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In the code of public health, misuse is defined as intentional and inappropriate use of a medicine or product, which is not in accordance with the terms of the marketing authorisation or the registration as well as with good practice recommendations. Very often this involves an individual or the interaction of several individuals including the patient, his/her carers, prescriber(s) and/or dispensers. Misuse is common; it is the source of medicinal adverse effects for which a significant part is avoidable. Medicines initially prescribed or dispensed in the context of their marketing authorization (MA) can also be the subject of primary dependency and misappropriation. Companies which develop medicines nationally make declarations to the ANSM (French National Agency for the Safety of Medicines and Health Products) and implement measures to limit non-compliant use of their products. Recently, the coronavirus disease-2019 (COVID-19) pandemic has highlighted the influence and societal impact of drug misuse. The finding of the existence of systemic misuse, the impossibility of proposing simple solutions leads us to propose two main areas for improved information and the training of users and health professionals in medicines in the context of multi-faceted interventions: prevention of misuse on the one hand and its identification and treatment on the other hand.

We describe five cases of severe necrotizing vasculitis following the RNA-based vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including four relapsing anti neutrophil cytoplasmic antibodies (ANCA) vasculitis, 27 days (1–60) after vaccination and one patient with quiescent chronic hepatitis B and de novo polyarteritis nodosa (PAN) 21 days after vaccination. Ten other cases were reported to the French national pharmacovigilance database: six patients with ANCA-associated vasculitis and four patients with PAN (first symptoms 19 days on average after vaccination). Five of these 10 patients developed kidney dysfunction. In conclusion, coronavirus disease 2019 (COVID-19) vaccines can be associated with de novo or recurrent ANCA vasculitis or PAN. Attention should be paid to patients with known ANCA vasculitis or patients with a history of hepatitis B infection.

Rituximab is a chimeric anti-CD20 antibody commonly used to treat patients with autoimmune diseases. Such diseases mainly affect young people, but older patients may also be concerned. So far, very little data exist concerning the safety of rituximab in older patients with autoimmune diseases.This study was intended to describe the adverse reaction profile of rituximab in patients over 75 years of age treated for autoimmune diseases and to compare such profile to those observed in patients below 75 years of age. Adverse reactions related to rituximab were reported to the French Pharmacovigilance Network. From such reports, a descriptive analysis as well as a disproportionality analysis were performed to identify safety signals.1096 reports of rituximab-related adverse reactions reported in France between 2006 and 2019, were included in the study, such as 127 in the older group (75 years) and 969 in the younger group (75 years). Infusion reactions were less frequently reported than other adverse drug reaction in older patients (11 vs. 27%, P0.001). By contrast, a higher rate of opportunistic infection due to Pneumocystis jirovecii was reported in the older subject group (3.9 vs. 0.6%, P0.001), along with neutropenia (22.8 vs. 9.3%, P0.0001). These results were confirmed by the disproportionality analysis.Pneumocystis jirovecii infection was significatively more reported in older patients treated by Rituximab which probably reflects a higher incidence in this population. The use of anti-pneumocystis prophylaxis should be considered in this population.

International audience; The French-style organization in the field of rare diseases allows a close contact between reference centres and regional pharmacovigilance centres thanks to their implementation within the French university hospital. This collaboration leads to highlight more and more drug-induced rare diseases. Through several historical examples (eosinophilia-myalgia syndrome due to L-tryptophan, type 1 narcolepsy with H1N1 pandemic influenza vaccine, capillary leak syndrome, acquired von Willebrand syndrome), it remains clear that pharmacovigilance is the cornerstone of the alert system. Clinicians from the rare disease reference centres can easily report adverse drug reactions (ADRs) to pharmacologists from their regional pharmacovigilance centre. Through experience, collaboration between countries, large database, and sometimes pharmacoepidemiological studies, an alert can then be raised. This collaboration underlines also similarities between the two disciplines, through the frequency of ADRs and diseases, the difficulty of the diagnosis in front of scarce data, and through the unusual worsening symptoms. Patients and associations of patients play also a proactive role as research partners at different steps, to quantify and qualify symptoms and ADRs, and also to develop orphan drugs. These several collaborations are a precious tool to improve patients' outcomes. These close contacts between the different actors are important to make earlier diagnosis of rare diseases and severe ADRs. Rare disease does not have to mean overlooked diseases.

In clinical trials, few investigations have been conducted to determine the mechanism involved in teriflunomide-associated kidney stone formation. We report the first case of recurrent teriflunomide-induced uric acid urolithiasis. A 55-year-old man with relapsing-remitting multiple sclerosis experienced three occurrences of urolithiasis several months after the initiation of teriflunomide. While serum uric acid remained stable at 280 mmol/L, 24-hour urine uric acid was increased to 2195 mmol/24h. For the third episode, computed tomography showed three bladder stones and one stone in the right calyceal group. Endovesical lithotripsy was used to extract four orange-colored stones of more than 20 mm. Stone analysis exhibited morphology subtype IIIb with 100% of anhydrous uric acid. Given the disease control, teriflunomide was continued. After urinary alkalinisation by potassium citrate, the patient remained asymptomatic at 18 months follow-up. An inhibitory effect of dihydroorotate and/or teriflunomide on urate tubular reabsorption could explain teriflunomide-associated uric acid urolithiasis. This case in a patient without risk factors suggests that multiple sclerosis patients may be at greater risk of forming uric acid urinary stones when taking teriflunomide. Alkalinization of the urine may reduce the risk of recurrence, allowing further treatment with teriflunomide.

