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Maude Laberge,1– 3 Caroline Sirois,2– 5 Carlotta Lunghi,3,6 Myriam Gaudreault,7 Yumiko Nakamura,8 Carolann Bolduc,4 Marie-Laure Laroche9,10 1Department of Operations & Decision Systems, Faculty of Administration, Université Laval, Quebec City, Quebec, Canada; 2Vitam, Centre de recherche en santé durable-Université Laval, Quebec, Canada; 3Centre de recherche du CHU de Québec-Université Laval, Quebec City, Quebec, Canada; 4Faculty of Pharmacy, Université Laval, Quebec City, Quebec, Canada; 5Institut National de santé publique du Québec, Quebec City, Quebec, Canada; 6Department of Health Sciences, Université du Québec à Rimouski, Rimouski, Quebec, Canada; 7Faculty of Administration, Université Laval, Quebec City, Quebec, Canada; 8College of Medicine, University of Florida, Gainesville, FL, USA; 9Centre de Pharmacovigilance, de Pharmacoépidémiologie et d’information sur les médicaments, Service de Pharmacologie, Toxicologie et Pharmacovigilance, CHU de Limoges, Limoges, France; 10Laboratoire Vie-Santé, Faculté de Médecine, Université de Limoges, Limoges, FranceCorrespondence: Maude LabergeDepartment of Operations & Decision Systems, Faculty of Administration, Université Laval, 2325 rue de la Terrasse, Bureau 2519, Quebec City, Québec, G1V 0A6, CanadaTel +1 418-656-2131 ext 407670Fax +1 418-656-2180Email Maude.laberge@fsa.ulaval.caPurpose: To conduct a systematic review of the economic impact of interventions intended at optimizing medication use in older adults with multimorbidity and polypharmacy.Methods: We searched Ovid-Medline, Embase, CINAHL, Ageline, Cochrane, and Web of Science, for articles published between 2004 and 2020 that studied older adults with multimorbidity and polypharmacy. The intervention studied had to be aimed at optimizing medication use and present results on costs.Results: Out of 3,871 studies identified by the search strategy, eleven studies were included. The interventions involved different provider types, with a majority described as a multidisciplinary team involving a pharmacist and a general practitioner, in the decision-making process. Interventions were generally associated with a reduction in medication expenditure. The benefits of the intervention in terms of clinical outcomes remain limited. Five studies were cost-benefit analyses, which had a net benefit that was either null or positive. Cost-utility and cost-effectiveness analyses resulted in incremental cost-effectiveness ratios that were generally within the willingness-to-pay thresholds of the countries in which the studies were conducted. However, the quality of the studies was generally low. Omission of key cost elements of economic evaluations, including intervention cost and payer perspective, limited interpretability.Conclusion: Interventions to optimize medication use may provide benefits that outweigh their implementation costs, but the evidence remains limited. There is a need to identify and address barriers to the scaling-up of such interventions, starting with the current incentive structures for pharmacists, physicians, and patients.Keywords: polypharmacy, economic evaluation, potentially inappropriate medication, cost-effectiveness, cost-utility, cost-benefit

BACKGROUND: Potentially inappropriate prescriptions (PIPs) in the older population remain a growing public health concern due to the many associated adverse events increasing healthcare service use and health costs. This study aimed to assess the prevalence and direct costs of PIPs in older adults aged ≥65 years in France. METHODS: A population-based cross-sectional study was conducted in 2017 using a representative sample of the French national healthcare reimbursement system database. PIPs were defined using the French REMEDI[e]S tool. Overall reimbursed direct costs and by PIP category were extrapolated to the French older population. RESULTS: The overall PIP prevalence was estimated at 56.7% (95% CI: 56.4-57.0). Medications with an unfavorable benefit/risk ratio had the highest prevalence (34.0%, 95% CI: 33.7-34.3). Direct costs associated with PIPs represented 6.3% of the total reimbursed medication costs in 2017 (€507 million). Drug duplications were the main contributors to these costs (39.2% of the total reimbursed PIP costs, €199 million) and among all PIPs, proton pump inhibitors (>8 weeks) were the most expensive PIPs (€152 million). CONCLUSIONS: PIP prevalence is still high among French older adults, with substantial direct costs. Large-scale interventions targeting the most prevalent and/or costly PIPs are needed to reduce their clinical and economic impacts.

Background: The revised Patients’ Attitudes Towards Deprescribing (rPATD) questionnaire allows capture of the beliefs and attitudes of older adults and caregivers towards deprescribing. Objectives: To translate and validate the rPATD questionnaire into French. Methods: The French rPATD was translated using forward-backward translation. Psychometric properties were evaluated in both older adults ≥65 years living in the community or in institutions and who were taking at least one chronic medication and in caregivers of older adults with similar characteristics. Participants were recruited in four French-speaking countries (Belgium, Canada, France and Switzerland). Face and content validity were assessed during the translation process. Construct validity (exploratory factor analysis (EFA)) and internal consistency (Cronbach's alpha) were investigated in questionnaires without missing data. Test-retest reliability was evaluated using intra-class correlation coefficient (ICC) in a sample of participants. Results: In total, 320 questionnaires from older adults and 215 questionnaires from caregivers were included to evaluate construct validity and internal consistency. EFA extracted four factors in the older adults' and caregivers' versions of the questionnaire consistent with the English rPATD. The extracted factors related to the perceived burden of medication taking, the beliefs in appropriateness of medications, concerns about stopping medications and the level of involvement in making decisions and of knowledge of medications. Internal consistency was satisfactory for three factors for both versions (Cronbach's alpha >0.70), with lower internal consistency in the concerns about stopping factor. Test-retest reliability was overall good for all factors in the caregivers' version (ICC > 0.75) while for the older adults' version, moderate (ICC range: 0.75–0.50) to good ICC values were found. Conclusions: The French rPATD presents globally good psychometric properties and can be used to explore attitudes towards deprescribing in French-speaking older adults and caregivers. Refereed/Peer-reviewed

The use of multiple medications is common in older adults but is associated with negative health outcomes. However, polypharmacy is not uniformly defined, and there is scant data on how the variety of definitions and their limitations hinder the development of sound scientific knowledge. The article intends to illustrate the challenges of this exposure definition. The array of thresholds for defining polypharmacy renders comparisons between results difficult. Few studies take into account the fact that polypharmacy is a changing exposure over time. In addition, although studies tend to recognize the confounding effect of multimorbidity, residual bias remains a concern. Current studies in polypharmacy often ignore basic epidemiological principles for defining exposure. Future research should integrate time-varying exposure and methods to better control confounding bias. This will help determine the positive/negative impacts of polypharmacy and help establish if polypharmacy conveys information beyond being a marker of health status.

Background: The high burden of disease-oriented drugs among older adults with limited life expectancy raises important questions about the potential futility of care. Aim: To describe the use of drugs of questionable clinical benefit during the last 3 months of life of older adults who died from life-limiting conditions. Design: Longitudinal, retrospective cohort study of decedents. Death certificate data were linked to administrative and healthcare registries with national coverage in Sweden. Setting: Older adults (≥75 years) who died from conditions potentially amenable to palliative care between 1 January and 31 December 2015 in Sweden. We identified drugs of questionable clinical benefit from a set of consensus-based criteria. Results: A total of 58,415 decedents were included (mean age, 87.0 years). During their last 3 months of life, they received on average 8.9 different drugs. Overall, 32.0% of older adults continued and 14.0% initiated at least one drug of questionable clinical benefit (e.g. statins, calcium supplements, vitamin D, bisphosphonates, antidementia drugs). These proportions were highest among younger individuals (i.e. aged 75–84 years), among people who died from organ failure and among those with a large number of coexisting chronic conditions. Excluding people who died from acute and potentially unpredictable fatal events had little influence on the results. Conclusion: A substantial share of older persons with life-limiting diseases receive drugs of questionable clinical benefit during their last months of life. Adequate training, guidance and resources are needed to rationalize and deprescribe drug treatments for older adults near the end of life.

