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Resume Introduction Les erreurs medicamenteuses sont parmi les plus frequents des evenements indesirables associes aux soins en France. La methodologie de gestion des erreurs medicamenteuses utilisee en milieu hospitalier n’a pas fait l’objet d’etudes specifiques en milieu ambulatoire. Objectifs L’objectif principal de notre travail etait d’experimenter la gestion des erreurs medicamenteuses en soins primaires. Les objectifs secondaires etaient de caracteriser ces erreurs et d’analyser leurs causes profondes pour mettre en œuvre des actions correctives. Methodologie L’etude a ete mise en place dans une maison de sante pluriprofessionnelle en appliquant les etapes et les outils valides et preconises par la Haute autorite de sante que nous avons adaptes a la pratique ambulatoire. Resultats Pendant les 3 mois de l’etude, 4712 consultations medicales ont ete effectuees et 64 erreurs medicamenteuses ont ete recueillies. Elles concernaient les patients aux âges extremes de la vie (9,4 % avant l’âge de 9 ans et 64 % apres 70 ans) et survenaient au domicile du patient dans 39,1 % des cas, a la maison de sante dans 25,0 %, a la pharmacie dans 17,2 %. Les erreurs ont conduit a une atteinte clinique grave (classee majeure, critique ou catastrophique) dans 17, 2 % des cas. Des effets indesirables dus aux medicaments sont survenus dans 5 cas (7,8 %) dont 3 ont ete hospitalises (1 cas d’evolution favorable, 1 cas avec sequelles, 1 deces). Dans plus de la moitie des cas, la prescription etait l’etape initiale de survenue de l’erreur. Les erreurs les plus frequentes etaient l’erreur de medicament qui ne correspondait pas a celui qu’aurait du recevoir le patient (37,5 %) et la mauvaise observance (18,75 %). Les causes systemiques mises en evidence etaient : un defaut dans le processus de soins (coordination ou procedure), le contexte d’action du soignant (lieu de prise en charge, execution d’un acte non planifie, ou surcharge de travail), et les facteurs humains (etat du patient et du soignant). L’adhesion des personnels de sante a l’etude a ete excellente avec mise en œuvre d’actions correctives. Conclusion Cette etude a demontre qu’il etait possible mettre en œuvre la gestion des erreurs medicamenteuses en medecine generale au sein d’une equipe pluriprofessionnelle. Les conditions prealables au succes de cette demarche sont la presence d’un coordonnateur forme au sein de l’equipe, et l’utilisation de methodes et d’outils valides et simples d’utilisation. Ce travail revele egalement que les erreurs medicamenteuses en ambulatoire sont specifiques de l’organisation du circuit de soins avec des points de fragilite tels que les interfaces entre etablissements et domicile, la coordination des soins et l’implication du patient lui-meme dans sa prise en charge.

Resume Il y a 40 ans les Centres regionaux de pharmacovigilance (CRPV) francais etaient crees afin de recueillir et analyser les effets indesirables medicamenteux. A ce jour, ces structures hospitalo-universitaires animees par des pharmacologues cliniciens ont gere et transmis plus de 583 000 effets indesirables medicamenteux aux autorites de sante francaises et europeennes et ont ainsi permis l’amelioration de la securite des patients traites. Les Centres regionaux de pharmacovigilance assurent egalement une activite de conseil et d’aide au diagnostic de la maladie medicamenteuse en renseignant et informant les professionnels de sante et les patients sur toute question relative au medicament et son bon usage. L’analyse de ces demandes d’informations permet en outre d’ajuster et de cibler la formation des professionnels de sante en matiere de prevention du risque et de bon usage du medicament. Outre la detection des signaux et l’identification des alertes, les CRPV collaborent aux travaux de l’Agence nationale de securite sanitaire des produits de sante (ANSM), par leur expertise et leur participation aux differents groupes de travail et commissions. Enfin, les CRPV participent au progres scientifique dans le cadre d’activites de recherche et de publication.

International audience; Background:Iodinated and gadolinium-based contrast media (ICM; GBCM) induce immediate hypersensitivity (IH) reactions. Differentiating allergic from non-allergic IH is crucial; allergy contraindicates the culprit agent for life. We studied frequency of allergic IH among ICM or GBCM reactors.Methods:Patients were recruited in 31 hospitals between 2005 and 2009. Clinical symptoms, plasma histamine and tryptase concentrations and skin tests were recorded. Allergic IH was diagnosed by intradermal tests (IDT) with the culprit CM diluted 1:10, "potentially allergic" IH by positive IDT with pure CM, and non-allergic IH by negative IDT.Findings:Among 245 skin-tested patients (ICM = 209; GBCM = 36), allergic IH to ICM was identified in 41 (19.6%) and to GBCM in 10 (27.8%). Skin cross-reactivity was observed in 11 patients with ICM (26.8%) and 5 with GBCM (50%). Allergy frequency increased with clinical severity and histamine and tryptase concentrations (p 50% of life-threatening ones. GBCM and ICM triggered comparable IH reactions in frequency and severity. Cross-reactivity was frequent, especially for GBCM. We propose considering skin testing with pure contrast agent, as it is more sensitive than the usual 1:10 dilution criteria.

