Psychosis with use of amphetamine drugs, methylphenidate and atomoxetine in adolescent and adults.

BACKGROUND: Use of psychostimulants and relative drugs has increased worldwide in treatment of attention-deficit hyperactivity disorder (ADHD) in adolescents and adults. Recent studies suggest a potential association between use of psychostimulants and psychotic symptoms. The risk may not be the same between different psychostimulants. OBJECTIVE: To assess whether amphetamine or atomoxetine use is associated with a higher risk of reporting symptoms of psychosis than methylphenidate use in adolescents and adults, particularly in patients with ADHD. METHODS: Using VigiBase, the WHO's pharmacovigilance database, disproportionality of psychotic symptoms reporting was assessed among adverse drug reactions related to methylphenidate, atomoxetine and amphetamines, from January 2004 to December 2018, in patients aged 13-25 years. The association between psychotic symptoms and psychostimulants was estimated through the calculation of reporting OR (ROR). FINDINGS: Among 13 863 reports with at least one drug of interest, we found 221 cases of psychosis with methylphenidate use, 115 with atomoxetine use and 169 with a prescription of an amphetamine drug. Compared with methylphenidate use, amphetamine use was associated with an increased risk of reporting psychotic symptoms (ROR 1.61 (95% CI 1.26 to 2.06)]. When we restricted the analysis to ADHD indication, we found a close estimate (ROR 1.94 (95% CI 1.43 to 2.64)). No association was found for atomoxetine. CONCLUSION: Our study suggests that amphetamine use is associated with a higher reporting of psychotic symptoms, compared with methylphenidate use. CLINICAL IMPLICATIONS: The prescription of psychostimulants should consider this potential adverse effect when assessing the benefit-risk balance.

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.

Optimizing therapeutic decision-making for off-label medicines use: A scoping review and consensus recommendations for improving practice and research.

PURPOSE: Off-label medicines use is a common and sometimes necessary practice in many populations, with important clinical, ethical and financial consequences, including potential unintended harm or lack of effectiveness. No internationally recognized guidelines exist to aid decision-makers in applying research evidence to inform off-label medicines use. We aimed to critically evaluate current evidence informing decision-making for off-label use and to develop consensus recommendations to improve future practice and research. METHODS: We conducted a scoping review to summarize the literature on available off-label use guidance, including types, extent and scientific rigor of evidence incorporated. Findings informed the development of consensus recommendations by an international multidisciplinary Expert Panel using a modified Delphi process. Our target audience includes clinicians, patients and caregivers, researchers, regulators, sponsors, health technology assessment bodies, payers and policy makers. RESULTS: We found 31 published guidance documents on therapeutic decision-making for off-label use. Of 20 guidances with general recommendations, only 35% detailed the types and quality of evidence needed and the processes for its evaluation to reach sound, ethical decisions about appropriate use. There was no globally recognized guidance. To optimize future therapeutic decision-making, we recommend: (1) seeking rigorous scientific evidence; (2) utilizing diverse expertise in evidence evaluation and synthesis; (3) using rigorous processes to formulate recommendations for appropriate use; (4) linking off-label use with timely conduct of clinically meaningful research (including real-world evidence) to address knowledge gaps quickly; and (5) fostering partnerships between clinical decision-makers, researchers, regulators, policy makers, and sponsors to facilitate cohesive implementation and evaluation of these recommendations. CONCLUSIONS: We provide comprehensive consensus recommendations to optimize therapeutic decision-making for off-label medicines use and concurrently drive clinically relevant research. Successful implementation requires appropriate funding and infrastructure support to engage necessary stakeholders and foster relevant partnerships, representing significant challenges that policy makers must urgently address.

Geographic Trends in Pediatric Psychotropic Medication Dispensing Before and After the Start of the COVID-19 Pandemic.

