21st ISoP Annual Meeting “A New Era of Pharmacovigilance: Challenges and Opportunities” 20–23 September 2022 Verona, Italy

ABSTRACTS

21st ISoP Annual Meeting

“A New Era of Pharmacovigilance: Challenges and Opportunities”

20–23 September 2022

Verona, Italy

The International Society of Pharmacovigilance (ISoP) aims to develop its activities on a worldwide basis towards supporting safer use of medicines in clinical practice.

ISoP encourages and supports the use of all types of information and methodologies in providing optimal drug treatment for patients. The Society is open to anyone interested in learning about better ways for patients to receive and use medicines safely, including academics, epidemiologists, medicines regulators, clinical pharmacologists, pharmaceutical industry representatives, practising clinicians, pharmacists, and other healthcare professionals.

Countries where there are ISoP members:

From Argentina to Zimbabwe, in countries in Europe to Asia, across the Americas, and from Australia to Africa, we have members in all five continents.

''By becoming a member of ISoP, you will have the opportunity to share your knowledge and ideas and to contribute to improving pharmacovigilance activities worldwide.''

Dr Mira Harrison-Woolrych, President of the International Society of Pharmacovigilance

ISoP Membership incentives include:

• Discounted online subscription to the Drug Safety journal

• Face-to-face meetings and webinars

• Annual conference and training courses

• Involvement in ISoP’s Chapters and Special Interest Groups

• Opportunities for networking and other professional collaborations

• Regular newsletters and copies of the ISoP Star

For more information, please visit www.isoponline.org, the Society’s official website.

International Society of Pharmacovigilance

ISoP Secretariat Ltd

140 Emmanuel Road, London SW12 0HS, UK

Tel and Fax: +44 (0)20 3256 0027

administration@isoponline.org

ISoP 2022 Local Organising Committee

Chair: Gianluca Trifirò, University of Verona (Italy)

• Annalisa Capuano, University of Campania “L. Vanvitelli” (Italy)

• Cristiano Chiamulera, University of Verona (Italy)

• Salvatore Crisafulli, University of Verona (Italy)

• Barbara De Bernardi, Pfizer (Italy)

• Carmen Ferrajolo, Italian Medicines Agency (Italy)

• Ylenia Ingrasciotta, University of Verona (Italy)

• Roberto Leone, University of Verona (Italy)

• Giuseppe Lippi, University of Verona (Italy)

• Anna Rosa Marra, Italian Drug Agency (Italy)

• Pietro Minuz, University of Verona (Italy)

• Ugo Moretti, University of Verona (Italy)

• Giovanna Scroccaro, Pharmaceutical and Medical Device Department, Veneto Region (Italy)

• Evelina Tacconelli, University of Verona (Italy)

• Marco Tuccori, University of Pisa, Chair of ISoP Italian Chapter (Italy)

ISoP 2022 Scientific Committee

Chair: Angela Caro Rojas, Pontificia Universidad Javeriana (Colombia)

Co-Chair: Gianluca Trifirò, University of Verona (Italy)

• Andrew Bate, GlaxoSmithKline (UK)

• Ghita Benabdallah, Centre Anti Poison et de Pharmacovigilance du Maroc (Morocco)

• Gianmario Candore, Bayer (Germany)

• Linda Härmark, Pharmacovigilance Centre Lareb (The Netherlands)

• Deirdre McCarthy, Gates MRI (USA)

• Antoine Pariente, University of Bordeaux (France)

• Saad Shakir, Drug Safety Research Unit (UK)

• Mónica Tarapués, Central University of Ecuador (Ecuador)

Abstracts reviewers

Chairs: Angela Caro Rojas, Pontificia Universidad Javeriana (Colombia) and Gianluca Trifirò, University of Verona (Italy)

Omar Aimer, Pfizer (Canada)

Mayada Alkhakany, Boehringer Ingelheim (Germany)

Thamir Alshammari, King Saud University (Saudi Arabia)

Elena Arzenton, University of Verona (Italy)

Andrew Bate, GlaxoSmithKline (UK)

Ghita Benabdallah, Centre Anti Poison et de Pharmacovigilance du Maroc (Morocco)

Melissa Bernal, Colombian Pharmacovigilance Association (Colombia)

Helen Byomire Nagije, National Drug Authority (Uganda)

Gianmario Candore, Bayer (Germany)

Rebecca Chandler, Coalition for Epidemic Preparedness Innovations (Sweden)

Salvatore Crisafulli, University of Verona (Italy)

Paola Maria Cutroneo, University Hospital of Messina (Italy)

Carmen Ferrajolo, Italian Medicines Agency (Italy)

Ulrich Hagemann, Germany

Linda Härmark, Pharmacovigilance Centre Lareb (The Netherlands)

Mira Harrison-Woolrych, ISoP President (New Zealand)

Ylenia Ingrasciotta, University of Verona (Italy)

Roberto Leone, University of Verona (Italy)

Lara Magro, University of Verona (Italy)

Deirdre McCarthy, Gates MRI (USA)

Ugo Moretti, University of Verona (Italy)

Antoine Pariente, University of Bordeaux (France)

Emanuel Raschi, University of Bologna (Italy)

Souad Skalli, Mohammed V University (Morocco)

Mónica Tarapués, Universidad Central del Ecuador (Ecuador)

Marco Tuccori, University of Pisa, Chair of ISoP Italian Chapter (Italy)

Manal Younus, Iraqi Pharmacovigilance Center (Iraq)

Zhang Li, Dongfang Hospital, Beijing University of Chinese Medicine (China)

Qun-Ying Yue, Uppsala Monitoring Centre (Sweden)

Patricia Zuluaga, Colombian Pharmacovigilance Association (Colombia)

ISoP 2022 Poster Prize Committee

Chair: Ghita Benabdallah, Centre Anti Poison et de Pharmacovigilance du Maroc (Morocco)

Helaine Carneiro Capucho, Brazilian Health Regulatory Agency (Anvisa) (Brazil)

Ylenia Ingrasciotta, University of Verona (Italy)

ISoP Executive Committee and Advisory Board 2019-2022

Mira Harrison-Woolrych, President (New Zealand)

Rebecca Chandler, Vice-President (Sweden)

Deirdre McCarthy, Secretary General (USA)

Jean-Christophe Delumeau, Treasurer (Czech Republic)

Board Members

Angela Caro (Colombia)

Jan Petracek (Czech Republic)

Mónica Tarapués (Ecuador)

Gianluca Trifirò (Italy)

Manal Younus (Iraq)

Zhang Li (P.R.China)

Disclaimer

ISoP requests a high standard of science is followed concerning publications and presentations at all its annual conferences and training courses. However, ISoP as a whole or its Advisory Board and Executive Committee (EC) or appointed Scientific Committees, or its members, do not take any responsibility for the completeness or correctness of data, or references given by authors in publications and presentations at ISoP scientific meetings.

It is not within the remit of ISoP or its advisory committees, to seek clarification or detailed information from authors about data in submitted abstracts. Moreover, it is not within the scope of ISoP and its committees to monitor compliance with any legal obligations, for example, reporting requirements or regulatory actions.

1 ORAL PRESENTATIONS

1.1 O-001 Oral presentation: Effectiveness and Tolerance of Biotherapy in the Treatment of Chronic Inflammatory Diseases and Rheumatism in Children

1.1.1 R. Mourchid ¹, Y. Cherrah¹, B. Chkirate², S. Serragui¹

1.1.1.1 ¹School of Medicine and Pharmacy-Mohammed V University, Rabat-Morocco, Department of Pharmacology and Toxicology Faculty of Medicine and Pharmacy University Mohammed V Rabat-Morocco, Rabat-Morocco; ²Ibn Sina Children’s Hospital in Rabat HER-Rabat-Morocco, the pediatric ward IV of rheumatology at Ibn Sina Children’s Hospital in Rabat, Rabat, Morocco

Introduction: The use of biotherapy has vastly improved the treatment of patients with juvenile idiopathic arthritis and certain auto-inflammatory diseases by preventing long-term damage, and improving quality of life (1,2)

Objective: The main goal of our study was to evaluate the effectiveness and tolerance of biotherapy on the treatment of rheumatism and chronic inflammatory diseases in children in the pediatric ward IV at the Children's Hospital in Rabat.

Methods: We conducted a retrospective observational study in the pediatric ward IV at Ibn Sina Children’s Hospital in Rabat (HER) with children treated for chronic rheumatic and inflammatory diseases for the period from February 2021 to June 2021. Data collection was carried using an excel datasheet from the pediatric department register, the record of pediatric rheumatology consultations and patient records. The data extracted concerned the socio-demographic data of patients, also the evolution of pathology, effectiveness of biotherapy used based on Giannini score. The second part of our study focused on the collection of adverse reactions reported of the biotherapy treatment and their classification.

Results: In the course of our study, the results showed that among (n = 100) patients were treated using Anti-Tumor necrosis factor, Anti-Interleukin 1, or Anti-interleukin 6. (n = 42) had a systemic form of arthritis, (n = 30) had polyarthritis, (n = 10) had oligoarthritis, (n = 14) with Spondyloarthritis, (n = 2) had BEHÇET'S disease, and one patient had familial Mediterranean fever, we found that (87%) of our patients had good progress under etanercept, infliximab and adalimumab with Giannini scores of (90%), (80%) and (70%), the effectiveness exceeded (70%) in patients on Anakinra and (90%) Tocilizumab. Our study also reported 15 adverse reactions in patients receiving Biotherapy with a single severe adverse reaction, which was severe hepatitis type A under Tocilizumab.The most common adverse reaction was the development of infections.

Conclusion: The children's short-term tolerance was overall good, the only biotherapy treatment that has caused a severe adverse reaction was Tocilizumab. prospective studies are required to assess long-term effectiveness and tolerance.

References/Further Sources of Information

• 1. Ardoin SP, Daly RP, Merzoug L, Tse K, Ardalan K, Arkin L, et al. Research priorities in childhood-onset lupus: results of a multidisciplinary prioritization exercise. Pediatr Rheumatol Online J. 2019 Jul 1;17(1):32.

• 2. Davies R, Gaynor D, Hyrich KL, Pain CE. Efficacy of biologic therapy across individual juvenile idiopathic arthritis subtypes: A systematic review. Semin Arthritis Rheum. 2017;46(5):584–93.

1.2 O-002 Oral Presentation: European Pharmacovigilance Analysis of Cardiac Arrhythmias Events with Immune Checkpoint Inhibitors

1.2.1 A. Mascolo ¹, L. Sportiello¹, C. Rafaniello¹, L. Scisciola², M. Barbieri², F. Rossi¹, G. Paolisso², A. Capuano¹

1.2.1.1 ¹University of Campania “Luigi Vanvitelli”, Department of Experimental Medicine-Section of Pharmacology “L. Donatelli”, Napoli, Italy; ²University of Campania “Luigi Vanvitelli”, Department of Advanced Medical and Surgical Sciences, Napoli, Italy

Introduction: Immune checkpoint inhibitors (ICIs) are novel biological agents with proven efficacy for several types of cancers. However, ICIs have also been associated with the onset of cardiac immune-related adverse events, which are rare but associated with high morbidity and mortality [1,2]. Moreover, these events are highly arrhythmogenic despite their related clinical manifestations are still poorly understood [3].

Objective: The objective of this study was to evaluate the occurrence of cardiac arrhythmias related to ICIs by analyzing European Pharmacovigilance data.

Methods: Individual case safety reports (ICSRs) on ICI-associated cardiac arrhythmias were retrieved from the website of suspected adverse drug reactions of the European pharmacovigilance database (Eudravigilance), available at www.adrreports.eu. Data were retrieved from the date of the marketing authorization of each ICI (pembrolizumab, nivolumab, atezolizumab, ipilimumab, durvalumab, avelumab, cemiplimab, and dostarlimab) to 30 April 2022. ICSRs were classified based on the ICI. If more than one ICI was reported, the ICSR was classified as a combination of ICIs. To assess the reporting frequency of cardiac arrhythmias for each ICI/combination of ICIs compared to all other ICIs, the reporting odds ratio (ROR) and its 95% confidence interval (95% CI) were computed. The RORs and 95% CI were also computed for comparing ICIs’ drug classes: anti-PD1 (nivolumab, pembrolizumab, cemiplimab, dostarlimab), anti-PDL1 (atezolizumab, durvalumab, avelumab), and anti-CTLA4 (ipilimumab). Finally, RORs and 95% CI were computed for the three most reported events of cardiac arrhythmias.

Results: A total of 1,262 ICSRs related to an ICI and an event of cardiac arrhythmia were retrieved from Eudravigilance, of which 147 (11.6%) were related to combinations of ICIs. The most reported combination was nivolumab/ipilimumab (N = 140; 95.2%). The three most reported single ICIs were pembrolizumab (N = 456; 36.1%), nivolumab (N = 433; 34.3%), and atezolizumab (N = 74; 5.9%). A total of 1,426 events of cardiac arrhythmias were identified, of which 1,187 were serious (83.2%) and 429 had a fatal outcome (30.1%). The three most reported events were atrial fibrillation, tachycardia, and cardiac arrest. The ROR of ipilimumab was compared to all other ICIs was 0.71 (95% CI 0.55–0.92; p = 0.009). In the comparison between ICIs’ drug classes, anti-PD1 were associated with a higher reporting frequency of cardiac arrhythmias compared to anti-CTLA4 (ROR 1.47, 95% CI 1.14–1.90; p = 0.003). In the analyses of the three most reported events, no statistically significant difference was observed for all comparisons.

Conclusion: The anti-CTLA4 ipilimumab was the only ICI associated with a reduced reporting frequency of cardiac arrhythmias. Further specific high-quality studies are needed on this topic.

References/Further Sources of Information

• 1. Michel L, Rassaf T, Totzeck M. Cardiotoxicity from immune checkpoint inhibitors. Int J Cardiol Heart Vasc. 2019;25:100420. Published 2019 Sep 7. https://doi.org/10.1016/j.ijcha.2019.100420.

• 2. Mascolo A, Scavone C, Ferrajolo C, Rafaniello C, Danesi R, Del Re M, Russo A, Coscioni E, Rossi F, Alfano R, Capuano A. Immune Checkpoint Inhibitors and Cardiotoxicity: An Analysis of Spontaneous Reports in Eudravigilance. Drug Saf. 2021 Sep;44(9):957-971.

• 3. Power JR, Alexandre J, Choudhary A, Ozbay B, Hayek S, Asnani A, Tamura Y, Aras M, Cautela J, Thuny F, Gilstrap L, Arangalage D, Ewer S, Huang S, Deswal A, Palaskas NL, Finke D, Lehman L, Ederhy S, Moslehi J, Salem JE; International ICI-Myocarditis Registry†. Electrocardiographic Manifestations of Immune Checkpoint Inhibitor Myocarditis. Circulation. 2021 Nov 2;144(18):1521-1523.

1.3 O-003 Oral Presentation: Potentially Inappropriate Medication in Older Adult’s Adverse Drug Reactions Spontanueous Reports

1.3.1 D. Gomes^1,2, M. Herdeiro³, I. Ribeiro-Vaz^4,5, P. L. Ferreira^2,6, F. Roque ¹

1.3.1.1 ¹Polytechnic of Guarda UDI-IPG, Research Unit for Inland Development, Guarda, Portugal; ²University of Coimbra, Centre for Health Studies and Research, Coimbra, Portugal; ³University of Aveiro, Institute of Biomedicine-Department of Medical Sciences iBiMED-UA, Aveiro, Portugal; ⁴University of Porto, Porto Pharmacovigilance Centre, Porto, Portugal; ⁵University of Porto, Center for Health Technology and Services Research CINTESIS-Faculty of Medicine, Porto, Portugal; ⁶University of Coimbra, Faculty of Economics, Comibra, Portugal

Introduction: A medicine is considered potentially inappropriate (PIM) when the potential risk of it in the older population exceeds the potential benefit, and for which there are safer alternatives [1]. This is highly prevalent in their medication therapy [1,2], enhancing adverse reactions. PIM are already identified from various tools developed, being the most common ones the explicit Beers criteria [3], the START/STOPP, which requires additional patient data [4] and in Europe the EU-7-PIM list [5].

Objective: The aim of this study was to identify suspected medicines classified as PIM in the Adverse Drug Reactions (ADR) reports received by the Portuguese Pharmacovigilance System of the National Authority of Medicines and Health Products (INFARMED, I.P.) in older adults, analysing in dept the reports including PIM as suspected medication.

Methods: A retrospective study was designed including all ADR reports received by INFARMED, IP., between January and December 2019 in 65 and more year-old patients. ADR were characterized according with MedDRA System Organs Classes (SOC), seriousness, and medication according with the Anatomical Therapeutical Classification. PIM were identified in the report’s suspected medication applying the operationalization for the Portuguese reality of the EU (7) PIM list [5] as well as the Beers criteria from 2019 [3].

Results: Beers and EU (7) PIM criteria were applied in 2337 reports. PIM were found in 299 (12,8%). From the 3170 suspected medicines identified, 337 (10.6%) were classified as PIM. From the 299 reports including PIM as suspected medication, the population showed a mean age of 73.0 ± 6.6 years, being 56.5% (n = 169) female. 45.2% (n = 135) were reported by physicians. 71,4% (n = 215) of the reports were classified as serious, and hospitalization was the most common seriousness criteria identified (35.1%/n = 105). “Nervous System disorders” was the most common SOC criteria reported (49,1%/n = 147). Amiodarone (C01BD01) was the most frequent PIM identified by the criteria (n = 34/10.1%), followed by dabigatran etexilat (B01AE07), (7.1%/n = 24) and Rivaroxaban (B01AF01) (6.2%/n = 21). Reports including PIM in suspected medicines had a significant higher number of ADR (p = 0.025) and number of suspected medicines per report (p < 0.001). Seriousness of the ADR report classification (p = 0.005) and hospitalization (p < 0.001) were more associated in reports including PIM.

Conclusion: These results reinforce the importance of improving medication appropriateness in older adults and promote the development and use of clinical decision support systems to avoid inappropriate prescriptions and, therefore, severe adverse reactions.

Funding: APIMedOlder [PTDC/MED-FAR/31598/2017].

References/Further Sources of Information

• 1. Almeida A, Santos M, Santos M. Consumo de medicamentos potencialmente inapropriados e reconciliação de medicamentos em pessoas idosas. Servir. 2017;(1):93–103.

• 2. Lavan AH, Gallagher P. Predicting risk of adverse drug reactions in older adults. Ther Adv Drug Saf. Published online 2016.

• 3. Beers MH, Ouslander JG, Rollingher I, Reuben DB, Brooks J, Beck JC. Explicit Criteria for Determining Inappropriate Medication Use in Nursing Home Residents. Arch Intern Med. 1991;151(9):1825–1832.