International audience; INTRODUCTION: Rituximab induced serum sickness (RISS) is a rare delayed hypersensitivity reaction. The aim of this study was to describe the epidemiological and clinical characteristics of the RISS cases reported in France. METHOD: Serum sickness cases involving rituximab were identified from the French PharmacoVigilance Database from 1998 to 2016. RESULTS: We analyzed 37 cases of RISS. Rituximab was prescribed for an autoimmune disease in 78% of cases. Serum sickness occurred mainly after the first injection (54%) with a median time to onset of 12 days. The most frequent manifestations were rheumatologic symptoms (92%), fever (87%), and skin lesions (78%). The incidence was significantly higher when rituximab was used for autoimmune diseases than for a hematological malignancies. Taking into account the existence of a Systemic Lupus Erythematosus (SLE) as the indication of rituximab or as a comorbidity, the incidence of RISS in patients with SLE was even higher. DISCUSSION: We report on the largest series of RISS studied to date and confirm that this reaction preferentially occurs in patients with autoimmune disease, especially SLE. This may be due to B-cell lysis, leading to the release of intracellular antigens into the serum and subsequent antigen-antibody complex formation, especially in patients with elevated autoantibody production. This could also explain why RISS often occurred after a single injection. CONCLUSION: Patients generally recovered from RISS rapidly without obvious benefit from corticosteroid therapy. The risk of recurrence should prompt clinicians to question the use of rituximab after an episode of RISS.

International audience; Strategies for diets in chronic spontaneous urticaria (CSU) are controversial. This systematic review assessed the interest in diet for managing CSU. We searched for original reports in MEDLINE, EMBASE, CENTRAL and LILACS. Among the 278 reports screened, 20 were included, involving 1,734 patients. Reports described 3 types of systematic diet: pseudoallergen-free diet (n = 1,555 patients), low-histamine diet (n = 223) and diet without fish products (n = 47), which induced complete remission in 4.8%, 11.7% and 10.6% of patients, respectively, and partial remission in 37.0%, 43.9% and 4.3%. Eight reports described personalized exclusion diets (66 patients) adapted to symptoms/allergological test results and led to complete remission in 74.6% of patients, although the diagnosis of CSU was doubtful. No comparative randomized studies of diets were available. The only randomized studies were based on oral provocation tests with the suspected responsible diet. Population and outcomes were heterogeneous. In conclusion, there is evidence for the benefit of diets in CSU only in individual patients with clinical symptoms. However, the level of evidence is low for the benefit of systematic diets in CSU because systematic double-blind controlled trials of diet are lacking.

International audience; In this special issue, we present the main highlights of the first weeks of pharmacovigilance monitoring of coronavirus disease 2019 (COVID-19) vaccines in this unprecedented situation in France: the deployment of a vaccination during an epidemic period with the aim of vaccinating the entire population and the intense pharmacovigilance and surveillance of these vaccines still under conditional marketing authorizations. In this unprecedented situation, the cross approach and interaction between the French pharmacovigilance network and French National Agency for the Safety of Medicines and Health Products (ANSM) has been optimized to provide a real-time safety related to COVID-19 vaccines. Every week, pair of regional pharmacovigilance centers gathered safety data from the French pharmacovigilance network, to acutely expertise all the adverse drug reactions (ADRs) reported with each COVID-19 vaccine within a direct circuit with ANSM. Results of this expertise are presented and discussed with ANSM in order to raise safety signals and take appropriate measures if necessary. These reports are then published online. At the 25th of March 2021, more than 9 815 000 doses were injected and 20,265 ADRs were reported, mostly non-serious (76%). Several potential or confirmed signals were raised at the european level for those vaccines and others ADRs are under special attentions. This underlines the adaptiveness of the French pharmacovigilance system to both the identification of new patient profiles experiencing ADRs and the evolution of the vaccine strategy. Such an efficiency is necessary to manage a careful and acute surveillance of these new COVID-19 vaccines for and to face the pandemic at the same time.

Therapies - Sous presse. Epreuves corrigees par l'auteur. Disponible en ligne depuis le mardi 13 avril 2021

International audience; The current COVID-19 pandemic is an exceptional health situation including for drug use. As there was no known effective drug for COVID-19 at the beginning of the pandemic, different candidates were proposed. In this short article, we present the French public pharmacovigilance activities during this health crisis. Although COVID-19 is a confounding factor per se, owing to its potential for multi-organ damage including the heart and kidney, the quality of the transmitted data in adverse drug reaction reports, the timeliness of feedback from clinicians, and the real-time pharmacological and medical analysis by the French network of the regional pharmacovigilance centers made it possible to swiftly identify relevant safety signals. The French National Agency of Medicine was thus able to validate the data and convey their findings very early. This decentralized organization based on medical and pharmacological evaluation of case reports has proven to be efficient and responsive in this unique and challenging healthcare emergency.

International audience; BACKGROUND: Oral alitretinoin is a retinoid used for severe chronic hand eczema. Although caution is recommended for patients with uncontrolled dyslipidaemia or cardiovascular risk factors, the actual atherothrombotic risk has not been investigated thus far. OBJECTIVES: Our aim was to detect any excess of atherothrombotic events among patients exposed to alitretinoin, during the treatment or in the 2 years following initiation. METHODS: Using the French Health Insurance database, we compared the number of patients having had an atherothrombotic event (coronary artery disease, ischemic stroke or peripheral artery disease requiring revascularisation) in the population exposed to oral alitretinoin versus the general population of the same age, gender and baseline cardiovascular risk, using standardized morbidity ratios (SMRs). RESULTS: Between 2009 and 2017, 19,513 patients were exposed to oral alitretinoin in France. Sixty-four (0.3%) patients had an atherothrombotic event while on alitretinoin. Patients receiving alitretinoin experienced no more atherothrombotic events than the general population: patients without cardiovascular risk factors or previous atherothrombotic events reached a SMR of 0.65, 95%CI [0.26-1.34] during alitretinoin treatment, and 1.21, 95%CI [0.90-1.59] in the 2 years following initiation; patients with cardiovascular risk factors or previous atherothrombotic events reached a SMR of 0.82, 95%CI [0.60-1.08] during alitretinoin treatment, and 0.95, 95%CI [0.82-1.09] in the 2 years following initiation. Taken separately, SMRs for each outcome did not increase either. CONCLUSIONS: These data from an exhaustive nationwide population-based study did not support an increase in the incidence of atherothrombotic events under alitretinoin, regardless of the baseline cardiovascular risk of the patient.