OBJECTIVE: This study examined trends and geographic variability in dispensing of prescription psychotropic medications to U.S. youths before and after the start of the COVID-19 pandemic. METHODS: Using national data on prescription medication dispensing, the authors performed a cross-sectional study examining the monthly percent change in psychotropic medications dispensed (total N=95,639,975) to youths (ages 5-18 years) in 2020 versus 2019, across medication classes and geographic regions. RESULTS: For many medications, more were dispensed in March 2020 than in March 2019 and fewer in April-May 2020 versus April-May 2019. Stimulants had the largest decline: -26.4% in May 2020 versus May 2019. The magnitude of the monthly percent change varied by region. CONCLUSIONS: Fewer psychotropic medications were dispensed to U.S. youths after the start of the COVID-19 pandemic compared with 2019. Although some medication classes rebounded to prepandemic dispensing levels by September 2020, dispensing varied by class and region.

Weight Gain During Antipsychotic Treatment in Children, Adolescents, and Adults: A Disproportionality Analysis in the Global Pharmacovigilance Database, Vigibase®.

INTRODUCTION: While antipsychotic-induced weight gain has been widely described in adults, it has yet to be better characterized in children and adolescents. OBJECTIVE: The aim of this study was to assess antipsychotic-induced weight-gain reporting in children and adolescents as compared to adults, and according to the type of antipsychotic. METHODS: The study is an observational, case-non-case study using individual case safety reports from the WHO global pharmacovigilance database VigiBase® from 1 January 2000 to 2 June 2021. Disproportionality in antipsychotic-related weight-gain reporting in children and adolescents compared to adults was evaluated based on reporting odds ratios (RORs) with corresponding 95% confidence intervals (CIs) through multivariate logistic regression modeling. Analysis was adjusted for sex, region of reporting, year of notification, reporter qualification, concomitant use of antidepressants, and use of more than one antipsychotic. RESULTS: Among 282,224 antipsychotic-related spontaneous reports included in this analysis, we identified 16,881 (6.0%) weight-gain cases. Disproportionality in weight-gain reporting was found in children (adjusted ROR (aROR) 3.6; 95% CI 3.3-3.8) and in adolescents (aROR 2.3; 95% CI 2.2-2.4) compared to adults. Use of risperidone was associated with the highest increase in weight-gain reporting in children (aROR 4.9; 95% CI 3.9-6.1) and adolescents (aROR 3.6; 95% CI 3.1-4.1). CONCLUSIONS: Compared to adults, weight-gain reporting with antipsychotics was disproportionally higher in the pediatric population, especially in children under 12 years of age. Considering the impact of weight gain on global morbidity and mortality, physicians should closely monitor weight gain in young patients, especially children on risperidone.

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.

Serious bradycardia and remdesivir for coronavirus 2019 (COVID-19): a new safety concerns.

OBJECTIVES: In recent clinical trials some cardiac arrhythmias were reported with use of remdesivir for COVID-19. To address this safety concern, we investigated whether use of remdesivir for COVID-19 is associated with an increased risk of bradycardia. METHODS: Using VigiBase®, the World Health Organization Global Individual Case Safety Reports database, we compared the cases of bradycardia reported in COVID-19 patients exposed to remdesivir with those reported in COVID-19 patients exposed to hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids. All reports of patients with COVID-19 registered up to the 23 September 2020 were included. We conducted disproportionality analyses allowing the estimation of reporting odds ratios (RORs) with 95% CI. RESULTS: We found 302 cardiac effects including 94 bradycardia (31%) among the 2603 reports with remdesivir prescribed in COVID-19 patients. Most of the 94 reports were serious (75, 80%), and in 16 reports (17%) evolution was fatal. Compared with hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids, the use of remdesivir was associated with an increased risk of reporting bradycardia (ROR 1.65; 95% CI 1.23-2.22). Consistent results were observed in other sensitivity analyses. DISCUSSION: This post-marketing study in a real-world setting suggests that the use of remdesivir is significantly associated with an increased risk of reporting bradycardia and serious bradycardia when compared with the use of with hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids. This result is in line with the pharmacodynamic properties of remdesivir.

Amiodarone and Parkinsonism: a pharmacovigilance study.

