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Over the last 10 years, the use of an unknown drug called "chimique" has emerged, among adolescents and young adults in precarious situations in Mayotte Island. To date, the exact composition of "chimique" is still poorly documented, but seizures made on the Island at the same time indicated that it would be mainly composed of synthetic cannabinoids receptor agonists (SCRAs). The objective of this study was to identify which substances, among those consumed under the name of "chimique", leading to hospital admissions.Between 1Twelve patients were included: 11 males and 1 female. The mean age was 26 years (median age: 22). There were 2 minors. Clinical presentations varied, mainly psychiatric and neurologic disorders were observed. No death was reported. Toxicological analysis identified psychoactive substances such as THC and/or its metabolites (n=3) and MDMB-4en-PINCA (n=2). The other substances identified were mainly part of the patients' treatment.This is the first study conducted in the Indian Ocean confirming the presence of SCRAs in the "chimique". For a while, the consumption of SCRAs in France seemed to be of limited importance. However, their use has become important in the Indian Ocean since the spread of "chimique" in Mayotte. It continues to spread especially in Reunion Island since 2017 under the name of "chamane".

Aims 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. Methods Cases of CF in patients treated with AZA were retrospectively collected and described from several centres of the Groupe Francophone des Myelodysplasies. 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. Results 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). Conclusion 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.

International audience; Background: Monoclonal antibodies acting on the calcitonin gene related peptide or its receptor (CGRP-mabs) are novel drugs for resistant migraine prophylaxis. As CGRP-mabs cause inhibition of vasodilatation, their use is reserved to patients with no recent history of cardiovascular diseases. We report a case of myocardial infarction associated with erenumab.Case: A 57-year-old woman with a familial history of coronaropathy, was first treated with erenumab 70 mg for 6 months, then increased to 140 mg. Almost five months after, the patient presented chest pain, increased troponin and abnormal electrocardiogram. A myocardial infarction without coronarography abnormality was diagnosed through MRI.Conclusion: Further evidence is needed to assess the risk of myocardial infarction in patients treated with a CGRP-mab. In patients over 40 years of age, the risk of coronary or cardiovascular events should be assessed using risk tables or algorithms to take into account cardiovascular risk factors. This may be complemented by appropriate exams to measure the burden of coronary atherosclerosis, if necessary.

Owing to a broad spectrum and low cost antimicrobial, cotrimoxazole is largely prescribed. However, its use is associated with various adverse drug reactions (ADRs) that warrant to ensure rational prescribing. This study aimed to describe spontaneous reports of cotrimoxazole ADRs and to evaluate the quality of prescription in patients who had ADRs. Suspected cotrimoxazole-induced ADRs cases reported to the Bordeaux regional pharmacovigilance centre (France) during a five-year period were described. Seriousness was assessed according to international criteria. Quality of prescription was assessed by compliance with the Summary of Product Characteristics (SPC) and relevance of cotrimoxazole indication. Then, an ADR was considered as preventable if the cotrimoxazole indication was not relevant, or potentially preventable if indication was relevant but the prescription was not compliant with the SPC. A total of 96 cases were analyzed: median age was 60.5 years (range: 4-94); 59.4% of patients were male. ADRs were mostly cutaneous disorders (n = 46) and hematological disorders (n = 25). A total of 60 serious ADRs occurred in 55 patients. Prescribers complied with all SPC recommandations in 21.9% of cases. Indication of cotrimoxazole was relevant or highly relevant in 41 cases. In 58% of cases, the occurrence of a cotrimoxazole-induced ADR would have been preventable or potentially preventable. In a context of increasing interest for this antibiotic to treat infections due to resistant bacteria, physicians should be more aware of the potential consequences of inappropriate prescribing cotrimoxazole and reserve its use when there is no alternative and under suitable monitoring.

Analgesics are among the most widely used drugs worldwide. This study describes the population treated with narcotic analgesics, their therapeutic indications and how the data have evolved over a decade.A cross-sectional, national, multicentre survey study was conducted that included surveys taken every year from 2007 to 2019 in a national sample of 1500 randomly selected dispensing pharmacies.The mean age of patients, mostly women (around 60%), remained stable over the study period (63.2 ± 17.1 years in 2007, 68.2 ± 17.2 years in 2019). The proportion of patients treated for more than 3 months increased from 2007 to 2019. Most prescriptions involved morphine, oxycodone and fentanyl (98.5% of all prescriptions in 2019). Morphine prescriptions dropped dramatically from 49.6% (2007) to 32.3% (2019) of the total narcotic analgesics. Fentanyl prescriptions varied from 40.1% in 2007 to 32.2% in 2019. Prescriptions of oxycodone, regardless of the indication, increased steadily from 2007, from 8.3 to 34% in 2019, becoming the most prescribed narcotic analgesic for the first time since the beginning of the survey.This study demonstrates how narcotic opioids are prescribed, thanks to the active participation of health professionals, and confirms the striking increase in the prescription of oxycodone.

Two off-label use of ketamine are framed by recommendations: in intractable pain in palliative situations or in postoperative pain. Ketamine is used in hospital but can also be used outside hospital with dispensations by hospital pharmacy to outpatients. Few data are available on ketamine use outside hospital. In this context, the French Addictovigilance Network has set up a study with hospital pharmacies.This survey assesses ketamine dispensations from 1 January to 30 April 2019, for patients who have an administration of ketamine outside hospital.Sixty-five (65) hospital pharmacies have dispensed ketamine for 553 patients. Ketamine was indicated within non-palliative care in 86% of cases. Most of non-cancer pain were in fibromyalgia (44%) and neuropathic pain (29%). During the 4-month monitoring period, 1352 dispensations were analysed. The frequency of administration is daily in 91% of cases within palliative care whereas it is much more diverse within non-palliative care (33% daily, more than 15 different frequency in fibromyalgia). Within palliative care, ketamine is most administered intravenously or by Patient Controlled Analgesia or syringe pump (78% of cases) whereas in non-palliative care, ketamine is most used subcutaneously (44%), orally (32%) or both subcutaneously and orally (20%). A large number of ampoules could be dispensed (more than 30 ampoules for 10% of dispensations).These data highlighted that recommendation in pain are not respected because most of ketamine is used within non-palliative care context and it should be noted a great heterogeneity of practice. This study underlines the urgency of targeted and clear information on certain off-label uses of ketamine for which no robust clinical studies are available and for which the risk of health complications like psychiatric (addiction), urologic and hepatologic complications is proven.

BackgroundSafety of rechallenge of immune checkpoint inhibitor (ICI) after grade ≥2 immune-related adverse events (irAEs) leading to ICI discontinuation remains unclear.MethodsAll adverse drug reactions involving at least one ICI reported up to December 31, 2019 were extracted from the French pharmacovigilance database. Patients were included if they experienced at least one grade ≥2 irAE resulting in ICI discontinuation, with subsequent ICI rechallenge. The primary outcome was the recurrence of at least one grade ≥2 irAE in these patients after ICI rechallenge.ResultsWe included 180 patients: 61.1% were men (median age of 66 years), 43.9% had melanoma and 78.9% were receiving anti-programmed cell death 1. First ICI discontinuation was related to 191 irAEs. After ICI rechallenge, 38.9% of the patients experienced at least one grade ≥2 irAE. Among them, 70.0% experienced the same irAE, 25.7% a distinct irAE, and 4.3% both the same and a distinct irAE. Lower recurrence rates of irAEs were associated with rechallenge with the same ICI treatment (p=0.02) or first endocrine irAEs (p=0.003). Gastrointestinal irAEs were more likely to recur (p=0.007). The median duration from ICI discontinuation to rechallenge and the severity of the initial irAE did not predict recurrent irAEs after ICI rechallenge (p=0.53 and p=0.40, respectively).ConclusionsIn this study, 61.1% of the patients who discontinued ICI treatment for grade ≥2 irAEs experienced no recurrent grade ≥2 irAEs after ICI rechallenge. Although ICI rechallenge appears to be safe under close monitoring, it should always be discussed balancing usefulness of rechallenge, patient comorbidities and risk of recurrence of first irAE(s). Due to inherent bias associated with pharmacovigilance studies, further prospective studies are needed to assess risk factors that may influence patient outcomes after ICI rechallenge.