• 4. Rei T, Ramôa A, Pereira C, et al. Prescrição potencialmente inapropriada em idosos numa unidade de saúde familiar do norte do país–aplicação dos critérios stopp/start versão 2. AIMGF Mag. 2018;8(2).

• 5. Renom-Guiteras A, Meyer G, Thürmann PA. The EU(7)-PIM list: a list of potentially inappropriate medications for older people consented by experts from seven European countries. Eur J Clin Pharmacol. 2015;71(7):861–875.

1.4 O-004 Oral Presentation: Analysis of Medication Errors in Children and Adolescents Reported to HALMED

1.4.1 M. Pavičić ¹, N. M. Skvrce¹, I. Kuliš¹, L. Miletić¹, S. Tomić¹

1.4.1.1 ¹Agency for Medicinal Products and Medical Devices of Croatia, Department for Pharmacovigilance and Rational Pharmacotherapy, Zagreb, Croatia

Introduction: A medication error is an unintended failure in the drug treatment process that leads to, or has the potential to lead to, harm to the patient [1]. Use of medicinal products in children is identified as a risk factor for occurrence of medication errors [2, 3].

Objective: Aim of this study is to describe medication errors and identify causes of medication errors in children and adolescents spontaneously reported to HALMED, in order to propose and implement appropriate risk minimisation measures.

Methods: We performed a search of HALMED’s adverse drug reaction database using Standardised MedDRA Query (SMQ): Medication errors (Broad) with data lock point April 30th 2022. Cases in which medication errors occurred in patients up to 18 years of age were analysed according to the patient’s age and gender, Preferred Terms (PTs) reported and root causes of medication errors.

Results: Out of 8603 cases in patients up to 18 years of age, 1684 cases included terms pertaining to SMQ: Medication errors (Broad). Medication errors were most frequently reported for male patients (54%) and in the age group 2–11 years (67%). The most commonly reported PTs for medication errors were Accidental exposure to product by child (65%) and Accidental overdose (19%). Grouping of cases was observed for the following pharmaceutical formulations of the active substances: salbutamol nebuliser solution, paracetamol solution for infusion, valproate oral solution and syrup and cholecalciferol oral drops, solution. Identified root causes for medication errors were the following: misinterpretation of prescribed dosage due to very small volume resulting in 10 times higher administered dose (e.g. 3 ml instead of 0.3 ml) for salbutamol; confusion between units millilitres and milligrams resulting in overdose for paracetamol; interchange between medicinal products due to primary package similarities resulting in overdose for cholecalciferol (e.g. swapping with simethicone, dimetindene, bromhexidine); interchange between oral solution and syrup resulting in overdose for valproate.

Conclusion: Medication errors were reported in 20% of all cases in patients up to 18 years of age, which highlights the importance of medication errors prevention in children and adolescents. Review of root causes for medication errors led to implementation of further risk minimisation measures, namely notifications for healthcare professionals (salbutamol and valproate), additional risk minimisation measures i.e. poster and dosage card (paracetamol) and workshops for healthcare professionals (salbutamol, valproate, paracetamol, cholecalciferol). Following implementation of risk minimisation measures, it is concluded there is a further need for evaluation or their effectiveness.

References/Further Sources of Information

• 1. EMA. Good practice guide on recording, coding, reporting and assessment of medication errors (EMA/762563/2014) [cited 2022 May 10]. Available from: https://www.ema.europa.eu/en/human-regulatory/post-authorisation/pharmacovigilance/medication-errors.

• 2. Ghaleb A, Barber N, Franklin B, Yeung V, Khazi Z, Wong I. Systematic review of medication errors in paediatric patients. The Annals of Pharmacotherapy. 2006;40:1766–1776

• 3. Mirosevic Skvrce N, Galic I, Pacadi C, Kandzija N, Mucalo I. Adverse drug reactions that arise from the use of medicinal products outside the terms of the marketing authorisation. Res Social Adm Pharm. 2020;16:928–934.

1.5 O-005 Oral Presentation: Animated Explainer Videos as an Effective Way to Communicate Statistical Methods in Pharmacovigilance

1.5.1 M. Barwick¹, E. L. Meldau ², G. Nadasy¹, N. Bezuidenhout¹

1.5.1.1 ¹Uppsala Monitoring Centre, WHO Collaborating Centre-Global Communications, Uppsala, Sweden; ²Uppsala Monitoring Centre, Research, Uppsala, Sweden

Introduction: Digital features such as videos and infographics are used to make scientific literature more understandable and accessible to a wider audience [1, 2]. Plain language summaries and graphical abstracts are fast becoming the norm in complementing scientific publications across disciplines, including pharmacovigilance. However, the use of video explainers is limited, and the usefulness of such features is not well known.

Objective: To evaluate the effectiveness of an animated explainer video in communicating a statistical method in pharmacovigilance.

Methods: An animated explainer video [3] previously created to complement an earlier scientific publication [4] and improve communication of UMC’s novel clustering method vigiGroup was used as a digital feature in this study. Communication specialists and data scientists collaborated to create the video, focusing on identifying key elements of the method and how to best illustrate its application in a visual narrative. A survey of 10 multiple choice and rating scale questions was used to assess comprehension, perceived effectiveness of communication, enjoyment, and desire to learn more. The survey was disseminated across 3 of UMC’s social media channels (approx. 50,000 followers), including Twitter, Facebook, and LinkedIn, to an audience of predominantly pharmacovigilance professionals. Subsequently, responses were collected and analysed.

Results: Fifty-four individuals from 30 countries participated in the survey. Forty-four (81%) of the participants worked in a pharmacovigilance-related field and 30 (56%) had 5 or more years of professional experience. Over 80% of participants answered all comprehension questions correctly, demonstrating a good level of understanding. Additionally, most participants (see Table 1 for detailed results) found the video to be an enjoyable and helpful way to learn about vigiGroup; agreed that an animated explainer video could be a useful alternative to reading a scientific paper and an effective way to visualise scientific methods; and would like to see more scientific methods presented in this way.

Conclusion: The vigiGroup animated explainer video was effective in communicating cluster analysis of adverse event reports to an audience of both pharmacovigilance and non-pharmacovigilance professionals. Increasing the use of such videos, to complement scientific literature, could be an effective way of building knowledge of complex statistical methodology and scientific developments more broadly.

References/Further Sources of Information

• 1. Finkler W, León B. The power of storytelling and video: a visual rhetoric for science communication. JCOM. 2019 Oct 14; 18 (5). Available from: https://doi.org/10.22323/2.18050202.

• 2. Bredbenner K, Simon SM. Video abstracts and plain language summaries are more effective than graphical abstracts and published abstracts. PLoS One. 2019 Nov 19; 14 (11). Available from: https://doi.org/10.1371/journal.pone.0224697.

• 3. Barwick M, Meldau EL, Nadasy G. vigiGroup Explainer—UMC's cluster analysis method. 2022 [cited 2022 May 11]. Available from: https://youtu.be/cF5-xDGQdMo.

• 4. Norén GN, Meldau EL, Chandler RE. Consensus clustering for case series identification and adverse event profiles in pharmacovigilance. Artif Intell Med. 2021 Dec; 122 (1). Available from: https://doi.org/10.1016/j.artmed.2021.102199.

1.6 O-006 Oral Presentation: Visual Communication of Safety Data in Ongoing Studies: The Adaptive Benefit-Risk Assessment tool for Clinical Trials (ABRA-CTV)

1.6.1 T. C. Bond ¹, S. Rayavaram², S. Dan³, I. Vaidya³

1.6.1.1 ¹Bristol Myers Squibb, Epidemiology, Princeton, NJ, USA; ²Bristol Myers Squibb, Digital Innovation- Analytics- and Reporting, Princeton, NJ, USA; ³Mu Sigma, Analytics, Bangalore, India

Introduction: Data from ongoing open-label clinical studies are assessed for safety signals on a set cadence, complying with regulatory requirements. One challenge is the need to contextualize safety when individual subjects have different exposure times (rolling enrollment). Such issues resolve at the end of the study. However, during the study, visualizations add considerable value to the multidisciplinary discussion of incoming safety data.

Objective: To develop an interactive dashboard (ABRA-CTV) to display patient safety data in a concise manner, identifying potential adverse event (AE) patterns across exposures (drug/dose) and time periods (exposure length).

Methods: The underlying data, used for various analytics and reporting purposes, were drawn from an Amazon Web Services (AWS) Redshift database and conformed to a standard data model via an extract, transform, and load (ETL) process using Enterprise Data Lake Services.

For a study, the user selects AEs of interest (filtered by intensity/grade, seriousness, and relatedness) and sets maximum exposure time of interest and risk period beyond last dose. The tool produces a column (x-axis) for each subject with a height (y-axis) corresponding to exposed time. Subjects are grouped by exposure (in open-label or completed studies), and AEs are displayed relative to start of exposure by symbols on each subject-column. The entire population can be displayed, or the display can be limited to the patients with the event(s) of interest. This allows viewing of AEs in the context of total study population (number of columns) and total exposed time (area of the graph as a whole), or to narrow the focus to affected patients.

Results: The pilot version of ABRA-CTV has been found most useful: (1) to display multiple events (overlap among subjects, relative timing), (2) to visually compare monotherapy and combination therapy (drug A, drug B, drug A+B), and (3) to compare results from ongoing and completed trials where the display of information from the completed trial is limited to an exposed time similar to the ongoing trial. Although the tool is capable of calculating AE incidence rates, its real value for the assessment of ongoing studies lies in the ability to display events and patient time in an adaptive and intuitive way that allows for meaningful discussion of safety data.

Conclusion: Interactive data visualizations can enhance internal risk communication and clinical decision-making during ongoing clinical trials.

References/Further Sources of Information

Not applicable.

1.7 O-007 Oral Presentation: Impact of the 2018 Pregnancy Prevention Program on the Use of Oral Retinoids in Childbearing Age Females in Europe

1.7.1 C. Durán ¹, J. R. Arnau^1,2, S. Abtahi³, R. Pajouheshnia³, M. Gamba³, P. García⁴, G. S. Gimeno⁵, V. Ientile⁶, E. Holthuis⁷, C. Bartolini⁸, G. Limoncella⁸, S. B. Kristiansen⁹, O. Klungel³, M. Sturkenboom¹, on behalf of Lot4 consortium of oral retinoids study¹⁰

1.7.1.1 ¹University Medical Center Utrecht, Department Data Science & Biostatistics, Utrecht, Netherlands; ²Vall Hebron Institut de Recerca VHIR, Clinical Pharmacology, Barcelona, Spain; ³Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht, Netherlands; ⁴Agencia Española de Medicamentos y Productos Sanitarios-Madrid-Spain AEMPS, Base de datos para la investigación farmacoepidemiológica en el ámbito público BIFAP, Madrid, Spain; ⁵The Foundation for the Promotion of Health and Biomedical Research of Valencia Region, Health Services Research Unit FISABIO-HSRU, Valencia, Spain; ⁶University Messina, n/a, Messina, Italy; ⁷PHARMO Institute for Drug Outcomes Research, n/a, Utrecht, Netherlands; ⁸ARS Toscana, n/a, Firenze, Italy; ⁹University of Copenhagen, n/a, Copenhagen, Denmark; ¹⁰n/a, n/a, n/a, Netherlands

Introduction: In 2018, European pregnancy prevention program for oral retinoids, i.e., isotretinoin (acne), acitretin (psoriasis) and alitretinoin (eczema) was updated as part of additional risk minimization measures (RMM) [1, 2] to prevent major congenital anomalies in new-borns whose mothers were exposed to these drugs [3, 4].

Objective: To measure the impact of the 2018 RMMs on utilization patterns of oral retinoids, alternative medications, contraceptives, and on rates of pregnancies occurring concurrently with retinoid prescriptions.

Methods: Retrospective cohort study between Jan-2010 and Dec-2020 in females of childbearing age (12–55 years) derived from six electronic healthcare record data sources in the Netherlands (PHARMO), Spain (BIFAP and VID-Valencia), Italy (Caserta and ARS-Tuscany), and Denmark (Danish National Registries-DNR). Information from data sources was transformed into the ConcePTION Common Data Model [5]. Common analysis scripts were implemented by study sites. Monthly utilization patterns of isotretinoin, alitretinoin and acitretin (incidence/1000 person-months, prevalence/1000 persons, and percentage of discontinuers) were estimated. An interrupted time series analysis was performed to assess immediate changes after the implementation (level change) and over time (trend change). Contraceptive use (percentage) and concurrent pregnancies during retinoid treatment episodes (rates/1000 users) were calculated as well.

Results: The study population comprised 11,570,047 females of childbearing age (12–55 years), 88,992 persons used an oral retinoid at any point during the study period. Monthly incidence and prevalence rates showed that retinoid prescriptions have a strong seasonal pattern with peaks of use in winter months. No significant (p < 0.05) level and trend changes were seen after the implementation of RMMs in August 2018 for incidence, prevalence, and discontinuation rates in any of the study sites. The low level of recording of pregnancy tests did not allow for trend analysis. Contraceptive use could not be measured in ARS and DNR, and was very low in Caserta; in PHARMO, recorded contraceptive use in retinoid users was far below 100%, in VID and BIFAP, recorded contraceptive use increased over time. In BIFAP, there was a significant trend increase after 2018 RMMs in the utilization of contraceptives before the initiation of an oral retinoid treatment, but still far below 100% (15% maximum). Pregnancy rates varied between 0.1 and 0.4 per 1000 retinoid users and occurred in all study sites pre- and post-intervention.

Conclusion: Based on the findings, there is very limited measurable impact of the 2018 RMMs among females of childbearing age in the included databases. Moreover, pregnancies still happen during oral retinoid treatment after the implementation.

References/Further Sources of Information

• 1. European Medicines Agency (EMA). Updated measures for pregnancy prevention during retinoid use. 2018. Available on: https://www.ema.europa.eu/en/news/updated-measures-pregnancy-prevention-during-retinoid-use.

• 2. Referral under Article 31 of Directive 2001/83/EC resulting from pharmacovigilance data. Retinoids containing medicinal products: Pharmacovigilance Risk Assessment Committee (PRAC) assessment report. European Medicines Agency (EMA). Available on: https://www.ema.europa.eu/en/documents/referral/retinoid-article-31-referral-prac-assessment-report_en.pdf.

• 3. Crijns HJ, Straus SM, Gispen-de Wied C, et al. Compliance with pregnancy prevention programmes of isotretinoin in Europe: a systematic review. Br J Dermatol. 2011 Feb;164(2):238–44.

• 4. Zomerdijk IM, Ruiter R, Houweling LM, et al. Isotretinoin exposure during pregnancy: a population-based study in the Netherlands. BMJ Open 2014;4:e005602.

• 5. Thurin NH, Pajouheshnia R, Roberto G, et al. From Inception to ConcePTION: Genesis of a Network to Support Better Monitoring and Communication of Medication Safety During Pregnancy and Breastfeeding. Clin Pharmacol Ther. 2022 Jan;111(1):321–331. https://doi.org/10.1002/cpt.2476.

1.8 O-008 Oral Presentation: Performance of an Artificial Intelligence System Tool for the Detection of ADRs from Patients’ Reports During the Covid-19 Vaccination Campaign

1.8.1 A. Contini¹, A. Bellec², B. Malbos¹, J. Jouganous², C. Goehrs ¹, G. L. Martin ^1,3, L. Létinier ¹, C. Périer²

1.8.1.1 ¹Synapse Medicine, Medical, Bordeaux, France; ²Synapse Medicine, Technological, Bordeaux, France; ³Sorbonne Université-INSERM-Institut Pierre Louis d'Epidémiologie et de Santé Publique, Département de Santé Publique, Paris, France

Introduction: During the recent covid-19 vaccination campaign, the number of ICSRs reported by patients and professionals has dramatically increased, reaching up to almost 1 M declarations only in Europe (EMA numbers). To deal with such growing amount of data, Synapse Medicine^®, in collaboration with The French National Agency for Medicines and Health Products Safety (ANSM), have developed an artificial intelligence (AI) tool, the Medication Shield, which, based on a natural language processing algorithm, is able to detect ADRs from patients’ reports and to code them into an appropriate MedDRA preferred term (PT). Before the covid-19 pandemic, this system was successful in detecting ADRs from the patient reports declared through the French web national reporting system (1, 2). However, how it behaves in conditions of higher reporting flow rate is unknown at present.

Objective: To evaluate the performance of the Medication Shield in detecting vaccine-related ADRs from patients’ ICSRs declared across the covid-19 vaccination campaign.

Methods: A machine learning (ML) pipeline composed by a light Gradient Boosting Machine ensemble model was employed to detect and code covid-19 vaccine-related ADRs from patients’ ICSRs declared through the web reporting system during the vaccination campaign (Jan 2021–Apr 2022). The encoding of regional pharmacovigilance centers was employed as the reference ground truth to train the algorithm in a supervised manner. Moreover, a panel of three pharmacologists, with significant experience in ADRs encoding, was set-up to perform a case-by-case analysis of 200 hundreds reports for which the algorithm provided improper encoding.

Results: Overall, 65.191 ICSRs were extracted and used to train our ML algorithm. Of this, 54.987 were employed to validate the system. Importantly, almost 86% of the ICSRs were related to covid vaccines. Because the percentage of newly reported ADRs increased over time and was higher for vaccine than not-vaccine related reports, we split the training and validation sets in batches with similar ADRs distribution. Performance evaluation is currently under process. Initial feedbacks from the analysis performed by the experts are showing an uneven distribution of false positive and false negative across samples. Results from the other experts are needed to confirm this finding.

Conclusion: The core findings of this study will be gathered in the forthcoming weeks and be ready for the ISoP meeting in September. This work will provide new insights about the effectiveness of deploying AI as a support to treat real world data in a context of sanitary crisis.

References/Further Sources of Information

• 1. Martin G, Jouganous J, Savidan R, Bellec A, Goehrs C, Benkebil M, et al. Validation of an artificial intelligence pipeline to support the automatic coding of patient adverse drug reaction reports, using nationwide pharmacovigilance data. Drug Safety. 2022.

• 2. Létinier L, Jouganous J, Benkebil M, Bel‐Létoile A, Goehrs C, Singier A, et al. Artificial Intelligence for Unstructured Healthcare Data: Application to Coding of Patient Reporting of Adverse Drug Reactions. Clin Pharmacol Ther. août 2021;110(2):392–400.