The management of pharmacological therapy in older patients is challenging in clinical practice. Older subjects experience age-related changes that influence pharmacokinetics and pharmacodynamics of drugs, they also usually have multiple diseases, i.e., multimorbidity, and are often cared for, and hence, prescribed by a number of physicians over a long period of time. Therefore, it is not surprising that polypharmacy, literally the use of multiple drugs, is extremely common in older patients and is increasing over time, at least in developed countries. Appropriate geriatric pharmacotherapy, global assessment of patients’ clinical and functional parameters, and integration of skills from different healthcare professionals are needed to address the medical complexity of older adults. In this special issue, the most relevant aspects of geriatric pharmacotherapy are presented and critically discussed. The optimal management of drugs in older patients is a corner stone of the practice of geriatric medicine and one of the most important contributions to the evolution of health care in the direction of adapting contemporary clinical practice to the specific needs of older patients. However, while the tasks are clear, i.e., tailoring drug therapy according to the personal preferences and characteristics, increase patient safety by reducing adverse drug reactions, achieve the most favorable risk benefit ratio for each patient, periodically reviewing pharmacological therapy including deprescribing, as appropriate, the implementation in practice is often difficult, particularly when health care professionals are not geriatricians or clinical pharmacists.

International audience; Purpose To establish a consensus on both explicit and implicit criteria in order to identify potentially inappropriate prescribing (PIP) in French older people aged 75 years and over or 65 years and over with multimorbidity. Methods Fifteen experts in geriatrics, general practice, pharmacy, and clinical pharmacology were involved in a two-round Delphi survey to assess preliminary explicit and implicit criteria based on an extensive literature review and up-to-date evidence data. Experts were asked to rate their level of agreement using a 5-level Likert scale for inclusion of criteria and also for rationale and therapeutic alternatives. A consensus was considered as reached if at least 75% of the experts rated criteria as "strongly agreed" or "agreed." Results The new tool included a seven-step algorithm (implicit criteria) encompassing the three main domains that define PIP (i.e. overprescribing, underprescribing, and misprescribing) and 104 explicit criteria. Explicit criteria were divided into 6 tables related to inappropriate drug duplications (n = 7 criteria), omissions of medications and/or medication associations (n = 16), medications with an unfavourable benefit/risk ratio and/or a questionable efficacy (n = 39), medications with an unsuitable dose (n = 4) or duration (n = 6), drug-disease (n = 13), and drug-drug interactions (n = 19). Conclusion The REMEDI[e]S tool (REview of potentially inappropriate MEDIcation pr[e]scribing in Seniors) is an original mixed tool, adapted to French medical practices, aimed at preventing PIP both at the individual level in clinical practice and the population level in large-scale studies. Therefore, its use could contribute to an improvement in healthcare professionals' prescribing practices and safer care in older adults.

To analyze the process from the prescription of the drug to the health outcome, from a medical and pharmaceutical perspective, to prevent the occurrence of drug-related problems (DRPs) in older adults. A mapping of a logical process of drug use from the perspective of physicians, pharmacists, and patients has been established, but many fields remain unexplored (e.g. off-label use, substance use disorders, therapeutic failure), especially in some settings (e.g. home-dwelling) as little data is available in older adults. Prevention of DRPs imperatively requires taking into account the opinions of all healthcare professionals as well as those of patients and their caregivers. To lay the fundamentals of drug-related problems (DRPs) in older adults, and to organize them according to a logical process conciliating medical and pharmaceutical approaches, to better identify the causes and consequences of DRPs. A narrative overview. The causes of DRPs may be intentional or unintentional. They lie in poor prescription, poor adherence, medication errors (MEs) and substance use disorders (SUD). Poor prescription encompasses sub-optimal or off-label drug choice; this choice is either intentional or unintentional, often within a polypharmacy context and not taking sufficiently into account the patient’s clinical condition. Poor adherence is often the consequence of a complicated administration schedule. This review shows that MEs are not the most frequent causes of DRPs. SUD are little studied in older adults and needs to be more investigated because the use of psychoactive substances among older people is frequent. Prescribers, pharmacists, nurses, patients, and caregivers all play a role in different causes of DRPs. The potential deleterious outcomes of DRPs result from adverse drug reactions and therapeutic failures. These can lead to a negative benefit-risk ratio for a given treatment regimen. Interdisciplinary pharmacotherapy programs show significant clinical impacts in preventing or resolving adverse drug events and, suboptimal responses. New technologies also seem to be interesting solutions to prevent MEs. Better communication between healthcare professionals, patients and their caregivers would ensure greater safety and effectiveness of treatments.

Summary Aims To investigate the risk of intestinal obstruction associated with incretin-based drugs by performing a disproportionality analysis of adverse reaction reports in a global pharmacovigilance database. Methods We conducted a case/non-case analysis using VigiBase, the World Health Organization's adverse drug reactions (ADR) database, to assess intestinal obstruction reporting associated with incretin-based drugs (glucagon-like peptide 1 analogues [GLP-1a] and dipeptidyl peptidase 4 inhibitors [DPP-4i]. Cases were defined as reports of gastrointestinal stenosis and obstruction (MedDRA High Level Group Term) and non-cases were all other reactions recorded. Disproportionality analysis were performed by computing reporting odds ratios (ROR) with their 95% confidence interval (95%CI) within all ADR reports concerning diabetes drugs from January 2007 to January 2018 and in a restricted sample including only serious reports. Results A total of 501,244 ADR with diabetes drugs were reported in VigiBase during the study period. We identified 452 intestinal obstructions involving an incretin-based drug. In disproportionality analyses, intestinal obstructions were more than 4.5 times more frequently reported with incretin-based drugs than with other diabetes drugs (ROR 4.52, 95% CI: 3.87–5.28) with a higher signal for serious cases and for DPP-4i (ROR 8.66, 95% CI: 7.27–10.32) compared to GLP-1a (ROR 3.05, 95% CI: 2.54–3.66). Conclusions We identified a pharmacovigilance signal that suggests a risk of potentially serious intestinal obstruction associated with incretin-based drugs, as a class and with a greater signal for DPP4-i. Other studies are needed to confirm and better understand the potential risk of intestinal obstruction associated with incretin-based drugs.

Resume Introduction Les inhibiteurs de la pompe a protons (IPP) sont frequemment prescrits par les medecins generalistes (MG), qui les considerent comme surs. Cependant, de plus en plus d’effets indesirables (EI) associes aux IPP sont decrits. Objectif Determiner le niveau de connaissance et l’attitude des MG vis-a-vis des EI des IPP utilises chez les adultes. Methode Les MG de Nouvelle-Aquitaine et les chefs ou anciens chefs de clinique des 35 departements universitaires de medecine generale de France ont ete interroges en ligne sur une liste de 12 EI etablie a partir d’une revue semi-systematique de la litterature (neutropenie, thrombopenie, anemie, hypomagnesemie, augmentation des enzymes hepatiques, insuffisance renale, pneumopathie, reactions cutanees, fracture, polype gastrique, colite microscopique, colite a Clostridium difficile) et sur leur attitude vis-a-vis de ces EI. Resultat Sur les 232 MG participants, 38,4 % avaient ete confrontes aux EI des IPP (essentiellement digestifs) au cours des 6 derniers mois. Ces EI n’avaient ete rapportes a la pharmacovigilance que dans 2,3 % des cas. Aucun EI n’etait connu par plus de 70 % des MG. Pour les MG qui les connaissaient, l’attitude etait majoritairement l’arret de l’IPP. Aucune difference de connaissance n’a ete constatee entre les maitre de stage et les non-maitres de stage universitaire. Enfin, 74,7 % des MG ont declare avoir besoin d’informations sur les EI des IPP et 80,4 % etaient prets a les « deprescrire ». Conclusion Les EI lies aux IPP, hormis ceux d’ordre digestif, sont mal connus des MG. Ceux qui les connaissent ont une attitude appropriee en les arretant. L’information souhaitee par les MG sur les risques des IPP a toute sa place en particulier dans une demarche de prescription appropriee des IPP, qui passe aussi par savoir les « deprescrire ».

Aims To assess the 1-year persistence of potentially inappropriate medication (PIM) use and identify associated factors in community-dwelling older adults in Quebec, Canada. Methods A population-based cohort study was conducted using the Quebec Integrated Chronic Disease Surveillance System. Individuals insured by the public drug plan and aged ≥66 years who initiated a PIM between 1 April 2014 and 31 March 2015 were followed-up for 1 year. PIMs were identified using the 2015 Beers criteria. One-year persistence of PIM use was defined as continuous treatment with any PIM, without interruption for more than 60 days between prescriptions refills. Poisson regression models were performed to identify factors associated with 1-year persistence of any PIM. Results In total, 25.1% of PIM initiators were persistent at 1 year. In non-persistent individuals, the median time to PIM discontinuation was 31 days (interquartile range 21-92). Individuals were more persistent at 1 year with antipsychotics (43.9%), long-duration sulphonylureas (40.2%), antiarrhythmics/immediate-release nifedipine (36.5%) and proton pump inhibitors (36.0%). Factors significantly associated with persistence were an increased age, being a man and having a high number of medications and chronic diseases, especially dementia, diabetes and cardiovascular diseases. Conclusions One-quarter of community-dwelling older adults are continuously exposed to PIMs. To optimize medication prescribing in the older population, further interventions are needed to limit the use of PIMs most likely to be continued, especially in individuals most at risk of being persistent and also particularly vulnerable to adverse events.

