[Bariatric surgery and drugs: Review of the literature and Adverse Drug Reactions analysis in French National Pharmacovigilance Database]. / Chirurgie bariatrique et médicaments : revue de la littérature et analyse des effets indésirables dans la banque nationale de pharmacovigilance.

INTRODUCTION: Bariatric surgery is the only treatment for severe obesity (BMI>35kg/m2) currently recognized as effective both in achieving tangible and lasting weight loss, and in improving obesity-related comorbidities such as type 2 diabetes, hypertension, and cardiovascular complications. Bariatric surgery, like any other surgery of the digestive tract, can have an impact on nutrient absorption, as well as on drug absorption. The literature on drug management in bariatric surgery patients concerned mainly of case reports and retrospective studies involving a small number of patients. No official guidelines are available. METHODS: We conducted a literature search on the consequences of bariatric surgery in terms of drug bioavailability and/or effect. The Medline® (PubMed) database was searched using the following keywords: "bariatric surgery", "bioavailability", "gastric bypass", and "obesity". We completed this review with an analysis of reports of adverse drug reactions (ADRs) in post-bariatric surgery patients for obesity registered in the National pharmacovigilance database (PVDB). We selected all cases with the mention of "bariatric surgery and/or gastrectomy" as "medical history". After reading the cases, we excluded those in which the patient had undergone surgery for an indication other than obesity, where the route of administration was other than oral, and cases in which ADRs resulted from voluntary overdose, attempted suicide, allergy, switch to Levothyrox® new formulation, meningioma under progestative drugs, inefficacy related to generic substitution and medication error. RESULTS: The literature search identified mainly "case report" about the impact of bariatric surgery on so-called "narrow therapeutic window" drugs. We identified 66 informative cases out of a total of 565 cases selected (11%) in the PVDB. Nevertheless, the information does not allow a clear relationship between the occurrence of the ADR and the influence of bariatric surgery. CONCLUSION: There is a lack of official information and/or recommendations on medication use in subjects who have undergone bariatric surgery. Apart from under-reporting, ADRs reports remain largely uninformative. Health professional and patients would be awareness for improving, quantitatively and qualitatively the reporting of ADRs in this population.

Sudden Sensorineural Hearing Loss after COVID-19 Vaccination: A Review of the Available Evidence through the Prism of Causality Assessment.

Sudden sensorineural hearing loss (SSNHL), a rare audiological condition that accounts for 1% of all cases of sensorineural hearing loss, can cause permanent hearing damage. Soon after the launch of global COVID-19 vaccination campaigns, the World Health Organization released a signal detection about SSNHL cases following administration of various COVID-19 vaccines. Post-marketing studies have been conducted in different countries using either pharmacovigilance or medico-administrative databases to investigate SSNHL as a potential adverse effect of COVID-19 vaccines. Here, we examine the advantages and limitations of each type of post-marketing study available. While pharmacoepidemiological studies highlight the potential association between drug exposure and the event, pharmacovigilance approaches enable causality assessment. The latter objective can only be achieved if an expert evaluation is provided using internationally validated diagnostic criteria. For a rare adverse event such as SSNHL, case information and quantification of hearing loss are mandatory for assessing seriousness, severity, delay onset, differential diagnoses, corrective treatment, recovery, as well as functional sequelae. Appropriate methodology should be adopted depending on whether the target objective is to assess a global or individual risk.

Teaching pharmacovigilance to French medical students during the COVID-19 pandemic: Interest of distance learning clinical reasoning sessions.