Medication errors are the most frequent medical care adverse events in France. Their management process used in hospital remains poorly applied in primary ambulatory care.The main objective of our study was to assess medication error management in general ambulatory practice. The secondary objectives were the characterization of the errors and the analysis of their root causes in order to implement corrective measures.The study was performed in a pluriprofessionnal health care house, applying the stages and tools validated by the French high health authority, that we previously adapted to ambulatory medical cares.During the 3 months study 4712 medical consultations were performed and we collected 64 medication errors. Most of affected patients were at the extreme ages of life (9,4 % before 9 years and 64 % after 70 years). Medication errors occurred at home in 39,1 % of cases, at pluriprofessionnal health care house (25,0 %) or at drugstore (17,2 %). They led to serious clinical consequences (classified as major, critical or catastrophic) in 17,2 % of cases. Drug induced adverse effects occurred in 5 patients, 3 of them needing hospitalization (1 patient recovered, 1 displayed sequelae and 1 died). In more than half of cases, the errors occurred at prescribing stage. The most frequent type of errors was the use of a wrong drug, different from that indicated for the patient (37,5 %) and poor treatment adherence (18,75 %). The systemic reported causes were a care process dysfunction (in coordination or procedure), the health care action context (patient home, not planned act, professional overwork), human factors such as patient and professional condition. The professional team adherence to the study was excellent.Our study demonstrates, for the first time in France, that medication errors management in ambulatory general medical care can be implemented in a pluriprofessionnal health care house with two conditions: the presence of a trained team coordinator, and the use of validated adapted and simple processes and tools. This study also shows that medications errors in general practice are specific of the care process organization. We identified vulnerable points, as transferring and communication between home and care facilities or conversely, medical coordination and involvement of the patient himself in his care.

Resume Objectif Analyser l’interaction entre la pristinamycine et les antivitamine K (AVK) en utilisant les notifications spontanees enregistrees dans la base nationale de pharmacovigilance francaise (BNPV). Methodes Les cas d’augmentation de l’activite d’un AVK lorsque la pristinamycine etait associee notifies dans la BNPV entre 1985 et le 30 novembre 2013 ont ete inclus. Les donnees relatives aux patients, aux traitements par AVK et aux effets indesirables, ont ete recueillies pour une analyse descriptive. Resultats Durant cette periode, 31 cas d’effets indesirables temoignant d’un surdosage en AVK lors de l’association avec la pristinamycine ont ete inclus. La fluindione etait l’AVK majoritairement implique (77% des cas). Dans 20 cas (64,5 %), le surdosage en AVK s’est manifeste par une hemorragie et 24 cas (77,4 %) ont ete graves. Conclusion Bien que le mecanisme ne soit pas identifie, l’interaction pristinamycine/AVK est une realite qui necessite d’etre signalee dans le resume des caracteristiques du produit de ces medicaments et surtout d’etre mieux connue des praticiens dans l’interet des patients.

International audience; What is known and objective The risk of dosage Prescription Medication Error (PME) among manually written prescriptions within ‘mixed’ prescribing system (computerized physician order entry (CPOE) + manual prescriptions) has not been previously assessed in neonatology. This study aimed to evaluate the rate of dosage PME related to manual prescriptions in the high-risk population of very preterm infants (GA \textless 33 weeks) in a mixed prescription system. Methods : The study was based on a retrospective review of a random sample of manual daily prescriptions in two neonatal intensive care units (NICU) A and B, located in different French University hospitals (Dijon and La Reunion island). Daily prescription was defined as the set of all drugs manually prescribed on a single day for one patient. Dosage error was defined as a deviation of at least ±10% from the weight-appropriate recommended dose. Results and discussion : The analyses were based on the assessment of 676 manually prescribed drugs from NICU A (58 different drugs from 93 newborns and 240 daily prescriptions) and 354 manually prescribed drugs from NICU B (73 different drugs from 131 newborns and 241 daily prescriptions). The dosage error rate per 100 manually prescribed drugs was similar in both NICU: 3·8% (95% CI: 2·5–5·6%) in NICU A and 3·1% (95% CI: 1·6–5·5%) in NICU B (P = 0·54). Among all the 37 identified dosage errors, the over-dosing was almost as frequent as the under-dosing (17 and 20 errors, respectively). Potentially severe dosage errors occurred in a total of seven drug prescriptions. None of the dosage PME was recorded in the corresponding medical files and information on clinical outcome was not sufficient to identify clinical conditions related to dosage PME. Overall, 46·8% of manually prescribed drugs were off label or unlicensed, with no significant differences between prescriptions with or without dosage error. The risk of a dosage PME increased significantly if the drug was included in the CPOE system but was manually prescribed (OR = 3·3; 95% CI: 1·6–7·0, P \textless 0·001). What is new and conclusion : The presence of dosage PME in the manual prescriptions written within mixed prescription systems suggests that manual prescriptions should be totally avoided in neonatal units.

