review the characteristics of acute liver injury associated with intravenous (IV) or oral MP registered in the French pharmacovigilance database (FPD).Methods: All cases with MP coded as suspected, concomitant, or interacting drug associated with liver injury as the adverse effect reported up to May 2016 were extracted from the FPD. Cases were identified using the "Drug related hepatic disorders" Standard Medical Query.Results: A total of 97 cases of liver injury associated with MP were analysed; 58.8% were women and the median age was 46 years (range: 1-91). MP was used for an autoimmune disease in 47.6% of cases including 26 cases of multiple sclerosis, and was IV in 79.4% of cases. Nearly three-quarters of patients (73,2%) had a hepatocellular type of injury, the severity of which was mainly mild (45%) or moderate (31%). Most patients (92%) spontaneously and fully recovered within a mean 38.4 days. A rechallenge using the IV route was performed in 13 patients and for 10 (76.9%) this was positive (the initial type of injury was hepatocellular for all these cases). Regarding IV route of administration (n=77), MP was coded as the only suspected drug in 22% of cases.Discussion: The results suggest that IV MP causality should be considered in case of acute liver injury while data for oral MP is insufficient; systematic liver monitoring for high-dose IV MP may be recommended.

Spontaneous reporting of adverse drug reactions (ADRs) remains the cornerstone of postmarketing drug safety surveillance (pharmacovigilance); however, one of its main limitations is incomplete data, thus limiting conclusions about causality assessment.The primary aim of this study was to assess the completeness of ADR reports sent by general practitioners (GPs) to regional pharmacovigilance centres and the secondary objective was to identify factors associated with complete ADR reports.All ADR reports sent by GPs to the Midi-Pyrénées Regional Pharmacovigilance Center (Toulouse, France) from 1 January 2010 to 31 December 2013 were reviewed. Healthcare professionals and patients can forward an ADR using either an online form through the Pharmacology Information Bulletin website ( http://www.bip31.fr ) or 'traditional' ADR reports (i.e. email, letter or fax). According to information provided in ADR reports (i.e. patient identification, ADR, date of occurrence, clinical description, drugs, etc.), reports were classified into three groups: 'well-documented', 'slightly documented' or 'poorly documented'. A multivariate logistic regression was performed to investigate potential factors associated with a 'well-documented' ADR report.During the study period, 613 ADR reports were analysed. Among these reports, only 12.7 % were classified as 'well-documented', 68.5 % as 'slightly documented' and 18.8 % as 'poorly documented'. An association between a 'well-documented' ADR report and its 'seriousness' was found (odds ratio = 1.70 [95 % CI 1.04-2.76], p = 0.01). No association between report completeness ('well-documented' report) and GP practice location or mode of ADR reporting was found.The study shows that only one out of eight ADR reports from GPs was 'well-documented'. Therefore, it appears to be important to promote further information being available regarding the data required in ADR reports to optimise the evaluation of drug causality.

Self-medication means resorting to one or more drugs in order to treat oneself without the help of a doctor. This phenomenon is developing fast. In this review, we will discuss the main definitions of self-medication; we will then present a few important characteristics of this therapeutic practice: prevalence, reasons, populations involved and drugs used. Whilst the theoretical risks of self-medication have been abundantly discussed in the literature (adverse effects, interactions, product, dosage or treatment duration errors, difficulty in self-diagnosis, risk of addiction or abuse…), there is in fact very little detailed pharmacovigilance data concerning the characteristics and the consequences of this usage in real life. This study therefore describes the all too rare data that is available: patients, clinical characteristics, "seriousness" and drugs involved in the adverse effects of self-medication. It also discusses leads to be followed in order to minimize medication risks, which are obviously not well known and clearly not sufficiently notified.

Resume L’automedication correspond au recours, dans une intention de soin, a un ou plusieurs medicaments sans l’aide d’un medecin. Son importance s’avere croissante. Apres avoir discute les principales definitions de l’automedication, cette revue presente quelques grandes caracteristiques de cette pratique therapeutique : prevalence, motifs, populations concernees et medicaments utilises. Alors que les risques theoriques de l’automedication (effets indesirables propres, interactions, erreurs de produit, de posologie ou de duree de traitement, difficulte de l’autodiagnostic, risque d’abus ou d’addiction…) sont largement discutes dans la litterature, il existe en fait peu de donnees detaillees de pharmacovigilance concernant les caracteristiques et les consequences de cet usage en vie reelle. Ce travail decrit donc les trop rares donnees disponibles : patients, caracteristiques cliniques, « gravite » et medicaments en cause dans les effets indesirables medicamenteux des conduites d’automedication. Il discute enfin des pistes a retenir pour une minimisation de ce risque medicamenteux, a l’evidence mal connu et dans tous les cas sous-notifie.