BACKGROUND: Considering data from the literature in favor of active educational intervention to teach pharmacovigilance, we describe an innovative model of distance learning clinical reasoning sessions (CRS) of pharmacovigilance with 3rd year medical French students. METHODS: The three main objectives were to identify the elements necessary for the diagnosis of an adverse drug reaction, report an adverse drug reaction and perform drug causality assessment. The training was organized in 3 stages. First, students practiced clinical reasoning (CRS) by conducting fictive pharmacovigilance telehealth consultations. Second, students wrote a medical letter summarizing the telehealth consultation and analyzing the drug causality assessment. This letter was sent to the teacher for a graded evaluation. In the third stage was a debriefing course with all the students. RESULTS: Of the 293 third-year medical students enrolled in this course, 274 participated in the distance learning CRS. The evaluation received feedback from 195 students, with an average score of 8.85 out of 10. The qualitative evaluation had only positive feedback. The students appreciated the different format of the teaching, with the possibility to be active. CONCLUSION: Through distance CRS of pharmacovigilance, medical students' competences to identify and report adverse drug reactions were tested. The students experienced the pharmacovigilance skills necessary to detect adverse drug reactions in a manner directly relevant to patient care. The overall evaluation of the students is in favor of this type of method.

Patient's reporting of adverse drug reactions: Which added value in 2023?

Several studies were focused on the qualitative and quantitative analysis of serious adverse drug reactions (ADRs) leading to hospitalisation or death. These figures do not take into account ADRs in ambulatory patients affecting their quality of life. Patient reporting has the advantages of bringing novel information about ADRs. It provides a more detailed description of ADRs, and reports about different drugs and system organ classes when compared with health care professional (HCP) reporting. A certain amount of information is crucial in order to determine the drug-reaction relationship. European regulation and patient support programs have contributed widely to increased patient reporting but the quality of ADR reports is still unequal from one country to another. Patient reports of ADRs have contributed enormously to pharmacovigilance signal detection in a number of ways. Over the last decades, countries have developed dedicated websites for direct patient reporting. The increasing involvement of patients in ADR reporting activities facilitated by a web portal was confirmed by some studies. Patients are now recognised as having a legitimate part to play in the decision-making process. The contribution of patient reports to drug safety was acknowledged and consolidated by European Union (EU) PV legislation in 2012 aiming to involve patients more actively, nowadays called "patient centricity in pharmacovigilance". Patient organisations are involved in regulatory issues and collaborate with health institutions on the development of guidelines. However, some studies suggested that a substantial number of patient organisations have potential financial conflicts of interest but limited disclosure practices. Pharmaceutical companies integrate into patient associations, particularly for chronic diseases by different strategies: educational therapeutic or observance support programs. The question of conflict of interest of patient associations is important requiring better transparency.

Sublingual/Buccal buprenorphine and dental problems: a pharmacovigilance study.

BACKGROUND: The association between dental problems and sublingual/buccal buprenorphine is unclear. We conducted an analysis of dental adverse drug reactions reported with sublingual/buccal buprenorphine in VigiBase®, the pharmacovigilance database of the World Health Organization. RESEARCH DESIGN AND METHODS: We performed disproportionality analyses to compare the reporting rates of dental problems with sublingual/buccal buprenorphine, compared to other buprenorphine formulations and methadone. Significant signals were considered if the lower boundary of the 95% confidence interval of the Reporting Odds Ratio (ROR) was > 1; cases were ≥ 3 and p-value <0.05. We conducted sensitivity analyses by calculating the ROR according to the reporter's qualification and the reporting continent (United States of America and Europe). RESULTS: We included 30,769 reports with all buprenorphine forms. We found 20 cases of dental problems with sublingual/buccal buprenorphine. Sublingual/buccal buprenorphine was associated with an overreporting of dental problems compared to other buprenorphine formulations (ROR = 15.10; 95% CI [7.50-30.39]; p < 0.005) and compared to methadone (ROR = 6.02; 95% CI [3.21-11.30]; p < 0.005). Overreporting of dental problems was consistent in sensitivity analyses, except in Europe compared with other buprenorphine formulations and with methadone. CONCLUSIONS: Sublingual/buccal buprenorphine might increase the risk of reporting dental problems. However, these results do not modify the benefits of sublingual/buccal buprenorphine in the treatment of opioid use disorders.

Pharmacovigilance signals from active surveillance of mRNA platform vaccines (tozinameran and elasomeran).