1.9 O-009 Oral Presentation: Investigating Hidden Networks in Spontaneous Reporting Systems

1.9.1 M. Fusaroli ¹, V. Giunchi¹, E. Raschi¹, E. Poluzzi¹

1.9.1.1 ¹University of Bologna, Department of Medical and Surgical Sciences-Pharmacology Unit, Bologna, Italy

Introduction: The analysis of spontaneous reporting systems aims to identify potential adverse drug reactions in a timely and cost-effective manner. For their apparent simplicity, disproportionality analyses assessing the disproportionate presence of single drug-adverse event associations in spontaneous reports are rapidly expanding as a source of safety evidence complementary to clinical trials. However, the world (and spontaneous reports) is more complex than that: events occur in syndromes, drugs are taken in polytherapy, and patients are mosaics of multiple comorbidities. Network science is one of the most promising approaches to tackle such complexity.

Objective: To investigate the applications and promises of network science to spontaneous reporting data.

Methods: We identified four key examples to highlight the potentiality of network approaches to pharmacosurveillance: multiple drug intake in suicidal attempts, iatrogenic syndromes (i.e., adversome) in Covid-19 and immunotherapy, psychosocial adverse reactions to oxycodone. We used data collected by the FDA Adverse Event Reporting System. Entities (e.g., drugs, events, indications) were represented as nodes, and co-reporting relations as links. Depending on the aim, links’ weights were estimated in two ways. We used co-reporting frequencies to describe cooccurrence patterns for example, polytherapy and iatrogenic syndromes. We used marginal and partial correlations to investigate the associations between entities and their direction: for example, to identify biases and secondary adverse events. We used multilevel algorithms to identify clusters of interest, and network measures to identify trends of co-reporting.

Results: The multiple drug intake network showed paracetamol at the center, as a drug of choice both alone and in combinations, and common combinations separated by therapeutic area, plausibly because of availability The Covid-19 adversome identified a cluster of drug-induced hepatic injury and arrhythmia, and a disease-related cluster with Covid-19 infection and respiratory conditions (1). The immunotherapy adversome identified not only the known overlap syndrome (cooccurrence of myocarditis, myasthenia, and myositis), but also another cluster with hepatitis, colitis and thyroiditis. Finally, investigating reactions to oxycodone, we observed that the reporting of crime and psychosocial reactions was secondary to the reporting of drug dependence.

Conclusion: Networks allow to visualize and compare individual relations, identify clusters, and gather insights into the direction of correlation (e.g., to investigate biases). Networks can complement traditional descriptive and disproportionality analyses characterizing the complexity of spontaneous reporting data.

References/Further Sources of Information

• 1. Fusaroli M, Raschi E, Gatti M, De Ponti F, Poluzzi E. Development of a Network-Based Signal Detection Tool: The COVID-19 Adversome in the FDA Adverse Event Reporting System. Frontiers in Pharmacology. 2021;12:3542.

1.10 O-010 Oral Presentation: Search for Additional Cases in Electronic Health Records (EHRs) to Strengthen Potential Signals from Spontaneous Reporting

1.10.1 A. Kant ¹, J. Zwaveling², H. A. Kalkhoran³, F. V. Hunsel¹

1.10.1.1 ¹Netherlands Pharmacovigilance Centre Lareb, Signal Detection, 's Hertogenbosch, Netherlands; ²Leiden University Medical Centre, Dept of Clin Pharm and Tox, Leiden, Netherlands; ³University of Utrecht, Department of Pharmaceutical Sciences, Utrecht, Netherlands

Introduction: The spontaneous reporting system (SRS) has proven to be a cornerstone in the early and cost-effective detection of adverse drug reactions (ADRs) [1-3]. Electronic Health Records (EHRs) are relatively untapped sources of real-world information that can be used in order to facilitate signal detection in pharmacovigilance (PV).

EHRs are a rich source of information on (pharmaco)therapies, diagnoses, laboratory test results, and physicians’ notes. However, utilizing the EHR for PV involves a number of critical challenges including the efficient extraction of valuable pieces of information from unstructured bulk of free-text.

Objective: To explore whether targeted searches in structured and unstructured fields in EHRs can be used as a method to detect possible cases in addition to spontaneous reports to strenghten a (potential) safety signal.

Methods: Searches were performed in the EHRs of the Leiden University Medical Centre (LUMC) in NL, to identify potential cases for two established and two suspected ADRs generated by signal detection of the SRS of Lareb. Suspected ADRs refer to potential signals based on the analysis of spontaneous reports with insufficient evidence insight into a possible relationship between the ADR and the drug.

The selected established ADRs:

• Hypokalemia caused by flucloxacillin.

• High anion gap acidosis (HAGMA) caused by the concurrent use of flucloxacillin and paracetamol.

The selected established ADRs:

• Atraumatic splenic rupture associated with direct oral anticoagulants (DOACs).

• Renal failure and acute tubular necrosis induced by ibrutinib.

Per (potential) signal, a search with a validated text-mining software tool (Ctcue) was performed via combined queries on both structured and unstructured data [4]. In order to perform the process of case detection systematically, a step-by step search plan was developed and applied to each signal based on:

• 1. Identify drug users.

• 2. ADR identification: based on reports of Lareb and literature.

• 3. Develop and apply the search strategy.

• 4. Identify and manually validate potential cases.

• 5. Case review by PV experts of Lareb

Results: The search retrieved 27 cases with flucloxacillin induced hypokalemia. For HAGMA after use flucloxacillin and paracetamol 21 potential cases were identified. After five confirmed cases via manual validation, no further validation was performed for the established ADRs. For each suspected ADR (potential signal), one validated case was detected.

Conclusion: A targeted search on structured and unstructured fields in EHRs using text-mining can be used as a method to detect additional cases next to spontaneous reports for a potential safety signal. It is recommend to implement this as a complementary method in the current pharmacovigilance system.

References/Further Sources of Information

• 1. Lester J, Neyarapally GA, Lipowski E, et al. Evaluation of FDA safety-related drug label changes in 2010. Pharmacoepidemiol Drug Saf 2013;22(3):302–305.

• 2. Pacurariu AC, Coloma PM, van Haren, A et al. A description of signals during the first 18 months of the EMA pharmacovigilance risk assessment committee. Drug Saf 2014;37(12):1059–1066.

• 3. Raine J. Risk management: a European Regulatory view. In: Mann RM, Andrews EB, eds. Pharmacovigilance. 2nd ed. New Jersey, USA: John Wily & Sons Ltd.; 2007:553–558.

• 4. van Laar, S. A., Gombert-Handoko, K. B., Guchelaar, H. J., & Zwaveling, J. (2020). An Electronic Health Record Text Mining Tool to Collect Real-World Drug Treatment Outcomes: A Validation Study in Patients With Metastatic Renal Cell Carcinoma. Clinical pharmacology and therapeutics, 108(3), 644–652. https://doi.org/10.1002/cpt.1966.

1.11 O-011 Oral Presentation: Do Monitored Dosage Systems Increase Risk for Patients' Safe Discharge from Hospital? A Retrospective Analysis of Pharmacists' Interventions

1.11.1 L. Stewart ^1,2, A. R. Cox¹

1.11.1.1 ¹University of Birmingham, School of Pharmacy-College of Medical and Dental Sciences, Belfast, United Kingdom; ²Belfast Health and Social Care Trust, n/a, Belfast, United Kingdom

Introduction: Many patients who are admitted to hospital use Monitored Dosage Systems (MDS). Governing bodies such as NICE (1) recognise that for some patients, the use of MDS is essential. Research has proven that when patients are admitted to hospital, there are often changes to medication regimens (2, 3). Further research is necessary to establish if pharmacists' interventions on ensuring safety during patients' healthcare journey from hospital admission to discharge, differs between MDS using patients and non-MDS using patients.

Objective: The aim of this study was to analyse hospital pharmacists' interventions for patients' healthcare journeys for MDS using and non-MDS using patients.

Methods: The retrospective analysis was conducted at the Royal Victoria Hospital, a large general teaching hospital in the Belfast Health and Social Care Trust (BHSCT). The study took place over four months from 1st July to 31st October 2021. There were initially 487 admission episodes included in the study, and for each adult patient their healthcare journey from hospital admission to discharge was analysed for interventions and workforce input. Interventions were ranked using the validated Eadon Scale (4). The Royal Stoke Pharmacy Workforce Calculator (RSPWC) (5) was used to evaluate the times associated with the various pharmacist activities between MDS and non -MDS using patients.

Results: A total of 387 patients' healthcare journeys were analysed. Patients whom did not have complete healthcare journeys from hospital admission to discharge were excluded. These patients had either died, had been transferred to another hospital, or were still inpatients when the study ended. There were 31.5% of patients using MDS and 68.5 % of patients not using MDS. Of the total MDS using patient journeys, 99.2% needed hospital pharmacist interventions and were ranked by Eadon Scale; 3 (34.7%), 4 (32.2%) and 5 (33.1%). Of the total non-MDS using patient journeys, 50.9% needed hospital pharmacist interventions and were ranked by Eadon Scale ; 3 (41.5%), 4 (52.2%) and 5 (5.9%). The median time in minutes for pharmacist workforce activity based on RSPWC was 160.9 minutes for MDS using patients, and 99.5 minutes for non-MDS using patients.

Conclusion: This study has identified that the use of MDS increase the burden to pharmacist workforce input. It is evident from the findings, that interventions may be needed for the majority of MDS using patients. It has highlighted that more significant interventions, Eadon Scale 5, are more prevalent for MDS using patients in comparison to non-MDS using patients

References/Further Sources of Information

• 1. National Institute for Health and Care Excellence (NICE) guideline [NG67]: Managing medicines for adults receiving social care in the community; 2017.

• 2. Weiss A, Beloosesky Y, Mansur N. Relationship of in-hospital medication modifications of elderly patients to postdischarge medications, adherence, and mortality. Ann Pharmacother. 2008;42(6):783–9.

• 3. Himmel W, Kochen MM, Sorns U, Hummers-Pradier E. Drug changes at the interface between primary and secondary care. Int J Clin Pharmacol Ther. 2004;42(2):103–9.

• 4. Eadon H. Assessing the quality of ward pharmacists' intervention. International Journal of Pharmacy Practice. 2011;1:145–7.

• 5. Bednall R, White S, Mills E, Thomson S. Validation of a hospital clinical pharmacy workforce calculator: a methodology for pharmacy? International Journal of Clinical Practice. 2021;75(5).

1.12 O-012 Oral Presentation: Signal of Hypertension Associated with COVID-19 Vaccination: VigiBase^® Data and Evidence from Real World

1.12.1 M. Bonaso ¹, U. Moretti², G. Valdiserra¹, E. Cappello¹, I. Convertino¹, S. Ferraro¹, M. Tuccori³

1.12.1.1 ¹University of Pisa, Unit of Pharmacology and Pharmacovigilance-Department of Clinical and Experimental Medicine, Pisa, Italy; ²University of Verona, Section of Pharmacology-Department of Diagnostics and Public Health, Verona, Italy; ³University Hospital of Pisa, Unit of Adverse Drug Reaction Monitoring-Unit of Pharmacology and Pharmacovigilance-Department of Clinical and Experimental Medicine, Pisa, Italy

Introduction: Hypertension is a serious disease that occurs when blood pressure is persistently elevated over time¹. During the COVID-19 vaccination campaign, several reports of hypertension occurred in plausible temporal relationship with immunization have been reported.

Objective: To explore a possible signal of risk of hypertension associated with COVID-19 immunization using VigiBase^® the World Health Organization (WHO) pharmacovigilance database and to review the evidence available from real world.

Methods: We performed a disproportionality analysis using data on spontaneous reports recorded in VigiBase^®. Data have been extract on May 8th, 2022. We calculated reporting odds ratio (ROR) as a measure of disproportionality for hypertension defined by the Standardized Medical Dictionary for Regulatory Activities (MedDRA) query (SMQ) narrow. ROR was estimated for all reports including the MedDRA preferred term (PT) “hypertension”, “blood pressure increased” and “hypertensive crisis” (cases). All other reports have been defined as non-cases. All reports in which the suspected causative agent was a COVID-19 vaccine were used as index reports and all other reports as reference. A signal was defined by at least three reports of the PT of interest and ROR₀₂₅ > 1. We reviewed the medical literature using MEDLINE from January 2021 to May 2022 using “COVID-19 vaccines” AND “hypertension” as a search terms to check for evidence from observational studies.

Results: As of May 8th, 2022, VigiBase^® included 3,746,090 reports of adverse events following immunization for COVID-19 vaccines and 87,653 de-duplicated reports of hypertension define by the SMQ. We identified 34,955 reports of “hypertension” (ROR:1.3; ROR₀₂₅:1.2), 47,733 reports of “blood pressure increased” (ROR:2.6; ROR₀₂₅:2.6) and 3,741 reports of “hypertensive crisis” (ROR:4.0; ROR₀₂₅:3.8) in which a COVID-19 vaccine was indicated as suspected causative agent. Most frequently co-reported symptoms (> 9%) included headache (n = 16.817; 19.2%), dizziness (n = 12,892; 14.7%), fatigue (n = 8,406; 9.6%). Overall, 75% of cases (n = 65,761) have been classified as not serious. A meta-analysis of observational studies that includes 357,387 individuals reported 13,444 events of blood pressure abnormal or increased². These events have been often described as short periods of hypertensive response and often observed in patients with risk factors.

Conclusion: Our results confirmed a signal of risk of events of elevated blood pressure following immunization with COVID-19 vaccines. However, there is no evidence that these episodes could result in serious complication typically associated with hypertension, such as stroke, aneurysms, heart failure, myocardial infarction and chronic kidney disease.

References/Further Sources of Information

• 1. Hypertension—Cardiovascular Disorders—MSD Manual Professional Edition. https://www.msdmanuals.com/professional/cardiovascular-disorders/hypertension/hypertension.

• 2. et al. Blood Pressure Increase following COVID-19 Vaccination: A Systematic Overview and Meta-Analysis. J. Cardiovasc. Dev. Dis. 2022, Vol. 9, Page 150 9, 150 (2022).

1.13 O-013 Oral Presentation: Risk of Glaucoma Diagnosis in Patients Who Received Intravitreal Injections of VEGF Inhibitors: A Cohort Study

1.13.1 A. Spini ^1,2, S. Giometto³, S. Donnini⁴, M. Posarelli², F. Dotta^1,2, G. Tosi^1,2, A. Girardi⁵, E. Lucenteforte³, R. Gini⁵, M. Etminan⁶, G. Virgili⁷

1.13.1.1 ¹University of Siena, Department of Medicine-Surgery and Neuroscience, Siena, Italy; ²Azienda Ospedaliera Universitaria Senese, Azienda Ospedaliera Universitaria Senese, Siena, Italy; ³University of Pisa, Department of Clinical and Experimental Medicine, Pisa, Italy; ⁴University of Siena, Life Sciences, Siena, Italy; ⁵Agenzia regionale di sanità della toscana, Osservatorio di epidemiologia, Firenze, Italy; ⁶University of British Columbia, Departments of Ophthalmology and Visual Sciences-Pharmacology and Medicine-, Vancouver, Canada; ⁷Queen’s university, Centre for public health, Belfast, United Kingdom

Introduction: Intravitreal drugs such as bevacizumab, ranibizumab, and aflibercept are widely used to treat a wide range of retinal diseases. Several studies suggest that repeated injections of these drugs may lead to a sustained rising of intraocular pressure increasing risk for glaucoma. To date, a comparative safety study of these three drugs with respect to the incidence of glaucoma diagnosis has not been done.

Objective: The objective of this study was to evaluate the risk of glaucoma diagnosis compared among new users of bevacizumab, ranibizumab, and aflibercept in Tuscany.

Methods: A retrospective cohort study using the Tuscan regional administrative database was conducted. Subjects with a first intravitreal injection (index date) between January 2011–June 2020 were identified and followed to the first occurrence of glaucoma diagnosis. Patients with less than a five-year look-back period, those with less than one year of follow-up, and those with previous use of intravitreal dexamethasone, diagnosis of diabetes or glaucoma were excluded. We also excluded patients for whom we could not track the first injection to bevacizumab, ranibizumab or aflibercept. Glaucoma diagnosis was identified from exemptions, diagnosis in hospital discharge records or drug dispensations. An intention-to-treat analysis was conducted to analyze risk of glaucoma diagnosis between the three drugs. A Cox model was constructed to compute hazard ratios adjusting for age, sex comorbidities, corticosteroid use and binocularity. To control for retinal vein occlusion, a potential confounder for this question, a stratification by use of anticoagulants in the six months prior/after cohort entry was performed.

Results: A total of 6593 new users were included in the analysis (Aflibercept = 1749, Bevacizumab = 1115, Ranibizumab = 3729). Women made up 60% of the cohort with a mean age of 73 years (± 12.3 years). Overall, the incidence of a glaucoma diagnosis was 2%, 5.3% and 5.9% in the aflibercept, ranibizumab, and bevacizumab group, respectively. The risk of incident glaucoma diagnosis compared to aflibercept was significantly higher among non-anticoagulant users who had received ranibizumab (HR 2.55; CI 95% 1.77–3.66) and bevacizumab (HR 3.07; CI 95% 2.03–4.66). Among anticoagulant users no statistically significant difference was observed.

Conclusion: Our study reported an incidence of glaucoma diagnosis of approximately 5% in patients treated with anti-VEGF drugs. Moreover, we found an increase in the risk of glaucoma with ranibizumab and bevacizumab compared to aflibercept among non-anticoagulant users. A time dependent exposure analysis is ongoing to confirm these results.

References/Further Sources of Information

Not applicable.

1.14 O-014 Oral Presentation: A Revised Time-to-Onset Signal Detection Algorithm in the Context of Mass Vaccination

1.14.1 L. V. Holle ¹

1.14.1.1 ¹OpenSourcePV, Pharmacovigilance, Court-Saint-Etienne, Belgium

Introduction: A method of time-to-onset (TTO) signal detection for screening unexpected temporal patterns from vaccine spontaneous report data has been published in 2012 [1]. EMA listed TTO analysis as one of the methods to be considered for signal detection [2]. Due to the large number of spontaneous reports associated to covid-19 vaccines, highly significant TTO signals could be detected whereas there are no clinically relevant unexpected temporal patterns.

Objective: Objective was to revise the original method so that it is less sensitive to small differences and test it on two covid-19 vaccines (Pfizer/BioNTech and Moderna).

Methods: The revised method used only the most predictive measure [3] of the two Kolmogorov-Smirnov (KS) tests originally designed: the p-value of the KS test of the TTO distribution of a given event post a given vaccine against the TTO distribution of the same event post other vaccines. A threshold on the Kolmogorov-Smirnov distance, that can have values between 0 and 1-0 for no difference between time-to-onset distributions and 1 for extreme differences—was set at 0.2. A threshold on the p-value of the KS test was set at 0.05.