Background Numerous studies have pointed out the need for better training of healthcare professionals in drug-drug interactions management in order to minimize adverse drugs reactions impacts on patients. The aim of this study was to evaluate the benefits of a blended learning strategy based on peer evaluation (PE) for teaching drug-drug interactions to undergraduate pharmacy students. Methods Third-year pharmacy students (n = 72) from the University of Limoges were involved in a hybrid teaching using the Moodle platform (2.9 version). After the theoretical lectures, an online activity was proposed to students. Each student submitted a report addressing a clinical case for peer evaluation. Students evaluated the pedagogical approach using an online survey. Quantitative benefits were assessed from students randomly assigned into two groups: PE in pharmacodynamics items (PE-PD) or PE in pharmacokinetics items (PE-PK). During this activity, three marks were given: one from peers for their evaluation work and two from teachers for oral group presentation of the clinical cases and for the final written examination. Statistics were performed using two-tailed unpaired t-test and significance was set for p Results Only a few students (n = 14, 20.6%) were aware of the peer evaluation principle and even less, only one student (n = 1, 1.5%), had already encountered it. Students considered that they benefited from this evaluation (n = 65, 95.6%); from their work being reviewed (n = 62, 91.2%) and that they participated in improving their classmates understanding (n = 59, 86.8%). Peers’ allocated marks were similar in the two PE groups (PE-PD = 17.4 ± 1.4; PE-PK = 17.3 ± 1.4). Teachers’ marks for oral presentation were significantly lower for pharmacodynamics than for pharmacokinetics items (PE-PD = 15.2 ± 1.2; PE-PK = 16.1 ± 2.1; p Conclusions Besides the fact that a major short-term quantitative improvement was not detected, our teaching approach was qualified as being a positive and stimulating learning tool by students.

Background Clinical guidance is needed to initiate, continue, and discontinue drug treatments near the end of life. Aim To identify drugs and drug classes most often adequate, questionable, or inadequate for older people at the end of life. Design Delphi consensus survey. Setting/participants Forty European experts in geriatrics, clinical pharmacology, and palliative medicine from 10 different countries. Panelists were asked to characterize drug classes as “often adequate,” “questionable,” or “often inadequate” for use in older adults aged 75 years or older with an estimated life expectancy of ≤ 3 months. We distinguished the continuation of a drug class that was previously prescribed from the initiation of a new drug. Consensus was considered achieved for a given drug or drug class if the level of agreement was ≥ 75%. Results The expert panel reached consensus on a set of 14 drug classes deemed as “often adequate,” 28 drug classes deemed “questionable,” and 10 drug classes deemed “often inadequate” for continuation during the last 3 months of life. Regarding the initiation of new drug treatments, the panel reached consensus on a set of 10 drug classes deemed “often adequate,” 23 drug classes deemed “questionable,” and 23 drug classes deemed “often inadequate”. Consensus remained unachieved for some very commonly prescribed drug treatments (e.g., proton-pump inhibitors, furosemide, haloperidol, olanzapine, zopiclone, and selective serotonin reuptake inhibitors). Conclusion In the absence of high-quality evidence from randomized clinical trials, these consensus-based criteria provide guidance to rationalize drug prescribing for older adults near the end of life. Electronic supplementary material The online version of this article (10.1007/s00228-018-2507-4) contains supplementary material, which is available to authorized users.

Resume Introduction L’utilisation des anticoagulants oraux directs (AOD) est complexe : indications, posologie, contre-indications, interactions, etc. Nous avons evalue leur mesusage et leurs effets indesirables dans un service d’urgence. Methode Il s’agissait d’une etude observationnelle prospective incluant les patients traites par AOD et admis dans le service des urgences du CHU de Limoges entre aout 2013 et avril 2014. Les criteres d’evaluation etaient le suivi des recommandations actuelles (indication, posologies, âge, adaptation a la fonction renale, etc.) et les effets indesirables. Resultats Cent quatre-vingt-dix-huit patients ont ete inclus traites par rivaroxaban (68,7 %), dabigatran (30,8 %) ou apixaban (0,5 %). Les principales indications etaient la prevention de l’accident vasculaire cerebral et de l’embolie pulmonaire dans le contexte de fibrillation auriculaire (78,7 %) et le traitement curatif de la maladie thromboembolique (17,2 %). La survenue d’un effet indesirable concernait 25,8 % d’entre eux (hemorragies 18,0 %, thromboses 7,8 %) avec 44,4 % d’hemorragies graves (criteres Haute Autorite de sante 2008). Au total, 16,2 % des patients etaient traites en dehors des recommandations ; 22 % de mauvaise indication, 78 % d’erreur posologique. Les accidents hemorragiques concernaient 36 patients et un mesusage etait retrouve dans 11,1 % des cas ; les evenements thrombotiques concernaient 15 malades, sans situation de mesusage. Conclusion Notre etude observationnelle dans un service d’urgence confirme l’existence d’un mesusage mais souligne le risque d’hemorragies spontanees.

Resume La prescription d’une specialite pharmaceutique en dehors d’une indication, d’une posologie ou chez une population particuliere peut conduire a un non-respect strict de l’autorisation de mise sur le marche (AMM) initiale, voire se situer hors AMM. Le respect de l’AMM impose des precautions et des responsabilites particulieres pour le prescripteur mais aussi, lors de la dispensation, pour le pharmacien.

Introduction Pristinamycin is an antibiotic of the streptogramin family; few adverse effects of this drug are reported, only cutaneous and digestive ones. Arthralgia and myalgia may however be observed although not mentioned in the summary of product characteristics. Objective Description and analysis of cases of pristinamycin-induced arthralgia and/or myalgia registered in the French database of pharmacovigilance. Method We carried out a targeted search of the database, selecting case patients presenting with arthralgia and muscle pain and excluding those associated with sensitivities or allergies to pristinamycin. Results We retrieved 15 case patients of pristinamycin-induced arthralgia and myalgia. Pristinamycin was the only potentially incriminated drug for seven case patients. Conclusion Although not serious, this adverse effect deserves to be better known by physicians to optimize therapeutic management.

Objectives Geriatric patients with hematologic malignancies (HMs) are prescribed targeted and supportive care treatments that add to the preexisting polypharmacy (PP). PP is associated with an increased risk of potentially inappropriate medications (PIM) and drug-drug interactions (DDI) resulting in increased hospitalization and mortality in the elderly. As very few data exist on these medication issues in the context of HMs, the objective of this study was to evaluate prevalence of PP, DDI and PIM use at baseline and 3 months among elderly patients with HMs who received baseline geriatric assessment. Methods PP, DDI and PIM use were assessed by a clinical pharmacist at two time points in patients over 75 years with HMs undergoing chemotherapy. PP was defined as the concurrent use of five or more medications. DDIs were evaluated according to the literature and prescription analysis software. PIMs were assessed according to the Laroche list. Results 122 patients (mean age 81.5; 6.6 medications) were included and after 3 months, 86 patients (5.8 medications) were available for a second assessment. Prevalence of PP, PIM and DDI at inclusion was 75.4%, 34.4% and 71.3%, respectively. PP was the only medication risk that was significantly reduced (p Conclusion This observational study highlighted that PP decreased over time but neither DDI nor PIM use were reduced. A pharmacist-led evaluation might help to manage these medication issues.

EnglishIn France, the missions of regional pharmacovigilance centres are to monitor, assess and prevent potential or proven medication risks and to promote the correct use of medicines. These organisations also play a role in informing and training health professionals whose involvement, by reporting adverse effects, is essential for the proper functioning of the national pharmacovigilance system. francaisEn France, les centres regionaux de pharmacovigilance ont pour missions de surveiller, evaluer et prevenir les risques medicamenteux potentiels ou averes et de promouvoir le bon usage du medicament. Ces structures ont aussi un role d’information et de formation des professionnels de sante. L’implication de ces derniers, via les notifications, est indispensable au fonctionnement du systeme national de pharmacovigilance.