BACKGROUND: Some case reports have described parkinsonism with amiodarone. We investigated a putative association between parkinsonism and exposure to amiodarone. METHODS: We used the WHO pharmacovigilance database (VigiBase® ). All adverse drug reactions with 'Parkinson-like events' and amiodarone were included. Four disproportionality analyses were performed: 1/after inclusion of all reports, 2/according to sex, 3/for the twenty last years (2000-2019), and 4/after exclusion of concomitant drugs known to induce parkinsonism (antipsychotic, antivertigo, antiemetic antinauseant drugs, flunarizine). Results are expressed as reporting odds ratios (ROR; 95% CI) and information component (IC). RESULTS: No significant association was found in the whole population [ROR = 0.83 (0.65-1.06), IC = -0.7 (IC025  = -0.65)], in men, in women, for the 2000-2019 years, or after exclusion of drugs inducing parkinsonism. CONCLUSION: We failed to find any signal of parkinsonism with amiodarone. We suggest that reports of parkinsonism with amiodarone could be mainly explained by other underlying causes.

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.

Drug-Induced Hearing Loss in Children: An Analysis of Spontaneous Reports in the French PharmacoVigilance Database.

INTRODUCTION: Hearing loss can have a negative impact on communication, with significant vocational, educational, and social consequences. Drugs are one of the causes of hearing loss in children. OBJECTIVES: The objective of our study was to describe drug-induced hearing loss in the pediatric population. METHODS: Reports of hearing loss from 1985 to December 2019 in the pediatric population (< 18 years) were extracted from the French PharmacoVigilance Database (FPVD). We performed a retrospective and descriptive analysis of adverse drug reaction (ADR) reports. RESULTS: A total of 70 ADR reports were identified among the 51,216 reports registered in the FPVD, 37 involving adolescents (12-17 years, 52.9%), 28 children (2-11 years, 40.0%), and 5 infants (28 days-23 months, 7.1%). Overall, 40 reports (57.1%) involved girls. A total of 56 reports (80.0%) were "serious." The most frequent hearing disorders were deafness (n = 31, 44.3%) and hypoacusis (n = 22, 31.4%). Suspected drugs (ATC 5th level) were amikacin (n = 11, 15.7%), cisplatin (n = 11, 15.7%), doxorubicin (n = 4, 5.7%), vincristine (n = 4, 5.7%), clarithromycin (n = 4, 5.7%), ceftriaxone (n = 3, 4.3%), isotretinoin (n = 3, 4.3%), and vancomycin (n = 3, 4.3%). CONCLUSIONS: This study shows that about three out of four cases of drug-induced hearing loss in the pediatric population were "serious". It also underlines the under-reporting of these ADRs and the importance of strengthening hearing monitoring in children during and long after drug exposure.

Hepatic Disorders With the Use of Remdesivir for Coronavirus 2019.

Remdesivir is a nucleotide analog prodrug with antiviral activity against a broad spectrum of human coronavirus in cell cultures and mouse models including severe acute respiratory syndrome-associated coronavirus 2. Recently, the Food and Drug Agency (FDA) and the European Medicines Agency (EMA) recommended remdesivir for the treatment of patients hospitalized with severe coronavirus disease 2019 (COVID-19) infection.1,2 In the remdesivir clinical development program, some cases have raised concerns regarding potential hepatobiliary disorders associated with remdesivir, including in healthy volunteers and patients with COVID-19.3 In cohort studies of patients hospitalized for severe COVID-19 who were treated with compassionate-use remdesivir, elevated hepatic enzymes were the most frequent adverse drug reaction reported.4,5 In the first randomized, double-blind, placebo-controlled clinical trial assessing the effect of intravenous remdesivir in adults admitted to hospital with severe COVID-19 (n = 237), a higher proportion of remdesivir recipients than placebo recipients had dosing prematurely stopped by the investigators because of adverse events including aminotransferase or bilirubin increases (3 versus 0).6 Although there is no signal from the available data of severe hepatotoxicity or drug-induced liver injury in clinical trials, the number of patients exposed to remdesivir was too limited. Therefore, there is an urgent need to investigate the hepatic safety profile associated with remdesivir in COVID-19 patients.