INTRODUCTION: Two severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines, tozinameran/BNT162b2 (Comirnaty®, Pfizer-BioNTech) and elasomeran/mRNA-1273 (Spikevax®, Moderna), were approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) at the end of 2020, less than a year after the start of the coronavirus disease 2019 (COVID-19) pandemic. In France, the health authorities have requested an intensive vaccination campaign, accompanied by a reinforced and active pharmacovigilance surveillance. This surveillance and analysis of real-life data, based on spontaneous reports received by the French Network of Regional PharmacoVigilance Centers (RFCRPV), has enabled to identify numerous pharmacovigilance signals. Some of them, such as myocarditis and heavy menstrual bleeding, have been confirmed as adverse effects of these vaccines. METHOD: We propose a descriptive review of the main pharmacovigilance signals identified by the RFCRPV concerning vaccines from the mRNA platform. RESULTS: Most pharmacovigilance signals were common to both mRNA vaccines: myocarditis, menstrual disorders, acquired haemophilia, Parsonage-Turner syndrome, rhizomelic pseudo-polyarthritis and hearing disorders. Other signals were more specific, such as arterial hypertension with tozinameran or delayed reaction site injection with elasomeran. CONCLUSION: This non-exhaustive review illustrates the experience of RFCRPV in identifying and monitoring pharmacovigilance signals related to mRNA vaccines in France during the COVID-19 pandemics, and the crucial role of pharmacological and clinical expertise in this area. It also highlights the predominant contribution of spontaneous reporting in the generation of pharmacovigilance signals, particularly for serious and rare adverse events not detected before marketing.

Role of spontaneous reporting in investigating the relationship between mRNA COVID-19 vaccines and myocarditis: The French perspective.

AIM OF THE STUDY: Post-mRNA coronavirus diseases 2019 (COVID-19) vaccines myocarditis emerged as a rare adverse effect, particularly in adolescents and young adults, and was labeled as such for both vaccines in the summer of 2021. This study aims to summarize the timeline and process of signal detection, substantiation, and quantification of myocarditis cases related to mRNA vaccines in France. METHODS: The intensive monitoring plan for COVID-19 vaccine safety was based on case-by-case analysis of all cases collected in the French spontaneous reporting database (Base nationale de pharmacovigilance, BNPV). Cases were evaluated by drug safety medical professionals and discussed at a national level for signal detection purposes. Reported cases were compared to the number of vaccine-exposed persons up to September 30th, 2021. Reporting rates (Rr) of myocarditis per 100,000 injections were calculated and stratified according to age, gender, and injection rank of BNT162b2 and mRNA-1273 vaccines. Poisson distribution was used to compute Rrs 95% Confidence Interval (95% CI). RESULTS: The case-by-case analysis detected a possible cluster of myocarditis in April 2021 (5 cases, 4 after the 2nd injection). In June 2021, the signal was substantiated with 12 cases (9 related to BNT162b2, and 3 to mRNA-1273). As of September 2021, almost 73 million BNT162b2 and 10 million mRNA-1273 doses had been injected. The Rr per 100,000 injections was 0.5 (0.5-0.6) for BNT162b2 and 1.1 (95% CI 0.9-1.3) for mRNA-1273. The difference among vaccines was more pronounced after the second injection, particularly in men aged 18-24 years (4.3 [3.4-5.5] for BNT162b2 vs. 13.9 [9.2-20.1] for mRNA-1273) and aged 25-29 years (1.9 [1.2-2.9] vs. 7.0 [3.4-12.9]). CONCLUSION: The study highlighted the role of the spontaneous reporting system in the detection, assessment, and quantification of myocarditis related to m-RNA vaccines. It suggested from September 2021 that mRNA-1273 was reasonably related to a higher risk of myocarditis than BNT162b2 in people under 30, particularly after the second injection.

Safety Signal Generation for Sudden Sensorineural Hearing Loss Following Messenger RNA COVID-19 Vaccination: Postmarketing Surveillance Using the French Pharmacovigilance Spontaneous Reporting Database.