Use of atropinic drugs remains controversial in Parkinson's disease (PD) because there is insufficient evidence about their efficacy and they can induce serious adverse drug reactions. Atropinic risk scales were developed to help to identify atropinic drugs in prescription forms and to evaluate their burden in clinical practice. In the present review, we discuss the few studies investigating atropinic burden in PD and present the results of our study indicating that atropinic drugs are still widely prescribed in PD (almost 3 of 5 prescriptions) with a clinically significant atropinic burden in around 1 of 6 PD patients. Drugs mainly responsible for high values of atropinic burden were those used for nonmotor symptoms. Clinically significant atropinic burdens were mainly induced by associations of several "low-risk" drugs. Physicians must be aware that in addition to classical atropinic antiparkinsonian drugs, many others (psychotropics) can contribute to increased atropinic burden in PD patients. © 2016 International Parkinson and Movement Disorder Society.

Introduction The risk of cataracts (C) associated to lipid-lowering drugs (LLD) is discussed. Following early warnings in animal models, several clinical and observational studies led to conflicting results. We assessed in real life the association between LLD and C using the WHO individual case safety reports database, VigiBase®, including reports from over 130 countries worldwide. Methods We performed a disproportionality analysis with all reports between 1/1/1988 and 31/12/2018 to measure the reporting risk of “cataract” in patients ≥ 45 years. Primary analysis compared LLD users to non-users. We performed 2 sensitivity analyses: (1) exclusion of reports with 2 LLD associated, (2) exclusion of patients with antidiabetics and glucocorticoids, known to induce C. Finally, we investigated the drugs more at risk in each class. Results We identified 14,664 reports of cataract (3,049 in users, 66% women, 66 ± 20 y). The most frequently involved LLD were statins [84%, atorvastatin (n = 1.016), simvastatin (626), rosuvastatin (392), lovastatin (343), pravastatin (268)] followed by fibrates [5.7%, fenofibrate (117), gemfibrozil (56)], nicotinic acid (3%), bile acid sequestrants (2%), herbal cholesterol and triglyceride reducers (2%) and others (15%). LLD users were associated to a greater C risk than non-users ROR: 2.47 (95%CI: 2.37–2.57). This risk was also found for statins in general, fibrates, bile sequestrants, nicotinic acid, herbal drugs and others (ezetimibe, PCSK9 inhibitors). Similar trends were observed in sensitivity analyses. The most important risk was found for statins with lovastatin followed by pravastatin and atorvastatin and for fibrates with fenofibrate. Conclusion Using a large real life database (18.5 million reports), we found for the first time a signal of cataract for all LLD, i.e. not only statins but also fibrates and other classes suggesting that a decrease in cholesterol is involved in the pathophysiology of C with LLD.

New regulations have come into force in Europe and the US establishing the pediatric development as an integral part of the early development of medicinal products. Parallel to the advances in pediatric clinical research, it became obvious that all available sources and research tools to gather valuable information for the safe and efficacious prescription of medicines in children should be used. Real-life, pharmacoepidemiological studies provide information that contribute to the better knowledge of drug utilization, effects and safety in the pediatric population and thereby, a better prescribing in children. In this paper, we suggest some possible applications, provide examples of impact of pharmacoepidemiological and pharmacovigilance studies and expose future perspectives in pediatric pharmacoepidemiology.