The Vaccine Adverse Event Reporting System was prospectively frozen every week of the first quarter 2021 and the revised TTO signal detection method was prospectively applied on the two covid-19 vaccines.

The performance in detecting events that were posteriori determined as causally related to the exposure of the covid-19 vaccines, namely Pericarditis and Myocarditis, was retrospectively assessed.

Results: Pericarditis post Pfizer/BioNTech covid-19 vaccine emerged as a significant TTO signal as early as 15JAN21 (N: 4, distance: 0.80, p-value: 0.012). Myocarditis post Pfizer/BioNTech covid-19 vaccine emerged as a significant TTO signal as early as 29JAN21 (N:5, distance: 0.59, p-value: 0.031).

Pericarditis post Moderna covid-19 vaccine emerged as a significant TTO signal as early as 12FEB21 (N: 13, distance: 0.55, p-value: 0.00093). Myocarditis post Moderna covid-19 vaccine emerged as a significant TTO signal as early as 05FEB2021 (N:7, distance: 0.73, p-value: 0.0014).

Conclusion: The revised TTO method allowed early detection of unexpected TTO patterns post exposure to covid-19 vaccines by controlling both the level of significance and the magnitude of difference between the TTO distributions in a context of mass vaccination where individual case review is challenging.

References/Further Sources of Information

• 1. Van Holle L et al. Using time-to-onset for detecting safety signals in spontaneous reports of adverse events following immunization: a proof-of-concept study, PDS 21 (6), 603–610.

• 2. Consideration on core requirements for RMPs of COVID-19 vaccines, coreRMP19 guidance v3.0. EMA/PRAC/73244/2022 (8 February 2022).

• 3. Van Holle L et al. Use of logistic regression to combine two causality criteria for signal detection in vaccine spontaneous report data, Drug Safety 37 (12), 1047–1057.

1.15 O-015 Oral Presentation: Adverse Events to COVID-19 Vaccines and Policy Considerations that Inform the Funding of Safety Surveillance in Low- and Middle-Income Countries

1.15.1 C. Ogar ¹, J. Quick^1,2, H. N. Gilbert¹, R. A. Vreman³, A. K. M. Teeuwisse³, J. C. Mugunga¹

1.15.1.1 ¹Harvard Medical School, Department of Global Health and Social Medicine, Boston, USA; ²Duke University School of Medicine, Duke Global Health Institute, Durhan, USA; ³Utrecht University, Utrecht Centre for Pharmaceutical Policy and Regulation-Utrecht Institute for Pharmaceutical Sciences, Utrecht, Netherlands

Introduction: As of April 3, 2022, 31 COVID-19 vaccines had received approval for use globally (1). With the fast-tracked development and concurrent introduction of vaccines in all countries, there is a need for equitable safety surveillance to monitor adverse events following immunization (AEFIs) in high-income and low- and middle-income countries (LMICs).

Objective: To profile the AEFIs to COVID-19 vaccines, explore the difference in reported AEs between Africa and the rest of the world (RoW), and understand the policy considerations that inform the decision by funding organizations to strengthen safety surveillance systems in LMICs.

Methods: We used a convergent mixed methods design involving secondary analysis of 14,671,586 AEFIs to COVID-19 vaccines reported to VigiBaseâ by countries in the WHO Africa Region and the RoW between December 2020 and March 2022. The qualitative component consisted of 12 in-depth interviews with key policymakers from some donor/funding organizations.

Results: With 87,351 out of 14,671,586 total reported AEFIs to COVID-19 vaccines (0.6%) Africa had the second-lowest crude AEFI reporting rate of 180 AEs per 1million administered doses. Reports from females made up 73.6% of reports from African and RoW compared to 24.4% for males. The highest number of reports came from persons 18–44 years. 26.0% of the reports were serious, with death being the reason for seriousness in 5% of the reports. Statistically significant differences in AEFI reporting by gender, age group, and serious AEs were found between Africa and the RoW. AstraZeneca, PfizerBioNtech, and Janssen vaccines were the most frequently associated with AEFIs in terms of the absolute number of AEs for Africa and RoW. Sputnik V contributed the highest percentage of AEs per vaccine for Africa. Headache, pyrexia, injection site pain, dizziness, and chills were the top 5 reported AEs for Africa and RoW. Qualitative findings revealed decisions of many funding organizations to fund safety surveillance in LMICs were influenced by considerations about country priorities, the perceived utility of the evidence generated for local decision making, and the contributions to global health by safety surveillance systems.

Conclusion: Countries in Africa reported fewer AEFIs to COVID-19 vaccines in VigiBase relative to the RoW, with statistically significant differences in reporting of key parameters that warrant further investigation. Funding decisions by donor organizations were influenced by country priorities and the perceived value added by data generated from safety surveillance systems in LMICs to local and global decision making.

References/Further Sources of Information

• 1. Zimmer C, Corum J, Wee SL. Coronavirus Vaccine Tracker. The New York Times [Internet]. 2022 Apr 21 [cited 2021 Feb 9]; Available from: https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html.

1.16 O-016 Oral Presentation: Factors Associated with Hospital Death in Patients with Adverse Drug Events in Brazil, from 2011 to 2020

1.16.1 J. R. R. Melo¹, E. C. Duarte ², A. S. Sá ³, R. A. Monteiro⁴, P. Arrais ⁵

1.16.1.1 ¹Brazilian Health Regulatory Agency, General Management of Sanitary Inspection, Brasilia-DF, Brazil; ²Faculty of Medicine-University of Brasilia-Brasilia, Public Health Department, Brasilia, Brazil; ³Brazilian Health Regulatory Agency Anvisa, Pharmacovigilance, Brasilia, Brazil; ⁴Ribeirão Preto Medical School-USP, Public Health Department, Ribeirão Preto, Brazil; ⁵Federal University of Ceara, Pharmacy department, Fortaleza, Brazil

Introduction: Therapeutic advances have reduced morbidity and mortality, but have led to an increase in adverse drug events (ADE). The study analyzed the factors associated with hospital death of patients admitted to UHS with ADE.

Objective: To describe patients with ADE identified in the SIH-SUS in Brazil over a ten-year period and to analyze the factors associated with in-hospital death in this study population.

Methods: This study is reported following the STROBE guideline. This is a case-control type study, with the original information from the administrative data from the hospital information system of the public health system in Brazil-SIH-SUS, in the period from 2011 to 2020.

Results: A total of 116,084,449 Authorization for Hospital Admissions (AHA) in SIH-SUS were evaluated, related to 112,882,404 hospitalizations paid by UHS in the period 2011–2020. After applying the exclusion criteria, 600,944 hospital admissions associated with at least one ADE were included in the study. 659,754 ADEs were reported,with an average of 1.1 ADE/inpatient and an ADE identification rate of 5.7 per 1,000 admissions. The proportion of patients with ADE in hospitalizations was 0.53%, and the risk of death among them was 1.8%. Among people with inpatient ADE, those with higher chances of in-hospital death were: women and older people; people living in more unequal and less developed municipalities—measured by the Gini index and HDI—; patients admitted to hospitals with larger size (number of beds) and medium complexity; patients who presented severity markers of the event that led to admission—shorter hospital stay (up to seven days), use of ICU and admission for urgent/emergency care. The main drugs involved were antineoplastics and immunomodulators (OR = 2.2; 95% CI = 1.6 to 2.9), causing mainly hepatobiliary (OR = 7.7; 95% CI = 6.8 to 8.7) or cardiac (OR = 3.7; 95% CI = 3.0 to 4.5) disorders. Drug intoxication (OR = 6.6; 95% CI = 3.5 to 12.4;) and drug abuse were the EADs most associated with increased risk of death (OR = 3.9; 95% CI = 2.0 to 7.6).

Conclusion: Our findings indicate that patients with ADE who are female, older, of black/purple and yellow race/color, living in municipalities with lower human development and more unequal, who use antineoplastic and immunomodulatory drugs have a higher risk for in-hospital death. Drug poisoning and drug abuse are the adverse event classes most associated with increased risk of death. This study, confirm that the SIH-SUS is a robust source of data for the field of pharmacovigilance, enabling the identification of risk factors for death and facilitating the monitoring of ADEs in the hospital environment.

References/Further Sources of Information

• 1. OMS/OPAS. Segurança dos medicamentos: um guia para detectar e notificar reações adversas a medicamentos. [Internet]. Organização Mundial da Saúde. Brasília: OPAS/OMS. 2005. Available from: https://iris.paho.org/handle/10665.2/359.

• 2. Patel PB, Patel TK. Mortality among patients due to adverse drug reactions that occur following hospitalisation: a meta-analysis. Eur J Clin Pharmacol. 2019;75(9):1293–307. https://doi.org/10.1007/s00228-019-02702-4.

• 3. Parameswaran Nair N, Chalmers L, Peterson GM, Bereznicki BJ, Curtain CM, Bereznicki LR. Prospective identification versus administrative coding of adverse drug reaction-related hospitalizations in the elderly: A comparative analysis. Pharmacoepidemiol Drug Saf. 2018;27(11):1281–5. https://doi.org/10.1002/pds.4667.

• 4. Melo JRR, Duarte EC, De Freitas SM, Pinheiro EG, Francelino EV, Arrais PSD. International Classification of Diseases Codes as screeners for Adverse Drug Events. Med. 2021;54(3):1–17. https://doi.org/10.11606/issn.2176-7262.rmrp.2021.178993.

• 5. Hohl CM, Kuramoto L, Yu E, Rogula B, Stausberg J, Sobolev B. Evaluating adverse drug event reporting in administrative data from emergency departments: a validation study. BMC Health Serv Res. 2013;13(1). https://doi.org/10.1186/1472-6963-13-47.

• 6. Stausberg J, Hasford J. Drug-related admissions and hospital-acquired adverse drug events in Germany: a longitudinal analysis from 2003 to 2007 of ICD-10-coded routine data. BMC Health Serv Res [Internet]. 2011;11(1):134. Available from: https://doi.org/10.1186/1472-6963-11-134.

1.17 O-017 Oral Presentation: Effectiveness and Safety of Maintenance Immunosuppressive Drug Therapies in Kidney Transplant: A Real-World Retrospective Cohort Study in Italy

1.17.1 M. Finocchietti ¹, A. C. Rosa¹, F. R. Poggi¹, M. Massari², A. Ricci³, S. Pierobon⁴, A. Mazzone⁵, S. Ledda⁶, CESIT Project CESIT Study Group⁷, V. Belleudi¹

1.17.1.1 ¹Lazio Regional Health Service-ASL Roma 1-Rome-Italy, Department of Epidemiology, Rome, Italy; ²Istituto Superiore Di Sanità-Rome-Italy, National Center for Drug Research and Evaluation, Rome, Italy; ³Istituto Superiore Di Sanità-Rome-Italy, Italian National Transplant Center, Rome, Italy; ⁴Veneto Region-Padua-Italy, Azienda Zero, Padua, Italy; ⁵S.p.A-Milan-Italy, a.r.i.a., Milan, Italy; ⁶Sardinia Region, Sardinia Regional Health Department-Cagliari-Italy, Cagliari, Italy; ⁷Italian, Network, Rome, Italy

Introduction: Transplant recipients are chronically ill patients, who require lifelong drug therapies to prevent reject and graft loss. Maintenance therapy usually involves calcineurin inhibitors, tacrolimus (TAC) or cyclosporine (CsA), combined with mycophenolate (MMF) or mechanistic target of rapamycin (mTOR). To date, there is no consensus on the optimal immunosuppressive strategy [1-4].

Objective: The aim of the study was to assess the effectiveness and safety of maintenance immunosuppressive drug therapies in kidney transplant.

Methods: A retrospective multicentre observational study, involving 4 Italian regions, was conducted based on the national transplant Information system and regional healthcare claims data. Specifically, the regional analytical datasets regarding incident patients underwent to kidney transplant in the years 2009–19 were created using an open-source tool for distributed analysis. In the first step, patients in CsA and TAC-based therapy were matched by propensity score 1:1 considering donor/receipt demographical and clinical characteristics. The effectiveness (mortality or reject/graft failure) and safety (incidence of severe infections, cancer and diabetes) of treatments were estimated comparing outcomes between the two groups by a Cox proportional hazard model (HR; CI95%). Analyses were replicated comparing mTOR vs MMF treatment within patients in TAC therapy.

Results: Overall, 3,622 kidney recipients were considered, of which 21.7% treated with CsA-based therapy. Among patients in TAC-based therapy (N = 2,835), 69.8% and 19.7% were in combination with MMF and mTOR, respectively. During a median follow-up period of 4.0 years mortality and reject/graft failure incidence rates were equal to 1.9 and 2.1 per 100 patient-years (p-y), respectively. Among safety outcomes, serious infections had the highest incidence (9.4 per 100 p-y) followed by diabetes (3.6 per 100 p-y), and cancer (2.4 per 100 p-y). The first comparison showed that patients treated with CsA had higher risk of reject/graft loss (1.69; 1.16–2.46) and incidence of severe infections (1.25; 1.00–1.55) and a lower risk of diabetes (0.66; 0.47–0.91) respect those treated with TAC. While, among TAC users, patients with mTOR had a lower risk of severe infections (0.81; 0.63–1.06) respect those with MMF.

Conclusion: In clinical practice, a significantly better benefit profile has been demonstrated for kidney recipients treated with TAC compared to CsA. In particular, the combination of TAC and mTOR appears to be the optimal strategy reducing the incidence of severe infections. Our findings on long term risk-benefit profile of immunosuppressive therapy may be helpful to define the optimal drug therapy in kidney recipients.

References/Further Sources of Information

• 1. Azarfar A, Ravanshad Y, Mehrad-Majd H, et al. Comparison of tacrolimus and cyclosporine for immunosuppression after renal transplantation: An updated systematic review and meta-analysis. Saudi J Kidney Dis Transpl. 2018 Nov–Dec;29(6):1376–1385.

• 2. Gomes RM, Barbosa WB, Godman B, et al. Effectiveness of Maintenance Immunosuppression Therapies in a Matched-Pair Analysis Cohort of 16 Years of Renal Transplant in the Brazilian National Health System. Int J Environ Res Public Health. 2020 Mar 17;17(6):1974.

• 3. Hahn D, Hodson EM, Hamiwka LA, et al. Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients. Cochrane Database Syst Rev. 2019;12(12):CD004290

• 4. Lim LM, Kung LF, Kuo MC, Huang AM, Kuo HT. Timing of mTORI usage and outcomes in kidney transplant recipients. Int J Med Sci. 2021;18(5):1179–1184. Published 2021 Jan 9. https://doi.org/10.7150/ijms.53655.

1.18 O-018 Oral Presentation: Are COVID-19 Vaccines Safe in Children? Comparative Analysis of European Web-Based Prospective Monitoring vs. Pivotal Trials

1.18.1 N. Luxi ¹, M. Raethke², S. Schmikli³, F. Ahmadizar³, C. Bucsa⁴, M. Liddiard⁵, C. M. C. Alves⁶, G. Petrelli¹, S. Sonderlichová⁷, N. Thurin⁸, F. V. Martínez⁹, M. Sturkenboom³, G. Trifirò¹

1.18.1.1 ¹University of Verona, Department of Diagnostics and Public Health, Verona, Italy; ²LAREB, Netherlands Pharmacovigilance Centre, 's Hertogenbosch, Netherlands; ³University Medical Centre Utrecht, Department Data science & Biostatistics, Utrecht, Netherlands; ⁴University of Medicine and Pharmacy Cluj, Department of Fundamental Sciences with Pharmaceutical Direction, Cluj-Napoca, Romania; ⁵University of Portsmouth, Drug Safety Research Unit, Portsmouth, United Kingdom; ⁶University of Coimbra, Laboratory of Social Pharmacy and Public Health-School of Pharmacy, Coimbra, Portugal; ⁷SLOVACRIN Pavol Jozef Šafárik University, Faculty of Medicine, Košice, Slovakia; ⁸University of Bordeaux, Bordeaux PharmacoEpi, Bordeaux, France; ⁹Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina, IDIAPJGol, Barcelona, Spain

Introduction: To date, only two COVID-19 vaccines, Comirnaty and Spikevax, have received an extension of indication of use by European Medicines Agency (EMA) in 5–17 years old children/adolescents. Due to the small sample size of pivotal trials in pediatrics, real-world evidence on the safety of those vaccines in the pediatric population is urgently required.

Objective: (i) To investigate the safety of COVID-19 vaccines by measuring frequencies of solicited and serious adverse events following immunization (AEFIs) with the first and the second doses of vaccines through active surveillance and, (ii) to compare the results with the published clinicaltrials in children and adolescents.

Methods: In 5–17 years old vaccinees, and up to April 21, 2022, we explored the COVID-19 vaccine safety using prospectively collected data from the “Covid Vaccine Monitor” (CVM) project [1]. CVM comprises several safety assessment approaches amongst which an active surveillance project of COVID-19 vaccines in Europe through web-based baseline + 6 follow-up questionnaires filled by vaccinees (or their parents). We measured the frequency of local/systemic solicited, and serious adverse reactions following COVID-19 vaccination (first and second doses). The results were compared with findings of pivotal trials in children/adolescents.

Results: Overall, 1,033 children/adolescents (5–11 years old: 32.9%; 12–17 years old: 67.1%) who received a first/second dose of vaccine (mostly Comirnaty: 98.2%) were enrolled in the study. Of them, only 658 (63.7 %) filled baseline and at least one follow-up questionnaire and were included in the CVM analysis. Overall, 293 (44.5%) reported at least one AEFI following first dose of COVID-19 vaccine, with injection site pain being the most frequently reported local solicited AEFI (N = 192; 29.2%) in both age groups. Fatigue was the most frequently reported systemic solicited AEFIs (N = 106; 16.1%) in both age groups, followed by myalgia (N = 90; 13.7%) and headache (N = 84; 12.8%). Similar trend was observed after administering the second dose of COVID-19 vaccine.

Conclusion: This study confirmed safety profile of COVID-19 vaccines in the pediatric population as already documented in the pivotal trials, with a high frequency of local solicited adverse events and an extremely low rate of serious adverse events.

References/Further Sources of Information

Not applicable.

1.19 O-019 Oral Presentation: The Risk of Oligospermia with Tyrosine Kinase Inhibitors: A Disproportionality Analysis from Vigibase and AERS Databases

1.19.1 L. Velez ¹, A. Das², V. Parulekar³, N. Chhabra³, M. Izquierdo⁴, M. Nicolaides⁵, P. D. Zeeuw⁵, A. Rossiter⁶, J. Eisinger⁵, C. Michel⁷

1.19.1.1 ¹Novartis AG/University of Basel, Patient Safety/Pharmacoepidemiology Unit, Zürich, Switzerland; ²Novartis, Signal Detection, Hyderabad, India; ³Novartis, Patient Safety, Hyderabad, India; ⁴Novartis, Clinical Development, Basel, Switzerland; ⁵Novartis, Patient Safety, Basel, Switzerland; ⁶Novartis, Patient Safety, Boston-Massachusetts, USA; ⁷Novartis, Signal Detection, Basel, Switzerland

Introduction: Advances in the treatment of cancer in young patients have led to great improvements in life expectancy.