Many drugs are responsible, through different mechanisms, for peripheral oedema. Severity is highly variable, ranging from slight oedema of the lower limbs to anasarca pictures as in the capillary leak syndrome. Although most often noninflammatory and bilateral, some drugs are associated with peripheral oedema that is readily erythematous (eg, pemetrexed) or unilateral (eg, sirolimus). Thus, drug-induced peripheral oedema is underrecognized and misdiagnosed, frequently leading to a prescribing cascade. Four main mechanisms are involved, namely precapillary arteriolar vasodilation (vasodilatory oedema), sodium/water retention (renal oedema), lymphatic insufficiency (lymphedema) and increased capillary permeability (permeability oedema). The underlying mechanism has significant impact on treatment efficacy. The purpose of this review is to provide a comprehensive analysis of the main causative drugs by illustrating each pathophysiological mechanism and their management through an example of a drug.

The current COVID-19 pandemic is an exceptional health situation including for drug use. As there was no known effective drug for COVID-19 at the beginning of the pandemic, different candidates were proposed. In this short article, we present the French public pharmacovigilance activities during this health crisis. Although COVID-19 is a confounding factor per se, owing to its potential for multi-organ damage including the heart and kidney, the quality of the transmitted data in adverse drug reaction reports, the timeliness of feedback from clinicians, and the real-time pharmacological and medical analysis by the French network of the regional pharmacovigilance centers made it possible to swiftly identify relevant safety signals. The French National Agency of Medicine was thus able to validate the data and convey their findings very early. This decentralized organization based on medical and pharmacological evaluation of case reports has proven to be efficient and responsive in this unique and challenging healthcare emergency.

International audience; No abstract available

On March 16, 2020, the French Society of Pharmacology and Therapeutics put online a national Question and Answer (Q&A) website, http://https%20%5Ch://sfpt-fr.org/covid19 on the proper use of drugs during the COVID‐19 pandemic. The working group “Drugs and COVID‐19” was composed of a scientific council, an editorial team and experts in the field. The first questions were posted online during the first evening of home‐confinement in France, March 17, 2020. Six weeks later, 140 Q&As have been posted. Questions on the controversial use of hydroxychloroquine and to a lesser extent concerning azithromycin have been the most consulted Q&As. Q&As has been consulted 226,014 times in 41 days. This large visibility was obtained through an early communication on Twitter, Facebook, traditional print and web media. In addition, an early communication through the French Ministry of Health and the French National Agency for Medicines and Health Products Safety ANSM had a large impact in terms of daily number of views. There is a pressing need to sustain a public drug information service combining the expertise of scholarly pharmacology societies, pharmacovigilance network, and the Ministry of Health to quickly provide understandable, clear, expert answers to the general population’s concerns regarding COVID‐19 and drug use and to counter fake news.

International audience; PURPOSE: Despite their frequent use in children and adolescents, the evidence for efficacy and safety of antidepressants (ATDs) in this population is scarce and off-label prescribing common. The aim of this study was to describe reported adverse drug reactions (ADRs) associated to ATDs over a 30-year period using the French Pharmacovigilance Database (FPVD). METHODS: We performed an analysis of ADRs registered in the FPVD from 1985 to 2016, occurred in children and adolescents receiving an ATD. Descriptive statistics were used to obtain an overview of ADRs types and characteristics, and data were stratified by age. RESULTS: Among the 45,070 pediatric cases reports registered into the FPVD, we identified 1366 reports (3.0%) in which ATDs were "suspected" as the cause of 2922 ADRs. ADRs were more frequently reported in female (n\,=\,743; 55.5%) and adolescents (n\,=\,627; 49.3%). Neuropsychiatric ADRs were the most reported, mainly sleepiness, agitation, and suicidal thinking and behavior, followed by gastrointestinal and hepatobiliary disorders, mainly vomiting, abdominal pain, hepatitis, nausea, and three unexpected ADRs of pancreatitis. There was an increase of annual reporting between 1986 and 2003, followed by a plateau state then a decrease from 2003 to 2012, and a rapid escalation until 2016, while an increase in the number of reporting of suicidal thinking and behavior was observed after 2003, highlighting a possible impact of black box warnings on reporting practices and ATD use. CONCLUSION: This pediatric pharmacovigilance study underscored the high prevalence of neuropsychiatric and gastrointestinal ADRs, including three unexpected cases of pancreatitis.