Etat de la question Le role de l’endotoxemie liee a la translocation bacterienne sur l’aggravation de la cirrhose fait l’objet de nombreuses etudes, mais son impact sur la mortalite au cours de la cirrhose est mal connu. Le but de ce travail etait d’etudier l’impact de la concentration sanguine de 3-hydroxymyristate (3-HM) total (composant specifique des lipopolysaccharides, endotoxine), sur le risque de deces et de complications des malades cirrhotiques. Materiel et methodes Au total, 593 patients atteints de cirrhose alcoolique ou virale, sans carcinome hepatocellulaire ont ete inclus entre 2008 et 2012 dans six centres hospitalo-universitaires francais. Le dosage de 3-HM total, libre et lie aux lipoproteines a ete realise en l’absence de complication aigue de la cirrhose par une methode innovante et brevetee de dosage massique des LPS. Le suivi annuel pendant cinq ans a permis de relever la survenue de complications ou du deces. L’analyse de survie a ete realisee par un modele de Cox multivarie avec stratification sur le centre et la severite de la cirrhose. Resultats Les patients avec une concentration de 3-HM elevee avait une cirrhose plus severe que les autres selon les scores de Child-Pugh et de Meld (p Conclusion Une concentration elevee de 3-HM, marqueur specifique de l’endotoxemie, est associee a un sur-risque de deces a cinq ans chez les patients avec cirrhose alcoolique ou virale compensee (Child Pugh A) suggerant un role majeur de la translocation bacterienne dans l’aggravation de la cirrhose.

Resume La plupart des etudes sur les effets indesirables medicamenteux (EIM) montrent qu’un certain nombre sont « evitables ». Des methodes de mesure de l’evitabilite des EIM existent mais aucun auteur n’a clairement evalue la validite de telles methodes. Ainsi, a ce jour, aucune echelle de mesure de l’evitabilite ne represente un « gold standard ». Pour etre validee, une echelle doit posseder les qualites d’un bon instrument de mesure : la convenance (ou validite de contenu), la fiabilite, la validite contre critere et l’applicabilite. Ce travail presente les deux premieres etapes d’une etude de validation d’une echelle francaise d’evitabilite des EIM (convenance et fiabilite). La premiere etape a consiste a construire une echelle d’evitabilite (choix et formulation des items, choix d’un score global et de categories d’evitabilite, par consensus entre experts). Durant la seconde etape, plusieurs experts ont teste cette nouvelle echelle pour evaluer l’evitabilite d’un echantillon d’EIM. La comprehension de certains items et l’accord interjuges se sont reveles mediocres. Cette etude montre la faisabilite d’une etude de validation et surtout la necessite de poursuivre cette demarche afin de disposer d’une echelle de mesure fiable d’evaluation de l’evitabilite des EIM.

Resume Objectif. – Decrire les effets indesirables osteo-articulaires du bupropion. Methodes. – Les observations d’effets indesirables lies au bupropion notifiees entre octobre 2001 et decembre 2002 au centre de pharmacovigilance de Bourgogne ont ete retrospectivement relues. Celles faisant etat d’effets indesirables rhumatologiques, imputes au bupropion apres l’enquete de pharmacovigilance ont ete collectees et analysees. Resultat. – Quatre observations ont ete collectees. Il s’agissait trois fois de reactions d’hypersensibilite semi-retardee, type maladie serique, se traduisant cliniquement par une urticaire, des arthralgies et parfois de la fievre. La derniere observation etait tout a fait originale, etant constituee par une monoarthrite aigue du poignet, survenue dans les jours suivant l’introduction du traitement. Conclusion. – Les reactions d’hypersensibilite sous bupropion sont relativement frequentes et parmi elles, il faut signaler de rares cas d’equivalents de maladies seriques. Une urticaire et des arthralgies invalidantes dominent le tableau clinique et peuvent mener a des hospitalisations de courte duree. Les antihistaminiques constituent le traitement de choix. D’autres manifestations a type de monoarthrite aigue semblent possibles, mais cette premiere observation necessite une confirmation.

Acute liver enzyme elevations (ALEE) have been associated with a first-line highly active antiretroviral therapy (HAART) and/or viral hepatitis coinfections in HIV-infected patients. By comparison, the frequency and the risk factors of ALEE in untreated patients and in patients treated with several antiretroviral regimens need to be assessed.To describe the long-term frequency and the characteristics of ALEE in antiretroviral treated and untreated patients and to define risk factors for ALEE in a retrospective cohort of HIV-1-infected patients.An HIV-infected cohort was retrospectively examined. ALEE was defined as levels of alanine amino transferase and/or alkaline phosphatase rising to at least 2.5 times above baseline values. Hazard ratios (HR) for ALEE were estimated using an extension of the Cox proportional model taking into account recurrent events.Out of 239 assessable patients, 12 (5%) were coinfected with hepatitis B virus (HBV) and 34 (14.2%) with hepatitis C virus (HCV). The incidence rate of ALEE was 9.9/100 patients-year and the cumulative incidence was 20.9%. HCV genotype 3 tended to give a higher risk of ALEE. Independent factors for developing ALEE in multivariate logistic regression were HBV (HR = 4.0) and HCV (HR = 3.4) coinfections, antiretroviral therapy (HR = 2.6), CDC stage C (HR = 2.5), and high alkaline phosphatase baseline values (HR = 1.7).The occurrence of ALEE is influenced more by the past medical history and the clinical background of the patients than by antiretroviral therapy. These patient-linked variables must be taken into account to avoid unwarranted treatment withdrawal.