Resume Le pharmacien d’officine est bien souvent un acteur de sante de premier recours pour la personne âgee face a son traitement. Comprendre les principaux facteurs de risque de survenue des effets indesirables chez les seniors permet d’ameliorer le bon usage des medicaments dans cette population.

An inappropriate immunologic response has been suggested to play a role in the pathogenesis of hidradenitis suppurativa (HS). Adalimumab was the first TNF-α inhibitor approved for moderate to severe HS. We report on a case of HS (Hurley stage 2) in a 39-year-old man, who had received fusidic acid and isotretinoin treatments without evident benefit during the last 8 years. The patient noticed a reduction in the number of lesions and quality of life (DLQI from 27 to 6) in the 2 months following verapamil initiation for cluster headache. When verapamil was stopped, the lesions recurred within 1.5 months. The patient resumed taking verapamil as before and a remission occurred. Verapamil has been shown to inhibit TNF-α and IL-1β in vitro and in vivo. We hypothesize that verapamil inhibits the inflammatory process through the TNF-α/IL-1 pathway involved in the HS physiopathology. Compared to biologic agents as anti-TNF-α (adalimumab) and anti-IL1 (anakinra), verapamil is safer and cheaper. Given its possible role on TNF-α/IL-1, verapamil may represent an alternative therapeutic option in mild and moderate HS.

BackgroundNon-optimal medication use among older adults is a public health concern. A concrete picture of potentially inappropriate medication (PIM) use is imperative to ensure optimal medication use.ObjectiveTo assess the prevalence of PIMs in community-dwelling older adults and identify associated factors.MethodsA retrospective population-based cohort study was conducted using the Quebec Integrated Chronic Disease Surveillance System (QICDSS). The QICDSS includes data on drug claims for community-dwelling older adults with chronic diseases or at risk of developing chronic diseases aged ≥65 years who are insured by the public drug insurance plan. Individuals aged ≥66 years who were continuously insured with the public drug plan between 1 April 2014 and 31 March 2016 were included. PIMs were defined using the 2015 Beers criteria. We conducted multivariate robust Poisson regression analyses to explore factors associated with PIM use.ResultsA total of 1 105 295 individuals were included. Of these, 48.3% were prescribed at least one PIM. The most prevalent PIMs were benzodiazepines (25.7%), proton-pump inhibitors (21.3%), antipsychotics (5.6%), antidepressants (5.0%) and long-duration sulfonylureas (3.3%). Factors associated with PIM exposure included being a woman [rate ratio (RR): 1.20; 95% confidence interval (CI): 1.20–1.21], increased number of medications and having a high number of chronic diseases, especially mental disorders (RR: 1.50; 95% CI: 1.49–1.51).ConclusionAlmost one out of two community-dwelling older adults use a PIM. It is imperative to reduce the use of PIMs, by limiting their prescription and by promoting their deprescribing, which necessitates not only the active involvement of prescribers but also patients.

There are numerous definitions of polypharmacy to describe the use of many medications among older adults, but there is a need to clarify if they are purposive and meaningful. By means of a systematic review, we identified definitions of polypharmacy used in multimorbid older adults (≥65 years). We evaluated if the definitions align among the domains of research, clinical practice, and public health and appraised whether concepts of polypharmacy are based on strong foundations. More than 46 definitions of polypharmacy were retrieved from 348 publications (research: n = 243; clinical practice: n = 88; public health: n = 17). Several thresholds based on the number of medications were mentioned. The majority of the publications (n = 202, 58%) used a minimal threshold of five medications. Heterogeneous qualitative definitions were identified, mostly stating that polypharmacy is “more drugs than needed”. There was no significant divergence between domains as to the type of definitions used, although qualitative definitions were more common in clinical practice. Nearly half (n = 156, 47%) of the publications provided no justification for the polypharmacy definition used. The wide variety of definitions for polypharmacy precludes comparisons, appropriate identification and management of polypharmacy in multimorbid older adults. Standardized definitions would allow more coherent judgments regarding the individual and collective stakes of polypharmacy.

Knowledge of the benefit/risk ratio of drugs in older adults is essential to optimise medication use. While randomised controlled trials are fundamental to the process of drug development and bringing new drugs to the market, they often exclude older adults, especially those suffering from frailty, multimorbidity and/or receiving polypharmacy. Therefore, it is generally unknown whether the benefits and harms of drugs established through pre-marketing clinical trials are translatable to the real-word population of older adults. Pharmacoepidemiology can provide real-world data on drug utilisation and drug effects in older people with multiple comorbidities and polypharmacy and can greatly contribute towards the goal of high quality use of drugs and well-being in older adults. A wide variety of pharmacoepidemiology studies can be used and exciting progress is being made with the use of novel and advanced statistical methods to improve the robustness of data. Coordinated and strategic initiatives are required internationally in order for this field to reach its full potential of optimising drug use in older adults so as to improve health care outcomes. Refereed/Peer-reviewed

Background Multimorbidity and polypharmacy are common in older people. Despite the existence of quality criteria for medication use among this population, there is little guidance for managing the complex pharmacological arsenal in a multimorbidity context. Objective To establish consensus on benefits, risks and impacts on quality of life of medications used in an older adult with three chronic diseases that require complex pharmacotherapy. Setting International experts in pharmacology. Method A panel of experts responded to three rounds of a Delphi survey. They assessed the benefits, risks and positive impacts on quality of life of 50 different medications or medication classes that could be used by a hypothetical multimorbid older patient aged 65–75years, with type2 diabetes, heart failure and chronic obstructive pulmonary disease. Each aspect was evaluated on a 5-level Likert scale. Main outcome measure Percentage of agreement on each of the three aspects for all medication. Results Consensus was reached on 95% of items (166/174). Only two medication classes were associated with both the highest category of benefits and positive impacts on quality of life, and the lowest risk category: long-acting anticholinergics and long-acting beta-2-agonists. Nine other medications/classes of medications were categorized within the highest benefits level (metformin, DPP-4-inhibitors, short-acting beta-2-agonists, ACE inhibitors, beta-blockers, warfarin, non-vitamin K oral anticoagulants, nitrates and acetaminophen). Fifteen medications were included in the highest level of risks, among which warfarin and Non-vitamin K oral anticoagulants. Conclusions Medications recommended in clinical guidelines for individual diseases are generally considered positive for multimorbid older patients. Nevertheless, a non-negligible number of medications was deemed negative or very negative by our panelists. For multimorbid patients, individualizing treatment according to their preferences seems of utmost importance.

To assess the evolution and quality of drug therapy throughout the last 3 months of life of older adults in need of palliative care. This study highlights the preferential prescription of essential drugs and deprescription of unnecessary drugs during the last 3 months of life in older adults. However, palliative care occurs principally during the last week of life and a high burden of unnecessary drugs is still found on the day of death. Both earlier implementation of palliative care and an improvement of prescribing practices are needed by setting up interventions to raise awareness and promote early physician–patient communication about care goals and potential benefits of deprescribing unnecessary drugs. Near the end of life, drugs to ensure comfort and improve quality of life should be prioritized, and unnecessary drugs should be avoided. The aim was to assess the evolution and quality of drug therapy throughout the last 3 months of life of older adults in need of palliative care. A single-center retrospective cohort study included older adults (≥ 65 years) who died in a teaching hospital between 1 January 2014 and 30 June 2014 and had been identified as patients in need of palliative care in their last 3 months of life. Drugs were collected from electronic medical records and defined as ‘unnecessary’ or ‘essential’ based on a review of the literature. A total of 149 patients were included [age: 82.1 (SD 8.6) years, women: 46.3%]. The mean number of medications varied from 6.7 (SD 3.3) drugs 90 days before death, to 7.5 (SD 4.1) 7 days before death, to 5.6 (SD 3.6) on the day of death. During the final week of life, one additional prescription of essential drugs was observed for 75.2% of patients and 79.3% of patients had at least one unnecessary drug deprescribed. The most prescribed and deprescribed drug classes were, respectively, analgesics (56.4%) and antithrombotic agents (38.2%) during the last week of life. Near the end of life, medication therapy is adapted to the goals of palliative care. However, this only occurs during the last week of life. Earlier transition to palliative care is necessary to avoid exposure to unnecessary drugs.

Frailty is a complex geriatric syndrome linked to the overall decrease of physiological reserves. It could lead to disability and to an increase in mortality. Frailty could have an impact on the effect and on the use of medications. Drugs could also affect the frailty process. Currently, no specific guidelines exist for appropriately prescribing medications to frail older people. The aim of this paper is to explore the body of current knowledge about the relationship between drugs and frailty in older people and to introduce a new nosological entity: pharmacological frailty.