International audience; Non-steroidal anti-inflammatory drugs (NSAIDs) have an optional prescription status that has resulted in frequent use, in particular for the symptomatic treatment of fever and non-rheumatic pain. In 2019, a multi-source analysis of complementary pharmacological data showed that using NSAIDs in these indications (potentially indicative of an underlying infection) increases the risk of a severe bacterial complication, in particular in the case of lung infections. First, the clinical observations of the French Pharmacovigilance Network showed that severe bacterial infections can occur even after a short NSAID treatment, and even if the NSAID is associated with an antibiotic. Second, pharmacoepidemiological studies, some of which minimized the protopathic bias, all converged and confirmed the risk. Third, experimental in vitro and in vivo animal studies suggest several biological mechanisms, which strengthens a causal link beyond the well-known risk of delaying the care of the infection (immunomodulatory effects, effects on Streptococcus pyogenes infections, and reduced antibiotics efficacy). Therefore, in case of infection, symptomatic treatment with NSAIDs for non-severe symptoms (fever, pain, or myalgia) is not to be recommended, given a range of clinical and scientific arguments supporting an increased risk of severe bacterial complication. Besides, the existence of a safer drug alternative, with paracetamol at recommended doses, makes this recommendation of precaution and common sense even more legitimate. In 2020, such recommendation is more topical than ever with the emergence of COVID-19, especially since it results in fever, headaches, muscular pain, and cough, and is further complicated with pneumopathy, and given experimental data suggesting a link between ibuprofen and the level of expression of angiotensin-converting enzyme 2.

International audience; INTRODUCTION: According to French guidelines on good pharmacovigilance practices, a pharmacovigilance survey is an assessment of the available drug safety data. It is requested by the French national agency for medicines and health products safety (ANSM). The objective is to validate a signal, to characterize it, or to provide strengthened monitoring of a drug. MATERIAL AND METHODS: All the available data were retrieved by ANSM/Regional Pharmacovigilance Centers (RPC) and assessed by a nominate RPC which provides a report for discussion during the monthly Committee between ANSM and the Regional Pharmacovigilance Network (RPN). A descriptive analysis of the minutes available on the ANSM website between 2016 and 2018 has been done: objective, data sources, duration of the survey, number of suspected adverse drug reactions, nature of the drugs and of the signals and recommendations for actions. RESULTS: Between 2016 and 2018, a total of 115 surveys were discussed concerning 135 drugs, mainly from the nervous system according to the anatomic therapeutic chemical classification (n=31, 27%). They involved a whole pharmacological class for 18 ones. The main objective of the 115 surveys was to provide a strenghtened monitoring for some drugs (72%) or to validate one or more than one signal (28%). Result from surveys allowed to detect one or several new potential safety signals in 63 ones (55%), an off-label-use in 12 (10%) or to characterize some others signals in all the studies. The Committee recommended one or several actions by survey: 67 prolongations (58%) of the survey and regulatory or investigatory actions which included 43 European actions (37%), 37 label changes (32%), 30 national communications (26%) and 29 additional monitoring (25%). DISCUSSION/CONCLUSION: The current process allows a collegiate, clinical and pharmacological discussion with integration of the regulatory framework. A significant number of new signals are detected and/or validated. This efficient tool which is unique in Europe and is allowed by the decentralized pharmacovigilance which leads to a great reactivity of decision-making. It has to be reassessed and to be adapted continuously to the new challenges of the growing multiplication of signals.

International audience; OBJECTIVE(S): To describe the features of etonogestrel implant (Nexplanon and Implanon) migration into the pulmonary vasculature and to estimate its incidence in France. STUDY DESIGN: We retrospectively reviewed French cases of implant migration into the pulmonary vasculature reported up to 2018. Patient clinical data were collected. The annual incidence of migration was estimated from the number of cases reported and number of implants sold. RESULTS: Twenty-seven cases of migration into the pulmonary vasculature were identified. In 19 cases (70%) it was stated that this was into the pulmonary artery (nine into the left branch, four into the right branch and six unspecified) and in the other eight cases (30%) it was it not specified whether this was into the pulmonary artery or one of its branches. The migration was discovered following a request for implant removal in 59% of cases, following respiratory complaints in 24%, and because the implant was no longer palpable in 17%. In the 24 cases for which information on removal (or not) was available, the implant was removed in 15 (60% by an endovascular procedure and 40% by invasive surgery); in the remainder it was left in situ. The incidence of migration into the pulmonary vasculature was 1.23 per 100,000 implants sold [95% CI 0.25-3.58] in 2014, increasing to 3.17 per 100,000 implants sold [1.37-6.24] in 2017. In 2016, the French National Agency for Medicines and Health Products Safety (ANSM) had recommended performing a systematic search for non-palpable implants, including at thorax level. CONCLUSIONS: The incidence of migration into the pulmonary vasculature is low. Nonetheless, because the consequences are potentially serious, in December 2019 the ANSM made recommendations to reduce this risk.

International audience; Purpose There is little data on the effects of cancer chemotherapy in pregnant women. The objective of this study was to describe pregnancy outcomes of women exposed to cancer chemotherapy, recorded in the French Terappel database. Methods We performed a descriptive, prospective study of the pregnancies of women exposed to cancer chemotherapy recorded in Terappel between June 1984 and December 2016. Terappel is a French database that has recorded questions of health professionals and/or individuals at the Regional Pharmacovigilance Centres about drugs and pregnancy. For each question, pregnancies are monitored and the outcome is recorded in the database. Results In total, 75 questions about ``anti-cancer drugs and pregnancy'' received by 16 Regional Pharmacovigilance Centres between 1997 and 2016 were recorded in Terappel. Breast cancer accounted for 62.7% of the cases, followed by leukaemia (13.3%) and lymphoma (9.3%). Cyclophosphamide is the leading anti-cancer drug with 40.0% of exposed pregnant women, followed by 5-fluorouracil (34.7%), epirubicin (32.0%), tamoxifen (26.7%), and doxorubicin (16.0%). Among the 75 pregnancies, we observed 55 births with 57 children (73.3%) (two cases of twins), nine medical terminations of pregnancy (12.0%), six voluntary terminations of pregnancy (8.0%), three intrauterine foetal deaths (4.0%), and two miscarriages (2.7%). We found a malformation rate of 7.8%. Sixteen of 57 (28.1%) newborns developed one or more neonatal pathologies. Conclusion Pregnancy of women taking anti-cancer drugs resulted in birth in 73% of cases. Nevertheless, pregnant women exposed to cancer chemotherapy remains at risk of malformations and neonatal conditions related to prematurity and drugs.