International audience; Introduction Qualitative approaches based on drug causality assessment estimate the causal link between a drug and the occurrence of an adverse event from individual case safety reports. Quantitative approaches based on disproportionality analyses were developed subsequently to allow automated statistical signal detection from pharmacovigilance databases. This study assessed the potential value of causality assessment for automated safety signal detection. Methods All drug–serious adverse event pairs with a positive rechallenge and a semiology suggestive of drug causality were identified in the French pharmacovigilance database (BNPV) from 2011 to 2017. The results were compared with those obtained from automated disproportionality analyses of the BNPV/World Health Organization (WHO) VigiBase®, complemented by the list of signals validated by the WHO-UMC (Uppsala Monitoring Centre). Summary of Product Characteristics (SmPCs), Martindale®, Meyler’s® and MedLINE® were used as other sources of information for the purpose of comparison. Results Of the 155 pairs of interest, 115 (74.2%) were also identified by another source of information. Since the individual case reporting in the BNPV, 23 (14.8%) of the adverse events (AEs) have been added to the SmPC, seven of which were not identified by disproportionality. Finally, 40 pairs were not identified by any other source of information, 13 of which were considered as potential new safety signals after analysis of case reports by pharmacovigilance experts. The signals identified by causality assessment involved antineoplastic and immunomodulatory drugs especially, in comparison with signals identified by WHO-UMC or by disproportionality within the BNPV. Conclusion The approach therefore appears useful as an additional tool for safety signal detection, especially for antineoplastic and immunomodulating agents.

International audience; We thank Brož et al. for their interest in our study aiming to determine if drug-induced hypoglycemia could be a class effect for opioids [1] and for their useful comments.The French PharmacoVigilance Database (FPVD) contains a narrative description of cases provided by the declarant, which we examined for this study. The description of the report’s narrative in pharmacovigilance study is a complement to disproportionality analysis that may identify potential mechanisms underlying the associations found between drugs and adverse drug reactions. We are glad that they shared our interest in finding such mechanisms to further investigate the link between hypoglycemia and opioids. As they accurately mentioned, 45 of the 93 tramadol-associated hypoglycemia cases included in our descriptive study in the FPVD were related to diabetic patients. Indeed, hypoglycemia in these patients could have been favored by the antihyperglycemic treatment they received. We agree with them that sleepiness, one of the common side effect of opioids, combined to the use of those antihyperglycemic treatments could have been one of the factors leading to the onset of hypoglycemia in those patients. However, not all the reports mentioned sleepiness and the prescription of opioids appeared to be the trigger factor causing the hypoglycemia even in diabetic patients, regardless of the underlying mechanism.

Following a severe case of rhabdomyolysis in our University Hospital after a co-administration of atorvastatin and fusidic acid, we describe this interaction as this combination is not clearly contraindicated in some countries, particularly for long-term treatment by fusidic acid. All cases of rhabdomyolysis during a co-administration of a statin and fusidic acid were identified in the literature and in the World and Health Organization database, VigiBase® . In the literature, 29 cases of rhabdomyolysis were identified; mean age was 66 years, median duration of co-administration before rhabdomyolysis occurrence was 21 days, 28% of cases were fatal. In the VigiBase® , 182 cases were retrieved; mean age was 68 years, median duration of co-administration before rhabdomyolysis was 31 days and 24% of cases were fatal. Owing to the high fatality associated with this co-administration and the long duration of treatment before rhabdomyolysis occurrence, fusidic acid should be used if there is no appropriate alternative, as long as statin therapy is interrupted for the duration of fusidic acid therapy, and perhaps a week longer. Rarely will interruption of this sort have adverse consequences for the patient.

Objectifs “Chimique” ou “chamane” est le nom donne dans l’ocean Indien aux cannabinoides de synthese (CS) fumes dans des cigarettes artisanales. Les premiers cas ont ete observes a Mayotte en 2015, majoritairement chez des adolescents et jeunes adultes, puis a la Reunion en 2018 ou un circuit specifique a ete mis en place afin de confirmer les substances impliquees au laboratoire de Pharmaco-Toxicologie du CHU de Bordeaux. Les autorites regionales et nationales ont ete alertees du probleme. Cette etude fait le point sur la situation en 2018 et 2019. Methode Une premiere analyse descriptive retrospective a ete realisee a partir des donnees locales et nationales d’addictovigilance depuis 2018. Une seconde a ete realisee aux urgences du CHU de la Reunion a partir du codage CIM10 de juin a septembre 2019. Les analyses toxicologiques (urine/sang/produit) ont ete realisees en spectrometrie de masse haute resolution (UPLC-HRMS) avec un detecteur de type Xevo XS G2 QTOF (Waters, USA). Resultats Les donnees issues de l’addictovigilance representent 37 cas de consommation de “chimique” provenant de la Reunion (service des urgences et addictologie), 7 femmes et 30 hommes (âge median : 25,5 ans ; [15–67]) ainsi que 4 cas en provenance de la France metropolitaine parfois avec la notion de consommation a l’insu du sujet. Les effets observes etaient principalement des troubles du comportement (n = 20) et des troubles lies a l’usage (n = 7). Aucun cas grave ou de deces n’a ete repertorie. Les donnees issues de l’enquete realisee aux urgences concernent 17 hommes et 1 femme qui se sont presentes aux urgences apres avoir ete suspecte d’avoir consomme de la “chimique” (âge median : 23,5 ans ; [13–77]). Dans 4 cas, les patients pensaient n’avoir consomme que du tabac ou du cannabis. Une analyse toxicologique a ete effectuee dans 33 cas : 6 CS differents, seuls ou associes, ont ete identifies dans 6 cas (1 produit ; 5 patients). Les principaux CS identifiees etaient le 5F-MDMB-PICA (n = 3) et 5F-AMB (n = 2). Les principales substances associees etaient le cannabis et les benzodiazepines. Ces CS ne font pas partie de ceux les plus frequemment saisis en 2016 en Europe qui etaient le MDMB-CHMICA, l’AB-CHMINACA, l’UR-144, le 5F-AKB48 et l’AMB-FUBINACA (EMCDDA, 2018). Conclusion La diffusion large et rapide de la chimique dans l’Ocean Indien est un probleme de sante publique qui necessite la sensibilisation des autorites sanitaires locales et nationales. L’identification toxicologique de ces nouvelles substances apparait comme indispensable pour faire le lien entre la nature des substances consommees et les risques lies a leur consommation.

International audience; Objective: 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.

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.

Addictovigilance in the French Public Health Code, in the section related to poisonous substances, refers to a monitoring system developed since 1990: control of psychoactive substances and products, with medicinal use or not, was completed by a specific system focused on evaluation and information on pharmacodependance in 1999. The French medicines agency (Agence du medicament) created in 1993 was involved in this monitoring system; pharmacodependance evaluation was added by law to the missions of the agencies that followed: the Agence francaise de securite sanitaire des produits de sante missions (AFSSAPS, 1998) and the Agence nationale de securite du medicament et des produits de sante (ANSM, 2011). "Addictovigilance" first appears in French Law in 2017 whereas it was used by pharmacodependance centers and AFSSAPS since 2007. Legal definition of addictovigilance in the French Public Health Code testified to public authorities action against addictive behavior whatever products status, legal or not. The visibility of addictovigilance is growing on the Internet as well (ANSM website, web portal for reporting adverse health events).