Resume La nouvelle legislation europeenne, entree en vigueur en juillet 2012, a renforce l’organisation de la pharmacovigilance en mettant en place un Comite pour l’evaluation des risques en matiere de pharmacovigilance (Pharmacovigilance Risk Assessment Committee ou PRAC). Le PRAC est charge d’evaluer tous les aspects de la securite et de la gestion des risques des medicaments a usage humain au sein de l’Union europeenne. Il traite des questions portant sur les signaux de pharmacovigilance, les rapports periodiques de l’evaluation du rapport benefice/risque communiques par les laboratoires, les plans de gestion des risques, les etudes post-commercialisation, les variations ou renouvellements d’autorisation de mise sur le marche, la gestion de la liste des medicaments sous surveillance, les inspections pour un motif de pharmacovigilance et l’audit des systemes de pharmacovigilance. Le PRAC s’appuie sur les systemes de pharmacovigilance des Etats-membres qui sont charges de rediger des rapports d’evaluation. Ces evaluations sont echangees et discutees entre Etats-membres pour aboutir a des recommandations qui serviront pour d’autres instances europeennes du medicament, le Comite des medicaments a usage humain (Committee for Medicinal Products for Human Use ou CHMP) ou le Groupe de coordination des procedures de reconnaissance mutuelle et decentralisees pour les medicaments a usage humain (Coordination Group for Mutual Recognition and Decentralised Procedures-Human ou CMDh), qui donneront leur avis. La decision finale, qui s’applique a tous les Etats-membres et aux laboratoires titulaires de l’autorisation de mise sur le marche (AMM) concernes, revient a la Commission europeenne (CE). Ce systeme decisionnaire repose donc sur une coordination entre le PRAC, le CHMP, le CMDh, la CE, les Etats-membres et les laboratoires pharmaceutiques. Apres 3 ans d’existence, le PRAC a traite pres de 4500 procedures et continue a faire face a une charge d’activite croissante.

International audience; Background Renal transplantation is considered as the treatment of ă choice for patients with end-stage renal disease. Health-related quality ă of life (HRQoL) of renal transplant recipients (RTR) is very important ă to assess, especially during the first year after transplantation. To ă provide new evidence about the suitability of HRQoL measures in RTR ă during the first post-transplant year, we explored the internal ă structure, reliability and external validity of a French specific HRQoL ă instrument, the Renal Transplant Quality of life Questionnaire Second ă Version (RTQ V2). ă Methods The data were issued from the French multicenter cohort of renal ă transplant patients followed during 4 years (EPIGREN). The HRQoL of RTR ă was assessed five times (at 1, 3, 6, 9 and 12 months after ă transplantation) with the RTQ V2, a specific instrument consisting of 32 ă items describing five dimensions. Socio-demographic information, ă clinical characteristics and HRQoL (i.e., RTQ V2 and SF-36) were ă collected. For the five times, psychometric properties of the RTQ V2 ă were compared to those reported from the reference population assessed ă in the validation study. ă Results Three hundred and thirty-four patients were enrolled. The ă proportions of well-projected items, item-internal consistency, ă item-discriminant validity, floor and ceiling effects, Cronbach's alpha ă coefficients and item goodness-of-fit statistics were satisfactory for ă each dimension at the five times of the study. The suitability indices ă of construct validity were higher than 90 % for each time ă (minimum-maximum: 90.8-97.4 %). The external validity was less ă satisfactory, with a suitability indices ranged from 46.7 % at M1 to ă 66.7 % at M12. However, the discrepancies with the reference population ă (mainly for the gender) appeared logical considering the scientific ă literature on HRQoL of RTR during the first post-transplant year and may ă not compromise the external validity. ă Conclusion These results support the validity and reliability of the RTQ ă V2 for evaluating HRQoL in RTR during the first post-transplant year, ă and confirm that the RTQ V2 is a useful tool to assess the HRQoL ă precociously after transplant.

OBJECTIVE To evaluate the chronicity of polypharmacy among older adults and to identify factors associated with chronic polypharmacy. DESIGN Longitudinal cohort study using register data. SETTING Nationwide, Sweden. PARTICIPANTS All 711,432 older adults (aged 65 years and older) living in Sweden with five or more prescription drugs in October 2010 were included and followed up until December 2013. Mean age at baseline was 77 (SD = 7.8) years, 59% were women, and 7% lived in nursing homes. MEASUREMENT Monthly changes in the exposure to polypharmacy. Data regarding prescription drug use were extracted from the Swedish Prescribed Drugs Register. RESULTS Overall, 82% were continuously exposed to polypharmacy for 6 months or longer, and 74% for 12 months or longer. The proportion of individuals who remained exposed until the end of the study was 55%. Among the 21,361 individuals who had not been exposed to polypharmacy during the 6-month period before baseline (ie, with a new episode of polypharmacy), only 30% remained exposed for 6 months or longer. The proportion of older adults who spent at least 80% of their follow-up time with polypharmacy was substantially higher among prevalent polypharmacy users at baseline than among those with a new polypharmacy episode (80% vs 24%; P < .01). Factors associated with chronic polypharmacy included higher age, female sex, living in an institution, chronic multimorbidity, and multidose dispensing. CONCLUSION Polypharmacy is most often chronic, although a substantial share of older adults experience short, recurring episodes of polypharmacy and are thus exposed to its potential harms in a transient rather than persistent manner. J Am Geriatr Soc 67:455-462, 2019.

Lucas Morin,1 Kristina Johnell,1 Marie-Laure Laroche,2,3 Johan Fastbom,1 Jonas W Wastesson1 1Aging Research Center, Karolinska Institutet, Stockholm, Sweden; 2University Hospital of Limoges, Service de Pharmacologie, Toxicologie et Pharmacovigilance, Limoges, France; 3Faculté de Médecine, Université de Limoges, Limoges, France Objective: Polypharmacy is the concomitant use of several drugs by a single person, and it increases the risk of adverse drug-related events in older adults. Little is known about the epidemiology of polypharmacy at the population level. We aimed to measure the prevalence and incidence of polypharmacy and to investigate the associated factors. Methods: A prospective cohort study was conducted using register data with national coverage in Sweden. A total of 1,742,336 individuals aged ≥65 years at baseline (November 1, 2010) were included and followed until death or the end of the study (December 20, 2013). Results: On average, individuals were exposed to 4.6 (SD =4.0) drugs at baseline. The prevalence of polypharmacy (5+ drugs) was 44.0%, and the prevalence of excessive polypharmacy (10+ drugs) was 11.7%. The incidence rate of polypharmacy among individuals without polypharmacy at baseline was 19.9 per 100 person-years, ranging from 16.8% in individuals aged 65–74 years to 33.2% in those aged ≥95 years (adjusted hazard ratio [HR] =1.49, 95% confidence interval [CI] 1.42–1.56). The incidence rate of excessive polypharmacy was 8.0 per 100 person-years. Older adults using multi-dose dispensing were at significantly higher risk of developing incident polypharmacy compared with those receiving ordinary prescriptions (HR =1.51, 95% CI 1.47–1.55). When adjusting for confounders, living in nursing home was found to be associated with lower risks of incident polypharmacy and incident excessive polypharmacy (HR =0.79 and HR =0.86, p

Background Clinical practice guidelines are useful to suggest pharmacological therapies for the treatment of single chronic diseases. However, there is little guidance for multimorbidity, and specific quality measures for people with multimorbidity that can be used at a population level are lacking. Objective To describe what pharmacists and geriatricians consider to be an optimal basic pharmacological therapy for an older individual with type 2 diabetes (DM), chronic obstructive pulmonary disease (COPD) and heart failure (HF). Methods An online cross-sectional survey among 162 pharmacists and geriatricians, in Quebec, Canada, was performed. Participants were invited to choose, from a list of 32 medications or classes, the optimal basic therapy for an individual aged 65–75 years with the 3 chronic diseases. Descriptive statistics were used to calculate the median number of medications chosen and the proportions of participants who chose each medication, according to the participant's specialty. A Kruskall-Wallis test was performed to detect whether there were differences in the median number of medications recommended according to speciality. Results There was little consensus on the optimal basic pharmacological therapy for this hypothetical multimorbid individual, with 157 different combinations provided by the 162 participants. Nevertheless, 5 classes were chosen by at least 75% of the participants: metformin, long-acting anticholinergic agents, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), beta-blockers, and short-acting beta-agonists. The median number of recommended medications was 10 (interquartile range [IQR]: 6–13). There was a statistically significant difference between specialties (p = 0.0396). Geriatricians recommended the lower median number of medications, 7 (IQR: 5–10). Conclusions At least half of the participants considered polypharmacy (≥10 medications) inevitable for an optimal basic treatment of DM, COPD and HF. The heterogeneity of responses raises issues when considering quality indicators in population-based studies.