However, treatment with chemo or radiotherapy causes reduction of sperm counts often to azoospermic levels that may persist for several years or be permanent.

Oligospermia or azoospermia and long-lasting testicular atrophy are common adverse consequences of cancer treatment (1).

Objective: To quantify disproportionate reporting (Disp-Rep) (2-4) for the risk of drug-associated oligospermia/azoospermia for 29 tyrosine kinase inhibitors (TKIs) in 2 groups: (1) Anti-angiogenic (AA) TKIs; (2) Non-anti-angiogenic (NAA) TKIs.

Methods: We used the AERS and VigiBase databases, with data up to June 2021 and Oct 2021 respectively for analysis.

Cases of oligospermia and azoospermia were identified using MedDRA (v24.0) and the high-level-term (HLT) ‘Spermatogenesis and semen disorders’ (SSD).

Empirical Bayes Geometric Means (EBGM) with 90%CI were calculated to quantify Disp-Rep.

We considered Dis-Rep as confirmed if the lower bound, EB05, was > 2.

We studied 3 groups of drugs: (1) Positive control group (non-TKIs associated with oligospermia/azoospermia: sulfasalazine, colchicine and cisplatin) and two groups of TKIs: (2) AA TKIs (14 drugs) & (3) NAA TKIs (15 drugs).

Drugs were identified by non-proprietary name.

Results: We retrieved 101 SSD cases in AERS and 83 in VigiBase.

In AERS, Disp-Rep with EBGM [90% CI, EB05–EB95] was confirmed for the positive control group: cisplatin 4.36 [3.31–5.70], and colchicine 3.53 [2.20–5.59] and in VigiBase for sulfasalazine 3.18 [2.07–4.72].

In AERS, Disp-Rep was confirmed for only 1 of 15 NAA TKIs: ibrutinib 3.37 [2.24–4.96].

No Dis-Rep (EB05 < 2) was found for the rest of NAA TKIs: afatinib, bosutinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, osimertinib and vemurafenib.

No Dis-Rep was found for any of the 14 AA TKIs: acalabrutinib, axitinib, cabozantinib, dacomitinib, lenvatinib, neratinib, nintedanib, pazopanib, ponatinib, regorafenib, sorafenib, sunitinib, tivozanib and vandetanib. The analysis in VigiBase database yielded similar results.

Conclusion: Ibrutinib (NAA TKI) was the only drug among the 29 different TKIs studied with Disp-Rep for oligospermia/azoospermia in both databases.

Our results however, should be interpreted with caution as disproportionality analyses are hypothesis generating rather than hypothesis testing.

References/Further Sources of Information

• 1. Meistrich, M. L. (2013). "Effects of chemotherapy and radiotherapy on spermatogenesis in humans." Fertil Steril 100(5): 1180–1186.

• 2. Michel C, Scosyrev E, Petrin M, Schmouder R. Can Disproportionality Analysis of Post-marketing Case Reports be Used for Comparison of Drug Safety Profiles? Clinical drug investigation. 2017;37(5):415–22.

• 3. Bate A, Evans S. Quantitative signal detection using spontaneous ADR reporting. Pharmacoepidemiology & Drug Safety. 2009;18:427–36.

• 4. van Puijenbroek EP, Bate A, Leufkens HG, Lindquist M, Orre R, Egberts AC. A comparison of measures of disproportionality for signal detection in spontaneous reporting systems for adverse drug reactions. Pharmacoepidemiol Drug Saf. 2002;11(1):3–10.

1.20 O-020 Oral Presentation: Perception and Utilization of Skin Lightening Agents Among Females of Asmara City: A Lesson for Strengthening Cosmetovigilance

1.20.1 S. Tesfamariam¹, M. Bahta¹, D. G. Weldemariam², E. H. Tesfamariam³, H. Yemane¹, I. Bahta¹, M. Russom ^1,4,5

1.20.1.1 ¹Ministry of Health, National Medicines and Food Administration, Asmara, Eritrea; ²Ministry of Health, Hazhaz Zonal Referral Hospital, Asmara, Eritrea; ³Eritrean Institute of Technology, Department of Statistics, Mai-Nefhi, Eritrea; ⁴University of Bordeaux, European Programme for Pharmacovigilance and Pharmacoepidemiology, Bordeaux, France; ⁵Erasmus Medical Centre, Department of Medical Informatics, Rotterdam, Netherlands

Introduction: Skin lightening agents (SLA) have been commonly self-used by African females to make their skin color lighter for cultural/social perception that equates beauty with fairer skin (1, 2). Skin lightening products contain high concentrations of harmful ingredients such as hydroquinone, mercurials, and corticosteroids, and are reported to cause serious complications such as hyperpigmentation, exogenous ochronosis, wound dehiscence, nephropathy, steroid addiction syndrome, predisposition to infections, and other endocrinologic complications. Despite all these public health risks, they have been used in many countries without regulation and consultation of healthcare professionals (3). Similarly, in Eritrea, there is uncontrolled marketing and use of SLAs even those with banned harmful ingredients.

Objective: This study was conducted to assess the perception and utilization of SLAs among females of Asmara, the capital city of Eritrea.

Methods: A cross-sectional descriptive study was conducted in representative samples of all beauty salons available in Asmara between May and July 2021. The study participants were selected using two-stage stratified cluster sampling technique. The data collected through face-to-face interview was entered and analyzed using CSPro 7.3 and SPSS ver. 26, respectively.

Results: The study enrolled 721 females. The majority of the respondents agreed that SLAs can make someone white (84.4%), look beautiful (67.8%), trendy and fashionable (55.0%), and had the perception that white skin is more attractive than dark skin (58.8%). About two-third (64.2%) of the participants reported that they have ever used SLAs, mainly influenced by friends (60.6%). Of those who ever used SLAs, 46.4% were current users while 53.6% stopped it due to serious adverse effects, fear of adverse effects, and/or ineffectiveness of products. About half of the respondents (51.7%) used SLAs on a daily basis and the mean duration of use was 4 years (SD = 5.6; range = 0 to 38). With the use of SLAs, 43.7% experienced at least one adverse effect and 66.5% were satisfied with its use. Employed females (AOR: 1.68, CI 1.16, 2.43; p = 0.006) were more likely to be current users of SLAs compared to the unemployed and females who had favorable attitude against the use of SLAs were less likely to be current users (AOR: 0.96, CI 0.93–0.98; p = 0.001).

Conclusion: Utilization of SLAs among females was prevalent. They were satisfied with its use despite experiencing adverse effects which urges coordinated efforts in tightening the regulation of cosmetics in general and establishment of cosmetovigilance systems in particular.

References/Further Sources of Information

• 1. Widespread use of toxic skin lightening compounds: medical and psychosocial aspects. Dermatologic Clinics, 2011. 29(1): p. 111–123.

• 2. Darj E, Infanti JJ, Ahlberg BM, Okumu J. "The fairer the better?" Use of potentially toxic skin bleaching products. Afr Health Sci. 2015 Dec;15(4):1074–80. https://doi.org/10.4314/ahs.v15i4.4. PMID: 26958006; PMCID: PMC4765398.

• 3. Sagoe D, Pallesen S, Dlova NC, Lartey M, Ezzedine K, Dadzie O. The global prevalence and correlates of skin bleaching: a meta-analysis and meta-regression analysis. Int J Dermatol. 2019 Jan;58(1):24–44. https://doi.org/10.1111/ijd.14052.

1.21 O-021 Oral Presentation: Drug-Related Hospital Admissions in Paediatrics—Is There Potential for Prevention?

1.21.1 I. Toni ¹, G. Ahne¹, I. Marek¹, K. Moritz¹, C. Schulze¹, F. Schreeck², D. M. Makosi³, W. Rascher¹, A. Neubert¹

1.21.1.1 ¹Universitätsklinikum Erlangen, Department of Paediatrics and Adolescent Medicine, Erlangen, Germany; ²Robert Bosch Gesellschaft für medizinische Forschung mbH, Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, Germany; ³Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Institute of Medical Biostatistics-Epidemiology and Informatics IMBEI-Division of Pediatric Epidemiology, Mainz, Germany

Introduction: Drug therapy in paediatrics is often associated with uncertainties due to lack of data from clinical trials. 42–90% of hospitalised children and adolescents are therefore treated with medication outside their product licence, in the outpatient setting 46–64% of patients are affected [1,2]. Due to this off-label use, missing paediatric dosage forms and complex dose calculations, medication errors (ME) occur up to three times more frequently compared to adults [3]. In addition, it can be assumed that 3–5% of admissions to paediatric hospitals are due to an adverse drug reaction (ADR) [4,5].

Objective: The aim of the study was to investigate the nature, characteristics and preventability of drug-related hospital admissions in paediatrics.

Methods: Within the study, all patients aged 0 to < 18 years, admitted non-electively to one of the 12 participating children’s hospitals in Germany between 07/2018 and 06/2020, were screened for drug-related hospitalisations. A screening tool was used to systematically identify suspected ADRs and MEs. If parents had given consent for data transfer and further analysis, the suspected ADRs resp. MEs were subsequently validated by a blinded, independent expert team [6]. All ADRs and MEs were assessed with regard to their nature, preventability, severity and drug association.

Results: Of 41.829 patients admitted to these paediatric hospitals, 54.7% (22.875) had at least one drug administration before hospitalisation. Consent for further analysis was obtained for 9.732 (42.5%) of the patients with medication. Through the use of the screening tool, almost 40% (38.6%, 3.753) of these were suspected to be drug-related.

615 (16.4%) suspected cases were positively validated as drug(s) being the reason for hospital admission; the remaining cases in question were unlikely to be drug-related or suspected in error. 346 ADRs and 269 MEs were identified. Allergic conditions, seizures (incl. subtypes) and respiratory tract infections associated with the administration of immunosuppressants, viral vaccines and antiepileptic drugs were the main reasons for hospitalisation due to ADRs. Treatment noncompliance, accidental exposure to product and dosing problems (mainly underdosing) were primarily identified as MEs in connection with the use of antiepileptic drugs, insulins and analogues and other beta-lactam-antibacterials. 47.3% (291) of drug-related hospital admissions were preventable.

Conclusion: Drug-related hospital admissions play a significant role in paediatrics. Moreover, almost half of them are considered preventable and therefore result in unnecessary harm and treatment costs. Dosing databases, training, and systematic screening for ADRs and MEs have great potential to increase the safety of drug therapy in children.

References/Further Sources of Information

• 1. Kimland, E. and V. Odlind, Off-label drug use in pediatric patients. Clin Pharmacol Ther, 2012. 91(5): p. 796–801.

• 2. Magalhaes, J., et al., Use of off-label and unlicenced drugs in hospitalised paediatric patients: a systematic review. Eur J Clin Pharmacol, 2015. 71(1): p. 1–13.

• 3. Kaushal, R., et al., Medication errors and adverse drug events in pediatric inpatients. JAMA, 2001. 285(16): p. 2114–20.

• 4. Smyth, R.M., et al., Adverse drug reactions in children—a systematic review. PLoS One, 2012. 7(3): p. e24061.

• 5. Gallagher, R.M., et al., Adverse drug reactions causing admission to a paediatric hospital. PLoS One, 2012. 7(12): p. e50127.

• 6. Schulze, C., et al., Development and Adjustment of an Algorithm for Identifying Drug-Related Hospital Admissions in Pediatrics. J Patient Saf, 2021.

1.22 O-022 Oral Presentation: Development and Evaluation of a Blended Pharmacovigilance e-Learning Course in Africa

1.22.1 L. Magro ¹, M. Venegoni¹, F. Schievano¹, S. Pagani², R. Lora³, A. Sabaini³, K. W. Mwamwitwa⁴, S. Kisenge⁴, A. Duga⁵, S. Nhlabatsi⁵, B. Fraden⁶, C. Elagbaje⁷, F. Cobelens⁸, L. Härmark⁹, U. Moretti¹

1.22.1.1 ¹Section of Pharmacology, Department of Diagnostics and Public Health-University of Verona, Verona, Italy; ²Unit of Medicine, Hospital of Vimercate, Monza and Brianza, Italy; ³MedBrains, Department of Computer Science-University of Verona, Verona, Italy; ⁴Section of Clinical Trials Control and Pharmacovigilance, Tanzania Medicines and Medical Devices Authority, Dar es Salaam, Tanzania-United Republic of; ⁵Eswatini National Pharmacovigilance Center, Medicine Regulatory Unit, Matsapha, Swaziland; ⁶Pharmacovigilance and Post Marketing Surveillance, National Agency for Food and Drug Administration and Control NAFDAC, Abuja, Nigeria; ⁷KNCV, Tuberculosis Foundation, Abuja, Nigeria; ⁸University of Amsterdam, Department of Global Health-Amsterdam UMC, Amsterdam, Netherlands; ⁹Netherlands Pharmacovigilance Centre, Lareb, 's-Hertogenbosch, Netherlands

Introduction: PhArmacoVIgilance Africa is a project aiming at improving pharmacovigilance (PV) systems in Africa. The lack of staff trained in PV is one of the most serious limiting factors affecting the development of PV in resource-constrained settings. Previous experiences suggest that blending learning programmes can be implemented in resource-limited countries to train health care professionals (HCP) with remarkable gains in terms of knowledge acquisition.

Objective: To evaluate the effectiveness of our blended learning training programme

Methods: We developed the blended-courses integrated with a Train of Trainers scheme [1]. Two e-learning courses were made available on a web-based application, together with a manual on how to combine the e-learning courses together with face-to-face interactions. The blended course were given in Tanzania, Eswatini and Nigeria. We compared the participants pre- and post course test results (Students t-test evaluation), assessed the participants’ satisfaction and changes in attitudes towards PV (questionnaires survey) and the total number of Individual Case Safety Reports (ICSRs) submitted to each National PV Agency twelve months before and after the training, although we did not match the reporters to the participants that took the courses.

Results: In the three countries 95 participants were trained (Table 1). All participants completed the two courses and the mean score of the post-test was significantly greater than on the pre-test (Table 1). In the second level, the participants from the first training were training others. The training was delivered to 360 and 283 HCPs respectively in Tanzania and Eswatini, out of which 48% and 39%, respectively, completed the two courses with a significant positive difference (Table 1). The majority of respondents to questionnaires have been satisfied, declared they felt more involved in PV and reported at least an ADR after the training both in the first and second level. The trends of reporting increased in the twelve months after the training if compared to the previous twelve months: 14523 vs 2369 and 1224 vs 729 ICSRs were reported to Vigibase for Tanzania and Eswatini National Agency respectively.

Conclusion: Our results demonstrated that a blended course can reach an important number of participants and improve their knowledge. The participants’ satisfaction was high and a more positive attitude towards PV was observed. It is difficult to establish how much of the increase of reports was attributed to the blended learning training.

References/Further Sources of Information

• 1. Alammary A. Blended learning models for introductory programming courses: a systematic review. Plos one. 2019; 14 (9): e0221765.

This abstract was produced by the PAVIA project. This project is part of the EDCTP2 programme supported by the European Union (Grant Number CSA2016S-1627–PAVIA). The views and opinions of authors expressed herein do not necessarily state or reflect those of EDCTP.

1.23 O-023 Oral Presentation: Teaching Pharmacovigilance to French Medical Students During the Covid-19 Pandemic: Interest of Distance Learning Clinical Reasoning Sessions

1.23.1 F. Montastruc ¹, F. Muscari², I. Tack², J. Benevent¹, L. Lafaurie¹, C. D. Canecaude¹, H. Bagheri¹, F. Despas¹, C. Damase-Michel¹, G. Durrieu¹, A. Sommet¹

1.23.1.1 ¹Toulouse University Hospital, Department of Medical and Clinical Pharmacology-Centre of PharmacoVigilance and Pharmacoepidemiology, Toulouse, France; ²Toulouse University Hospital, Department of Health Education, Toulouse, France

Introduction: 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.

Objective: 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.

Methods: 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.

References/Further Sources of Information

Not applicable.

1.24 O-024 Oral Presentation: Recommended Best Practices of Pharmacovigilance of Herbal Medicinal Products

1.24.1 S. Wiarda^1,2, S. v. d. Koppel¹, H. Woerdenbag², S. Souad³, F. V. Hunsel ¹

1.24.1.1 ¹Netherlands Pharmacovigilance Centre Lareb, Signal Detection, 's Hertogenbosch, Netherlands; ²University of Groningen, Pharmacy department-Faculty of Science and Engineering, Groningen, Netherlands; ³Mohammed V University, Faculty of Sciences, Rabat, Morocco

Introduction: Herbal medicinal products (HMP’s) are commonly believed by consumers to be safe. In contrary to that believe, HMP’s can cause adverse drug reactions (ADR’s) and/or interactions with conventional medicines (CM). HMP’s often do not have the same legal status as CM, but are often on the market as food supplements. To ensure the safety of the HMP’s and to protect consumers, optimal pharmacovigilance (PV) practices must be in place.

Objective: To create an overview of the current state of herbal pharmacovigilance and to give recommendations about the best practices of PV of HMP’s based on a study with interviews held with experts in herbal PV from different countries across the world.

Methods: This research used a qualitative inductive methodology through thematic analysis. The first step was to identify, through a literature review, current practices for herbal pharmacovigilance. Based on the findings a semi-structured interview guide was designed, and purposive sampling was used to recruit the interview participants. Through two different networks, the ISoP-Herbal & Traditional Medicines Special Interest Group (SIG) and the Nutrivigilance netwerk, 46 experts in herbal pharmacovigilance were invited via e-mail to participate in an interview. By using a snowballing technique more potential participants were reached. The interviews were originally performed face to face via Zoom^® but to increase the number of participants, the possibility to hand in written answers to the questions was added. Transcripts were analyzed with NVIVO^®. This study was performed to adhere to the Consolidated criteria for reporting qualitative research (COREQ) [1].

Results: Sixteen people out of eleven countries (China, Ethiopia, Italy, Japan, Malawi, Morocco, New Zealand, Portugal, Saudi-Arabia, Thailand and The Netherlands) participated in the study in twelve interviews. Out of those twelve interviews, five general and two specific recommendations of best practices that are applicable to a certain country/region emerged.

• Improving and implementing legislation/creating new guidelines (general).

• Improving awareness (general).

• Improving and introducing education (general).

• Adapting ATC-coding system/causality assessment for HMP’s (general).