Introduction « Chimique » ou « chamane » est le nom donne dans l’ocean Indien aux cannabinoides de synthese (CS), fumes dans des cigarettes artisanales. Les premiers cas ont ete observes a Mayotte en 2015, majoritairement chez des adolescents et jeunes adultes, puis a la Reunion en 2018 ou un circuit specifique a ete mis en place avec un laboratoire de toxicologie specialise afin de confirmer les substances impliquees. Les autorites regionales et nationales ont ete alertees du probleme. Cette etude fait le point sur la situation en 2018 et 2019. Materiel et methodes Une premiere analyse descriptive retrospective a ete realisee a partir des donnees locales et nationales d’addictovigilance depuis 2018. Une seconde a aussi ete realisee aux urgences du CHU de la Reunion a partir du codage CIM10 de juin a septembre 2019. Les analyses toxicologiques (echantillons d’urine/sang) ont ete realisees en spectrometrie de masse haute resolution (UPLC-HRMS) avec un detecteur de type Xevo XS G2 QTOF (Waters, USA). Resultats Les donnees issues de l’addictovigilance representent 37 cas de consommation de « chimique » en provenance de la Reunion (services des urgences et addictologie), soit 7 femmes et 30 hommes (âge median : 25,5 ans ; [15–67]). Les effets observes etaient principalement des troubles du comportement (n = 20) et des troubles lies a l’usage (n = 7). Une analyse toxicologique a ete effectuee dans 32 cas : un ou plusieurs CS (par exemple 5F-MDMB-PICA, 5F-ADB, 5F-AMB) ont ete identifies dans 6 cas. Les donnees de toxicovigilance representent 17 hommes et 1 femme qui se sont presentes aux urgences apres avoir consomme de la « chimique » (âge median : 23,5 ans ; [13–77]). Dans 4 cas, les patients pensaient n’avoir consomme que du tabac ou du cannabis. En France metropolitaine, 4 cas de consommation « chimique » ont ete signales aux centres d’addictovigilance, parfois avec la notion de consommation a l’insu du sujet. Discussion/Conclusion La diffusion large et rapide de la « chimique » dans l’Ocean Indien est un probleme de sante publique qui necessite la sensibilisation des autorites sanitaires locales et nationales. L’identification toxicologique de ces nouvelles substances apparait comme indispensable pour faire le lien entre la nature des substances consommees et les risques lies a leur consommation.

Introduction Le dextropropoxyphene (DXP) etait l’antalgique opioide faible le plus prescrit jusqu’a son retrait en 2011. L’objectif de cette etude est de decrire les delivrances d’antalgiques chez les utilisateurs chroniques de DXP au moment du retrait et pendant 18 mois suivant le retrait du DXP. Methodes Ce projet est derive de l’etude DANTE [1] . Les utilisateurs chroniques de DXP ont ete definis comme des patients ayant recu au moins 40 boites de DXP dans l’annee precedant l’arret du DXP. Les donnees sur la delivrance d’antalgiques chez ces patients ont ete analysees a l’arret du DXP (T0) puis tous les 6 mois pendant 18 mois. Resultats Soixante-trois mille six-cent soixante et onze (63671) sujets ont eu un remboursement de DXP dans l’annee precedant son arret dont 7,1 % (n = 4495) identifies comme utilisateurs chroniques (âge moyen : 71,5 ans, femmes : 68,7 %). Six mois apres le retrait du DXP, 8,5 % sont decedes et 11,7 % ont cesse de recevoir un antalgique ; 79,7 % ont ete traites avec au moins un autre antalgique : au moins un antalgique-peripherique (majoritairement paracetamol) pour plus de la moitie ; au moins un opioide-faible (majoritairement tramadol) pour pres de la moitie. Si l’on suit la trajectoire de chaque patient, parmi les patients prenant du DXP seul a T0 (74,6 %), 1/4 est passe a un antalgique-peripherique, 1/4 a une combinaison antalgique-peripherique/opioide-faible, 1/4 a un opioide-faible ; l’autre quart a principalement interrompu son traitement (14,1 %) ou est decede. Au cours des 12 mois suivants, parmi les sujets ne prenant que des antalgiques-peripheriques, la majorite a maintenu ce traitement, tandis que la moitie des sujets ayant une combinaison opioide-faible/antalgique-peripherique ou ne prenant qu’un antalgique-faible sont restes sous ce type de traitement. Discussion Apres l’arret du DXP, 11,7 % des patients ont cesse de prendre un antalgique, les autres ayant poursuivi majoritairement avec du paracetamol et/ou du tramadol. Il est necessaire d’etre vigilant a toute modification d’antalgiques, en reevaluant regulierement la douleur et, dans le cas des traitements opioides, en surveillant le risque de trouble de l’usage notamment avec le tramadol, compte tenu de l’augmentation croissante de ces signes de mesusage [2] .

Introduction La Guyane est un departement francais en Amerique du Sud. La consommation de substances psychoactives y est repandue (principalement alcool, cannabis et cocaine) [1] . Methode Ce travail presente l’action coordonnee d’acteurs de sante autour de la problematique d’un nouveau produit emergent dans un contexte particulier amazonien et necessitant des prises en charges sanitaires specifiques aux populations locales. Resultats Un medecin exercant en centre delocalise de prevention et de soins (CDPS), antenne medicale du centre hospitalier de Cayenne, dans les communes dites de l’interieur a informe le CEIP-A de Bordeaux d’une substance psychoactive, appelee Sukru, qui circulerait le long des fleuves frontieres avec le Bresil et le Surinam. La litterature scientifique ne fait pas etat de donnees sur le Sukru. Une veille a permis 5 signalements pour des sujets presentant coma, troubles du comportements, bouffees delirantes. A la demande du CEIP-A de Bordeaux qui a aide a la mise en place d’un circuit, avec le laboratoire de pharmaco-toxicologie du CHU de Bordeaux, 3 prelevements d’echantillons sanguins associes a 3 urinaires ont ete realises et envoyes pour analyse. Les analyses ont revele la presence de MDMA, ce qui pourrait correspondre aux effets observes. Parallelement, la coordination regionale SINTES portee par l’Association Guyanaise de reduction des risques (AGRRR) a collecte des echantillons confirmant ces resultats. L’Agence regionale de sante de Guyane informee, a sollicite le CEIP-A pour realiser une plaquette a destination des soignants sur la prise en charge optimale en cas d’intoxication par MDMA, produit peu consomme habituellement en Guyane sous sa forme cristal ; mentionnee sous forme comprime sur le littoral du territoire depuis 2001 [2] . Un document a ete realise en partenariat avec les equipes des CDPS et de l’AGRRR, afin qu’il soit adapte au mieux aux besoins des acteurs locaux et l’AGRRR a mene des formations sur le sujet a destination des soignants. Discussion La circulation de ce “nouveau” produit a permis de rappeler aux intervenants de sante l’importance de collecter des substances psychoactives nouvelles ou suspectes pour realiser des analyses toxicologiques mais aussi de sensibiliser les usagers pour une meilleure connaissance des produits circulants.