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

BACKGROUND Chronic spontaneous urticaria (CSU) is not frequent in children. Management guidelines have been developed for adults and randomized controlled trials (RCTs) included teenagers aged 12-18, but data for children under age 12 are limited. We performed a systematic review to assess comorbidities in children

Vedolizumab is a gut-selective humanized monoclonal antibody that binds selectively to the α4 β7 integrin and acts as a lymphocyte-homing antagonist. It is indicated in ulcerative colitis and Crohn disease. We report a case of acute interstitial nephritis following vedolizumab infusion in a 55-year-old white woman treated for severe Crohn disease resistant to several therapies. Other kidney disease causes were ruled out. Glucocorticoids were administrated, leading to full renal recovery. In the absence of other therapeutic options, vedolizumab was re-administered along with transient corticosteroids; this treatment was well tolerated. Fewer than 10 cases of immunoallergic acute interstitial nephritis following treatment with monoclonal antibody have previously been reported in the literature. The pathophysiology of delayed-type hypersensitivity secondary to monoclonal antibody therapeutics is discussed in this case report.

International audience; BACKGROUND: The European Medicines Agency (EMA) has developed risk minimization measures (RMMs) to reduce the use of the teratogenic drug, sodium valproate (VPA). The objective was to assess the impact of these RMMs among females with epilepsy in France. METHODS: We used data from the French National Health Insurance Database (SNDS), including 114,936 females aged under 50, with a reimbursement claim for an antiepileptic drug from January 2011 to December 2017, and identified as people with epilepsy. We used a controlled interrupted time series stratifying on age: girls (0-14 years old) and women of childbearing age (15-49 years), and with 129,917 males as controls. RESULTS: VPA prevalent use among girls and women of childbearing age with epilepsy decreased significantly after the issue of the RMMs (trend changes of, respectively, -5 and -4 users per 1000 females at-risk per quarter in comparison to the control group). We did not detect any significant change in VPA incident use. CONCLUSIONS: VPA use decreased over the study period among females with epilepsy but there were still 317 women and 206 girls started on VPA therapy VPA in 2017 (8 per 1000 at-risk and 18 per 1000, respectively). This suggests that either the measures should be strengthened or that the lowest level of VPA use has been reached. In this context, the introduction of a new RMM (in 2018) needs to be evaluated.

Resume Objectifs Le profil des effets indesirables de l’alitretinoine, derive retinoide indique chez l’adulte atteint d’eczema chronique severe des mains ne repondant pas au traitement par dermocorticoides puissants, est globalement superposable a celui des autres retinoides per os, en particulier de l’isotretinoine. L’objectif de cette etude etait de detecter de nouveaux effets indesirables (non references dans le resume des caracteristiques du produit [RCP]) et d’estimer le nombre de grossesses exposees. Materiel et methodes Tous les cas d’effets indesirables notifies en France avec l’alitretinoine entre le 1er octobre 2012 et le 29 fevrier 2016 ont ete analyses. Resultats Au cours des 41 mois de suivi, 52 cas d’effets indesirables graves et 88 cas d’effets indesirables non graves inattendus ont ete analyses. Les effets indesirables graves les plus frequents etaient psychiatriques, neurologiques et dermatologiques. Les troubles psychiatriques, principalement la depression et les idees suicidaires, representaient 23 % des effets graves et plusieurs effets indesirables etaient nouveaux : infarctus du myocarde, pancreatite et hemorragie digestive. Trois grossesses exposees pendant la periode de risque teratogene ont ete notifiees. Discussion et conclusion Le profil de tolerance de l’alitretinoine est proche de celui des autres retinoides, mais les troubles psychiatriques semblent plus frequemment rapportes. Le risque d’infarctus du myocarde chez les patients a risque cardiovasculaire eleve merite d’etre suivi et d’etre evalue. Il pourrait s’expliquer par les effets hyperlipemiants de l’alitretinoine, en presence d’autres facteurs de risque cardiovasculaire. Les risques de pancreatite et d’hemorragie digestive sont egalement rapportes avec l’isotretinoine. L’estimation de l’incidence des grossesses exposees est proche de celle observee avec l’isotretinoine. L’incidence des effets indesirables graves et l’application necessaire du programme de prevention de la grossesse ont conduit l’Agence nationale de securite du medicament et des produits de sante (ANSM) a restreindre la primo prescription de l’alitretinoine aux dermatologues.

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.

Aim Term and preterm neonates are at high risk for serious adverse drug reactions (ADRs). Methods A descriptive study of reports registered in the French pharmacovigilance database from 1986 to 2012 were obtained. All reports concerning neonates (≤1 month of life) with direct drug exposure were retrieved. Characteristics of the reports, including reported ADR(s), drug(s) and the causality assessment using the French causality assessment method, were described. Results A total of 1688 reports were analyzed and more than half of them were classified as serious (n = 995). Median age at ADR occurrence was 9 days. Overall, 3127 ADRs were described in these reports in relation to 2238 suspect/interacting drugs. The most commonly reported system organ classes (SOCs) were injury, poisoning and procedural complications (16%), general disorders and administration site conditions (12.5%) and blood and lymphatic system disorders (12%). In the majority of ADRs reported (73%), infants fully recovered and less than 4% of neonates deceased as a consequence of the reported ADR. One out of five ADRs was associated with drug administration errors. Therapeutic classes commonly incriminated were anti-infectives, nervous system and alimentary tract drugs. Substances most frequently related to serious ADRs were zidovudine, ibuprofen and nevirapine. Among the 10 most frequently encountered drug−ADR pairs, two substances were mainly implicated, zidovudine in haematological adverse reactions and phytomenadione in maladministrations. Conclusions Anti-infective drugs, mainly antiretroviral therapy, account for the majority of ADRs reported in neonates. The specific issue of drug maladministration and medication errors remains to be addressed in neonates.