• Improving underreporting (general).

• Funding (specific for region).

• Decentralization (specific for region).

Conclusion: This study identified barriers in the pharmacovigilance of HMP’s and yielded recommendations of best practices of pharmacovigilance of HMP’s. Most of these recommendations are applicable worldwide, while some are limited to certain regions.

References/Further Sources of Information

• 1. Tong, A., Sainsbury, P., & Craig, J. (2007). Consolidated criteria for reporting qualitative research (COREQ): a 32-item checklist for interviews and focus groups. International Journal for Quality in Health Care, 19(6), 349–357. 10.1093/i.

1.25 O-025 Oral Presentation: Safety of Medical Cannabis: A Descriptive Study Using the Quebec Cannabis Registry

1.25.1 Y. Moride ^1,2, Y. Hachem³, A. M. Castilloux¹, G. Castillon¹, M. O. Martel^4,5, P. Beaulieu⁶, M. Ware⁷, A. Vigano^3,8,9,10

1.25.1.1 ¹YOLARX Consultants, Pharmacoepidemiology & Therapeutic Risk Management, Montreal, Canada; ²Rutgers The State University of New Jersey, Center for Pharmacoepidemiolgy and Treatment Science, New Brunswick, USA; ³McGill University Health Center MUHC, Medical Cannabis Program in Oncology, Montreal, Canada; ⁴McGill University, Faculty of Dental Medicine and Oral Health Sciences, Montreal, Canada; ⁵McGill University, Department of Anesthesiology, Montreal, Canada; ⁶Université de Montréal, Pharmacology & Physiology, Montreal, Canada; ⁷McGill University, Depts. of Family Medicine and Anesthesia, Montreal, Canada; ⁸McGill University, Department of Oncology, Montreal, Canada; ⁹McGill University, McGill Research Center for Cannabis, Montreal, Canada; ¹⁰McGill University Health Center MUHC, Division of Supportive and Palliative Care Division, Montreal, Canada

Introduction: Although medical cannabis (MC) has been available in Canada since 1999, lack of recognition of MC as a drug has restricted patient access. The Quebec College of Physicians, between 2015 and 2018, authorized MC use only within a research framework. This consisted of the Quebec Cannabis Registry (QCR), a clinical surveillance program.

Objective: To describe patterns of adverse events (AEs) reported over up to 3 years after MC initiation, within the QCR registry.

Methods: The QCR is a prospective registry of adults (≥ 18 years) who were enrolled through participating physicians when they initiated MC for any medical reason between May 2015 and October 2018, after which time recreational cannabis was legalized in Canada. Follow-up ended due to either MC discontinuation, loss to follow-up, 3 years follow-up, or end of data collection (May 2019, 6 months after the last patient in). Data were collected at inclusion and at follow-up visits every 3 months for the first 2 years, then at least once per year in the third year. MC mode of administration (ingestion, inhalation, other), and cannabinoid content ratio (tetrahydrocannabinol (THC)-dominant, cannabidiol (CBD)-dominant, or balanced) were documented. AEs occurring since the last follow-up visit were recorded and coded using MedDRA preferred terms (PTs).

Results: 2,991 patients were enrolled in the registry (mean age 50.9 years, 50.2% females) and the most frequent primary indications for MC were pain (77.5%), anxiety (9.7%), and insomnia (4.8%). Over follow-up, 108 (3.6%) patients experienced moderate or severe AEs, yielding 111 AE reports (3 patients had 2 reports), of which 9 were certainly/probably related to MC and met the regulatory criteria of seriousness (5 required intervention, 3 disability [transient according to case narratives], 1 hospitalization prolongation). Reports included a total of 214 AEs (average 1.9 AEs per report). The most common PTs were dizziness (12.9%), nausea (11.3%), somnolence (9.7%), and vomiting (8.1%) for ingested MC, and headache (13.0%) for inhaled MC. Dizziness and somnolence were the most frequent PTs associated with THC-dominant MC (12.0% each); for CBD-dominant products, vomiting (19.0%) was most common; and dizziness (17.5%), nausea (14.0%), somnolence (10.5%), and headache (8.8%) were the most frequent for balanced content.

Conclusion: There were no new safety concerns identified in the Registry, although notable differences in AE profile between modes of administration and cannabinoid content ratios should be considered by health professionals. Further work identifying and managing risk factors for AEs is warranted to maintain a favorable risk-benefit ratio for MC.

References/Further Sources of Information

Not applicable.

1.26 O-026 When Public Health and Politics Clash—Communicating about Dengvaxia Between Science and Emotions

1.26.1 K. Hartigan-Go¹

1.26.1.1 ¹Ateneo Policy Center, Ateneo School of Government, Quezon City, Philippines

Introduction: Dengue is one of top ten global health threats and is a serious burden in the Philippines. Dengvaxia immunization program was launched on April 2016 for children 9–14-year-olds in three regions with high statistics of dengue, hospitalization, and deaths. This was coincidentally the campaign period for national elections. Use of vaccine, once available, was part of a strategy to control epidemic. Current measures were inadequate. On the 30 November 2017, Sanofi announced an advisory that vaccine should not be used in those who are dengue naïve otherwise they will have risk for severe dengue and additional hospitalization. What started as vaccine-vigilance information sparked a public outcry. This led to a series of parliamentary investigations, traditional and social media misinformation and disinformation vilifying the health decision makers and the company, and criminal charges filed against over 20 individuals by the state over alleged unproven vaccine caused deaths.

Despite attempts to correct these narratives by a few health professionals, the damage to institution, the program, the product, and individuals have been done. The consequences of such actions of emotional approach without understanding the science have resulted in creating general vaccine rejection, hesitancy, other outbreaks such as measles, lowered confidence even with recent COVID vaccines.

Objective: This abstract aim to describe the situation at that time in the Philippines and extract lessons that will inform better risk communications during crisis.

Methods: Literature analysis and environmental scans were undertaken.

Results: Some of the important lessons learned are in risk management and communications. Adverse health product information should be announced with circumspect considering the level of health literacy and risk appreciation in a country. Partisan politics interfered with poorly understood science, fueled by imprudent comments by officials and health professionals who spoke out of turn, amplified by the media and created chaos. The fear was so palpable that enlightened health professionals refused to provide countervailing facts. While the vaccine is listed as part of WHO EML and used in many countries, Philippines has imposed a ban on the product. Reinstating the vaccine would be perceived as the government had back-pedaled on a mistake. In the meantime, the drama contributed to vaccination hesitancy and outbreaks.

Conclusion: Public health decisions are policy and regulatory decisions anchored in ethical and utilitarian principles. Pharmacovigilance plays an important role in public health decisions but only if approached in a scientific and objective manner and in the context of a country’s culture.

References/Further Sources of Information

• 1. Edillo et al. 2015. Economic Cost and Burden of Dengue in the Philippines. https://www.researchgate.net/publication/269713693_Economic_Cost_and_Burden_of_Dengue_in_the_Philippines.

• 2. Lancet. 2014. Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease. https://www.nejm.org/doi/full/10.1056/nejmoa1506223.

• 3. Vannice, et al 2017. The value of multi-country joint regulatory reviews: The experience of a WHO joint technical consultation on the CYD-TDV (Dengvaxia^®) dossier. https://www.researchgate.net/publication/318730237_The_value_of_multi-country_joint_regulatory_reviews_The_experience_of_a_WHO_joint_technical_consultation_on_the_CYD-TDV_DengvaxiaR_dossier.

• 4. Mendoza, Dayrit, Valenzuela. 2020. A Crisis of Confidence: The Case of Dengvaxia in the Philippines. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3519736.

• 5. Executive Summary: Report of the PGH Dengue Investigative Task Force. https://up.edu.ph/executive-summary-report-of-the-pgh-dengue-investigative-task-force/.

• 6. Arkin. 2019. Dengue researcher faces charges in vaccine fiasco. https://www.science.org/doi/10.1126/science.364.6438.320.

• 7. Lasco et. al. 2019. Medical populism and immunisation programmes: Illustrative examples and consequences for public health. https://www.researchgate.net/publication/336683154_Medical_populism_and_immunisation_programmes_Illustrative_examples_and_consequences_for_public_health.

• 8. Rosenbaum. 2018. Trolleyology and the Dengue Vaccine Dilemma. https://www.nejm.org/doi/full/10.1056/NEJMp1804094.

• 9. Dayrit, Mendoza, Valenzuela 2020. The importance of effective risk communication and transparency: lessons from the dengue vaccine controversy in the Philippines. https://pubmed.ncbi.nlm.nih.gov/32518285/.

• 10. Pang. 2018. Dengue vaccination: a more balanced approach is needed. https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(18)30245-9.pdf.

1.27 O-027 Advancing the Science of Vaccine Safety: Introduction to the International Network of Special Immunisation Services

1.27.1 K. Top ^1,2

1.27.1.1 ¹Dalhousie University, Pediatrics, Halifax, Canada; ²IWK Health, Canadian Center for Vaccinology, Halifax, Canada

Introduction: Vaccines are vital tools to control epidemic and pandemic diseases, such as COVID-19, demonstrating safety and effectiveness. However, rare adverse events of special interest (AESIs) following vaccination arise with every new emerging pathogen vaccine program. The mechanisms underlying AESIs such as myopericarditis following COVID-19 mRNA vaccines are not known. Adversomics, a set of technologies that measure the inventory of molecules (e.g., DNA, RNAs, proteins, inflamatory mediators) in a given sample collected during and after an adverse reaction, has potential to uncover the etiologies of AESIs. The International Network of Special Immunization Services (INSIS) brings together vaccine safety, public health, and systems biology experts in middle- and high-income countries to investigate the causes of, and identify strategies to mitigate AESIs following vaccination (insisvaccine.org).

Objective: INSIS aims apply an ‘adversomics’ approach to identify molecular signatures and biomarker risk factors associated with AESIs to inform vaccine development and risk-benefit of assessment of vaccines for pandemic and epidemic diseases, with scalability to respond to new safety signals anywhere in the world.

Methods: INSIS-led studies will employ a case-control design. Well-characterized cases with AESIs post-vaccination, starting with thrombosis with thrombocytopenia syndrome (TTS) following COVID-19 viral vector vaccines and myopericarditis following COVID-19 mRNA vaccines, will be matched to controls. Brighton Collaboration case definitions and harmonized protocols will be employed to collect detailed clinical data and serial blood samples suitable for adversomics (e.g., transcriptomics, proteomics, metabolomics, flow-based immunophenotyping) analysis. A central database and centralized sample processing at INSIS-affiliated multi-OMICs labs will ensure internal validity. Integration of clinical and biological data will enable comparisons of analyte levels and immune responses within groups over time and between cases and controls. Global collaboration across five continents will ensure adequate sample size.

Results: The INSIS approach and its reach as a global network will enable characterization of molecular signatures and biomarkers associated with post-vaccination AESIs.

Conclusion: INSIS-led studies will provide insight into pathways triggered in these AESIs and susceptible populations to inform vaccine development strategies to reduce the potential to trigger pathways involved in AESIs, risk-benefit assessment, and personalized vaccination strategies. Through global collaboration, INSIS aims to reduce the potential for AESIs in the COVID-19 pandemic and beyond.

References/Further Sources of Information

International Network of Special Immunization Services, URL: insisvaccine.org (Accessed May 24, 2022).

2 POSTERS

2.1 P001 Pharmacovigilance and Drug Safety Simulation Game: Innovative Approach for Training and Capacity Building

2.1.1 H. Sefiani ¹, G. Benabdallah¹, A. Bencheikh², Y. Jbel³, R. Soulaymani¹

2.1.1.1 ¹Moroccan Pharmacovigilance Centre-Rabat WHO Collaborating Centre, Pv centre, Rabat, Morocco; ²WHO Rabat Collaborating Centre, Administration, Rabat, Morocco; ³NowEdge, Development, Casablanca, Morocco

Introduction: During the covid 19 period, several countries needed to set up or develop their pharmacovigilance systems, unfortunately containment and the closure of borders prevented the organisation of classic training sessions. the anti-poison centre of morocco, a WHO collaborating centre for the development of pharmacovigilance practices, set up several online training sessions and, in parallel, a pharmacovigilance simulation game was developed to allow for autonomous learning in this field Translated with www.DeepL.com/Translator (free version)

Objective: The objective of this work is to present the pharmacovigilance simulation game developed by CAPM, RCC and the results of its pilot use with 150 pharmacovigilants from 10 French-speaking African countries

Methods: Pharmacovigilance and drug safety simulation game was developed by the Rabat WHO collaborating centre (RCC) in collaboration with the IT company Nowedge. The game is based on good practices in Pharmacovigilance(PV), and inspired by the different WHO guidelines, the experience of the Moroccan PV center, and behaviors consensually considered as the norm in PV.

Results: The game allows the assessment of soft skills, and the evaluation of participants’ ability to make decisions in real life situations. In fact, they are put in a real-life situation to choose actions and strategies for the development of a PV center and must be able to optimize the human and material resources at their disposal to make their center shine within their national health system but also at the level of the international PV network.

The main objectives are to:

• Better understand the challenges and outlooks linked to the creation and management of a PV center.

• Improve the participants capacity to analyze and make decisions.

• Encourage the participants to look for the right information.

• Put into practice the theoretical concepts in causality assessment, signal detection and risk minimization actions.

• Gain a 360° vision of pharmacovigilance above its scientific aspect.

During the game, within 10 levels, participants have to set up a PV center following WHO pharmacovigilance indicators: a practical manual for the assessment of pharmacovigilance systems as structural indicators, process indicators and outcome indicators, and following the pharmacovigilance process from collecting data, analyzing them, detecting signals, and setting up national technical pharmacovigilance committee to discuss about safety signals and risk minimization actions to put in place.

Conclusion: The use of the game by the 150 pharmacovigilantes during the pilot phase gave good feedback on the ease of use and the effectiveness of the game in capacity building in pharmacovigilance

References/Further Sources of Information

• 1. WHO pharmacovigilance indicators: a practical manual for the assessment of pharmacovigilance systems available from https://apps.who.int/iris/bitstream/handle/10665/186642/9789241508254_eng.pdf.

• 2. Safety monitoring od medicinal product Setting up and Running of a Pharmacovigilance Centre, available from: https://who-umc.org/media/1703/24747.pdf.

• 3. Williams, Dina (2011) Impact of Business Simulation Games in Enterprise Education. In: Paper presentations of the 2010 University of Huddersfield Annual Learning and Teaching Conference. University of Huddersfield, Huddersfield, pp. 11–20 (13) (PDF) Impact of Business Simulation Games in Enterprise Education. Available from: https://www.researchgate.net/publication/277199289_Impact_of_Business_Simulation_Games_in_Enterprise_Education [accessed May 25 2022].

2.2 P002 Embedding Digital Health, AI/ML and RWD in Managing Safety Risks and Enhancing Pharmacovigilance

2.2.1 R. Ghosh ¹

2.2.1.1 ¹Genentech/Roche, Pharmacovigilance and scientific development, South San Francisco, USA

Introduction: Pharmacovigilance has traditionally been a reactive science with a significant dependence on spontaneous adverse event reporting. The pandemic on the other hand has accelerated application of novel technologies and approaches to engaging with the patient, remote connected care at their home and dependence on technologies to supplement regular communication channels. Telemedicine is evolving rapidly and playing a key role in clinical interventions

Objective: Digital Health and novel technologies offer a significant opportunity to enhance pharmacovigilance thru proactive patient monitoring, risk communication, personalized care plans and access to real world data. Leveraging such approaches will not only lead to early detection of risks but also to personalized interventions and improved patient outcomes.

Methods: Digital devices can monitor vitals for the patient while AI/ML methods could identify patterns within the data which indicate clinical changes as well as personalize thresholds for individual patients. Educational material which is more interactive, visual and multi-dimensional can replace paper or text based risk communication material.

Results: Embedding digital health approaches as well as AI/ML technologies along with enhanced analytics with RWD help monitor the patients changing state and indicate clinically significant events. This could provide early signal detection in individual patients and enable proactive patient level pharmacovigilance. Educational and risk related material can be dynamically updated based on patient preferences, interactions and profiles. Machine learning approaches which link material with outcome can enhance impact of pharmacovigilance methods and tools.

Conclusion: Digital Health, AI/ML and RWD have created opportunities to enhance and personalize pharmacovigilance. In order to utilize the full potential of such options it is critical that the regulatory framework is updated to enable such approaches which complement traditional PV and can drive efficiencies and higher effectiveness in the risk communication process. Collaboration within the network of industry and regulators is essential to further such research and maximize the impact on value for patients, HCPs and sponsors.

References/Further Sources of Information

To be provided along with presentation material.

2.3 P003 Integration and Modeling of Translational Safety Data for Post-Marketing Surveillance

2.3.1 J. Mestres ¹

2.3.1.1 ¹IMIM Hospital del Mar Medical Research Institute and Chemotargets SL, Research Group on Biomedical Informatics, Barcelona, Spain

Introduction: Large amounts of data associated with safety issues are generated along the entire lifetime of drugs, from its infancy as preclinical leads, through its adolescence as clinical candidates, all the way up to its adulthood as marketed drugs exposed to the human population. Across the different stages in the life of a drug, some of the data collected initially may be confirmed and consolidated with data at an advanced stage, whereas other data may not be translated, and in some cases may even contradict, those safety signals that are ultimately observed in the human population. Collecting and properly integrating such an heterogenous pool of data is a complex and tedious task. But even if one manages to put all data together, the construction of useful models to anticipate and detect drug safety signals remains a challenge.

Objective: The presentation will cover our efforts to connect data from in vitro safety pharmacology, preclinical toxicology, clinical safety and post-marketing spontaneous reports for over 9,000 small molecule drugs, combination drugs, and biologics. A novel consensus approach using various statistical and machine learning methods to anticipate side effects of potential safety concern, detect adverse drug reaction signals and perform pharmacovigilance analyses will be introduced. Use case application examples to individual drugs and drug classes will be discussed.

Methods: Our consensus approach to post-marketing surveillance integrates four different methodologies based on detection of prior safety markers, identification of class reactions, statistical projection of disproportionalities based on reporting frequencies and velocities, and machine learning models of translational safety data.

Results: Results on the validation of our approach to anticipating adverse drug reactions of safety concern to the population at the postmarketing stage based on (i) in vitro safety pharmacology data, (ii) preclinical toxicology data, (iii) clinical safety data and (iv) the first sample of 25 postmarketing spontaneous reports will be presented. Based on data available in each case, the performance of the different methods varies for different drugs, drug classes, and side effects. A discussion on performances in selected use cases will be included. As an example, the analysis of long-term PARP inhibition on circadian patterns and its dependence on the reporting bias by consumers will be discussed.