Introduction En 2011, un arrete a interdit la vente et la cession au public des precurseurs de l’oxybate de sodium (GHB) : la gammabutyrolactone (GBL) et le 1,4 butanediol (1,4-BD), en tant que matieres premieres, ainsi que des produits manufactures en contenant une concentration superieure a 10 % et/ou un volume de plus de 100 ML. Un point realise par le Reseau des centres d’addictovigilance en 2012, a montre que cela n’avait pas eu d’influence sur le nombre de cas d’intoxications ou de dependance. En 2018, l’augmentation des intoxications au GBL, son usage banalise dans le contexte du chemsex mais aussi en milieu festif, a conduit a analyser de nouveau les donnees disponibles. Methodes Le centre d’addictovigilance de Bordeaux a sollicite l’ensemble du reseau afin de recueillir les cas d’abus et de dependance rapporte avec la GBL, le 1,4-BD et le GHB entre le 5/11/2012 et la 31/06/2018 ainsi que les donnees des outils d’addictovigilance. Une recherche bibliographique a ete realisee. Resultats 341 cas ont ete notifies, pour la plupart des intoxications (66 %). Treize deces ont ete recenses. Trois mineurs ont ete soumis chimiquement par du GHB/GBL. Pour la premiere fois, le 1,4-BD a ete signale. Sur l’ensemble de la periode, on observe une augmentation inquietante du nombre des cas graves, et ce pour la plupart des outils du reseau : augmentation des deces, des intoxications accidentelles, des cas de dependance (13 %) et la persistance de son utilisation dans la soumission chimique. Dans 17,1 % des cas d’intoxication, le GHB/GBL est la seule substance consommee (dangerosite) ; sur les 7 deces recenses dans DRAMES, le GHB est retrouve dans 5 cas comme seule substance responsable du deces. Ces tendances sont observees de la meme facon au niveau international. Discussion Cette nouvelle enquete confirme que l’arrete de 2011 n’a pas eu d’influence et qu’il y a urgence a reglementer l’utilisation de la GBL, mais egalement le 1,4-BD qui doivent etre consideres comme aussi dangereux que le GHB, classe sur la liste des stupefiants depuis plusieurs annees.

Objectif La methamphetamine est un psychostimulant puissant, dont la longue duree d’action en fait une substance attractive. Utilisee sous differentes voies (intraveineuse, fumee ou inhalee), elle est responsable d’effets toxiques cardiovasculaires et neuropsychiatriques frequents pouvant aller jusqu’au deces. Le trouble de l’usage (TU) de methamphetamine est un grave probleme de sante publique mondial, en particulier en Amerique du Nord et en Asie. Cette consommation semble augmenter en France, en particulier dans le cadre du chemsex. L’objectif de cette etude est de faire le point sur la consommation de methamphetamine en France, a partir des donnees d’addictovigilance. Methode Le reseau francais d’addictovigilance a analyse tous les cas de consommation nocive lies a la prise de methamphetamine signale au reseau des centres d’addictovigilance, jusqu’au 31 decembre 2018 (analyse descriptive: âge, sexe, contexte, voie d’administration, effets, etc.). Les donnees des etudes pharmaco-epidemiologiques annuelles d’addictovigilance OPPIDUM et DRAMES ont egalement ete analysees. Resultats Entre 2003, date du premier cas signale au reseau, et decembre 2018, 134 cas et 36 DivAS (Divers Autres Signaux) ont ete signales, avec une nette augmentation a partir de 2010. Les consommateurs etaient principalement des hommes, plutot jeunes (âge median: 30 ans). Le contexte d’utilisation etait principalement sexuel et/ou festif. Les complications etaient essentiellement d’ordre psychiatrique (41 %), neurologique (14 %) et cardiaque (10 %); 2 deces (non inclus dans l’etude DRAMES) ont ete signales. Des analyses toxicologiques ont ete effectuees pour 55 cas, avec une identification de methamphetamine dans 45 cas (principalement qualitative). Dans l’etude OPPIDUM, il y a eu une augmentation de l’utilisation a partir de 2007 (principalement en Polynesie Francaise). L’etude DRAMES a enregistre 16 cas de deces entre 2010 et 2017, pour lesquels la methamphetamine a ete identifiee: dans 9 cas, la methamphetamine etait responsable ou co-responsable du deces. Dans la litterature, un seul cas francais est publie (syndrome de la veine cave superieure et symptomes psychotiques, non signale au FAN) [1] . Conclusion En France, la methamphetamine et son racemate, la levomethamphetamine, sont inscrits dans l’annexe III de la liste des stupefiants. La consommation de methamphetamine, bien que moderee par rapport aux autres pays d’Europe, est en augmentation en France, notamment dans les contextes sexuels et festifs. Le nombre de saisies de methamphetamine est egalement en augmentation. Il est important de sensibiliser les professionnels de la sante a cette augmentation de la consommation et aux risques qui y sont associes. Dans la mesure du possible, il est necessaire de confirmer par des methodes chromatographiques toute suspicion de consommation de methamphetamine.

Resume Les methodes d’imputabilite en pharmacovigilance ont ete developpees des les annees 1970–1980. La methode francaise d’imputabilite fait partie des premieres methodes d’imputabilite, apres les methodes pionnieres de Irey et de Karch et Lasagna ; initialement publiee en 1978, elle a ete actualisee en 1985, puis reactualisee en 2011. Les principales modifications de la methode francaise d’imputabilite sont resumees et presentees sous forme de tableaux. Les versions successives ont ameliore la presentation de la methode avec une definition plus formalisee des criteres d’imputabilite, tout en preservant sa facilite d’utilisation. L’imputabilite permet de formaliser et d’expliciter l’evaluation du lien de causalite entre la prise d’un medicament et la survenue d’un effet indesirable et constitue une aide pour le diagnostic et la conduite a tenir devant un effet indesirable. Elle peut contribuer a la qualite et a la pertinence des donnees enregistrees dans les bases de donnees de pharmacovigilance.

Addictovigilance in the French Public Health Code, in the section related to poisonous substances, refers to a monitoring system developed since 1990: control of psychoactive substances and products, with medicinal use or not, was completed by a specific system focused on evaluation and information on pharmacodependance in 1999. The French medicines agency (Agence du médicament) created in 1993 was involved in this monitoring system; pharmacodependance evaluation was added by law to the missions of the agencies that followed: the Agence française de sécurité sanitaire des produits de santé missions (AFSSAPS, 1998) and the Agence nationale de sécurité du médicament et des produits de santé (ANSM, 2011). "Addictovigilance" first appears in French Law in 2017 whereas it was used by pharmacodependance centers and AFSSAPS since 2007. Legal definition of addictovigilance in the French Public Health Code testified to public authorities action against addictive behavior whatever products status, legal or not. The visibility of addictovigilance is growing on the Internet as well (ANSM website, web portal for reporting adverse health events).

Introduction Les prescriptions d’antalgiques stupefiants ont evolue ces dernieres annees, dans le choix de l’antalgique prescrit mais surtout dans les indications therapeutiques. Cette synthese presente un focus sur les indications therapeutiques des antalgiques opioides (fentanyl transdermique ou transmuqueux, morphine, oxycodone) a partir des enquetes ASOS, de 2007 a 2017. Methode Etude annuelle transversale realisee, pendant une semaine, aupres de pharmacies d’officine sur un echantillon de 1500 pharmacies tirees au sort en France metropolitaine et dans les departements d’Outre-Mer (DOM). Une fiche enquete doit etre remplie pour chaque ordonnance comportant un antalgique stupefiant ou assimile. Resultats (1) Evolution du nombre de prescriptions : les prescriptions de morphine sont majoritaires. Depuis 2015, l’oxycodone est passee en deuxieme position, devant le fentanyl transdermique, de facon stable. (2) Comparaison des differents antalgiques opioides en fonction des indications : dans les indications rhumatologiques, la morphine reste majoritaire. Le fentanyl transdermique occupait la deuxieme place jusqu’en 2014, mais les prescriptions d’oxycodone ont double entre 2010 et 2017 et l’oxycodone se maintient en deuxieme position depuis 2015. Dans les indications cancerologiques, les prescriptions de fentanyl transdermique et la morphine etaient initialement majoritaires, mais l’oxycodone a nettement progresse jusqu’a etre en tete des prescriptions en 2012, 2015 et 2016. La diminution reguliere des prescriptions de fentanyl transdermique depuis 2010 et, parallelement, la hausse de celles de fentanyl transmuqueux a place la molecule fentanyl au premier rang, ou dans les memes proportions que l’oxycodone. Apres une baisse reguliere, les prescriptions de morphine sont similaires a celles de l’oxycodone et du fentanyl transdermique en 2017. Les indications neurologiques representent un faible pourcentage des prescriptions d’antalgiques opioides. La morphine et l’oxycodone sont les plus prescrites. Dans les autres indications, la morphine a toujours occupe la premiere place, rejointe en 2015 par l’oxycodone. Conclusion La morphine reste en tete des prescriptions d’antalgiques stupefiants ; une progression constante de l’oxycodone la place en deuxieme position depuis 2015. Toutes molecules confondues, les indications rhumatologiques sont majoritaires depuis 2009. La part des indications « autres » reste non negligeable : pour certaines molecules (morphine, oxycodone), depuis 2012, le pourcentage de prescriptions est proche ou superieur a celui des indications en cancerologie.