While physicians increasingly recognize nicorandil-related mucocutaneous ulcerations, there are still misdiagnoses, particularly in the case of unusual location and late onset ulceration after nicorandil introduction. The goal of our study was to remind clinicians about the link between nicorandil use and the development of cutaneous ulcerations and to highlight the risk of misdiagnosis. We describe five reports diagnosed by the same dermatologist, complemented by an analysis of the French pharmacovigilance database (FPVD) from 1 January 1994 to 5 January 2017. During this period, 28 reports of strict cutaneous ulcerations due to nicorandil, in addition to our five reports, were registered in the FPVD. For those 28 reports, the time to onset between nicorandil introduction and cutaneous ulcerations was quite long and exceeded one year in 16 reports (information specified in 25 reports). The delay between ulcerations observation and nicorandil discontinuation was variable, with immediate diagnosis in seven reports, but ranged from fifteen days to twelve years in 21 reports. The main locations were lower limbs, thorax and face. Ulcerations could be localized on surgery or trauma scars. Regression after nicorandil discontinuation was observed in all but two reports and ranged from three days to three months. Characteristics were comparable in our five patient's series. All patients exposed to nicorandil and healthcare practitioners prescribing nicorandil should be aware of the risk of cutaneous ulcerations to enable early diagnosis and drug withdrawal. The risk of misdiagnosis of this serious adverse drug reaction, along with the risk of sequelae, the costs of unnecessary additional investigations and the recent update on nicorandil as second-line treatment for stable angina, with existing alternative drugs, question about the benefit/risk balance of nicorandil.

Background Polypharmacy, the concurrent use of multiple medications, consistently evokes a negative connotation, notably because it is associated with a plethora of adverse events. Nonetheless, the number of individuals exposed to polypharmacy is increasing steeply, especially for older people with multiple diseases. There is a need to carefully study the phenomenon at the population scale to full assess the associated health outcomes. Yet, this reveals a complex task because there exists no consensus indicator of polypharmacy. In fact, the definitions of polypharmacy are heterogeneous and its predisposing factors and associated outcomes are not well defined. The goal of this systematic review is to summarize the literature on polypharmacy in multimorbid individuals aged 65 years and over, targeting three objectives: (1) to identify the definitions of polypharmacy that are used in the context of multimorbidity among older individuals (≥65 years); (2) to ascertain predisposing and concurrent factors associated with polypharmacy; and (3) to describe positive and negative outcomes of polypharmacy among older individuals, including hospitalizations, mortality and costs. Methods We will include publications from 2004 to 2016 that target four concepts: polypharmacy, older individuals, multimorbidity and positive/negative outcomes. The search will be performed using EBM Reviews, Embase, Global Health, MEDLINE, AgeLine, CINAHL, Health Policy Reference Center, Public Affairs Index, SocINDEX and Google Scholar. Two independent reviewers will screen the articles, extract the information and evaluate the methodological quality of included studies. The results will be presented in tables and narrative summaries will be performed. We will perform meta-analyses (objective 3) if the heterogeneity is not important. Discussion This review will help describe the various ways of conceptualizing polypharmacy and how it is associated with health outcomes. We have selected outcomes most relevant for public surveillance performed with administrative databases. Other positive and negative outcomes have been associated with polypharmacy but may not be included in the review. Systematic review registration PROSPERO CRD42014014989 Electronic supplementary material The online version of this article (doi:10.1186/s13643-017-0492-9) contains supplementary material, which is available to authorized users.

Introduction Therapeutic drug monitoring (TDM) of everolimus is not performed in oncology and no trough level (C 0 ) target has been yet defined. The aim of this study was to determine everolimus C 0 target for toxicity and efficacy. Materials and methods Clinical, biological and radiologic data from 54 patients were collected. Toxicity event was defined by termination, temporary interruption and/or dose reduction of everolimus while efficacy was defined as progression-free survival. C 0 values were dichotomized by ROC curve analysis and the association between exposure and outcome was determined using Cox models for repeated events (toxicity) or Cox model censured at the first event (progression free survival). Results Among the 42 patients (77.8%) with breast cancer, 10 (18.5%) kidney cancer and 2 (3.7%) neuroendocrine cancer, adverse events were reported in 75.9% of the patients (everolimus termination in 25.9% patients). C 0 everolimus higher than 26.3 ng/mL (Sen = 0.38,Spe = 0.88) were associated with a 4-fold increased risk of toxicity (HR = 4.12, IC95% = [1.48–11.5], p = 0.0067) whereas C 0 lower than 11.9 ng/mL were associated with a 3-fold increased risk of progression (HR = 3.2, IC95% = [1.33–7.81],p = 0.001). Discussion Further studies are required to evaluate the everolimus C 0 threshold proposed for toxicity (26.3 ng/mL) and for progression (11.9 ng/mL) especially with a large number of patients and more homogeneous types of cancer. However, these results are in favour of TDM for everolimus in oncology.

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

International audience; Health-related quality of life (HRQOL) usually improved after kidney transplantation; however, a non-negligible number of patients did not benefit from transplantation in HRQOL. The aims of this cohort study were to describe the evolution of HRQOL in kidney transplant recipients to search for subgroups with distinct time profiles and to investigate these determinants. Three hundred thirty-seven adult patients were followed up from 1 to 36 months after kidney transplantation. Each patient completed repeated HRQOL assessments (median, 5; range, 2-9). K-means for longitudinal data was used to identify homogeneous clusters of HRQOL time profiles obtained for the mental and physical composite scores (MCS and PCS) and for the 8 dimensions of the short-form 36 scale. Covariates associated with these clusters were investigated using random forest analysis. Magnitude and shape of the HRQOL variations over time were investigated using linear regression mixed models. Two longitudinal clusters were identified for the time profiles of PCS and MCS. Patients classified in the higher cluster (ie, 60% of the population) exhibited a steady-state HRQOL, similar on average to the general population, whereas in the lower cluster, PCS and MCS scores were significantly lower than in the general population. Muscular weakness in the first year after transplantation explained 19% of the interpatient variability of PCS 3 months after transplantation, whereas associated with anxiety, it explained 24% of interpatient MCS variability. This work suggests to promote (i) physical rehabilitation programs after transplantation to curb the muscular loss and (ii) systematic attention to the patient's anxiety.

Metformin-associated lactic acidosis (MALA) is a rare but serious adverse reaction with a mortality rate of up to 50%. Unfortunately, diagnosis and care management are often delayed. The objective was to assess the impact on the mortality rate and length of hospital stay of a MALA early diagnosis procedure in diabetic patients with metformin at emergency department (ED) admission.From 1/7/2012, a new MALA diagnosis procedure (pH, lactate, metformin) was implemented in all diabetic patients with metformin just after their admission to the ED. The pharmacovigilance staff confirmed the MALA cases (defined as pH≤7.35, lactate concentration5mmol/L) in patients exposed to metformin and after a causality assessment to eliminate other common causes of lactic acidosis. To assess the impact of this new diagnosis procedure, a before-after study was conducted between two groups: a series of cases with intervention (IG; 1/7/2012-30/6/2013) and a control series of past cases without intervention (CG; 1/1/2011-30/6/2012). The main outcome was the relative reduction of mortality rate and length of hospital stay between the two groups.Thirty-four MALA cases were confirmed in 745 subjects admitted with lactic acidosis, (IG: 12; CG: 22). A higher illness severity score in the IG vs. CG was observed: respectively arterial lactate (14.2±6.9 vs. 8.8±5.8mmol/L, P0.05), arterial bicarbonate (7.8±4.3 vs. 14.3±6.3mmol/L, P0.05). The median time up to MALA diagnosis was 20.5 (Q1-Q3: 11.3-38.5) minutes for IG and 55.0 (Q1-Q3: 33.0-132.0) minutes for CG. After procedure implementation, the mortality relative risk reduction was 26.7% (95% CI: -84.3%, 70.8%), and especially 54.2% (95% CI: -265.2%, 94.2%) in the ED. There was no difference in the hospital stay duration between the two groups.While the results were not significant, the study suggests that the implementation of a MALA early diagnosis procedure in all patients with metformin admitted to an ED tends to decrease mortality, especially for serious MALA cases detected earlier.