The incidence of hepatic adverse drug reactions (ADRs) remains unknown in the general population. The goal of this population-based study was to assess the incidence and seriousness of hepatic ADRs. All new cases of symptomatic drug-induced hepatic injuries were collected by 139 trained physicians (general practitioners [GPs] and specialists) between November 1997 and November 2000 in an area containing 81,301 inhabitants who could not go elsewhere for medical care. Over 3 years, 34 cases of hepatic ADRs were collected, 82% of them in outpatients. Global crude annual incidence rate was 13.9 +/- 2.4 per 100,000 inhabitants; corresponding standardized annual global rate was 8.1 +/- 1.5. There was no difference between urban and rural areas. Standardized incidence female/male ratio was 0.86 (0.26-2.90) until 49 years of age and 2.62 (1.00-6.92) after this age. Diagnosis was carried out by GPs in half of the cases. The outcome was recovery for 32 patients and death for 2. The main drugs implicated were anti-infectious, psychotropic, hypolipidemic agents, and nonsteroidal anti-inflammatory drugs (NSAIDs). Our results suggest that the number of hepatic ADRs in the French population would be 16 times greater than the number noted by spontaneous reporting to French regulatory authorities. In conclusion, the incidence and seriousness of drug-induced hepatitis are largely underestimated in the general population. These results may be useful for further evaluation of drug-induced hepatotoxicity.

Background and aim: Non-steroidal anti-inflammatory drugs (NSAIDs) represent one of the most frequently prescribed drugs. Gastrointestinal damage, the most common side effect of NSAIDs, can be limited by the prescription of cytoprotective agents. In order to assess determinants of NSAID-associated cytoprotective agent prescriptions in primary care practice, we performed a general practitioner (GP)-based study. Methods: After a 2-month intensive information campaign, the participation of all GPs of the Cote d'Or (France) administrative area was requested. During a 2-month period, GPs had to return a mailed questionnaire on NSAID prescription for up to ten consecutive patients aged over 18 years who required NSAIDs. This 30-item questionnaire included questions about the patient, the type of NSAID and the GP. Results: GP participation rate was 24%, and 791 prescriptions were provided. GPs who participated in the study were representative of GPs of the area in terms of sex, time elapsed since graduation and GP practice area. Around 80% of the patients included in the study were under the age of 65 years. The proportion of prescriptions combining NSAIDs and gastroprotective agents was 29.5%. Omeprazole accounted for 58% of the co-prescriptions and misoprostol for 29%. Independent determinants associated with the co-prescription of a cytoprotective agent were age [odds ratio (OR) 4.1; confidence interval (CI) 95% 2.3–7.4], previous history of poor NSAID tolerance (OR 10.4; CI 95% 5.8–18.6), previous history of moderate to severe digestive disorders (OR 13.4; CI 95% 5.1–35.4) and indication for chronic illness (OR 1.8, CI 95% 1.1–3.1). Prescriptions of cytoprotective drugs were in conformity with official guidelines for 78.3% of the patients. Although around 60% of the patients with risk factors for poor tolerance received a gastroprotective drug, 50% of the patients over 65 years did not receive it. Conversely, nearly 12% of the patients with no risk factors were prescribed cytoprotective agents. Patient history was the main reason put forward by GPs for prescribing cytoprotective drugs. Conclusion: Although a large majority of GP prescriptions were in accordance with official recommendations, inadequate NSAID prescription practices remain relatively frequent especially with regard to the elderly.

PURPOSE: To quantify the risk of acute leukemia after adjuvant therapy, especially chemotherapy with topoisomerase II inhibitors. PATIENTS AND METHODS: We performed a population-based study in a cohort of 3,093 women younger than 85 years who resided in the French administrative area of the Côte d’Or, who were given a first diagnosis of primary breast cancer between 1982 and 1996, and who received a curative treatment. Information about therapy and follow-up events was obtained from records of cancer registries that covered this area. RESULTS: Until December 1998, 10 cases of acute leukemia, including nonlymphoid acute leukemia and refractory anemia with excess of blasts, occurred in patients before any local or distant recurrence. All cases developed in the first 4 years of follow-up. Compared with the general female population, the incidence rate of leukemia was significantly increased in women who received radiotherapy and chemotherapy (standardized incidence ratio, 28.5; P < .0001). A dose-dependent increase in the risk of leukemia was observed in women treated with mitoxantrone. Cox regression analysis showed that the risk of leukemia was significantly lower in patients treated with anthracyclines than in those treated with mitoxantrone at cumulative doses ≥ 13 mg/m2. CONCLUSION: The combination of adjuvant radiotherapy and chemotherapy with mitoxantrone induces a high risk of acute leukemia in patients with breast cancer. A leukemogenic effect of chemotherapy with anthracyclines cannot be ruled out with certainty. However, there are some suggestions that these topoisomerase II inhibitors might be less leukemogenic than mitoxantrone and could be preferred in an adjuvant setting.

We report the case of a 54-year-old woman with aplastic anemia, who developed transient pulmonary infiltrates following intravenous infusion of rabbit antithymocyte globulin (ATG) for 3 days. There was no other explanation than the infusion of ATG for the infiltrates. Rechallenge with ATG induced the recurrence of opacities on the chest radiograph. Although rarely involved with only 4 previous reports, ATG should be included in the list of drugs capable of inducing pulmonary infiltrates.