International audience; Mammalian target of rapamycin (mTOR) inhibitors are a promising new treatment in vascular anomalies, but no published randomized controlled trials are available. The aim of this systematic review of all reported cases was to assess the efficacy and safety of mTOR inhibitors in all vascular anomalies, except cancers, in children and adults. In November 2014 MEDLINE, CENTRAL, LILACS and EMBASE were searched for studies of mTOR inhibitors in any vascular condition, except for malignant lesions, in humans. Fourteen publications and 9 posters, with data on 25 and 59 patients, respectively, all

The adverse reaction profile of alitretinoin, a retinoid indicated in severe topical corticosteroid-refractory chronic hand eczema, is similar to that of other oral retinoids, especially isotretinoin. The objective of this study was to detect new adverse effects (not listed) of alitretinoin and to estimate the number of pregnancies exposed.All cases of ADR reported in France with alitretinoin between October 1st, 2012 and February 29th, 2016 were analysed.During the 41 months of follow-up, 52 cases of serious adverse drug reaction (ADR) and 88 cases of non-serious and unexpected ADR were notified. The most frequent serious ADRs were psychiatric, neurological and dermatological. Psychiatric disorders, mainly depression and suicidal ideation represented 23% of serious ADRs. New adverse drug reactions were detected: myocardial infarction, pancreatitis and digestive haemorrhage. Three pregnancies exposed during the teratogenic risk period, were registered.The safety profile of alitretinoin matches that of other retinoids. However, the rate of psychiatric disorders appears to be high. Otherwise, the risk of myocardial infarction in patients with cardiovascular risk factor should be considered as a safety concern. It could be explained by the hyperlipemic effects of alitretinoin and studies suggest a cardiovascular risk with retinoids through their effects on lipids (class effect), especially for patients with others cardiovascular risk factors. Pancreatitis and digestive hemorrhage are described with isotretinoin. The rate of reporting of pregnancy induced by a non-compliance with the Pregnancy Prevention Program is near the rate observed with isotretinoin. The high incidence of serious ADR and the non-application of pregnancy prevention program lead the French National Agency for Medicines to limit the first prescription of alitretinoin to dermatologists.

Background: Nivolumab is approved worldwide as second-line treatment for metastatic non-small cell lung cancer (NSCLC). Despite the fact that most of these cancers are being diagnosed in the older patients, few of the patients were included in pivotal trials. We aimed to describe efficacy and safety in a ``real-world'' older population. Patients and Methods: We retrospectively collected data from older patients (>= 70 years old) with advanced or metastatic NSCLC treated with Nivolumab in our institution. We analyzed safety (CTCAE v4.0 criteria), efficacy (clinical benefit rate, progression-free survival, and overall survival), and correlated these features to geriatric parameters and PD-L1 expression. Along with this cohort, we assessed safety at a national level by retrieving all cases of Nivolumab (prescribed for NSCLC) induced adverse events analyzed by the French pharmacovigilance network during the inclusion period. Results: From July 2015 to September 2016, 30 patients were enrolled with a median age of 752. Clinical benefit rate was 30.6%. Median progression-free survival and overall survival were 33 and 7.1 months, respectively. Fifteen patients (50%) presented an immune-related adverse event (IrAE) of any grade, including four high grade IrAEs. Two hundred and eighty IrAEs had been notified to the French pharmacovigilance network including 91 (35.2%) concerning older patients. Frequency and pattern of IrAEs were similar for older patients and younger subjects. Conclusions: Even though frequency and patterns of IrAEs are different from pivotal studies, these results don't seem specific to older patients. Further prospective investigations are needed to better characterize and predict the impact of Nivolumab on older patients with NSCLC. (C) 2018 Elsevier Ltd. All rights reserved.

Introduction L’alitretinoine est un retinoide indique chez l’adulte atteint d’eczema chronique severe des mains, ne repondant pas au traitement par dermocorticoides puissants. Il est commercialise en France depuis 2009. En raison d’un risque de dyslipidemie induit par le traitement, l’alitretinoine est contre-indique en cas d’hypercholesterolemie ou d’hypertriglyceridemie non controlee. L’objectif etait de rechercher un risque d’evenement cardiovasculaire grave (ECVG) associe a l’alitretinoine. Materiel et methodes Nous avons compare la population exposee a l’alitretinoine a la population generale francaise, a partir de la base medico-administrative de l’Assurance-maladie (SNDS-SNIIRAM). Nous avons inclus tous les patients ayant recu de l’alitretinoine en France jusqu’en 2016. Les ECVG retenus etaient les syndromes coronariens aigus (SCA), accidents vasculaires cerebraux (AVC) ischemiques, et arteriopathies obliterantes des membres inferieurs (AOMI). Nous avons estime des SMR (Standardized Morbidity Ratio) en standardisant l’incidence d’ECVG sur la population generale francaise (echantillon generaliste des beneficiaires), en tenant compte de l’âge, du sexe, de la presence d’une dyslipidemie, d’un antecedent d’ECVG, et apres stratification sur le risque cardiovasculaire, defini comme la presence d’au moins un facteur de risque ou antecedent d’evenement cardiovasculaire. Resultats En France, 19513 patients ont recu de l’alitretinoine entre 2009 et 2016 : 64 ont fait un ECVG pendant la cure (duree mediane des cures : 3 mois), et 292 dans les 2 ans suivant le debut des cures. Dans la sous-population sans risque cardiovasculaire, les patients recevant de l’alitretinoine ne faisaient pas plus d’ECVG que la population generale. Dans la sous-population avec au moins un antecedent ou facteur de risque cardiovasculaire, il n’a pas ete identifie de risque d’ECVG pendant les cures ; dans les 2 ans suivant le debut des cures, les patients ont le meme risque de syndrome coronarien aigu que la population generale (SMR = 0,89, IC 95 % [0,75–1,06]), mais font deux fois moins d’AVC ischemique (SMR = 0,49, IC 95 % [0,30–0,75]). Discussion Nous n’avons pas identifie d’exces de risque d’evenement cardiovasculaire grave chez les patients ayant recu de l’alitretinoine. Une diminution du risque d’AVC dans les 2 ans suivant le debut du traitement est trouvee chez les patients ayant au moins un facteur de risque ou antecedent d’evenement cardiovasculaire. Deux hypotheses sont proposees : un effet neuroprotecteur, qui pourrait etre explique par une diminution de l’atherosclerose et une inhibition de l’agregation plaquettaire observees sur modele murin. La seconde hypothese est celle d’un « healthy user effect », traduisant un plus fort recours aux soins des patients recevant de l’alitretinoine. Conclusion Il n’est pas trouve d’exces de risque d’ECVG en cours ou apres un traitement par alitretinoine.