Drug induced adverse effects are frequently encountered in geriatrics. Their occurrence can be limited by an adapted prescription. Potentially inappropriate medications are drugs with an unfavourable benefit to risk ratio when other safer or more efficient therapeutic alternatives are available. An expert consensus allowed us to establish a new list of potentially inappropriate medications for people aged 75 or over, taking into account French prescribing habits. The drugs or the drug-classes proposed in this list are, generally speaking, and when possible, to be avoided in the elderly, but can be prescribed at times, under special clinical conditions, provided that the benefit to risk ratio is assessed. The French list proposed here could be considered as (i) an epidemiological tool for evaluating the quality of drug prescription in geriatrics and as (ii) a prescription guide suggesting an alternative treatment whenever a therapeutic alarm is raised. This guide could be used both as a base for the education of prescribers and as a way of increasing patients awareness. This French list should be kept up-to-date so as to remain adapted to the evolution of the knowledge on the effect of drugs in the elderly and of the pharmaceutical market.

OBJECTIVE: To report a case of cerebral ischemia in a patient receiving oral isotretinoin for severe acne. CASE SUMMARY: A 30-year-old right-handed man was admitted for left facial paralysis and dysarthria. He had received oral isotretinoin 45 mg/day for 3 months for treatment of severe acne. A cerebral computed tomography scan showed hypodensity in the right middle cerebral territory corresponding to cerebral ischemia. The patient reported having experienced a similar episode 7 years before, after 3 months' treatment with oral isotretinoin. No risk factors were identified. Isotretinoin was discontinued on admission and the disorders resolved. DISCUSSION: Our patient did not present thrombotic risk factors and was not being treated with any drug other than isotretinoin; however, he developed 2 episodes of cerebral ischemia following 2 episodes of oral isotretinoin treatment. According to the Naranjo probability scale, the relationship of cerebral ischemia to administration of isotretinoin was probable. Other reports of thrombotic accidents, as well as some cases of hemorrhage in patients receiving isotretinoin, have been published. This drug seems to act on the coagulation process by a still unexplained mechanism. CONCLUSIONS: Given that isotretinoin is a treatment prescribed most frequently for adolescents and young adults and that cerebral ischemia can produce serious handicaps, an evaluation of vascular risk should be made prior to treatment with this drug.

The new European legislation that came into force in July 2012 reinforced the organisation of pharmacovigilance by setting up a committee in charge of risk assessment for medicines, the Pharmacovigilance Risk Assessment Committee (PRAC). The PRAC has a remit covering the assessment of all aspects of the safety and the risk management of medicinal products for human use in the European Union. It deals with issues regarding pharmacovigilance signals, the periodic evaluation of benefit/risk reports from marketing authorization holders (MAH), risk management plans, post-marketing studies, variations or renewals of marketing authorisations, management of under surveillance drugs lists, inspections for pharmacovigilance reasons and audits of pharmacovigilance systems. The PRAC works with the pharmacovigilance systems of the European Member States, which draw up evaluation reports. These evaluations are circulated and discussed by Member States so as to issue recommendations, which serve as a basis for other European medicines committees, the Committee for Medicinal Products for Human Use (CHMP) or the Coordination Group for Mutual Recognition and Decentralised Procedures-Human (CMDh) which then give their opinion. The final decision, which applies to all Member States and to the concerned MAH, lies with the European Commission (EC). This decisional procedure thus rests on coordination involving the PRAC, the CHMP, the CMDh, the EC, the Member States and the pharmaceutical companies. In the 3 years from July 2012, the PRAC has processed nearly 4500 procedures and is still facing an increasing workload.

Background Romiplostim and eltrombopag, the two marketed thrombopoietin receptor agonists (TPO-RAs), have distinct binding sites and might have distinct pharmacodynamic mechanisms. The aim of this study was to compare their adverse drug reaction (ADR) patterns. Methods We selected in the French PharmacoVigilance Database all ADRs associated with TPO-RAs from TPO-RA marketing until the 31st of December 2013. Medical charts were reviewed. We conducted disproportionality analyses comparing romiplostim exposure in the reports of a given ADR pattern (thrombosis, neurological, cutaneous, gastrointestinal or hematological) to romiplostim exposure in all other TPO-RA-related ADR reports. Reporting Odds Ratios (RORs) were adjusted for age and gender. We also compared the number of reports of a given ADR pattern per million daily defined doses (DDDs) dispensed in France during the study period. Results We described 45 reports (53 ADRs) with romiplostim and 26 reports (37 ADRs) with eltrombopag. There were 19 venous thromboses. At least one other risk factor was present in 83.3% of the cases. Ten (55.6%) patients had been splenectomized previously. There were eight arterial thromboses. Another risk factor was noticed in all cases. There was no signal for an excess risk of thrombosis with romiplostim versus eltrombopag (ROR: 1.45, 95% CI [0.48–4.45]). There was a signal for a higher risk of gastrointestinal ADRs with eltrombopag (ROR: 30.28, 95% CI [3.23–383.86]) and of hematological ADRs with romiplostim (ROR: 14.36, 95% CI [1.73–119.08]). Dispensing data-adjusted comparisons led to similar results. Conclusions This study suggests different ADR patterns between romiplostim and eltrombopag.

International audience; OBJECTIVES: To estimate annual direct costs of early RA by resource component in an inception cohort, with reference to four distinct treatment strategies: no disease modifying antirheumatic drugs (DMARDs), synthetic DMARDs only, biologic DMARDs in the first year ('first-year biologic', FYB), and biologic DMARDs from the second year after inclusion ('later-year biologic', LYB); to determine predictors of total and non-DMARD related costs. METHODS: The ESPOIR cohort is a French multicentric, prospective study of 813 patients with early arthritis. Data assessing RA-related resource utilisation and disease characteristics were collected at baseline, biannually during the first two years and annually thereafter. Costs predictors were determined by generalised linear mixed analyses. RESULTS: Over the 4-year follow-up, mean annual direct total costs per treatment strategy group were €3,612 for all patients and €998, €1,922, €14,791, €8,477 respectively for no DMARDs, synthetic DMARDs only, FYB and LYB users. The main predictors of higher costs were biologic use and higher Health Assessment Questionnaire (HAQ) scores at baseline. Being a biologic user led to a higher total cost (FYB Rate Ratio (RR) 7.22, [95% CI 5.59-9.31]; LYB RR 4.39, [95% CI 3.58-5.39]) compared to non-biologic users. Only LYB increased non-DMARD related costs compared to all other patients by 60%. CONCLUSIONS: FYB users incurred the highest levels of total costs, while their non-DMARD related costs remained similar to non-biologic users, possibly reflecting better RA control.

International audience; : In the recent past, concerns have raised regarding the potential risk of acute pancreatitis among type 2 diabetic patients using incretin-based drugs such as glucagon-like peptide 1 (GLP-1) analogs and dipeptidyl peptidase 4 (DPP-4) inhibitors. The aim of this study is to investigate the association between exposure to incretin-based drugs and the occurrence of pancreatitis reported in the French Pharmacovigilance Database. The case/non-case method was performed from serious adverse drug reactions (ADRs) involving antihyperglycemic agents (except insulin alone) reported to the French pharmacovigilance system between March 2008 (first marketing of an incretin-based drug in France) and March 2013. Cases were defined as reports of pancreatitis, and all other serious ADRs were considered non-cases. Disproportionality was assessed by calculating reporting odds ratios (ROR) adjusted for age, gender, history of pancreatitis, other antihyperglycemic drugs and other drugs associated with a higher risk of pancreatitis. Among 3,109 serious ADRs, 147 (4.7 %) reports of pancreatitis were identified as cases and 2,962 reports (95.3 %) of other ADRs as non-cases. Among the cases, 122 (83.0 %) involved incretin-based drugs. Disproportionality was found for all incretin-based drugs (adjusted ROR: 15.7 [95 % CI 9.8-24.9]), all GLP-1 analogs (29.4 [16.0-53.8]), exenatide (28.3 [12.8-62.3]), liraglutide (30.4 [15.4-60.0]), all DPP-4 inhibitors (12.1 [7.3-20.0]), sitagliptin (12.4 [7.3-21.0]), saxagliptin (15.1 [4.3-52.7]), and vildagliptin (7.4 [3.1-17.6]). Temporal analysis found disproportionality for incretin-based drugs since their first year of marketing in France. Compared with other antihyperglycemic agents, use of incretin-based drugs is associated with an increased risk of reported pancreatitis in France.