Synthetic coumarin (benzopyrone) was launched in France in 1988 for the adjuvant therapy of lymphoedema of the upper limb following radiosurgical treatment of breast cancer. Further to the reporting of hepatic reactions, a national survey has been carried out. The survey dealt with 22 cases reported to the pharmacovigilance regional centres and 20 to Knoll France company (five duplicate cases) up to June 1996. Thirty-four cases corresponding to an elevation of ALT over 2N and/or alkaline phosphatase over 1·5N (criteria chosen for selection in this survey) had been taken into account. Among these cases, a causal relationship was considered likely or probable for 15 of them. Two positive rechallenges were reported. The hepatic reactions observed between 2 to 6 months of treatment in two-thirds of the cases (average dose: 90 mg/day; i.e. recommended dose) was essentially cytolytic in 85% of the cases, with jaundice in 14 cases and hyperbilirubinaemia reported in five other cases. In 23 cases (68%), the increase of ALT exceeded 10N. Of the patients 41% were hospitalized. Severe liver failure with encephalopathy justified liver transplantation once and likely led to encephalopathy and fatal evolution in two other cases. The evolution was favourable in the other cases. The drug was prescribed for other uses than the registered indication in more than 50% of these cases. No risk factors could be identified in the survey. This survey provides a strong signal for potential hepatotoxicity of coumarin (likely due to the production of a reactive metabolite in some patients exhibiting a coumarin 7-hydroxylation deficiency). © 1998 John Wiley & Sons, Ltd.

Resume Introduction Le tramadol est autorise en France depuis 1994 pour le traitement des douleurs moderees a intenses. Les effets indesirables les plus couramment rencontres affectent le systeme nerveux central et le tractus gastro-intestinal. Il n’y a pas a notre connaissance de cas d’hypogycemie decrits dans la litterature. Observations Nous rapportons ici 2 cas d’hypoglycemie imputables au tramadol, survenus, l’un chez une femme âgee non diabetique, l’autre chez une fillette atteinte d’un diabete insulino-dependant. L’evolution a ete favorable a l’arret de ce medicament. Discussion Quelques cas d’hypoglycemie survenus chez des patients traites par tramadol sont decrits dans la Banque nationale de pharmacovigilance. L’existence de cas rapportes dans la litterature avec le dextropropxyphene, un autre opiace, et une etude de l’action pharmacologique du tramadol effectuee chez le rat, suggerent l’implication du recepteur opioide μ dans le mecanisme de l’hypoglycemie.

on si de re d ne ga tiv e or in tr av en ou s ad m in is tr at io n w ith no re ac tio n. TO THE EDITOR: Although immediate hypersensitivity reactions to iodinated contrast media (ICM) are well recognized, delayed cutaneous reactions (1 hour to 7 days) are much less easily diagnosed. The clinical manifestation usually is moderate, but sometimes serious reactions may occur. To our knowledge, we report the largest series of cutaneous delayed reaction that presented as acute generalized exanthematous pustulosis (AGEP) after ICM administration confirmed by skin testing. Skin tests performed 6 weeks after AGEP included patch tests followed by intradermal tests (IDT). ICMs tested were the same for all patients (ioxaglate, iomeprol, iopamidol, iodixanol, iohexol, iobitridol). Patch tests were conducted with undiluted ICM. Readings were conducted on days 2 and 4. Positive results were considered in accordance with the recommendations of the European Society of Contact Dermatitis. IDTs were performed with 10-fold diluted and undiluted ICM, and readings were conducted after 20 minutes and on day 2. Intravenous administration was performed 1 month later by using an alternative ICM that had negative skin tests and was also selected in consultation with the radiologist based on the ICM needed. The first dose injected was 0.5 mL. Two hours later, if no reaction occurred, then 2 mL was injected. The entire dose was administered only for the radiologic examination. All skin tests and intravenous administrations were conducted in a dermatology hospital unit.

To analyse pristinamycin/vitamin K antagonists (VKA) drug interaction by using data recorded in the French pharmacovigilance database (FPVB).All cases with an increase effect of a VKA and an association with pristinamycin recorded in the FPVB between 1985 and 2013 were included. Data concerning patients, VKA treatments and side effects were recorded for a descriptive analysis.During this period, 31 reports with a VKA overdose after an association with pristinamycin were included. Fluindione is the most often involved VKA (77% of cases). In 20 cases (65.4%), VKA overdose caused bleeding and 24 cases (77.4%) were serious.Although mechanism is unknown, pristinamycine/AVK drug interaction is a reality that needs to be reported in the summary of product characteristics of these drugs and better known by practitioners to act in patients' interest.