Conclusion: Integration and modelling of the large amount of translational safety data currently available from all phases of drug discovery, development and post-marketing to anticipate and follow adverse drug reactions opens an avenue to a whole new perspective in pharmacovigilance.

References/Further Sources of Information

Not applicable.

2.4 P004 Online Interest in Cannabis and Psychedelics in Peri-Pandemic Europe for Robust Pharmacovigilance

2.4.1 A. Al-Imam ^1,2, M. Younus^3,4, M. Michalak²

2.4.1.1 ¹Poznan University of Medical Sciences PUMS, PUMS Doctoral School, Poznan, Poland; ²Poznan University of Medical Sciences PUMS, Department of Computer Science and Statistics, Poznan, Poland; ³Iraqi Ministry of Health, Iraqi Pharmacovigilance Centre-, Baghdad, Iraq; ⁴International Society of Pharmacovigilance ISoP, Middle East Chapter of the ISoP, Dubai, United Arab Emirates

Introduction: Psychedelics are unique psychoactive chemicals that can change consciousness by acting on 5-HT2A receptors [1-3]. There is limited knowledge concerning the online interest in psychedelics that we can extrapolate via trends websites.

Objective: We aim to examine the online information-seeking behavior concerning the most popular psychedelics, including cannabis—a quasi-psychedelic—in the European Union (EU) members of interest and the UK before and during the pandemic.

Methods: We designed a "dictionary" of terms to extract online search data from Google Trends concerning psychedelics and cannabis from 01-Jan-2017 to 1-Jan-2022. We conducted a triple (Holt-Winters) exponential smoothing—additive model—for time series analysis to infer seasonality [4, 5]. We utilized hierarchical clustering—an unsupervised machine learning method—to explore clusters of countries concerning the spatial (geographic) mapping of these chemicals. We also implemented—a t-test—for comparing the slope difference of two trends (before versus during the pandemic).

Results: There was an evident seasonal pattern for cannabis, NBOMe, and psilocybin in almost all nations of interest. In Italy, cannabis had a quarterly seasonality (p-value < 0.0177), while NBOMe and psilocybin exhibited a half-yearly and an annual seasonality, respectively (p = 0.0007 and p = 0.0126) (Table 1). Similar patterns existed in France and the UK, while those in Germany, Sweden, and Romania had relatively shorter periodicity. We could not infer seasonality concerning cannabis (Germany and UK) and psilocybin (Sweden and Romania). Analysis of slopes and hierarchical clustering conveyed differentiated patterns concerning the temporal and spatial mapping, respectively, while contrasting the two periods (before versus during the pandemic).

Conclusion: Cannabis and psychedelics follow somewhat a consistent pattern concerning seasonality across Europe; some correlate with the seasonal harvesting of mushrooms, and others with public holidays, including Christmas, the new year holiday, or school breaks. The pandemic influenced some significant changes concerning the online interest in the EU and the UK; nonetheless, we should rely on more rigorous longitudinal and experimental study designs—possessing a superior level of evidence—to confirm the causal relationship. However, these patterns might be insightful for decision-makers and regulatory authorities—like the EMCDDA—to prognosticate and prevent addiction catastrophes.

References/Further Sources of Information

• 1. Beard E, Marsden J, Brown J, Tombor I, Stapleton J, Michie S, West R. Understanding and using time series analyses in addiction research. Addiction. 2019; 114(10): 1866–84. https://doi.org/10.1111/add.14643.

• 2. Carhart-Harris RL. How do psychedelics work?. Current Opinion in Psychiatry. 2019; 32(1): 16–21. https://doi.org/10.1097/YCO.0000000000000467.

• 3. Tracy DK, Wood DM, Baumeister D. Novel psychoactive substances: types, mechanisms of action, and effects. British Medical Journal. 2017; 356: i6848. https://doi.org/10.1136/bmj.i6848.

• 4. Gelper S, Fried R, Croux C. Robust forecasting with exponential and Holt–Winters smoothing. Journal of Forecasting. 2010; 29(3): 285–300. https://doi.org/10.1002/for.1125.

• 5. Gardner Jr ES. Exponential smoothing: The state of the art—Part II. International Journal of Forecasting. 2006; 22(4): 637–66. https://doi.org/10.1016/j.ijforecast.2006.03.005.

2.5 P005 Challenges of Local Medical Literature Monitoring and Possible Automation

2.5.1 A. Horilyk ¹, D. Horilyk¹, M. Demchun¹

2.5.1.1 ¹DrugCards OÜ, Drug Safety, Lviv, Ukraine

Introduction: Continuous monitoring of the safety profile of drugs is one of the critical processes of pharmacovigilance. As medical literature might be valuable source of safety data, especially for rare, unlisted, serious cases, all MAHs are obliged to medical literature monitoring (MLM) in all marketing countries [1]. Current state of local MLM is manual reading “from cover to cover” without any automation. This approach can be changed through modern automation techniques.

Objective: To develop and test a tool for automated monitoring of local literature and enhance drug safety data identification.

Methods: Modern programming approaches were used to create PV platform, intended for automated literature screening. GAMP 5 recommendations were used to prove the validation status.

Results: We developed a tool—DrugCard PV platform which screens local medical sources for updates on a weekly basis. Till May 2022 we added around 150 local journals originated from 10 countries that cover different therapeutic areas. Our tool automatically searches for defined keywords (drug trade names, active substances) in published articles. Different file formats can be screened including text, pdfs, images etc. In case a new issue of a journal is published—a PV specialist will receive an email notification. The mandatory features of a validated computerized system, like audit trail, logs, reports are also present here. Instead of manual reading of the whole journal issue the user only should read a separate article, analyze whether there is a valuable safety data and label it depending on the content. PV specialists may work together inside the platform and provide a quality check for labeled articles.

Our pilot study of how a new tool may improve the efficiency revealed interesting results. We found out that around 12 times less time is needed for literature screening with automated approach vs traditional approach (average 24 hours/week vs 2 hours/week). This was calculated with the list of journals in Ukraine (n = 100) and portfolio of popular drugs (k = 50). Despite the dramatically decreased amount of time needed, the number of identified ICRSs from literature increased. During the abovementioned pilot study of automated local literature monitoring lasting 2 months, 31 safety cases were identified (valid and non-valid ICSRs). This is much more than usual rate of safety cases finding.

Conclusion: Automated local medical literature monitoring is current technological approach which should be widespread among PV departments of MAHs and CROs. It offers increasing efficiency in safety information identification with less time spent on routine activities.

References/Further Sources of Information

• 1. Guideline on good pharmacovigilance practices (GVP)—Module VI (Rev 2). 28 July 2017 EMA/873138/2011 Rev 2. https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/guideline-good-pharmacovigilance-practices-gvp-module-vi-collection-management-submission-reports_en.pdf.

• 2. Certificate of copyright in Ukraine. № 105705 Computer program "Electronic platform of pharmacovigilance DrugCard"/Demchun Myroslav, Horilyk Dmytro, Horilyk Artem/Date of registration June 22, 2021

2.6 P006 Hyperacute Multisystem Toxicities with Immune Checkpoint Inhibitors in the FDA Adverse Event Reporting System: The Immune-Adversome

2.6.1 E. Raschi ¹, V. Giunchi², M. Fusaroli², A. Ardizzoni³, E. Poluzzi², F. D. Ponti²

2.6.1.1 ¹Alma Mater Studiorum-University of Bologna, Department of Medical and Surgical Sciences, Bologna, San Marino; ²Alma Mater Studiorum-University of Bologna, Department of Medical and Surgical Sciences, Bologna, Italy; ³Alma Mater Studiorum-University of Bologna, Department of Experimental-Diagnostic and Specialty Medicine, Bologna, Italy

Introduction: A plethora of pharmacovigilance studies have recently described the spectrum, kinetics and other features of immune-related adverse events (irAEs) with immune checkpoint inhibitors (ICIs) [1], including rare but potentially fatal irAEs such as overlap syndrome (myocarditis with myositis/myasthenia gravis) [2]. Hyperacute toxicity is a recent newly described entity, albeit incompletely characterized [3].

Objective: To describe pharmacological and clinical features of hyperacute toxicities reported to the Food and Drug Administration Adverse Event Reporting System (FAERS) through a network-based approach (the Immune-Adversome).

Methods: We collected adverse events to ICIs (including anti-CTLA4/PD-1/PD-L1 agents) recorded in FAERS up to December 2021. We selected reports with available information to calculate a plausible time-to-onset. Events of interest were classified into fulminant (within 7 days) and hyper-acute cases (within 21 days, i.e., during the first infusion cycle). Cases were described in terms of demographic and clinical features: age, gender, anticancer regimen (combination vs monotherapy), therapeutic indications, seriousness (hospitalization), case fatality rate (CFR, namely the proportion of cases where death was reported as outcome), co-reported symptoms, co-reported irAEs. The Immune-Adversome was estimated considering events as nodes and co-reporting as links. Analyses were performed using the “R” software (v. 4.1.2).

Results: Out of 11,798,098 FAERS reports, ICIs were recorded in 64,112 cases (59,022 had plausible time to onset). Hyperacute cases (18,691) represented 31.7% of total ICI reports, and were mainly reported in males (62.7%), from Asia (34.8%), by clinicians (46%). No significant differences emerged with regard to seriousness between hyperacute and other cases (onset >21 days), namely hospitalization (42.9% vs 49.8%), death (27.9% vs 23.21%) and CFR (15.6% vs 13%; 16% for fulminant cases). Monotherapy was reported in the majority of cases (88.6%), mainly pembrolizumab (5,687). Pyrexia, diarrhea, fatigue, dyspnea were the most frequently reported symptoms. Hyperacute myocarditis was reported in 34.7% of cases with specified time-to-onset (862 over 1,583 total cases), with a CFR of 46.5%. Among fulminant cases, most frequent irAEs were interstitial lung disease (624), colitis (450), hypothyroidism (369), and myocarditis (234). The Immune-Adversome identified different hyperacute multisystem irAEs, including overlap syndrome (median onset 10 days, CFR 37%). Other co-occurring irAEs were colitis-hepatitis-thyroiditis, and arthritis and psoriasis.

Conclusion: The spectrum of hyperacute multisystem irAEs with ICIs is heterogeneous. Our network approach may complement traditional disproportionality analyses in pharmacovigilance for a more effective signal detection technique, thus supporting regulatory and clinical monitoring, especially in complex scenario such as oncology.

References/Further Sources of Information

• 1. Raschi E, Gatti M, Gelsomino F, Ardizzoni A, Poluzzi E, De Ponti F. Lessons to be Learnt from Real-World Studies on Immune-Related Adverse Events with Checkpoint Inhibitors: A Clinical Perspective from Pharmacovigilance. Target Oncol 2020; 15: 449–66

• 2. Pathak R, Katel A, Massarelli E, Villaflor VM, Sun V, Salgia R. Immune Checkpoint Inhibitor-Induced Myocarditis with Myositis/Myasthenia Gravis Overlap Syndrome: A Systematic Review of Cases. Oncologist 2021; 26: 1052–61

• 3. Dearden H, Au L, Wang DY, Zimmer L, Eroglu Z, Smith JL, et al. Hyperacute toxicity with combination ipilimumab and anti-PD1 immunotherapy. Eur J Cancer 2021; 153: 168–78

2.7 P007 Temporal Evolution of Disproportionality Parameters: Study of the Case of Opioids in Relation to QTc Interval Prolongation

2.7.1 G. A. Keller ¹, H. E. D. Salvo², G. D. Girolamo³

2.7.1.1 ¹Administración Nacional de Laboratorios e Institutos de Salud ANLIS Malbran, Instituto Nacional de Produccion de Biologicos, Ciudad Autonoma de Buenos Aires, Argentina; ²Hospital General de Agudos Donación Francisco J. Santojanni, Emergency Department, Ciudad Autónoma de Buenos Aires, Argentina; ³Universidad de Buenos Aires-Facultad de Medicina, Centro de Vigilancia y Seguridad de Medicamentos, Ciudad Autónoma de Buenos Aires, Argentina

Introduction: The prolongation of the QT interval is a serious and potentially fatal adverse reaction that has led to the discontinuation of many drugs (including some opioids). Data mining on pharmacovigilance databases can detect signals that identify early the risk associated with some drugs.

Objective: To examine the association between opioids and risk of QT prolongation in reports submitted to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) between 2004 and 2021.

Methods: Relevant reports in the FAERS were identified and analyzed. The reporting odds ratio (ROR ± IC95), Proportional ADR reporting ratio (PRR ± IC95), Chi square (Yates’ correction), and Yule’s Q (Q ± IC95) was used to detect spontaneous report signals, calculated using the case/non-case method. Cases were identified using Standard Medical Querry (SMQ) for QT Prolongation defined by MedDRA 21.0 in which opiods (Meperidine, Tramadol, Dextropropoxyphene, Methadone, Fentanyl, Morphine, Hydromorphone, Oxycodone, Buprenorphine, and/or Nalbuphine) were the suspected drug.

Results: A total of 36239 drug-reaction pairs was found in 580261 opioid reports. Significant Signal (ROR, PRR, Chi2, Q) were found for whole opioid group: ROR 1.28 (1.26-1.29), PPR 1.27 (1.25-1.29), Yule's Q 0.14 (0.12-0.16) and Chi2 With Yate's Correction: < 0.00001. Analysis of individual opioids show significant signals for QT prolongation for each drug. The temporal evolution of the different signals according to the number of reports included from 2004 to 2021 shows early significant positivization of signals in the first 6 to 12 months. Studying the parameters of disproportionality and their evolution over time, the reduction of 10% of the confidence interval for two or three consecutive years was associated in most cases with the appearance of clinical reports in publications, incorporation of alerts and measures risk minimization.

Conclusion: Analysis of the FAERS database showed significant signals for QT prolongation with opioid treatments. Underlying mechanism is unknown, but it seems to be linked to hERG channel blocking. We propose the evaluation of the trend of change in the confidence intervals of the disproportionality parameters as a measure that can predict the occurrence of clinical events at the population level and a posible usefull strategy to minimize adverse reactions.

References/Further Sources of Information

Sakaeda T, Tamon A, Kadoyama K, Okuno Y. Data mining of the public version of the FDA Adverse Event Reporting System. Int J Med Sci. 2013 Apr 25;10(7):796-803.

2.8 P008 Identifying Medications Underlying Communication Atypicalities: A Pharmacosurveillance Study Within the FDA Adverse Event Reporting System

2.8.1 M. Fusaroli ¹, A. Simonsens^2,3, S. Borrie⁴, D. Low^5,6, A. Parola^7,8, E. Raschi¹, E. Poluzzi¹, R. Fusaroli^3,8,9

2.8.1.1 ¹University of Bologna, Department of Medical and Surgical Sciences-Pharmacology Unit, Bologna, Italy; ²Aarhus University, Department of Clinical Medicine-Psychosis Research Unit, Aarhus, Denmark; ³Aarhus University, School of Culture and Society-The Interacting Minds Center, Aarhus, Denmark; ⁴Utah State University, Department of Communicative Disorders and Deaf Education, Logan, USA; ⁵Harvard Medical School, Program in Speech and Hearing Bioscience and Technology, Boston, USA; ⁶Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, Cambridge, USA; ⁷University of Turin, Department of Psychology, Turin, Italy; ⁸Aarhus University, Department of Linguistics-Cognitive Science and Semiotics, Aarhus, Denmark; ⁹University of Pennsylvania, Linguistic Data Consortium, Philadelphia, USA

Introduction: Language and speech are increasingly debated as potential markers for diagnosing and monitoring patients with affective and psychotic disorders (1–3). However, many neglected factors may confound communicative atypicalities. A comprehensive list of potential confounding drugs will support the design of robust communicative marker studies.

Objective: We aim at identifying a list of drugs potentially associated with speech and language disorders, within psychotic and affective disorders.

Methods: We identified terms from the Medical Dictionary for Regulatory Activities (MedDRA) inherent to speech and language Adverse Drug Reactions (ADRs) and segregated them into clusters of overlapping terms to structure a search on the FDA Adverse Event Reporting System (FAERS, updated to June 2021). Within the FAERS, we considered separately 3 populations (psychotic, affective and non-neuropsychiatric disorders), to account for the confounding role of different underlying conditions. We calculated the Reporting Odds Ratio (ROR) for individual drugs with a Bonferroni correction. Associations which were not already reported in the SIDER database of labelled ADRs, were further stratified based on expected biases (using Directed Acyclic Graph). Robustness analyses were performed to account for the biases.

Results: We identified a list of 291 potential expected and 91 unexpected confounding medications for the identification of communication markers of affective and psychotic disorders (e.g., anticholinergic agents associated with dysphonia, sedatives with motor control impairment, antineoplastic medications and fluoroquinolones with aphasia and incoherence). We developed also a MedDRA query proposal for speech and language conditions, formalization of possible biases, and related analyses to account for them.

Conclusion: We provided a list of medications to be accounted for in future studies of communicative bio-behavioral markers in affective and psychotic disorders. The methodological procedure we developed does not simply facilitate future investigations of communicative biomarkers in other conditions, more crucially it provides a case-study in more rigorous procedures for digital phenotyping in general.

References/Further Sources of Information

• 1. Insel TR. Digital Phenotyping: Technology for a New Science of Behavior. JAMA. 2017 Oct 3;318(13):1215–6.

• 2. Low DM, Bentley KH, Ghosh SS. Automated assessment of psychiatric disorders using speech: A systematic review. Laryngoscope Investigative Otolaryngology. 2020;5(1):96–116.

• 3. Parola A, Simonsen A, Bliksted V, Fusaroli R. Voice patterns in schizophrenia: A systematic review and Bayesian meta-analysis. Schizophr Res. 2020 Feb;216:24–40.

2.9 P009 Competitive Intelligence in Pharmacovigilance—A Case Study on Two Covid-19 Vaccines

2.9.1 L. V. Holle ¹

2.9.1.1 ¹OpenSourcePV, Pharmacovigilance, Court-Saint-Etienne, Belgium

Introduction: The comparison of safety profiles for products recently on the market is difficult. There is a lack of methodology for quantifying the potential differences between products that have the same indication.

Objective: Provide the tools to quantify the differences in spontaneous reporting between two products

Methods: Under the null assumption that two products have the same safety profile, the scatterplot of the Empirical Bayes Geometric Mean (EBGM) measured for the different MedDRA Preferred Terms (PTs) post Product A (axis x) and post Product B (axis y) should follow the diagonal line. An Euclidian distance from the EBGM to the diagonal line measures the deviation from what would have been expected under the null assumption of similar safety profiles. As the deviation does not capture the statistical uncertainty around the estimate, we propose as measure of the deviation the minimal distance of the four Euclidian distances calculated from each of the credibility intervals around the EBGM post Product A and Product B.