Background Slow-flow superficial vascular malformations (VMs) are rare congenital anomalies that can be responsible for pain and functional impairment. Currently, we have no guidelines for their management, which can involve physical bandages, sclerotherapy, surgery, anti-inflammatory or anti-coagulation drugs or no treatment. The natural history is progressive and worsening. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that acts as a master switch in cell proliferation, apoptosis, metabolism and angio/lymphangiogenesis. Sirolimus directly inhibits the mTOR pathway, thereby inhibiting cell proliferation and angio/lymphangiogenesis. Case reports and series have reported successful use of sirolimus in children with different types of vascular anomalies, with heterogeneous outcomes. Objective The objective of this trial is to evaluate the efficacy and safety of sirolimus in children with complicated superficial slow-flow VMs. Methods/design This French multicenter randomized observational-phase, phase 2 trial aims to include 50 pediatric patients 6 to 18 years old who have slow-flow (lymphatic, venous or lymphatico-venous) voluminous complicated superficial VM. Patients will be followed up for 12 months. All patients will start with an observational period (no treatment). Then at a time randomly selected between month 4 and month 8, they will switch to the experimental period (switch time), when they will receive sirolimus until month 12. Each child will undergo MRI 3 times: at baseline, at the switch time, and at month 12. For both periods (observational and treatment), we will calculate the relative change in volume of the VM divided by the study period duration. This relative change weighted by the study period duration will constitute the primary endpoint. VM will be measured by MRI images, which will be centralized and interpreted by the same radiologist who will be blinded to the study period. Hence, each patient will be his/her own control. Secondary outcomes will include assessment of safety and efficacy by viewing standardized digital photographs and according to the physician, the patient or proxy; impact on quality of life; and evolution of biological makers (coagulation factors, vascular endothelial growth factor, tissue factor). Discussion The main benefit of the study will be to resolve uncertainty concerning the efficacy of sirolimus in reducing the volume of VMs and limiting related complications and the safety of the drug in children with slow-flow VMs. This trial design is interesting in these rare conditions because all included patients will have the opportunity to receive the drug and the physician can maintain it after the end of the protocol if is found efficient (which would not be the case in a classical cross-over study). Trial registration ClinicalTrials.gov Identifier: NCT02509468, first received: 28 July 2015. EU Clinical Trials Register EudraCT Number: 2015-001096-43. Electronic supplementary material The online version of this article (10.1186/s13063-018-2725-1) contains supplementary material, which is available to authorized users.

Summary Aim of the study To evaluate whether azathioprine exposure during pregnancy increases the risk of birth defects and prematurity. Method Prospective comparative observational study using the French pregnancy database TERAPPEL. To evaluate birth defects, outcomes of pregnancies exposed to azathioprine during the 1st trimester were prospectively assessed and compared to that of pregnancies exposed to another drug used for the same indications. Secondly, the rate of preterm births was compared between fetuses exposed to azathioprine at least during the third trimester and those exposed during the first trimester only. Results From 447 requests for a risk assessment for women receiving azathioprine during pregnancy, 193 pregnancies meet inclusion criteria. One hundred and twenty-four of them were exposed to azathioprine during the 1st trimester and were compared to that of 124 pregnancies exposed to another drug used for the same indication. Azathioprine use during the first trimester was not statistically associated with the risk of all birth defects ([7.3% vs. 5.4%]; [OR = 1.36; 95%CI: 0.44–4.20]) nor with major birth defects (5.2% vs. 1.8% [OR = 2.96; 95%CI: 0.56–15.64]). The rate of preterm births (22.5% vs. 27.3%, P = 0.579) was similar regardless of the exposure period to azathioprine (at least during the third trimester or during the first trimester only). Conclusions This study confirms that first trimester exposure to azathioprine is not associated with an elevated rate of birth defects and that the high rate of preterm births among women exposed to azathioprine is probably explained by the underlying maternal disease.