BACKGROUND: The World Health Organization recently described sudden sensorineural hearing loss (SSNHL) as a possible adverse effect of COVID-19 vaccines. Recent discordant pharmacoepidemiologic studies invite robust clinical investigations of SSNHL after COVID-19 messenger RNA (mRNA) vaccines. This postmarketing surveillance study, overseen by French public health authorities, is the first to clinically document postvaccination SSNHL and examine the role of potential risk factors. OBJECTIVE: This nationwide study aimed to assess the relationship between SSNHL and exposure to mRNA COVID-19 vaccines and estimate the reporting rate (Rr) of SSNHL after mRNA vaccination per 1 million doses (primary outcome). METHODS: We performed a retrospective review of all suspected cases of SSNHL after mRNA COVID-19 vaccination spontaneously reported in France between January 2021 and February 2022 based on a comprehensive medical evaluation, including the evaluation of patient medical history, side and range of hearing loss, and hearing recovery outcomes after a minimum period of 3 months. The quantification of hearing loss and assessment of hearing recovery outcomes were performed according to a grading system modified from the Siegel criteria. A cutoff of 21 days was used for the delay onset of SSNHL. The primary outcome was estimated using the total number of doses of each vaccine administered during the study period in France as the denominator. RESULTS: From 400 extracted cases for tozinameran and elasomeran, 345 (86.3%) spontaneous reports were selected. After reviewing complementary data, 49.6% (171/345) of documented cases of SSNHL were identified. Of these, 83% (142/171) of SSNHL cases occurred after tozinameran vaccination: Rr=1.45/1,000,000 injections; no difference for the rank of injections; complete recovery in 22.5% (32/142) of cases; median delay onset before day 21=4 days (median age 51, IQR 13-83 years); and no effects of sex. A total of 16.9% (29/171) of SSNHL cases occurred after elasomeran vaccination: Rr=1.67/1,000,000 injections; rank effect in favor of the first injection (P=.03); complete recovery in 24% (7/29) of cases; median delay onset before day 21=8 days (median age 47, IQR 33-81 years); and no effects of sex. Autoimmune, cardiovascular, or audiovestibular risk factors were present in approximately 29.8% (51/171) of the cases. SSNHL was more often unilateral than bilateral for both mRNA vaccines (P<.001 for tozinameran; P<.003 for elasomeran). There were 13.5% (23/142) of cases of profound hearing loss, among which 74% (17/23) did not recover a serviceable ear. A positive rechallenge was documented for 8 cases. CONCLUSIONS: SSNHL after COVID-19 mRNA vaccines are very rare adverse events that do not call into question the benefits of mRNA vaccines but deserve to be known given the potentially disabling impact of sudden deafness. Therefore, it is essential to properly characterize postinjection SSNHL, especially in the case of a positive rechallenge, to provide appropriate individualized recommendations.

Impact of medication reviews on drug-related problems (DRPs) in older patients living in nursing homes in West Occitania.

Despite several guidelines for preventing potentially inappropriate medication (PIM) use in older, their prescription rates remain high (25%). The aim of this study was to determine the impact of medication reviews (MRs) on the drug-related problems (DRPs) in older patients in Elderly Residential Care Homes (nursing homes [NHs]). DRP was defined as an event or circumstance involving drug therapy that actually or potentially interferes with desired health outcomes. We conducted a retrospective study on 2819 residents of the 46 NHs between 1 January 2017 and 31 December 2018. Drug prescription was analysed according to European EU(7)-PIM list and START/STOPP list. We then linked each PIM to an appropriate type of DRP. Three months later, we requested the 'updated' drug prescriptions to assess whether the recommendations had been followed. A total of 17 850 prescription lines were registered. A DRP was identified for 25% of them. Following the second request, 13 NHs (28%) responded. About 26% (n = 1188) of the overall prescriptions lines identified as a DRP involved these 13 NHs, which resulted in a recommendation being made during the first MR. Data from the second MR suggested that 53.9% (n = 640) of recommendations were followed with the requested change: 32.0% involved drug withdrawal (n = 381), 9.7% concerned dose adjustment (n = 115) and 6.5% required drug changes (n = 77). Our results show the benefit impact of MR on the quality of drug prescription in older NH residents. MRs should be one of the tools used to improve drug prescriptions in the elderly.