International audience; PURPOSE: Fluindione is an oral vitamin K antagonist (indanedione derivative) exclusively marketed in France and Luxembourg, known to have immuno-allergic adverse effects such as hepatitis, fever or interstitial nephritis. A few cases of drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with fluindione. The aim of the present study was to investigate fluindione-induced DRESS cases reported in France and to describe their characteristics. METHODS: We searched for potential cases of DRESS with fluindione reported in the French pharmacovigilance database since 2000. RESULTS: Thirty-six cases of DRESS were included and concerned 17 women and 19 men. The mean age was 65 years (median: 68 years, range: 28-95 years). Kidneys and liver were the most frequent organs involved. Thirty-five cases were serious. In 5 cases, the effect was life-threatening. Most of the patients recovered. Fluindione was the only medicine suspected in 26 cases. Skin patch tests, performed in 10 cases, were positive with fluindione in 9 cases. CONCLUSIONS: Fluindione is not known to be a frequent cause of DRESS. However, the number of reports found is probably underestimated. The seriousness of DRESS, as all immuno-allergic adverse effects, contraindicates fluindione reintroduction. Coumarinic derivatives are the alternatives in patients who need oral anticoagulant treatment.

ERMA; International audience; PURPOSE: To report on a case of osteonecrosis of the jaw (ONJ) in a patient treated with clodronate, an alkylbiphosphonate, and to draw attention to the risk of ONJ following treatment with all biphosphonates, whether they are alkyl- or amino-biphosphonates. CASE REPORT: Beginning at age 58 years, a female patient took clodronate for almost 13 years for a metastatic bone cancer. She also underwent chemotherapy and radiotherapy. Three months after the end of biphosphonate therapy, she suffered from toothache, and tooth 27 (left maxillary second molar) was extracted. A maxillary focus of osteitis with an oral sinus communication was discovered, and a maxillofacial denture prosthesis was grafted in September 2006. Some days later, the patient consulted her dentist for an ulceration of the oral cavity floor in front of tooth 33 (left mandibular canine) extending to the left inferior side of the lip. In October 2006, teeth 33 and 34 (left mandibular first premolar) were extracted. No secondary infection occurred. A complete healing was only observed 3 months after the last extraction. ONJ due to alkylbiphosphonate treatment was diagnosed as bone reconstruction and mucous cicatrisation were delayed. METHODS: A systematic review was carried out to identify all cases of alkylbiphosphonate-induced ONJ by searching the Medline and Cochrane databases using 'osteonecrosis of the jaw', 'jaw diseases', 'osteonecrosis', 'diphosphonate', 'biphosphonate' (amino-, alkyl- or the international nonproprietary name) as the main search items. The search was limited to English- and French-language articles published between 1966 and February 2010. RESULTS: Our search identified 27 cases of alkylbiphosphonate-induced ONJ in the literature. Among these cases, only ten patients were on alkylbiphosphonate monotherapy; in the other cases, aminobiphosphonates had also been used. The clinical presentation of the alkylbiphosphonate-induced ONJ was similar to that most often encountered with aminobiphosphonate treatment. The duration of exposure before onset was higher with alkylbiphosphonates than with aminobiphosphonates, and dental procedures before ONJ were frequent. CONCLUSION: Osteonecrosis of the jaw has been widely reported with various aminobiphosphonates, but data on the role of alkylbiphosphonates are scarce. As these latter drugs are less potent, a high cumulative dose through long-term exposure would appear to be necessary and would favour ONJ. Although the degree of risk for ONJ occurrence in patients on alkylbiphosphonates remains uncertain, it would be wise to reconsider carefully the indications for using these agents and to apply preventive measures as is currently done for aminobiphosphonates.

LDM TEP COLL; International audience; BACKGROUND:In the prospective, randomized, multicenter APOMYGRE trial conducted in France, concentration-controlled mycophenolate mofetil (MMF) dosing based on mycophenolic acid (MPA) exposure significantly reduced the treatment failure and acute rejection during the first posttransplantation year compared with fixed-dose MMF. This analysis investigated the cost effectiveness of dose individualization.METHOD:The study included 65 patients per group (intent-to-treat population). Treatment failure (primary efficacy endpoint) was defined as death, graft loss, acute rejection, or MMF discontinuation because of adverse effects. Data on hospitalizations, drugs prescribed, physicians' fees, laboratory expenses, ambulatory visits, and transportation were retrieved. Costs were calculated from the French National Health System perspective.RESULTS:The mean (95% confidence interval) total yearly cost per patient was Euro 47,477 (Euro 43,933; Euro 51,020) in the concentration-controlled group and Euro 46,783 ( Euro 44,152; Euro 49,414) in the fixed-dose group (P=0.7). The observed incremental cost-effectiveness ratio was Euro 3757 per treatment failure (Purchasing Power Parities United States/France: $4129). Hospitalization and drug costs accounted for approximately 50% and 25% of total costs, respectively. The cost for MPA area under the concentration-time curve and dose calculation was Euro 452 per patient, less than 1% of the total cost.CONCLUSION:In the APOMYGRE trial, therapeutic MPA monitoring using a limited sampling strategy reduced the risk of treatment failure and acute rejection in renal allograft recipients during the first 12 months posttransplantation, at neutral cost.

The aging of the world population is a new medical challenge for the 21st century. There has been a striking increase in the proportion of elderly people, especially the very old, over the past decades. The elderly are living longer due, in part, to improved standards of living and the availability of social aid and medical care. Although some people reach a very old age completely free of physical ailments, most elderly people have several chronic diseases. Modern pharmacotherapy can slow down and delay the consequences of these ailments up to the eighth decade of life, but thereafter the complications of these diseases will usually become clinically significant. This often results in the administration of several drugs simultaneously. Clinical Pharmacology & Therapeutics (2008); 85, 1, 94–97 doi:10.1038/clpt.2008.214

ERMA; International audience; The use of generics results in savings for the budget of the health insurance, and no player of health could question seriously the principle. The generic drug of a reference medicinal product defines itself as a drug having the same qualitative and quantitative composition in active ingredients, the same dosage form and the bioequivalence with this reference medicinal product was demonstrated by appropriate studies of bioavailability. It is the right to switch granted to the pharmacists in 1999 that is at the origin of the real development of these specialties on the French pharmaceutical market. Nevertheless, about 10 years later, it seems that the system in place does not offer all the necessary securities with regard to pharmacovigilance, notably for the products with narrow therapeutic margin. By strengthening and/or by completing the role played by the health care professionals and the public institutions concerned, it is highly possible to improve the robustness of the system. Also, the recent arrival in Europe of the biosimilars, similar molecules but not bioequivalent to biological products, cause an even more tricky specific situation than that of the generics because of their nature, of the difficulty to manufacture them, and of the risk of immunogenicity. If the substitution is not permitted in several European countries including France, the other issues can appear especially in case of interchangeability requiring also, the reinforcement of certain measures.The various aspects are described in this article with concrete proposals on how the current system can be made safer, both for the generics and the biosimilars.

The size of the elderly population has been increasing steadily for several years. Individuals in this age group often have several concomitant diseases that require treatment with multiple medications. These drugs, for various reasons and especially as a consequence of potential accumulation, may be associated with adverse reactions. Of the numerous factors that can favour the occurrence of these adverse drug reactions, the most important are the pathophysiological consequences of aging, particularly as these apply to the very old. Although absorption of drugs is not usually reduced in the elderly, diffusion, distribution and particularly elimination decline with age. Furthermore, while hepatic metabolic function is fairly normal, renal function is usually markedly depressed in very old individuals, and this can translate into clinical consequences if it is not taken into account. This is why, before administration of any drug in the elderly, evaluation of glomerular filtration rate is essential. Validated estimations such as those obtained from the classical Cockcroft-Gault formula or from more recent methodologies are required. In addition to reductions in various organ functions, factors connected with very old age such as frailty, falls, abnormal sensitivity to medications and polypathology, all of which tend to be more common in the last years of life, all directly impact on adverse drug reaction occurrence. Given these characteristics of the elderly population, the best way to reduce the prevalence of adverse drug reactions in this group is to limit drug prescription to essential medications, make sure that use of prescribed agents is clearly explained to the patient, give drugs for as short a period as possible, and periodically re-evaluate all use of drugs in the elderly.