The aims of this study were to determine the patterns of analgesic adverse drug reactions (ADRs) and to assess their preventability and contributing factors. This is a retrospective, descriptive study conducted on ADRs of analgesics and other drugs indicated as analgesics, spontaneously reported to the Bordeaux pharmacovigilance center from January 2011 to June 2012. The 141 cases selected for the analysis included 16 cases of medication errors (11.3 %) and 15 addiction cases (10.6 %). In total, 214 ADRs were registered, for which 173 analgesic medicines were suspected. The most frequent ADRs reported were nervous system disorders (26.6 %), psychiatric disorders (15.0 %), and skin and subcutaneous tissue disorders (12.1 %). Tramadol alone or in combination (17.3 %), followed by morphine (15 %), fentanyl (9.8 %), and paracetamol (8.7 %) were the most frequently involved analgesics. More than half of the cases (54.6 %) were serious and led to hospitalization or prolonged hospitalization. Preventability was determined for 134 cases (95 %): 51.5 % were considered as preventable, 26.1 % not preventable, and 22.4 % not assessable. The main contributing factors for the preventable cases included negligence of recommendations for analgesic use and failure to consider patients’ risk factors when prescribing. A significant number of analgesic ADRs could be prevented, and being aware of their contributing factors promotes efficient analgesia with minimum risks to the patients.

Metastatic colorectal cancer (mCRC) is increasingly treated using targeted therapies. Post-marketing safety of these agents is understudied, especially in the elderly. This study aimed to compare, according to age, the adverse drug reactions (ADRs) of targeted therapies used for mCRC in real life. An extraction of VigiBase, which contains World Health Organization individual case safety reports (ICSRs), was performed. All ADR reports with aflibercept, bevacizumab, cetuximab, panitumumab, or regorafenib used in CRC were considered. For all drugs, chi-square tests were used to compare frequencies of serious ADRs between patients aged ≥75 and

Following a severe case of rhabdomyolysis in our University Hospital after a co‐administration of atorvastatin and fusidic acid, we describe this interaction as this combination is not clearly contraindicated in some countries, particularly for long‐term treatment by fusidic acid. All cases of rhabdomyolysis during a co‐administration of a statin and fusidic acid were identified in the literature and in the World and Health Organization database, VigiBase(®). In the literature, 29 cases of rhabdomyolysis were identified; mean age was 66 years, median duration of co‐administration before rhabdomyolysis occurrence was 21 days, 28% of cases were fatal. In the VigiBase(®), 182 cases were retrieved; mean age was 68 years, median duration of co‐administration before rhabdomyolysis was 31 days and 24% of cases were fatal. Owing to the high fatality associated with this co‐administration and the long duration of treatment before rhabdomyolysis occurrence, fusidic acid should be used if there is no appropriate alternative, as long as statin therapy is interrupted for the duration of fusidic acid therapy, and perhaps a week longer. Rarely will interruption of this sort have adverse consequences for the patient.

The objective of this study was to evaluate the performance of Standardised MedDRA® Queries (SMQs) in adverse drug reaction (ADR) identification.ADR cases included in the last complete year of the French Pharmacovigilance database for research were used to test four SMQs (narrow and broad): agranulocytosis, demyelination, osteonecrosis and psychosis. Reference cases were identified by free-text search and validated by two authors. Sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of narrow and broad searches of each SMQ were calculated and reported as proportions with 95% exact confidence interval (CI).Among 20,830 cases reported in 2009, 337 validated cases of agranulocytosis, 17 of demyelination, 52 of osteonecrosis and 230 of psychosis were included in the reference sets. Estimations of SMQ narrow search performance were as follows: Se 62.9% (95% CI 57.5-68.1) and PPV 46.8% (95% CI 42.1-51.5) for agranulocytosis; Se 88.2% (95% CI 63.6-98.5) and PPV 34.1% (95% CI 20.5-49.9) for demyelination; Se 94.2% (95% CI 84.1-98.8) and PPV 74.2% (95% CI 62.0-84.2) for osteonecrosis; and Se 75.1% (95% CI 69.0-80.6) and PPV 87.8% (95% CI 82.3-92.0) for psychosis. Results obtained using the broad search were similar except for PPV concerning osteonecrosis (52.7% [95% CI 42.1-63.1]) and psychosis (61.4% [95% CI 55.7-66.8]). For all selected SMQs, Sp and NPV were greater than 98% for both narrow and broad searches.Heterogeneous performance of SMQs for case retrieval was found and seems to be related to the characteristics of the condition of interest. It could therefore be expected that for other SMQs, performance may be affected in the same manner.

Objectif Les intoxications par les substances psychoactives (SPA) sont nombreuses en Europe, notamment dans les festivals de musique, et peuvent-etre responsables de deces pour lesquels les centres antipoison et d’addictovigilance sont regulierement sollicites. Les objectifs de cette etude sont de determiner les molecules circulant dans ces evenements festifs avec identification analytique a l’appui, et de decrire les tableaux cliniques les plus graves pour ameliorer la prise en charge ulterieure. Methode Apres avis favorable du CPP IDF1 (ClinicalTrials.gov ID : NCT03203213 ), etait inclu tout patient majeur admis au poste medical avance (PMA) du festival Garorock de Marmande (30 juin–2 juillet 2017) avec des troubles neurologiques et/ou du comportement (i) presentant une agitation a l’admission ou pendant la surveillance au PMA et qui dira (ou son entourage) avoir consomme des SPA ou qui sera dans l’incapacite de dire qu’il a pris une SPA et pour lequel aucune autre etiologie n’est evidente, et/ou (ii) pour lequel la gravite du cas necessite une admission aux urgences ou en reanimation, que le medecin ait connaissance ou non d’une prise de SPA (et en l’absence d’une autre etiologie evidente) et/ou (iii) si le medecin du PMA considere qu’une analyse toxicologique est necessaire pour la suite de la prise en charge. Chaque patient beneficiait d’un examen clinique, d’un prelevement sanguin sur buvard Dried Blood Spot ou DBS) et capillaire, ainsi que des soins adaptes. Resultats Vingt cinq patients (13 femmes, 12 hommes) de 18 a 30 ans ont ete inclus, 25 DBS analyses, et 24 prelevements de cheveux analyses. Quatorze (93 %) indiquaient qu’ils avaient pris des SPA. Les signes observes etaient neurologiques [mydriase (71 % – 17), troubles de la conscience (88 % – 22), hyper ou hypotonie (respectivement 40 % – 6 et 47 % – 7), agitation (44 % – 11), mouvements anormaux (36 % – 9)], cardiovasculaires [tachycardie 46 % (11)], respiratoires [polypnee 55 % (6)], ou autres [hypoglycemie 4 % (1), fievre 7 % (1)] et 16 % (4) ont ete hospitalises. L’evolution a ete favorable pour tous. Les substances avouees consommees (23 patients) etaient : « cristal », ecstasy, « MD », MDMA, champignons et cannabis, parfois associes. Dans les DBS etaient retrouves de l’ecstasy (surtout MDMA), du THC, de la cocaine et leurs metabolites, du paracetamol, de l’hydroxyzine, de la chloroquine, du levamisole, de la quinine, de la quinidine, et de la cetirizine. Les memes substances ont ete decelees dans les cheveux mais egalement de la MDEA, du MDMB-CHMICA, de la doxylamine, de l’oxomemazine et de la codeine. Conclusion L’etude a permis de decrire precisement les tableaux cliniques. Aucun nouveau produit de synthese n’a ete retrouve dans le sang, mais certains d’entre eux ont des concentrations sanguines circulantes tellement faibles qu’elles ont pu echapper a la detection dans les DBS.