Sodium-glucose cotransporter 2 inhibitors: A comprehensive review from cells to bedside.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2is) are oral medications approved for type 2 diabetes mellitus. Interestingly, during recent years, they have been promisingly considered as new medications for cardiovascular and kidney diseases. However, the mechanisms underlying these new benefits are not fully understood. Thanks to the discovery of multiple modes of action, the simple picture about mechanisms of action of SGLT2is has become more and more complex. Besides their effects in diabetes, there is increasing evidence for their beneficial effects in heart failure and chronic kidney diseases. In addition, many studies have provided evidence for the fruitful effects of SGLT2is in atherosclerotic cardiovascular disease. In this study, we present mounting evidence for the complex action modes of SGLT2is and their current applications in clinical practice.

Correction to "Hyper inflammatory syndrome following COVID-19 mRNA vaccine in children: A national post-authorization pharmacovigilance study".

[This corrects the article DOI: 10.1016/j.lanepe.2022.100393.].

Hyper inflammatory syndrome following COVID-19 mRNA vaccine in children: A national post-authorization pharmacovigilance study.

Background: Multisystem inflammatory syndrome in children (MIS-C) is the most severe clinical entity associated with pediatric SARS-CoV-2 infection with a putative role of the spike protein into the immune system activation. Whether COVID-19 mRNA vaccine can induce this complication in children is unknown. We aimed to assess the risk of hyper-inflammatory syndrome following COVID-19 mRNA vaccine in children. Methods: We conducted a post-authorization national population-based surveillance using the French enhanced pharmacovigilance surveillance system for COVID-19 vaccines. All cases of suspected hyper-inflammatory syndrome following COVID-19 mRNA vaccine in 12-17-year-old children between June 15th, 2021 and January 1st, 2022, were reported. Cases were reviewed according to WHO criteria for MIS-C. The reporting rate of this syndrome was compared to the MIS-C rate per 1,000,000 12-17-year-old children infected by SARS-CoV-2. Findings: Up to January 2022, 8,113,058 COVID-19 mRNA vaccine doses were administered to 4,079,234 12-17-year-old children. Among them, 12 presented a hyper-inflammatory syndrome with multisystemic involvement. Main clinical features included male predominance (10/12, 83%), cardiac involvement (10/12, 83%), digestive symptoms (10/12, 83%), coagulopathy (7/12, 58%), cytolytic hepatitis (6/12, 50%), and shock (5/12, 42%). 4/12 (33%) required intensive care unit transfer, and 3/12 (25%) hemodynamic support. All cases recovered. In eight cases, no evidence of previous SARS-CoV-2 infection was found. The reporting rate was 1.5 (95%CI [0.8; 2.6]) per 1,000,000 doses injected, i.e. 2.9 (95%CI [1.5; 5.1]) per 1,000,000 12-17-year-old vaccinated children. As a comparison, 113 MIS-C (95%CI [95; 135]) occurred per 1,000,000 12-17-year-old children infected by SARS-CoV-2. Interpretation: Very few cases of hyper-inflammatory syndrome with multi-organ involvement occurred following COVID-19 mRNA vaccine in 12-17-year-old children. The low reporting rate of this syndrome, compared to the rate of post-SARS-CoV-2 MIS-C in the same age-group, largely supports the vaccination in a context of an important circulation of SARS-CoV-2. Funding: ESPID Fellowship Award; Grandir-Fonds de Solidarité Pour L'enfance.

[Potentially inappropriate psychotropic drug prescription in elderly people in West Occitanie area]. / Prescription de psychotropes potentiellement inappropriés chez les sujets âgés en Occitanie Ouest.

