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.

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.

Will artificial intelligence chatbots replace clinical pharmacologists? An exploratory study in clinical practice.

PURPOSE: Recently, there has been a growing interest in using ChatGPT for various applications in Medicine. We evaluated the interest of OpenAI chatbot (GPT 4.0) for drug information activities at Toulouse Pharmacovigilance Center. METHODS: Based on a series of 50 randomly selected questions sent to our pharmacovigilance center by healthcare professionals or patients, we compared the level of responses from the chatbot GPT 4.0 with those provided by specialists in pharmacovigilance. RESULTS: Chatbot answers were globally not acceptable. Responses to inquiries regarding the assessment of drug causality were not consistently precise or clinically meaningful. CONCLUSION: The interest of chatbot assistance needs to be confirmed or rejected through further studies conducted in other pharmacovigilance centers.

French pharmacovigilance survey of casirivimab - imdevimab monoclonal antibodies in coronavirus disease (COVID-19).

INTRODUCTION: Casirivimab and imdevimab (Ronapreve®) are two recombinant human monoclonal antibodies (mAbs) that bind to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, preventing the virus from entering cells. In March 2021, this drug was granted emergency use authorisation (EUA) in France for early treatment of COVID-19 in patients at increased risk of progression to severe COVID-19. In August/September 2021, the indication was expanded to COVID-19 prevention (pre- or post-exposure prophylaxis) and treatment of hospitalised patients requiring non-invasive oxygen therapy. The aim of the study was to better describe the adverse drug reaction (ADR) profile and detect safety signals of this new drug used in COVID-19 treatment. METHODS: We described ADR profile with casirivimab/imdevimab reported as suspect/interacting drug to the French pharmacovigilance network and the pharmaceutical company between 17/03/2021 and 30/06/2022. Data presented correspond to the 2 periods of the pharmacovigilance survey: the first carried out by the pharmaceutical company for curative and prophylactic uses and the second by Toulouse university regional pharmacovigilance center (RPVC). RESULTS: A total of 384 reports were analysed and 256 were "serious". ADR profile was comparable between the 2 periods and between curative and prophylactic use, corresponding to expected ADRs such as infusion-related reactions and hypersensitivity, inefficiencies or worsened infections and deaths. Two potential pharmacovigilance signals were also studied: acute pulmonary oedemas and sudden deaths. DISCUSSION: No pharmacovigilance signal emerged from this 15 months French pharmacovigilance survey. Moreover data from published studies are also reassuring. This pharmacovigilance survey was the first one for the new version of EUA and with a new ADR reporting process i.e. declaration to the RPVC instead of the pharmaceutical company. Casirivimab/imdevimab is no longer used in France today but we continue to monitor this drug for any future evidence of resurgent activity on a new variant of Sars-CoV-2.

Increased reporting of venous and arterial thromboembolic events reported with tixagevimab-cilgavimab for coronavirus disease 2019.

OBJECTIVES: As two phase three clinical trials indicated a disproportion in the number of thromboembolic events in the tixagevimab/cilgavimab group than in the placebo group, there has been a cardiovascular safety concern with the use of anti-SARS-CoV-2 monoclonal antibody (mAb). Whether tixagevimab/cilgavimab use in real life increases the risk of thromboembolic events is unclear. METHODS: We used VigiBase, WHO's individual case safety reports database, to assess the risk of reporting arterial or venous thromboembolic events in patients with COVID-19 (aged ≥12 years) exposed to tixagevimab/cilgavimab compared with patients with COVID-19 exposed to other anti-SARS-CoV-2 mAbs, including casirivimab/imdevimab, bamlanivimab/etesevimab and sotrovimab. RESULTS: Among the 8952 reports of patients with an anti-SARS-CoV-2 mAb, 31 reports of thromboembolic events were associated with tixagevimab/cilgavimab, mainly deep vein thrombosis (10), pulmonary embolism (8) and myocardial infarction (7). Compared with other anti-SARS-CoV-2 mAbs, the use of tixagevimab/cilgavimab was associated with an increased risk of reporting arterial thromboembolic events (reporting OR 3.25; 95% CI 1.73, 6.10). Concerning venous thromboembolic events, a significant increase in the risk of reporting was observed with the use of tixagevimab/cilgavimab (reporting OR 3.59; 95% CI 2.16, 5.96). DISCUSSION: This observational study corroborates in a real-world setting in which the cardiovascular safety signal has already been found for tixagevimab/cilgavimab in two clinical trials. Owing to these thromboembolic safety concerns and considering the lack of clinical trials supporting protection against the omicron variant, there is an urgent need to improve knowledge on the effectiveness of tixagevimab/cilgavimab with new COVID-19 variants.