Introduction Iatrogenic events were defined as adverse drug reactions or complications induced by non-drug interventions, such as cardiac devices or stimulation techniques. Iatrogenic complications (IC) are associated with prolonged hospitalization and higher in-hospital mortality. In the real world IC are mainly evaluated during hospital stay. The present study focused on admission in a coronary care unit (CCU) for an adverse effect and we aimed: a) to evaluate the prevalence and the characteristics of these admissions and the types of iatrogeny; b) and to assess the in-hospital mortality. Methods From April 2008 to May 2012, all the consecutive admissions caused IC at the CCU were prospectively studied and classified in 2 groups: 1) pharmacological adverse effect (antiarrythmics, anticoagulant, and antiplatelets), 2) non pharmacological adverse effect (pace maker, Automatic Implantable Cardiovertor Defibrillator, radiofrequency, stent, cardiac surgery). Results On 7550 admissions, 302 (4%) IC as admission cause were included in the study. Most patients with IC were male (58%) with a mean age at 71±15 years. The in-hospital mortality of IC group was similar to those in the general population (8% for both). The following table presents the results of the 2 groups (N (%) or mean±SD). N (%) Men Age (y) Hospital death Total 302 178(58%) 71±15 25(8%) Non pharmacological adverse effect 161 (53%) 79(49%) 75±14 13(8.1%) Pharmacological adverse effect 141 (47%) 99(70%) 67±17 12(8.5%) p p p p=0.891 Conclusion This preliminary work shows the high frequency of iatrogenic events as a cause of CCU. Work will be necessary to better understand the causes of iatrogeny in order to limit this pathology.

Objective. – To describe joint symptoms related to bupropion therapy. Methods. – We retrospectively reviewed adverse events in bupropion-treated patients reported to the Bourgogne Drug Surveillance Center, France, between October 2001 and December 2002. Joint symptoms classified by the causality assessment as related to bupropion were identified and examined. Results. – Four cases were found. Three patients had semi-delayed hypersensitivity reactions resembling serum sickness, manifesting as urticaria and arthralgia with or without a fever. The remaining patient had an unusual presentation consisting in acute monoarthritis of the wrist that started a few days after bupropion initiation. Conclusion. – Hypersensitivity reactions to bupropion are fairly common and include rare cases of serum sickness-like reaction. Urticaria and incapacitating arthralgia are at the forefront of the clinical picture and may require a brief period of inpatient care. Antihistamines are the treatment of choice. Other manifestations such as acute monoarthritis might occur, although this awaits confirmation as we identified a single case.

Objectives: To compare characteristics of patients exhibiting cetuximab infusion reactions or another adverse drug reaction related to cetuximab and to identify factors associated with the severity of cetuximab infusion reactions. Methods: All cases of adverse drug reaction reported with cetuximab from 1985 to 2010 were extracted from the French Pharmacovigilance database. The severity of infusion reactions was assessed according to the NCI-CTCAE criteria (v4.0). Multiple logistic regression analysis was performed to identify factors associated with the severity of infusion reactions. Results: Among the 602 adverse drug reaction reported with cetuximab during the study period, 374 infusion reactions were identified. Indication is more likely to be head and neck than colorectal cancer among patients experiencing an infusion reaction ( p Conclusion: Our study found that reports of infusion reactions more often concerned patients treated for head and neck cancer, that in these patients the adverse drug reaction was more often fatal and severe infusion reactions were more likely during the first administration. In daily practice, the close monitoring of patients during the first infusion, especially patients with head and neck cancer, is recommended. Considering the possible immunoglobulin E–mediated mechanism, reliable tests for their detection need to be readily available.

To report the first case of severe hypoglycaemia episodes related to voriconazole, involving neither over dosage nor any identified interaction with hypoglycaemic drugs. A 51-year-old man developed faints without loss of consciousness, with sweating in the morning for 3-4 days and low blood glucose, about 1 month after initiating voriconazole therapy. Hypoglycaemia was diagnosed and the patient required permanent intravenous glucose solutions for 8 days after voriconazole was stopped, after which glycaemia remained normal. A hyperinsulinaemia peak was observed, which disappeared when glycaemia normalized. Hypoglycaemia is known as a less common adverse event resulting from high voriconazole concentration and hepatic dysfunction. The mechanism of hypoglycaemia may be linked to insulinemia as its serum values are similar to glycaemia. Voriconazole may induce hypoglycaemia in patients without over dosage nor drug interaction.

Tramadol has been approved in France since 1994 for the treatment of moderate to severe pain. The most commonly reported adverse effects involve the central nervous system and gastrointestinal tract. To our knowledge, hypoglycemia has not previously been reported.We report 2 cases of hypoglycemia related to tramadol, one in a nondiabetic 88-year-old woman, and the other in a diabetic 8-year-old girl. Hypoglycemia resolved after tramadol discontinuation.The French Pharmacovigilance (Adverse Drug Reports) database includes several cases of hypoglycemia in patients receiving tramadol. Reports from the literature of dextropropoxyphene-induced hypoglycemia and a pharmacological study of tramadol in rats suggest that the micro opioid receptor is the principal target involved in this hypoglycemic mechanism.