Background Diabetes and myelodysplastic syndrome are two conditions that may coexist in a single patient, since both diseases are prevalent in the elderly. The pathophysiology of myelodysplastic syndrome involves recurrent genetic mutations, especially in genes controlling epigenetic regulation. Although the pathophysiology of diabetes is not well understood, several studies suggest a role of epigenetics in type 2 diabetes. Case presentation We report here for the first time the case of a 75-year-old Caucasian man who was treated for both diabetes and acute myeloid leukemia secondary to myelodysplastic syndrome, with a temporal association between glycemic dysregulation and the intake of 5-azacitidine. In fact, 2–3 days after starting each 7-day cycle of 5-azacitidine, he reported higher blood glucose levels, requiring an increased dose of self-administered insulin. Conclusion This observation could help to understand the pathophysiology of these two conditions and could encourage physicians to monitor blood glucose levels in patients under hypomethylating agent with a history of diabetes.

International audience

Because of its teratogenicity, isotretinoin is contraindicated in pregnant women and also among women of childbearing age in the absence of effective contraception. The objective of this work is to summarize the results of studies assessing the effects of regulatory measures successively implemented in France since 1996 to prevent foetal exposure to isotretinoin. The five pharmacovigilance studies have shown persistence of pregnancies exposed to isotretinoin, with an estimated incidence in the latter study, between 0.32 and 0.95 per 1000 treated women of childbearing age. The strengthening of the prevention plan of pregnancies, established in France in March 2010, seems to have resulted in a decrease in the incidence of pregnancies exposed, but this trend needs to be confirmed. However, these pregnancies are almost preventable, because most of them are explained by the non-compliance with the conditions of prescribing and dispensing. Then it seems mandatory to not deliver oral isotretinoin if it is not prescribed in accordance with the prescription laid down by the authorities.

Introduction L’isotretinoine est le medicament de choix des acnes severes. Cependant, le lien entre ce medicament et la survenue de complications psychiatriques est controverse. Il est difficile a evaluer car l’acne en elle-meme a un impact sur la qualite de vie et peut parfois induire une anxiete, une depression ou des idees suicidaires. L’objectif de ce travail etait de realiser une etude de disproportionnalite a partir de la Base nationale francaise de pharmacovigilance (BNPV), en comparant la part des notifications de troubles psychiatriques rapportee avec l’isotretinoine orale a celle des autres medicaments de l’acne et des autres retinoides. Materiel et methodes Tous les cas concernant un medicament systemique de l’acne (isotretinoine, lymecycline, minocycline, doxycycline, erythromycine et gluconate de zinc avec la mention « acne » dans l’indication) ou un retinoide systemique (isotretinoine, acitretine, alitretinoine, bexarotene, tretinoine, quelle que soit l’indication) ont ete extraits de la BNPV sur la periode entre le 1er janvier 1984 et le 31 decembre 2014. Par ailleurs, les donnees de 3 autres medicaments (ustekinumab, mefloquine et phloroglucinol) utilises comme comparateurs ont egalement ete extraits. Chaque cas d’« affections psychiatriques » ou de « lesions, intoxications et complications liees aux procedures » rapporte avec un des medicaments etudies etait analyse en double aveugle par 2 experts psychiatres. Une analyse de disproportionnalite a ete menee en calculant pour chaque medicament le nombre de notifications de troubles psychiatriques sur le nombre total de notifications. Resultats Apres analyse des cas notifies avec les medicaments de l’acne, tous les effets indesirables psychiatriques severes (n = 71) etaient rapportes avec l’isotretinoine. L’isotretinoine avait egalement la plus forte proportion d’effets indesirables psychiatriques classes legers a moderes (14,1 %). L’analyse des retinoides systemiques a montre que les proportions de troubles psychiatriques juges severes etaient les plus elevees avec l’isotretinoine (13,3 %) et avec l’alitretinoine (5,9 %), mais aussi les troubles psychiatriques legers a moderes. Discussion L’alitretinoine et l’isotretinoine, tous deux derives de la vitamine A, ont des proportions elevees d’effets indesirables psychiatriques, ce qui souleve l’hypothese que les troubles psychiatriques sous isotretinoine ne sont pas seulement lies a l’impact psychologique de l’acne. Quoi qu’il en soit, cela reste un effet secondaire rare, qui ne doit pas remettre en cause ce traitement efficace des acnes severes. Conclusion Notre travail original souligne que les effets indesirables psychiatriques sont rapportes avec plusieurs retinoides ce qui est plutot en faveur d’un effet de classe et va a l’encontre du role de la pathologie sous-jacente.

We report the case of a patient with hypersexuality while he was treated with aripiprazole since 6 months. Clinical manifestations were an increased libido, unusual frequent masturbation and sexual instincts. All have resolved upon discontinuation of aripiprazole, and recurred after it was restarted. The partial dopaminergic agonist effect of aripiprazole could probably explain the occurrence of this compulsive behaviour.

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

Resume Objectif L’objectif etait de faire le point sur le risque de toxicite oculaire fœtale apres exposition in utero a l’hydroxychloroquine. Methodes Les publications rapportant un suivi ophtalmologique de nourrissons nes de meres traitees par hydroxychloroquine pendant la grossesse ont ete analysees. Resultats Dans les 9 etudes totalisant 246 nouveau-nes ayant beneficie d’un examen ophtalmologique, aucun n’avait de signe de toxicite oculaire au stade clinique. Parmi les 31 nourrissons ayant eu des explorations electrophysiologiques, 4 avaient des signes de toxicite retinienne au stade preclinique. La faible dose cumulee in utero , l’immaturite retinienne fœtale et la faible stimulation lumineuse pourraient expliquer l’absence de retentissement de l’hydroxychloroquine sur la retine fœtale. Cependant, il est difficile de conclure a l’absence de retentissement sans suivi a distance des nourrissons. Conclusion Les donnees ne sont pas en faveur d’un risque majeur de toxicite retinienne associee a une exposition in utero a l’hydroxychloroquine.