Introduction Le plan gouvernemental de lutte contre les drogues et les conduites addictives 2013–2017 comporte plusieurs actions concernant l’Outre-Mer, notamment le renforcement de l’information sur la pharmacodependance. Depuis plusieurs annees, les echanges entre le centre d’addictovigilance et les departements d’Outre-Mer (DOM) ont permis d’apporter des informations sur les consommations specifiques de ces regions. Methode Les differents moyens mis en place avec les DOM ont ete decrits. Les donnees issues des differents outils d’addictovigilance auxquels participent les DOM ont ete analysees (NoTS, OPPIDUM, OSIAP). Resultats Les departements de La Reunion, Martinique, Guyane et Guadeloupe participent a l’enquete OPPIDUM depuis 2008, ce qui a permis de confirmer les differentes specificites de ces territoire en termes de consommations de substances psychoactives : crack et cannabis en Antilles-Guyane, medicaments a La Reunion. Un reseau de pharmacies sentinelles a ete mis en place en 2011 a La Reunion. Il participe regulierement a l’enquete OSIAP, permettant d’identifier des specificites de consommations de medicaments par rapport a la metropole (trihexyphenidyle, clonazepam). En 2018, le systeme d’addictovigilance a ete presente a la section Outre-Mer du Conseil de l’Ordre des pharmaciens, pour mettre en place de tels reseaux dans les departements d’Antilles-Guyane, ce qui permettrait d’evaluer la part de detournement des medicaments dans ces territoires. De la meme facon, un reseau se met en place avec les centres specialises en addictologie. En 2015, la Mission interministerielle de lutte contre les drogues et les conduites addictives (MILD&CA) a missionne le centre d’addictovigilance de Bordeaux pour renforcer les echanges sur l’addictovigilance avec la Reunion et Mayotte. Cette mission a permis de renforcer les liens existants, mais surtout d’alerter les autorites sur la problematique de la « chimique », a l’origine de nombreuses hospitalisations de jeunes a Mayotte. Aussi, afin de connaitre les molecules et les symptomes associes a l’origine de ces hospitalisations, le centre d’addictovigilance va mettre en place une etude au centre hospitalier de Mamoudzou. En 2018, des cas d’hospitalisations a la Reunion apres prise de chimique ont egalement montre la necessite de mieux connaitre cette substance. Le centre d’addictovigilance est membre des reseaux regionaux de vigilance et d’appui mis en place par l’ARS Ocean Indien et l’ARS Martinique. Discussion Chaque DOM a ses propres specificites, qu’il convient de prendre en compte pour de futures interventions locales, mais egalement lors de l’evaluation nationale du potentiel d’abus et de dependance des substances psychoactives. Si les echanges peuvent se faire facilement a distance (e-mails, visioconferences), une premiere rencontre « physique » est primordiale pour les perenniser : a cet effet, il serait important de partir en mission en Antilles-Guyane.

Purpose To assess the prevalence of adverse drug reactions (ADRs) occurring in patients with Alzheimer’s disease (AD) or other dementia in France. Methods A cross-sectional multicentre study was conducted by the French network of the 31 regional pharmacovigilance centres on a given day. The subjects were selected by random draw to be a representative sample of French patients with dementia: consultations of dementia clinics, nursing-homes, acute and long care geriatric units, rehabilitation care geriatric units. The staff of each medical structure together with that of the pharmacovigilance centre defined a day for including the patients. Socio-demographic data, history, ADR and drugs given were registered. Results There were 1332 subjects included, 51.1% living at home, 48.8% in institutions, aged 82.08.0years (46–108); 61.3% suffered from AD. Meannumber of drugs was 6.33.1. Anti-dementia drugs were given to66.4%subjects. ADR prevalence was 5.0%(95% CI: 3.9–6.2) without a significant difference between at home and institutionalized patients. ADR consisted of gastro-intestinal (23.2%), central nervous system (17.4%) and psychiatric disorders (8.7%). Of the ADR, 31.9% were serious, and 47.8% preventable. The drugs most often involved were anti-dementia (28.9%), cardio-vascular (28.9%) and psychotropic drugs (26.4%, anxiolytics, hypnotics, antidepressants, neuroleptics). Conclusion This national scale study showed that iatrogenesis in patients with AD and related dementia can at times be serious and preventable. Therefore, special attention is required when prescribing psychotropic and anti-dementia drugs, as they are frequently used and induce half of the ADR in this population. Copyright © 2013 John Wiley & Sons, Ltd. key words—Alzheimer’s disease; dementia; adverse drug reaction; pharmacovigilance; cross-sectional study; pharmacoepidemiology

Purpose To test an automated method to decrease the number of false-positive (FP) signals of disproportionate reportings (SDRs) generated by co-prescription. Methods Automated backward stepwise removal of reports concerning the drug associated with the highest ranked SDR for an event was tested for gastric and oesophageal haemorrhages (GOH), central nervous system haemorrhages and cerebrovascular accidents (CNSH), ischaemic coronary artery disorders and muscle pains (MP) using the reporting odds ratio in the French spontaneous reporting research database. After ranking SDRs detected in the complete dataset on the lower limit of the reporting odds ratio 95% confidence interval, reports concerning the drug with the highest ranked SDR were removed. In the dataset thus generated, SDRs were again identified, ranked and reports related to the drug involved in the newly highest ranked SDR removed. The process was repeated until no signal was detected. Initially detected SDRs eliminated using this technique were assessed regarding the summary of products characteristics and the literature to determine their FP nature. Results Seventeen SDRs were successively eliminated for GOH, 37 for CNSH, 15 for ischaemic coronary artery disorders, and 36 for MP. Four were FP for GOH, 29 for CNSH, 7 for ACI and none were FP for MP. The positive predictive value of the backward stepwise removal procedure in identifying FP SDRs ranged from 0% (MP) to 78.4% (CNSH). Conclusions Although further adjustment is needed to improve the method presented herein, our results suggest that numerous FP signals because of co-prescription bias could be eliminated using an automated method. Copyright © 2013 John Wiley & Sons, Ltd. key words—pharmacovigilance; spontaneous reporting; adverse reaction; signal detection; bias; methods; pharmacoepidemiology

Background: Since the introduction of antiretroviral therapy (ART), human immunodeficiency virus (HIV)-infected patients have a drastically improved prognosis but at the same time they are also more affected by non-HIV related complications, such as chronic kidney disease. The objective of our study was to investigate the effect of proteinuria and tenofovir (TDF)-containing ART regimens on the temporal evolution of estimated glomerular filtration rate (eGFR). Methods: Between April 2008 and October 2012, we enrolled 395 patients with a complete renal evaluation among patients from the ANRS C03 Aquitaine cohort, a prospective hospital-based cohort of HIV-1-infected patients under routine clinical management in southwestern France. eGFR was estimated at each patient follow-up visit. A linear mixed model was used to analyze eGFR dynamics, accounting for change in TDF by modeling eGFR trajectory according to treatment periods. Results: At inclusion, 56.7% of patients were treated with TDF-containing ART regimens; prevalence of glomerular and tubular proteinuria was 7.9 and 10.8% respectively. A 1-year increase of cumulative exposure to TDF was significantly associated with a mean eGFR decrease of 1.27 mL/min/1.73 m2 (95% CI [-2.14 to -0.41]). Only a urine protein to creatinine ratio >100 mg/mmol and/or a urine albumin to creatinine ratio >70 mg/mmol were associated with eGFR trajectory (mean slope 6.18 mL/min/1.73 m2 per year; 95% CI [2.71 to 9.65]), whereas TDF use was not associated with such eGFR temporal evolution. Conclusion: Decline in kidney function is limited under routine clinical management with monitoring of renal function and interventions including decision to continue or discontinue TDF.