AIM: Psychotropic drugs remain frequently prescribed in elderly people. Some of them are classified as « inappropriate ¼ because they could increase the risk of adverse drug reactions. The aim of this study is to evaluate the prevalence of exposure to potentialy inappropriate psychotropic drugs (PIPs) in the elderly living in nursing home residents (EHPAD) in West Occitanie area. METHODS: We carried out a retrospective study on the cohort of PAAPI program (Personne âgée et amélioration des prescriptions inappropriées) participating in PAAPI program set up in West Occitanie in 2016 including 3095 patients during 2 years. PIPs were identified by the list EU(7)PIM and completed with the guidelines mailed by the National Drug Safety Agency. We measured the prevalence of exposure to PIPs in this population. RESULTS: The majority of the residents (n=2301, 74.4%) were female of the average age was 87.1±8.1 years and. The prevalence of exposure to psychotropic drugs was about 77.5% with an average of 1.6 prescription lines per patient (±1,1). We found antidepressants (36.5% of PIP) with mainly paroxetine (37.3% of antidepressants PIP), followed by venlafaxine (32.8%), hypnotics and sedatives (26.6% of PIP) with zopiclone with inappropriate dose (59.4% of hypnotics PIP), anxiolytics (25.8% of PIP) with alprazolam (37.9% of anxiolytics PIP), followed by bromazepam (16%) and antipsychotics (11.2% of PIP) with cyamemazine (100% of inappropriate prescription) followed by aripiprazole and haloperidol (respectively 100% and 14.7% of inappropriate prescription). CONCLUSION: According to our data, third of elderly people in Nursing Homes were exposed to a PIP suggesting that guidelines about psychotropic drugs prescription are not well followed. Then, information campaign of healthcare professionnals could be useful to improve psychotropic drug prescription in the elderly population.

Risk of Bleeding Associated With Nonsteroidal Anti-inflammatory Drug Use in Patients Exposed to Antithrombotic Therapy: A Case-Crossover Study.

Concomitant nonsteroidal anti-inflammatory drug (NSAIDs) and antithrombotic drug use is associated with an increased risk of bleeding, mainly gastrointestinal. The goal of this study was to quantify the transient increase in the risk of hospitalization for bleeding associated with NSAID use in patients treated with antiplatelet agents or anticoagulants. We performed a unidirectional case-crossover study using the EGB (Échantillon généraliste de bénéficiaires), a permanent random sample of the French nationwide health database. Patients receiving antithrombotic therapy and hospitalized for bleeding between 2009 and 2017 were included. We compared their NSAID exposure during a 15-day hazard window immediately before hospital admission to 3 earlier 15-day control windows. The risk of hospitalization for bleeding associated with the recent use of NSAIDs was estimated using conditional logistic regression to estimate odds ratios (ORs). During the study period, 33 patients treated with anticoagulants and 253 treated with antiplatelet agents received NSAIDs and were included in the case-crossover analysis. We found an increased risk of hospitalization for gastrointestinal bleeding after exposure to NSAIDs, with an adjusted OR of 3.59 (95%CI, 1.58-8.17) in patients receiving anticoagulant therapy and 1.44 (95%CI, 1.07-1.94) in patients receiving antiplatelet therapy. The risk of nongastrointestinal bleeding was also increased after exposure to NSAIDs with an adjusted OR of 2.72 (95%CI, 1.23-6.04) in patients exposed to anticoagulant therapy. The risk of gastrointestinal and nongastrointestinal bleeding increases after NSAID use in patients treated with anticoagulants, while the risk of gastrointestinal bleeding increases, but to a lesser extent in those treated with antiplatelets.

Lacosamide-induced personality changes: An unexpected adverse effect.

OBJECTIVES: To describe an 'unexpected' case of abrupt personality following the introduction of lacosamide. METHODS: A description of an 82-year-old male receiving neurological follow-up since 2010 due to epilepsy secondary to haemorrhagic stroke. We report a case of abrupt personality change in an 82-year-old male following the introduction of lacosamide with a return to the previous state after its discontinuation. We explored possible mechanisms and pharmacokinetic concerns explaining this personality change. RESULTS: In fact, a few days after introducing lacosamide, the patient was described as 'gentle', 'calm' and apologetic for his past aggressions against his family and caregivers which was in complete contrast to his usual personality. There was also marked insistence and the use of sexualised language towards women in his close circle, especially his home nurses. In view of his insistent behaviour towards his nurses and unusual sexualised language, lacosamide was withdrawn. A few days later, the patient displayed his usual, vindictive, aggressive and forceful character. He no longer made any sexualised remarks to his home nurses. CONCLUSION: To our knowledge, this is the first case of a sudden behavioural and personality change reported by family, friends and carers following the introduction of lacosamide.