Adverse drug reaction related to drug shortage: A retrospective study on the French National Pharmacovigilance Database.

AIM: Drug shortages are a growing global health issue. The aim of the study was to evaluate the consequences of drug shortages on patient safety based on data recorded in the French National Pharmacovigilance Database. METHODS: All cases involving drug shortages reported from 1985 to the end of 2019 were extracted from the database. RESULTS: Following the selection process, 462 cases were included. The number of cases increased significantly from 2004 to 2019. Cases mainly involved drugs from the nervous system (22.1%, 95% confidence interval [CI] 17.5-27.0%), the cardiovascular system (16.4%, 95% CI 11.9-21.4%) and anti-infectives for systemic use (14.3%, 95% CI 9.7-19.2%) ATC classes. Most of the cases reported an adverse drug reaction (ADR) belonging to the SOC nervous system (21%, 95% CI 18-24%), skin and subcutaneous (14%, 95% CI 11-17%), general (13%, 95% CI 10-17%) and gastrointestinal (8%, 95% CI 5-11%) disorders. Disease worsening was observed in 15.9% of the cases, mostly related to a lack of efficacy of the replacement drug. Half of the cases were considered as serious. Evolution was favourable in 79.4% of the cases. Death and/or life-threatening situations were reported in 5.8% of the cases. Medication errors (MEs) were identified in 51 cases (11%), mostly occurring at the administration step and involving a human factor. CONCLUSION: This study emphasizes the clinical impact of drug shortage in terms of ADRs, ME and inefficiency. These observations underline the importance of a global health policy programme to limit the occurrence of drug shortages and to reinforce the information provided to patients and health care professionals in this context to limit risk.

COVID-19 vaccines: A perspective from social pharmacology.

Social pharmacology is a branch of clinical pharmacology, which depicts relationships between society and drugs and in particular factors, reasons, social consequences of drug use as well as representations of drugs in the society. Recent development and marketing of coronavirus disease 2019 (COVID-19) vaccines raises a number of questions of social pharmacology: are vaccines drugs like any other? What is their perception at the individual, population and societal levels? How do individuals perceive the risks and benefits of these vaccines? What is the perception at the societal level? What is the individual and societal acceptability of these vaccines during a pandemic? All these questions are discussed in the light of recent data. A number of proposals, both at the individual and at the collective or population level, are formulated to help solve these problems of social pharmacology.

Fatal adverse drug reactions: A worldwide perspective in the World Health Organization pharmacovigilance database.

AIMS: Adverse drug reactions (ADRs) are important causes of death. However, the main involved drugs are relatively unknown. The present study was performed to characterise death-related drugs recorded in a large pharmacovigilance database during the last 10 years. METHODS: A retrospective analysis of VigiBase, the World Health Organization pharmacovigilance database, was performed investigating fatal ADRs registered between 1 January 2010 and 31 December 2019 in male and female patients aged ≥18 years and reported by physicians. Analyses were descriptive investigating age, sex and suspected drugs. Differences in reporting according to sex, age and continents were investigated using disproportionality analysis with calculation of reporting odds ratio and its 95% confidence interval. RESULTS: Among the 23 millions ADRs recorded in VigiBase, 3 250 967 were included with 43 685 fatal. They were reported mainly in patients older than 75 years. The 3 most frequently involved drug classes were antineoplastic/immunomodulating drugs followed by nervous system and cardiac drugs. The top 3 individual drugs were denosumab, lenalidomide and thalidomide with marked differences according to age, sex, continents and countries. The risk of reporting fatal ADRs was higher in males, in the Americas and in patients ≥65 years. CONCLUSION: Fatal ADRs registered in a large pharmacovigilance database during the last 10 years correspond to just over 1% of the total number of ADRs. They occurred more in males, after 65 years and with antineoplastic/immunomodulating drugs in general. Our study also highlighted, for the first time, important differences in fatal ADRs between continents and countries.

Tramadol-induced hypoglycemia: A pharmacovigilance study.

Several papers have reported that tramadol can induce hypoglycemia. However, in some reports, confounding factors can be found, like coadministration of hypoglycemic drugs. We used the WHO pharmacovigilance database (VigiBase®) to investigate whether tramadol alone could be associated with hypoglycemia. All 2010­2019 ICSRs (Individual Case Safety Reports) with the PT term "hypoglycemia" and tramadol were included. Two disproportionality analyses were performed: 1/after inclusion of all reports, 2/after exclusion of concomitant hypoglycemic drugs. Results are expressed as Reporting Odds Ratios (ROR; 95% CI). Among 10 038 436 ICSRs, 97 639 were included. In comparison with codeine, a significant association was found between tramadol use and reports of hypoglycemia before [ROR = 1.54 (1.43­1.66)] or after [ROR = 1.43 (1.31­1.56)] exclusion of hypoglycemic drugs. Tramadol use is associated with a higher risk of hypoglycemia reports than codeine, the other step 2 analgesic, in the presence as well as in the absence of other hypoglycemic drugs. We concluded that hypoglycemia is an adverse drug reaction of tramadol, which can be observed in diabetic as well as in non-diabetic patients.