Computerized hospital databases are used for clinical and economic research. In France, the hospital administrative database, Programme de medicalisation des systemes d'information (PMSI), could be an interesting means for identifying cases of abuse and dependence in hospitals. PURPOSE: To assess the capability of PMSI to identify cases of abuse and dependence (medicines or illicit drugs; tobacco and alcohol not included). METHODS: Cross-sectional study, from October 1 to December 31, 2008, in teaching hospitals of Bordeaux. All hospitalizations with an ICD-10 code related to possible abuse or dependence were selected. Cases were validated by a committee composed of three pharmacologists using discharge summaries. RESULTS: Among the 34 816 patients registered in the PMSI during the study period, a total of 227 patients were pre-selected as potential cases; 21 patients, hospitalized for abuse or dependence, or complications of which, were included in the analysis. Mean age was 35 years. Substances implicated were buprenorphine (n = 8), benzodiazepines (n = 7), cannabis (n = 6), cocaine (n = 4), heroin (n = 3), amphetamine, ecstasy, morphine, codeine, and tramadol (n = 1, respectively); there was polydrug use in six cases. CONCLUSIONS: The PMSI database can be useful to identify certain cases of abuse and dependence. This pilot study has been conducted at a local level; as the PMSI is available in all hospital settings in France, further analysis could be done at the regional and national levels. Such data could be a valuable indicator to analyze trends and assess the medical consequences of substance abuse. Copyright © 2012 John Wiley & Sons, Ltd. Language: en

The methods for causality assessment of adverse drug reactions were developed in the 1970s and 1980s, alongside the development of pharmacovigilance. The French method is one of the earlier of these, following on from the pioneering works by Irey and Karch and Lasagna. Initially published in 1978, it was updated in 1985, and again in 2011. The main alterations to the original method are presented in tables annexed to this paper. The successive versions improved the presentation, provided more formalised definitions of the criteria for assessing causality, while at the same time ensuring the method remained easy to use. Causality assessment enables the causal link between a drug and the occurrence of an adverse reaction to be formalised and explained. It contributes to diagnosis, and to determining the action to be taken in case of an adverse drug reaction. It can contribute to the quality and the relevance of the data stored in pharmacovigilance databases.

Abnormal kidney function is common in the course of human immunodeficiency virus (HIV) infection. Here, we performed a cross-sectional analysis using 399 patients within the Aquitaine cohort (a hospital-based cohort of HIV-1-infected patients receiving routine clinical management) to estimate the prevalence of proximal renal tubular dysfunction (PRTD) associated with HIV infection. These patients did not differ statistically by sociodemographics, median age, years since HIV diagnosis, AIDS stage, or median CD4 cell count from the entire 3080 patient cohort. Antiretroviral therapy was received by 352 patients, with 256 given tenofovir (TDF); 325 had undetectable HIV plasma viral load, and 26 were diagnosed with PRTD. In multivariate analysis, significant independent associations were found between PRTD and age (odds ratio (OR) 1.28 per 5-year increase), atazanavir (OR 1.28 per year of exposure), and TDF (OR 1.23 per year) treatment. Among patients having received TDF-containing regimens over a 5-year period, PRTD remained significantly associated with TDF exposure when treatment was ongoing (OR 5.22) or had been discontinued (OR 11.49). Thus, cumulative exposure to TDF and/or atazanavir was associated with an increased risk of PRTD, with concern about its reversibility in patients with HIV.

Background: Anti-tumour necrosis factor (TNF) agents, through their intense immunoregulatory effect, have been suspected to increase the risk of malignant lymphoma. However, the classical epidemiological approaches conducted over about the last 10 years have not totally succeeded in addressing the question of a causal or artifactual association. Therefore, the analysis of a substantial set of case reports, although usually considered as poorly generalizable to the general population, could be particularly informative. Two main sources of case reports in postmarketing settings are available; publications in medical journals and reports to pharmacovigilance systems. Objective: The aim of the study was to compare the characteristics of case reports from both these sources in order to understand whether they provided the same information for the investigation of the causal link between lymphoma and anti-TNF agents. Methods: All case reports of malignant lymphoma in patients treated with an anti-TNF agent published in MEDLINE and all reports to the French pharmacovigilance system up to 1 February 2010 were identified. Cases of malignant lymphoma identified in postmarketing surveillance from both sources were compared regarding the following variables: age, sex, anti-TNF agent involved, indication for use, type of lymphoma, prior or concomitant immunosuppressive drugs and time to onset of lymphoma. Results: A total of 81 published case reports and 61 cases reported to the French pharmacovigilance system were compared. In published reports, patients were younger (p = 0.03) and more frequently receiving a first anti-TNF treatment (p = 0.03), particularly infliximab (p = 0.03). Conversely, in the pharmacovigilance system reports, a succession of different anti-TNFs (p = 0.03) and adalimumab (p< 0.0001) were more frequently reported. Lymphomas in patients treated with anti-TNF agents for Crohn’s disease were more prevalent in published cases than in pharmacovigilance reports (p< 0.0001), and in particular involved hepatosplenic T-cell lymphoma. Conversely, rheumatoid arthritis was the main indication for anti-TNF agents in pharmacovigilance reports (p = 0.01). Time to onset was markedly shorter in published cases (median 12 months) than in pharmacovigilance reports (median 30 months; p = 0.0001). Conclusions: Characteristics of published cases and those reported to the French pharmacovigilance system differed markedly for all characteristics tested, except sex and the use of prior or concomitant immunosuppressive drugs. Published case reports favoured convincing arguments for drug causation whereas cases reported to the pharmacovigilance system were more disparate but could describe more accurately the reality of lymphoma occurrence in this particular population. These results argue for the use of the pharmacovigilance reports when case reports are used to investigate the causal link between lymphoma and anti-TNF agents at the population level. Data from cases notified to the French pharmacovigilance system did not indicate an increased risk of lymphoma during the early phase of anti-TNF treatment. To confirm this hypothesis, a study combining pharmacovigilance reports from several countries, or, if feasible, a cohort study both with a large sample size and a long duration of follow-up would be required.