Adverse drug reactions (ADRs) have been recognised as an important cause of hospital admission. Most of these drug-related admissions were expected ADRs and, thus, partly preventable. However, as far as we know, the assessment of the preventability of ADRs was addressed in only two studies performed in France. In contrast, several other studies have been performed, mainly in the USA, and using different methods of assessing preventability. None of these methods were clearly evaluated with regard to reproducibility, validity or relevance. The purpose of this study was to initiate the validation of a French preventability scale. Here, we propose the first two phases of validation: the content validity and reliability of the scale. A working group of pharmacovigilance experts has been specifically established for this purpose. The content validity was assessed by collecting items representative of preventability. The choice and the formulation of items and a proposal of a score (global and for each item) were adopted after the consensus of the experts. A definitive version of the ADR preventability scale was used for the assessment of reliability. During the second phase, experts independently tested the new scale from observations of ADRs (49 central nervous system haemorrhages with antivitamine K). The concordance of the experts' judgements was calculated using two statistical methods (Kappa statistic and correlation coefficient). The content validity phase was performed during several workshops where experts discussed the choice and formulation of the best items. We decided to construct a scale with a small number of items, allowing a rapid evaluation of the preventability of ADRs. On the basis of a global score, four categories of preventability of ADRs ("preventable", "potentially preventable", "unclassable", "not preventable" ADRs) were proposed. The agreement of experts regarding the global score was low, with a poor correlation coefficient value (coefficient interclass = 0.491). Classification of ADRs in the four categories by the experts showed discrepancies (Kappa = 0.1136). The preventability assessment using this scale was feasible, although poor concordance between the judges has raised some questions. Several experts found use of this scale difficult in terms of a clear understanding of the items, and found that two of them were redundant. We have oversimplified some items and revision of their formulation will be necessary. Moreover, most of ADR notifications were poorly documented, resulting in a frequent choice of an "unevaluable" item. This represented an important bias in the calculation of the global score. This experience suggests the need for further studies to improve this French ADR preventability scale and validate it in differing circumstances, in order to provide a useful tool to enhance the rational use of drugs.

To examine whether the risk of some selected adverse effects increases with the number of systemic non-steroidal anti-inflammatory (NSAID) drugs. The French Pharmacovigilance database was examined for an association between drug reaction reports and the exposure to one and two or more NSAIDs using a case/non-case study design. In the analysis, 54,583 spontaneous reports of adverse drug reactions were included, consisting of 2270 reports of hepatic injury, 994 reports of acute renal failure, 194 reports of gastrointestinal bleeding and 525 reports of angioedema, among others. Use of NSAIDs significantly increased the risk of hepatic injury, gastrointestinal bleeding, acute renal failure and angioedema. The odds ratios tended to increase with the number of NSAIDs for hepatic injury, gastrointestinal bleeding and acute renal failure but not for angioedema. In comparison with reports that did not mention any use of NSAIDs, the odds ratios associated with the use of a single NSAID and two or more NSAIDs were respectively 1.2 (95%CI: 0.9–1.5) and 2.2 (95%CI: 1.3–3.8) for hepatic injury, 7.3 (95%CI: 4.9–10.9) and 10.7 (95%CI: 2.9–40.2) for gastrointestinal bleeding, 3.2 (95%CI: 2.5–4.1) and 4.8 (95%CI: 2.6–8.8) for acute renal failure. For angioedema, the odds ratios were roughly similar when a single NSAID (OR=2.7; 95% CI: 2.2–3.4) or two or more NSAIDs (OR=2.0; 95%CI: 0.7–6.0) were used. The risk of severe ADRs (hepatic injury and acute renal failure) was six- to sevenfold higher in reports mentioning concomitant use of two NSAIDs or more than in those that did not. This study shows that concomitant use of two or more NSAIDs was associated with an excess risk of adverse effects such as hepatic injury, acute renal failure and gastrointestinal bleeding. Although simultaneous use of several systemic NSAIDs has no pharmacological justification, this may raise a serious public health problem with the increasing use of over-the-counter non-steroidal anti-inflammatory agents.

The incidence of hepatic adverse drug reactions (ADRs) remains unknown in the general population. The goal of this population-based study was to assess the incidence and seriousness of hepatic ADRs. All new cases of symptomatic drug-induced hepatic injuries were collected by 139 trained physicians (general practitioners [GPs] and specialists) between November 1997 and November 2000 in an area containing 81,301 inhabitants who could not go elsewhere for medical care. Over 3 years, 34 cases of hepatic ADRs were collected, 82% of them in outpatients. Global crude annual incidence rate was 13.9 +/- 2.4 per 100,000 inhabitants; corresponding standardized annual global rate was 8.1 +/- 1.5. There was no difference between urban and rural areas. Standardized incidence female/male ratio was 0.86 (0.26-2.90) until 49 years of age and 2.62 (1.00-6.92) after this age. Diagnosis was carried out by GPs in half of the cases. The outcome was recovery for 32 patients and death for 2. The main drugs implicated were anti-infectious, psychotropic, hypolipidemic agents, and nonsteroidal anti-inflammatory drugs (NSAIDs). Our results suggest that the number of hepatic ADRs in the French population would be 16 times greater than the number noted by spontaneous reporting to French regulatory authorities. In conclusion, the incidence and seriousness of drug-induced hepatitis are largely underestimated in the general population. These results may be useful for further evaluation of drug-induced hepatotoxicity.