Can tramadol really induce hyponatraemia? A pharmacovigilance study.

Several papers have described hyponatraemia with tramadol. However, in most reports, several confounding factors can be found. We used the WHO pharmacovigilance database (VigiBase®) to investigate if tramadol alone could be associated with hyponatraemia. All 1992-2019 ICSRs (individual case safety reports) with the preferred term (PT) "hyponatraemia" and tramadol were included. Two disproportionality analyses were performed: (1) after inclusion of all reports, and (2) after exclusion of concomitant hyponatraemic drugs. Results are expressed as reporting odds ratios (ROR; 95% CI) and information component (IC). Of 19 747 604 ICSRs, 225 575 were included. A significant association was found between tramadol use and reports of hyponatraemia (ROR = 1.49 [1.39-1.60], IC = 0.57 [IC025 = 0.47]). After exclusion of hyponatraemic drugs, the previously found association disappeared. The study failed to find any pharmacovigilance signal of hyponatraemia with tramadol alone. We suggest that reports of hyponatraemia with tramadol can be explained principally by other underlying causes of hyponatraemia, especially other concomitant hyponatraemic drugs.

Role of serotonin and norepinephrine transporters in antidepressant-induced arterial hypertension: a pharmacoepidemiological-pharmacodynamic study.

PURPOSE: Some reports have described arterial hypertension (AH) in patients treated by serotonin reuptake inhibitor (SRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants. The mechanism remains discussed, some authors suggesting a role of SERT (SERotonin Transporter) inhibition whereas others discussing NET (NorEpinephrine Transporter) involvement. The present study used the pharmacoepidemiological-pharmacodynamic (PE-PD) method to investigate the role of these transporters in SRI- and SNRI-induced AH. METHODS: The study involved two successive approaches: first, a PE study (disproportionality analysis) investigating in VigiBase®, the World Health Organization Individual Case safety Report (ICSR) database, the relationships between exposure to SRI AND SNRI, and reports of AH. The primary analysis compared patients receiving one SRI (or one SNRI) with non-users. Secondary analyses were performed according to the pharmacological classes. Results are expressed as reporting odds ratios (ROR) with 95% CI and information component (IC), an indicator for disproportionate Bayesian reporting. Second, we performed a PD study using linear regression analyses to explore the association between the AH signal and binding affinities for NET and SERT (expressed as their pKi ratio) of SRIs and SNRIs. RESULTS: A significant ROR value was found for each individual SRI (except fluvoxamine) and each individual SNRI. ROR values were also significant for SRIs and SNRIs in general with higher values for SNRIs than for SRIs. Similar trends were found using IC. A significant correlation was found between the signal of AH and the NET/SERT pKi ratio (y = 6.57x - 2.55, R2 = 0.68, Pearson coefficient correlation = 0.82). CONCLUSION: The present study found a positive association between the NET/SERT pKi ratio and the occurrence of arterial hypertension with SRI and SNRI antidepressants. These results are important for the selection of antidepressants in hypertensive and/or at risk depressive patients as well as for future development of antidepressants devoid of hypertensive effect.

Interest of a general practitioner pharmacovigilance network to provide drug information: A comparative study in France.