In contrast to statins, the risk of diabetes with fibrates was not clearly studied. This study investigates a putative signal of diabetes associated with the use of fibrates using the World Health Organization (WHO) global individual case safety reports database, VigiBase® . We included all reports registered until the 31st December 2017 in VigiBase® to measure the risk of reporting 'hyperglycemia or new onset of diabetes' (SMQ term) compared with all other reports [as a reporting odds ratio (ROR 95% CI)] for fibrates, statins, and the combination fibrates + statins. The likelihood that diabetes resulted from statin-fibrate interaction was also estimated. According to the interaction additive model, a ROR value for coexposure exceeding the sum of the RORs estimated for each individual class of drug supports a potential drug-drug interaction (DDI). To assess the stability of our results, we performed several sensitivity analyses, according to outcome definition and after exclusion of putative competitive (hyperglycemic) drugs. We included 19 149 patients exposed to fibrates (without statins), 177 323 to statins (without fibrates) and 3 247 to statins plus fibrates. In contrast to statins (ROR = 1.75, 95% CI 1.72-1.78), no association was found for fibrates (ROR = 0.76, 95% CI 0.71-0.82). The ROR value was lower for the combination statins plus fibrates (ROR = 1.46, 95% CI 1.28-1.67). Similar trends were found in sensitivity analyses. This study, performed in the real conditions of use, failed to find a signal of diabetes with fibrates. It strengths the association previously described with statin without any evidence for a statin-fibrate DDI.

General practitioners (GPs) report little adverse drug reactions (ADR), although it is mandatory in France. The objective was to evaluate the satisfaction of the GPs who participated to a pharmacovigilance ADR declaration support network via a clinical research assistant (CRA) moving to their GP office in the French South-West region of Midi-Pyrénées.A satisfaction questionnaire was sent to the 59 active GPs of this network in November 2016.A total number of 44 GPs responded to the survey (mean age 44±11years; 48% of women). The overall satisfaction grade was rated 9/10 (SD±1). The personalized help from a CRA was highly appreciated (n=39; 89%), reduced time-loss (n=35; 90%), and facilitated communication with the local pharmacovigilance department (n=33; 85%). Most GP (95%; n=35) stated that they would keep reporting ADRs, 83% (n=35) stated to declare ADRs via the CRA, the others stated to declare ADRs directly to the Regional Pharmacovigilance Center, mainly via numerical or online tools. For 59% (n=26) their participation to the network had a positive impact on their relationship with patients through the improvement of their vigilance to ADR.Most of the active GP answered. They were very satisfied of the pharmacovigilance CRA network helping ADR reports. It may corroborate the increase of ADRs reporting in Midi-Pyrénées since this network was set up.

Summary Introduction Off-label (OL) and unlicensed (UL) drug use is widely developed in the pediatric population according to previous reviews published in the early 2010s. The present study is a narrative review of the literature of OL-UL drug use from 2013. Methods We performed a literature search of research articles assessing OL-UL drug use in children ( Results Twenty-seven studies were included. OL drug use was defined by inappropriate age, indication, dosage or way of administration according to the summary of product characteristics in >80% of studies. UL drug used was defined by the use of drugs not licensed in the country or modifications of licensed drugs in >70% of studies. Among in- and out-patients, the frequency of patients exposed to at least one OL-UL drug ranged from 36.3 to 97.0% and from 18.6 to 40.2%, respectively. Drug use was categorized as OL mostly due to inappropriate age, dosage or indication. OL-UL drug use was the most prevalent in newborns (mainly preterms) and pre-school children (aged 2–5 years). Various drugs were involved, depending on patients’ age. Polypharmacy and long hospital stays were risk factors for OL-UL drug use. Whether OL-UL drug use leads to a higher incidence of adverse drug reactions is a controversial finding. Conclusions OL-UL drug use is frequent in children. A standardized definition of OL-UL drug use is needed to better assess its frequency, risk factors and impact.

The aim of the study was to detect adverse drug reactions (ADRs) in pediatric inpatients using the medical administrative database “Programme de Medicalisation des Systemes d′Information” (PMSI) and to compare these cases ADRs with those spontaneously reported to a regional PharmacoVigilance (PV) Centre. The study was conducted from January 2008 to December 2011 in the Children University Hospital of Toulouse (Midi-Pyrenees, South-west France). From PMSI database, all discharge summaries including selected ICD-10 codes (10th International Classification of Diseases) were analyzed. All ADRs spontaneously reported by the Children Hospital of Toulouse and registered in the French PV Database (FPVDB) were included. The capture–recapture method was applied to estimate the incidence of ADRs. During the study period, we identified 60 reports from the PMSI database and 200 from the FPVDB. The rate of “serious” ADRs was higher in PMSI reports (74.6 % vs 38.9 %, p