Purpose In order to assess biases occurring in primary care prescription studies, we compared non-steroidal anti-inflammatory drug (NSAID) prescribing patterns reported by general practitioners directly (GP-based survey) and from a pharmacy-based survey of general practitioner prescribing (pharmacy-based survey). Methods Volunteer GPs of the administrative area of Cote d'Or (France) returned a mailed questionnaire on NSAID prescribing patterns for consecutive patients seen during a 2-month period. In order to obtain a reference basis, pharmacies of the same administrative area provided all prescriptions that included NSAIDs during a 1-week period originating in general practice. Results The rate of participation was 25% for the GPs and 40% for the pharmacies. Participant GPs were representative of GPs of the area with regard to sex, year of graduation and practice area but pharmacies from rural areas were over-represented. The GP-based survey and the pharmacy-based survey provided respectively 770 and 1050 prescriptions. There were no differences between either survey in the type of NSAIDs prescribed and in the most frequently associated drugs. GPs who volunteered in the GP survey prescribed NSAIDs more frequently orally and at higher doses than GPs involved in the pharmacy-based survey. They also prescribed more gastroprotective drugs, especially in the elderly. None of these results could be explained by differences in patient characteristics and GP practice areas. Conclusion GPs who actively participate in prescription surveys exhibit prescribing patterns that fit better with official recommendations than the average. Although selection biases cannot be ruled out, it is suggested that some changes in GP prescription habits may have been induced by the survey itself. Copyright © 2001 John Wiley & Sons, Ltd.

Resume Introduction Parmi les causes de pancreatite aigue œdemateuse, la possibilite d’un surdosage nicotinique, meme si elle est exceptionnelle, doit etre envisagee. Observation Une femme âgee de 30 ans a ete hospitalisee pour le bilan etiologique d’un premier episode de pancreatite aigue œdemateuse. La mise en evidence d’anticorps anti-ADN natifs et d’anticorps anticardiolipides a fait discuter puis eliminer une pancreatite lupique et/ou un syndrome des antiphospholipides. Le diagnostic finalement retenu a ete celui d’un surdosage en nicotine lie a l’association entre des patchs de nicotine et la persistance d’un tabagisme actif. Conclusion Cette observation, bien qu’il n’ait pas ete decrit jusqu’alors de poussee de pancreatite aigue sous patch de nicotine, pourrait inciter a penser qu’une telle poussee peut etre une complication exceptionnelle d’un surdosage nicotinique.

Results: On-treatment platelet reactivity with clopidogrel 75mg, 150mg or prasugrel 10mg was always higher in elderly patients (n=197) than in younger patients (n=1074) whatever the test used. The difference in PRU in response to ADP-PGE1 agonist between the two populations was +45; p

This study investigated the effects of two K+ channel openers, aprikalim and pinacidil, on hypoxic pulmonary vasoconstriction induced in isolated rat lung perfused at constant flow. In order to evaluate the mechanism of the hypoxic vasoconstriction we also studied the effects of an inhibitor of the endothelium-derived relaxing factor (EDRF), NG-nitro-L-arginine methyl ester (100 microM), an inhibitor of the guanylate cyclase, methylene blue (30 microM), two K+ channel blockers, glibenclamide (1 microM) and tetraethylammonium (20 mM). In normoxia, NG-nitro-L-arginine methyl ester, methylene blue, glibenclamide or tetraethylammonium did not enhance significantly the baseline perfusion pressure, suggesting that neither EDRF nor K+ channels are involved in the modulation of the low basal pulmonary vascular tone. In hypoxia, aprikalim and pinacidil (0.03-3 microM) induced a concentration-dependent decrease of pulmonary pressure, exhibiting their spasmolytic effects in acute hypoxia. The hypoxic pressure response was significantly increased by NG-nitro-L-arginine methyl ester, methylene blue and tetraethylammonium, but not by glibenclamide suggesting that EDRF and K+ channels other than ATP-sensitive K+ channels are involved in the modulation of the hypoxic pressure response. The spasmolytic effects of aprikalim and pinacidil (1 microM) were not modified by NG-nitro-L-arginine methyl ester, but were partially reduced by tetraethylammonium and completely abolished by glibenclamide, suggesting that these effects are mainly but not exclusively mediated through ATP-sensitive K+ channel opening.

Introduction Iatrogenic complications are defined as adverse reactions that can be induced by non pharmacological cause, including cardiac devices or stimulation techniques. The use of cardiac devices has considerably increased over the last decade. However, only few data are available on non pharmacological iatrogeny (NPI) as cause of admission in coronary care unit (CCU). In patients admitted in CCU for iatrogenic, we aimed to determine the prevalence, characteristics and outcomes of NPI. Methods From 1st April 2008 to 31st December 2013, all the consecutive admissions at the coronary care unit caused by NPI defined as pacemaker (PM), Implantable Cardioverter Defibrillator (ICD), radiofrequency ablation (RFA), coronary angiography, valve surgery or transcatheter aortic valve implantation (TAVI) and any other cardiac procedure were prospectively included. Patients with NPI were compared with the other patients. Results Among the 11503 patients admitted in CCU over the inclusion period, 225(2%) had NPI. The major cause of admission was conduction disturbance, and acute coronary syndrome or dissection (figure).The most frequent origin was coronary angiography (25%), valve intervention (22%), PM (19%), ICD (18%). The number and rate of admission for NPI markedly increased from 2008(n= 15(1,1%)) to 2013(n=52(2,6%)). This trend was mostly linked to the increase between 2008 and 2013 in new devices such as ICD (n=4 vs n=10), TAVI (n=0 vs n=4) and RFA (n=0 vs n=2). The intra-hospital mortality was stable during this period for the overall patients and patients with NPI (8% and 7%). Conclusion Non pharmacological iatrogeny represents a non-negligible cause of admission in CCU, characterized by a increased rate of complications due to new techniques over the last 5 years. Multicentric studies are needed to investigate this public health issue. Download : Download full-size image Abstract 0121 – Figure