The early detection of adverse reactions caused by drugs that are already on the market is the prime concern of pharmacovigilance efforts; the methods in use for postmarketing surveillance are aimed at detecting signals pointing to potential safety concerns, on the basis of reports from health-care providers and from information available in various databases. Signal detection methods based on the estimation of false discovery rate (FDR) have recently been proposed. They address the limitation of arbitrary detection thresholds of the automatic methods in current use, including those last updated by the US Food and Drug Administration and the World Health Organization's Uppsala Monitoring Centre. We used two simulation procedures to compare the false-positive performances for three current methods: the reporting odds ratio (ROR), the information component (IC), the gamma Poisson shrinkage (GPS), and also for two FDR-based methods derived from the GPS model and Fisher's test. Large differences in FDR rates were associated with the signal-detection methods currently in use. These differences ranged from 0.01 to 12% in an analysis that was restricted to signals with at least three reports. The numbers of signals generated were also highly variable. Among fixed-size lists of signals, the FDR was lowered when the FDR-based approaches were used. Overall, the outcomes in both simulation studies suggest that improvement in effectiveness can be expected from use of the FDR-based GPS method. Clinical Pharmacology & Therapeutics (2010) 88 4, 492–498. doi:10.1038/clpt.2010.111

Background: Cholinesterase inhibitors are used in Alzheimer’s disease, mostly in elderly persons with co-morbidities and receiving co-medications that could increase the risk of serious adverse reactions. Objective: To identify factors associated with serious adverse drug reactions (ADRs) in patients treated with cholinesterase inhibitors. Methods: All ADRs associated with donepezil, rivastigmine or galantamine were identified in the French pharmacovigilance database, from the launching of these drugs to January 2007. Serious ADRs (SADRs) were those that led to death, hospitalization or prolongation of hospitalization, or that were life threatening. A multiple logistic regression analysis was used to identify factors associated with seriousness in the reported adverse reactions. Results: We identified 773 reports of ADRs related to cholinesterase inhibitor use, among which 438 (57%) concerned SADRs. The median age of patients was 80 years (interquartile range: 75–84 years); 65.1% were women. The most represented ADRs were those responsible for CNS disorders (17.0%), gastrointestinal disorders (16.2%) and cardiac rhythm disorders (11.2%). Factors associated with an increased risk of SADRs were: age (odds ratio [OR] 1.92; 95% CI 1.22, 3.02 for subjects aged 85 years and over), use of atypical antipsychotics (OR 2.15; 95% CI 1.04, 4.46), use of conventional antipsychotics (OR 2.06, 95% CI 1.10, 3.85), use of antihypertensive drugs (OR 2.11; 95% CI 1.47, 3.02) and use of drugs targeting the alimentary tract and metabolism (OR 1.62; 95% CI 1.06, 2.46). The use of benzodiazepines (long-acting or others), antidepressants (tricyclic or others) or antiarrhythmic drugs was not associated with the reporting of SADRs. Conclusions: An increased risk of SADRs related to cholinesterase inhibitors was associated with the use of antipsychotics (with no difference between conventional and atypical antipsychotics), drugs targeting the alimentary tract/metabolism and antihypertensive drugs. It was not associated with the use of other psychotropic drugs, other non-psychotropic CNS drugs or with the use of antiarrhythmic agents. The association with drugs targeting the alimentary tract and metabolism could result from a protopathic bias or reflect the particular sensitivity to serious nausea and vomiting in patients already treated for gastrointestinal disorders. These results confirm that attention needs to be paid to patients receiving both cholinesterase inhibitors and antipsychotics.

Pharmacovigilance spontaneous reporting systems are primarily devoted to early detection of the adverse reactions of marketed drugs. They maintain large spontaneous reporting databases (SRD) for which several automatic signalling methods have been developed. A common limitation of these methods lies in the fact that they do not provide an auto-evaluation of the generated signals so that thresholds of alerts are arbitrarily chosen. In this paper, we propose to revisit the Gamma Poisson Shrinkage (GPS) model and the Bayesian Confidence Propagation Neural Network (BCPNN) model in the Bayesian general decision framework. This results in a new signal ranking procedure based on the posterior probability of null hypothesis of interest and makes it possible to derive with a non-mixture modelling approach Bayesian estimators of the false discovery rate (FDR), false negative rate, sensitivity and specificity. An original data generation process that can be suited to the features of the SRD under scrutiny is proposed and applied to the French SRD to perform a large simulation study. Results indicate better performances according to the FDR for the proposed ranking procedure in comparison with the current ones for the GPS model. They also reveal identical performances according to the four operating characteristics for the proposed ranking procedure with the BCPNN and GPS models but better estimates when using the GPS model. Finally, the proposed procedure is applied to the French data.

SUMMARY Purpose Data mining on electronic health records (EHRs) has emerged as a promising complementary method for post-marketing drug safety surveillance. The EU-ADR project, funded by the European Commission, is developing techniques that allow mining of EHRs for adverse drug events across different countries in Europe. Since mining on all possible events was considered to unduly increase the number of spurious signals, we wanted to create a ranked list of high-priority events. Methods Scientific literature, medical textbooks, and websites of regulatory agencies were reviewed to create a preliminary list of events that are deemed important in pharmacovigilance. Two teams of pharmacovigilance experts independently rated each event on five criteria: ‘trigger for drug withdrawal’, ‘trigger for black box warning’, ‘leading to emergency department visit or hospital admission’, ‘probability of event to be drug-related’, and ‘likelihood of death’. In case of disagreement, a consensus score was obtained. Ordinal scales between 0 and 3 were used for rating the criteria, and an overall score was computed to rank the events. Results An initial list comprising 23 adverse events was identified. After rating all the events and calculation of overall scores, a ranked list was established. The top-ranking events were: cutaneous bullous eruptions, acute renal failure, anaphylactic shock, acute myocardial infarction, and rhabdomyolysis. Conclusions A ranked list of 23 adverse drug events judged as important in pharmacovigilance was created to permit focused data mining. The list will need to be updated periodically as knowledge on drug safety evolves and new issues in drug safety arise. Copyright #2009 John Wiley & Sons, Ltd. key words—adverse event; data mining; drug safety; database; signal detection

Warnings concerning an increased risk of suicide in patients treated with selective serotonin reuptake inhibitors (SSRIs) re-emerged in early 2003, culminating in the broadcast of a television programme in the UK. In the following months, cumulated proportional reporting ratios showed that the most recently marketed drug, escitalopram, had a much higher proportion of reports of suicide to other adverse drug reactions (ADRs) than the other drugs in the class.To study the reporting patterns over time concerning suicide with the six SSRIs marketed in the UK as of March 2003 and their potential effect on disproportionality signal detection.Monthly cumulated numbers of reports were obtained from the UK Medicines and Healthcare products Regulatory Agency (MHRA), from the time of the first marketing of the drugs concerned and monthly for the 2 months prior to and the 9 months following the broadcast of the television programme (broadcast date: 11 May 2003), and the monthly ratio of suicide to other reports was computed for each SSRI individually and for all SSRIs combined.Of the six SSRIs studied, five (citalopram, paroxetine, fluoxetine, sertraline and venlafaxine) had been marketed for several years and escitalopram for only a few months. At the end of the analysis period, 1.42% (4/281) of all ADR reports for escitalopram were of suicide versus 0.58% for the other five drugs combined (146/25 197). For all SSRIs combined, suicide represented 0.5% (123/24 315) of reports before the broadcast of the television programme, and increased to 2.3% (27/1163) following the programme. For escitalopram, suicide represented 1.1% (1/89) of all ADR reports before the television programme and 1.6% (3/192) afterwards. For the five other drugs combined, suicide represented 0.5% (122/24 226) of ADR reports before the television programme and 2.5% (24/971) afterwards (varying from 1.4% to 4.7% for the various drugs). The post-programme events represented 68% of all reports and 75% of suicides for escitalopram, whereas for older drugs they represented 3.6% of reports and 13% of suicides.For older drugs, the events reported during the high-reporting post-television programme period were diluted by years of low reporting. For escitalopram, although the television programme had little absolute impact on the number of reports, because the drug had been on the market for such a short period of time, a large relative effect was observed. Differential effects related to time on market on cumulated reporting of adverse drug reactions should be taken into account when analysing spontaneous reporting databases with automated signal generation methods after an alert has changed the spontaneous reporting patterns. Proper use of measures of disproportionality requires thorough knowledge of potential biases and careful analysis of reporting patterns. We found no obvious differences between SSRIs once these were taken into account.