INTRODUCTION: Since 2015, Toulouse University PharmacoVigilance Center (TUPVC) set up a pharmacovigilance (PV) general practitioner (GP) network, called PharmacoMIP-MG. A clinical research assistant (CRA) moves to the office of GPs included in the PharmacoMIP-MG network (PMIP-GPs). There, he collects the adverse drug reaction (ADR) reports and drug-related questions. This additional support is not available to GPs not included in the PV network (NoPMIP-GPs) who have to ask drug questions spontaneously to the TUPVC. OBJECTIVE: The objective of this study was to compare the number and characteristics of drug questions between PMIP-GPs and NoPMIP-GPs. METHODS: All questions asked by GPs to the TUPVC from 01 Jan 2015 to 31 Dec 2017 were reviewed. Questions were classified into two groups: "general" and "related to a patient". The "related to a patient" category was divided in three subgroups: "ADRs", Drug-Drug Interactions and "Drug Management". Drugs were classified according to anatomical therapeutic chemical (ATC) classification. For comparisons, Wilcoxon test, Chi2 test or Fisher test were used. RESULTS: During the study period, the CRA collected 293 questions from the 165 PMIP-GPs. TUPVC received 333 questions asked spontaneously by the 3400 NoPMIP-GPs. PMIP-GPs asked significantly 3 times more questions than NoPMIP-GPs. Most of the GP questions were classified in the "related to a patient" category (74.9%). When we compared the proportion of "related to a patient" to "general" questions, there was no statistically significant difference between PMIP-GPs and NoPMIP-GPs. PMIP-GPs asked more questions about "ADRs", but less on "Drug Management" and or "Drug-Drug Interactions". The drugs most frequently involved were amiodarone, rivaroxaban and levothyroxine. CONCLUSION: This is the first study about GPs' drug-related questions asked to a PV center. We found that an organization, such as a CRA-GP "face to face" visit, increased the number of drug questions. This kind of organization should be developed in order to improve independent drug information outreach.

Cushing's syndrome due to interaction between ritonavir or cobicistat and corticosteroids: a case-control study in the French Pharmacovigilance Database.

OBJECTIVES: To explore the frequent interaction between antiretroviral-boosting agents and corticosteroids causing Cushing's syndrome (CS) in the French Pharmacovigilance Database (FPVD). METHODS: We conducted a retrospective case-control study describing CS recorded in the FPVD between 1996 and 2018. Case was defined as CS occurring in people living with HIV (PLWH) and control was defined as CS in uninfected individuals. Drug-drug interaction (DDI) was defined as an interaction between corticosteroids and CYP3A4 inhibitors. Data concerning the DDI, corticosteroids involved, route of administration and seriousness of the CS were described. RESULTS: Among the 139 instances of CS identified, 34/35 cases (97%) had DDIs (31 with ritonavir and 3 with cobicistat) and 7/104 controls (7%) had DDIs (6 with itraconazole and 1 with verapamil). The main corticosteroid involved was inhaled fluticasone (28/35, 80%) among the cases and oral prednisone (38/104, 37%) among the controls. More CS cases (30/35, 86%) than CS controls (62/104, 60%) were serious (OR = 4.0, 95% CI = 1.4-14.4; P = 0.007). CONCLUSIONS: Antiretroviral-boosting agents were responsible for one out of four iatrogenic CS cases in a French national database. Prescribers should be aware of the risk of potentially serious DDIs between antiretroviral-boosting agents and corticosteroids, including single-tablet regimens containing cobicistat.

Are lipid-lowering drugs associated with a risk of cataract? A pharmacovigilance study.

Some reports have raised concerns regarding a potential risk of cataracts associated with statins. However, clinical and observational studies evaluating the risk led to conflicting results. We assessed whether lipid-lowering drugs (LLD) use is associated with an increased risk of cataract using the WHO's Individual Case Safety Reports database, VigiBase® . We performed a disproportionality analysis with all reports between 1/1/1988 and 12/31/2018 to measure the reporting risk of 'cataract' in patients ≥45 years. Primary analysis compared LLD users to non-users. To mitigate some potential confounding bias, we performed several sensitivity analyses excluding reports (i) with an association of at least two LLD, (ii) with antidiabetic and glucocorticoids and (iii) with lovastatin. We also analyzed the data according to the different classes of age limiting the period of study to years 2002-2012. We identified 14 664 reports of cataract (3 049 in LLD users, 66% women, 66 ± 20 years). Statins (84%, atorvastatin, simvastatin, rosuvastatin and lovastatin) were mostly reported, followed by fibrates (5.7%), nicotinic acid (3%), bile acid sequestrants (2%), herbal cholesterol and triglyceride reducers (2%) and others (ezetimibe, PCSK9 inhibitors, 15%). LLD users were associated with a greater risk of reports than non-users (ROR 2.47, 95% CI 2.37-2.57). This association was also found for statins in general, fibrates, bile sequestrants, nicotinic acid, herbal drugs and others. Similar trends were observed in sensitivity analyses (except for fibrates and nicotinic acid after exclusion of reports with at least two LLD or in older patients ≥75 years). Using a large real-life database (>18.5 million reports), we found a signal of cataract for LLD as a whole and statins, bile sequestrants and herbal drugs in particular. The signal disappeared for fibrates and nicotinic acid in older patients. No definite conclusions can be made for ezetimibe or PCSK9 inhibitors (evolocumab and alirocumab). This suggests that a decrease in cholesterol could be important in the pathophysiology of cataract in patients exposed to the main LLD.