Results: We quantified the most significant differences in reporting between the two vaccines that were approved in the US against covid-19 using publicly available data from the Vaccine Adverse Event Reporting System (VAERS). A visualization capturing the global trend of the most substantial differences in reporting was generated.

Conclusion: This relatively simple method can provide quantification of the differences in reporting and could help prioritize one product over the other for some population subgroups.

2.10 P010 A Method for Identification of Renal Disease in Unstructured Clinical Narratives

2.10.1 H. Davies ¹, P. Noble¹, I. Fins¹, G. Pinchbeck¹, D. Killick¹

2.10.1.1 ¹University of Liverpool, Institute of Infection-Veterinary and Ecological Sciences, Liverpool, United Kingdom

Introduction: The application of text mining approaches to identify adverse events (AEs) from electronic health records (EHRs) is a growing area of interest in pharmacovigilance research. In veterinary medicine, the majority of EHRs consist of unstructured clinical narratives, hence the development of appropriate methods for identifying AEs of interest is an important step in the research process. Identifying renal disease poses a specific challenge as the event may be described in narrative form or implied by reported test results or the use of renal disease specific medications. In this study we developed regular expressions (regexes) to identify relevant mentions of renal disease in veterinary free text clinical narratives.

Objective: To develop a method for identifying veterinary patients with renal disease in free text clinical narratives.

Methods: Using VeDDRA terminology as a starting point, we used an iterative approach to develop a series of regexes which were then applied to a random sample of 10,000 clinical narratives. In order to measure precision, clinical narratives containing a match to the regexes were reviewed against a case definition by two independent reviewers and disagreement was settled by consensus. Terms in the final regex were derived from three sources—VeDDRA, a word embedding model and expert opinion. To determine recall, the final regex was applied to a sample of consults where the main presenting complaint was deemed to be renal disease by a veterinary clinician.

Results: The regex containing only VeDDRA terms had a poor positive predictive value (PPV) (0.17). Expanding this terminology using a word embedding model improved the PPV to 0.27. Following changes suggested by a veterinary expert, the PPV of the final regex was improved to 0.43. When the regex was divided into three components, the PPV for these individual portions was mentions of renal disease (0.35), mentions of test results (0.44) and mentions of renal disease treatment (0.8). When compared against the veterinary clinician validated sample of renal disease consults recall was 0.07 for the VeDDRA regex, 0.52 for the word embedding model expanded regex and 0.68 for the final regex.

Conclusion: The developed regex can be used to identify animals with renal disease, with mentions of renal disease treatment being the most specific indicator of clinical disease. This method can be employed to filter potential cases of interest from large datasets for use in observational studies.

2.11 P011 Automated PV: What Are We Waiting for?

2.11.1 J. Markey ¹, M. H. Petersen ²

2.11.1.1 ¹Insife, Sales & Marketing, London, United Kingdom; ²Insife, Executive Management, Copenhagen, Denmark

Introduction: We use AI in our everyday lives probably without even realising it. If we trust and have confidence in AI technology, why haven’t we adopted it more in PV? There are many discussions about the use of AI in PV and the potential innovation that it could bring but given the conservative nature of our business and having to work in a highly regulated environment, how can we build confidence to get us over that barrier. Will having the regulators use the same AI make us more comfortable or will legislation be necessary to drive us forward?

Objective: Explore why PV has lagged behind with AI technology that is commonplace in other parts of our lives and business. Aspects of AI, such as machine learning, are used in areas such as early disease prediction, clinical diagnosis, outcome prediction and prognosis evaluation, personalized treatments, drug discovery, manufacturing, clinical trial research, and more. In our personal lives, services like Amazon and Google use AI to understand and target their customers and we accept that as normal. The objective of this presentation is to explore the reluctance of accepting AI in PV and how we can move towards overcoming those obstacles.

Methods: This presentation is based on the presenters’ experience of working in PV for 20+ years from an industry, consulting, technology vendor and regulatory authority perspective.

We will look at some real-life practical examples where AI in PV has worked and what it took to get there.

Results: N/A.

Conclusion: We will show that the practical application of AI is achievable and has been achieved in the high volume environment of a regulatory authority. Many of the AI features used by the RA, and the lessons learned from that project, can also be applied in industry, so why are we waiting?

References/Further Sources of Information

If accepted, we will invite a speaker from the regulator to join/replace one of the proposed speakers to discuss their experience of implementing AI solutions first hand.

2.12 P012 Automated De-Identification of Case Narratives Using Deep Neural Networks for the UK Yellow Card System

2.12.1 E. L. Meldau ¹, S. Bista¹, C. M. González², G. N. Norén¹

2.12.1.1 ¹Uppsala Monitoring Centre, Research, Uppsala, Sweden; ²Uppsala Monitoring Centre, WHO Collaborating Centre-Signal Management, Uppsala, Sweden

Introduction: Access to case narratives during signal assessment is crucial to provide a more complete picture of the cases [1], however patient confidentiality needs to be considered. Sharing of narratives while preserving privacy requires de-identification—the removal or replacement of personal identifiers. Automating this task can help with increasing data load. To ensure patient confidentiality throughout the full pharmacovigilance process, the narratives should be de-identified early in the process. Person names—one of the more common identifiers in case narratives—can lead to (in-)direct identification of patients but are challenging to recognise in free text.

Objective: To develop and evaluate a method for automated de-identification of names in case narratives.

Methods: We use an ensemble of BERT [2]—a state-of-the-art language model using deep-neural network—combined with hand-engineered rules for detecting names. Our model is trained on i2b2 2014 deidentification challenge data [3] combined with unprocessed data from the Yellow Card system[4] provided by the MHRA. Because names are rare in the Yellow Card data, the training dataset is prepared using active learning through an independent model. Model testing is done on a separate, manually annotated dataset.

Evaluation of the deidentification is guided by: (1) how often clinically relevant information is removed and (2) how identifiable the narratives that the model fails to completely de-identify are. We define three categories of identifiability: (a) Directly identifiable, where subject identification is very likely with the leaked information (e.g., full names); (b) Indirectly identifiable, where identification is possible through combination with information from the narrative context (e.g., surname & occupation); and (c) Non-identifiable, where identification is highly unlikely (e.g. initials).

Results: Out of the 71 narratives with names and initials, only 12 contained occurrences missed by the system. Manual evaluation found only one directly and one indirectly identifiable narrative due to leaks. It should be noted that the leaked direct identifier was a foreign, non-English name. Automated de-identification only affected 7% of all narratives and only 1% were assessed as missing clinically relevant information after de-identification. A single narrative may contain multiple occurrences of names, the table presents results per occurrence.

Conclusion: Automated de-identification of names is possible without compromising clinically relevant information. Our method can recognise and mask a vast majority of names and most initials while leaving most of the information untouched. Qualitative evaluation shows that the rare leaks that occur tend not to make cases identifiable.

References/Further Sources of Information

• 1. Karimi G, Star K, Lindquist M, Edwards IR. Clinical stories are necessary for drug safety. Clin Med. 2014;14(3):326–7.

• 2. Devlin J, Chang MW, Lee K, Toutanova K. BERT: Pre-training of Deep Bidirectional Transformers for Language Understanding. arXiv:181004805 [cs] [Internet]. 2019 May 24 [cited 2022 Apr 7]; Available from: http://arxiv.org/abs/1810.04805.

• 3. Stubbs A, Uzuner Ö. Annotating longitudinal clinical narratives for de-identification: The 2014 i2b2/UTHealth Corpus. J Biomed Inform. 2015;58(Suppl):S20–9.

• 4. Medicines and Healthcare products Regulatory Agency. The Yellow Card scheme: guidance for healthcare professionals, patients and the public [Internet]. [cited 2022 May 12]. Available from: https://www.gov.uk/guidance/the-yellow-card-scheme-guidance-for-healthcare-professionals.

2.13 P013 Prescription Error: A Case of Metronidazole-Induced Pancreatitis

2.13.1 M. Daldoul¹, I. Hamza¹, A. Zaiem¹, Y. Mahjoubi¹, W. Kaabi¹, F. E. Jabri¹, R. Daghfous¹, S. El Aidli ¹

2.13.1.1 ¹Université Tunis el Manar Faculté de médecine de Tunis/Unité de recherche UR17ES12., Centre national Chalbi Belkahia de pharmacovigilance/ Service de recueil et d'analyse des effets indésirables, tunis, Tunisia

Introduction: Metronidazole is a nitroimidazole antibacterial drug that is mostly used to treat anaerobic bacteria and protozoa infections. The adverse side effects of metronidazole include gastrointestinal upset, metallic taste, urticaria, headache, peripheral neuropathy. Metronidazole-induced pancreatitis has been rarely described in the literature so far.

Objective: We report a rare case of an acute pancreatitis associated with metronidazole which occurred as a result of a prescription error.

Methods: This case was reported in February 2022 to The National Centre of Pharmacovigilance and evaluated according to the updated French method of causality assessment.

Results: A 70-year-old male patient with a past medical history of chronic viral hepatitis B treated with entecavir since 2006, presented to the surgery department with an acute onset of a severe epigastric pain radiating through to the back associated with hepatic colic with nausea and vomiting. Symptoms started 7 days after initiation of metronidazole given by the patient’s dentist for treatment of a periodontal abscess. Metronidazole was prescribed twice under two different trade names Birodogyl^® (spiramycine, metronidazole) and Tamizol^®(metronidazole) medications. On exam, he had severe epigastric tenderness. Biochemical analysis showed lipase 632 U/L (6N), and amylase 322 U/L (3N). The abdominal CT scan showed an aspect of acute oedemato-interstitial pancreatitis stage B (CSTI 1). Relative negatives in the history included, no lithiasis, no known drug allergies, and no alcohol consumption. Patient symptoms and lipase improved within 3 days after metronidazole withdrawl and initiation of supportive care.

Conclusion: The likelihood of metronidazole as the incriminating agent was likely in front of a suggestive delay and favorable outcome after the drug withdrawl. It was suggested a the possible dose-response mechanism between metronidazole use and occurrence of pancreatitis, and this case draw attention to the possible acute pancreatitis associated with metronidazole due to a prescription error.

References/Further Sources of Information

Sura ME, Heinrich KA, Suseno M. Metronidazole-associated pancreatitis. Ann Pharmacother. 2000 Oct;34(10):1152–5. https://doi.org/10.1345/aph.10021.

2.14 P014 IoT and the Future of Signal Reporting, Medication Management, Clinical Research and Drug Safety with New Tools and Process

2.14.1 L. Nurse ¹

2.14.1.1 ¹Patient Advocate, Independent, Decatur, USA

Introduction: The possibilities of using current scientific principles to create tools to help give efficiency and help to nurses thereby reducing stress and the potential for errors. Also enable patients to maintain independence and less outside contact as technology is used to expand the reach of telehealth. Solutions will be adaptable for independent use by the sight, hearing and mentally challenged. The 1st hurdle is to make it easier for patients and staff to accomplish what they have to do safely and consistently.

Objective: To simplify the taking of all drugs and supplements using IoT technology. This a paradigm shift from the many efforts to mitigate the challenges of the many aspects of drug delivery. Here medication is always kept in the labelled, legal safety of the original dispensed container until consumed. Safety concerns of pre-pouring will no longer exist. Authentic real-tine medication usage data will be available. ISoP and other safety management organizations will be able to execute many tasks with precision.

Methods: The innovation is a multi-compartment device that holds a medication container in each compartment. The device has a display that resides in the lid or may be at the front of a drawer type or wall mounted unit. The concept of assigned location forms the basis for these innovations. Stored instructions for many aspects of care and follow-up resides in the device and will be communicated via the display appropriately. It can be connected to a larger display, cellphone or other mobile device.

Medicine containers are scanned to capture dosing instructions. The assigned location lights up. The container is placed within the compartment and receives an alert at dosing times. The compartment stays lit until the nurse picks up and replaces the container. Video may be activated. Biometric access ensures identity and pill count and time are automatically recorded.

Results: Feasibility indicates that the must touch to silent feature is a powerful feature that aids adherence. Also the timing methods that ensures safe dosing separation helps to ensure all doses are taken in a given day even if late taking a dose. Relative time rather than time of day dosing is used.

Conclusion: Believed to be unsolvable, these discoveries will open the door to the science of individual ingestion by effortlessly notifying and guiding individuals in the consumption and effects of medicines and other items for a safer and healthier life experience. Powerful data will be generated for use by ISoP.

References/Further Sources of Information

www.ownumhealth.com.

2.15 P015 Litigation Following Adverse Drug Reactions: Impact of Regulator Oversight—A Case Scenario of a Ceftriaxone Medication Error

2.15.1 I. Mugisa¹, J. Atuhaire¹, D. Walusimbi¹, H. N. Byomire ¹

2.15.1.1 ¹National Drug Authority, Product Safety, Kampala, Uganda

Introduction: The Summary of Product Characteristics for Ceftriaxone states that as with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported [1]. However, the frequency is stated as unknown. Out of 46 reports to Ceftriaxone in the Uganda ADR database, 7 of these are of anaphylactic reactions, and one of them was fatal for the paediatric patient. It is not clear in cases of injurious or fatal drug effects who should bear the liability. However, it is important to describe the role and actions of the National Regulatory Agency to such an ADR report.

Objective: To present a case study of a successful legal resolution of a fatal medication error to Ceftriaxone with the involvement of the regulator.

Methods: This is a retrospective case report. Consent was sought from the patient’s family and health care provider to share the case.

Results: A one-and-a-half-year-old male child was diagnosed with septicaemia with diarrhoea and admitted to a hospital. Day one treatment with Ceftriaxone was stopped due to a reaction of difficulty in breathing. A switch to Ciprofloxacin happened and the patient began to improve. Due to a weekend staff shift change, the change to ciprofloxacin was not noted resulting in re-administration of ceftriaxone and anaphylaxis that caused the death of the patient despite all efforts to resuscitate.

National Drug Authority performed a causality assessment of the serious adverse event and found that administration of Ceftriaxone was related to the outcome of death.

However, it was noted that this was a medication error with no malice aforethought and therefore the health care provider was not liable.

Conclusion: Timely and objective causality assessment from the Medicines Regulatory Agency is invaluable in providing scientific evidence that can help patients receive compensation and/or protect health care practitioners from wrongful liability for drug effects that are inadvertent. Health care providers hesitate to report due to fear of litigation but cases such as this one show that timely submission of quality reports is useful in establishing causality and therefore supporting compensation for the patient or protection from vicarious liability for the health care provider/manufacturer. Publication of these results can aid in encouraging reporting rates among patients and providers.

References/Further Sources of Information

• 1. Ceftriaxone 1g Powder for solution for injection. Available from: https://www.medicines.org.uk/emc/product/1361/smpc#UNDESIRABLE_EFFECTS. Accessed March 9, 2022.

• 2. Zheng ZQ, Jiang C, Yu RL, Zhou JQ, Wu ZJ, Luo JY. General characteristics, economic burden, causative drugs and medical errors associated with medical damage litigation involving severe cutaneous adverse drug reactions in China. Journal of Clinical Pharmacy and Therapeutics. 2020 Oct;45(5):1087–97.5.

• 3. Edersheim JG, Stern TA. Liability associated with prescribing medications. Primary care companion to the Journal of clinical psychiatry. 2009;11(3):11

• 4. Bhatt AD. Drug-related problems and adverse drug events: negligence, litigation and prevention. The Journal of the Association of Physicians of India. 1999 Jul;47(7):715–720. PMID: 10778594.

• 5. Kaufman MB, Stoukides CA, Campbell NA. Physicians' liability for adverse drug reactions. Southern Medical Journal. 1994 Aug;87(8):780–784. https://doi.org/10.1097/00007611-199408000-00002. PMID: 8052883.

2.16 P017 Clinical Impact of Pharmacotherapeutic Follow-up and Pharmaceutical Interventions in a Reference Hospital in Mexico City

2.16.1 J. A. Maza ¹, D. Z. Moreno¹, I. V. Gutiérrez¹, M. K. G. Peredo¹, S. R. Fernandez¹

2.16.1.1 ¹Instituto Nacional de Cardiología Ignacio Chávez, Clinical Pharmacology, Mexico, Mexico

Introduction: Pharmacotherapeutic Follow-up is a professional practice focused on identification, prevention and resolution of Drug-Related Problems and the causes or errors that originate these problems in patients [1–4].

Objective: To assess the clinical impact of Pharmacotherapeutic Monitoring and pharmaceutical interventions performed in hospitalized patients at the Instituto Nacional de Cardiología Ignacio Chávez.

Methods: Clinical pharmacists perform Pharmacotherapeutic Follow-up of hospitalized patients through three evaluations: drug reconciliation, pharmacotherapeutic profile and drug prescription suitability, identifying Drug-Related Problems and medication errors and recording their activities in two databases: the first consists of the evaluation that is carried out weekly and the second corresponds to the pharmaceutical interventions; these bases are validated monthly with each other. For this study, data is taken from both databases in the period from June to December 2021 and the risk that was reduced by accepted pharmaceutical interventions is calculated.

Results: In the review of the database of activities carried out, a progressive increase in the number of evaluations done by clinical pharmacists was observed in drug reconciliation, pharmacotherapeutic profile and drug prescription suitability, identifying discrepancies, medication errors and Problems Related to Medications. In the database of pharmaceutical interventions, a significant increase in the risk that was reduced associated with the interventions carried out and accepted was observed; as it can be identified in figure 1, which ranges from 23.02 to 66.4%, obtaining an average of 43.1% in the months of July to December.

Conclusion: The pharmaceutical interventions allowed to improve the prescriptions and with it, identify Problems Related to Medications and medication errors before causing harm to the patient, making the drugs safer

References/Further Sources of Information

• 1. Ucha Samartín, M.; Pichel Loureiro, A.; Vázquez López, C.; Álvarez Payero, M.; Pérez Parente, D.; Martínez López de Castro, N. (2013). Impacto económico de la resolución de problemas relacionados con medicamentos en un servicio de urgencias. Farmacia Hospitalaria, 37 (1), 59–64.

• 2. Chu, R. Z. (2016). Simple steps to reduce medication errors, Nursing, 46 (8), 63–65.

• 3. Martí Gil, C.; Sanz Ferrando, M. J.; Aznar Prats, J. (2011). Impacto de las actuaciones farmacéuticas realizadas en un servicio de farmacia hospitalaria., Pharmaceutical care, 13 (2), 66–73.

• 4. Ibáñez, J.; Caelles, N.; Dualde, E. (2003). Estrategias de intervención en seguimiento farmacoterapéutico. Seguimiento farmacoterapéutico, 1 (2), 82–86.

2.17 P018 Management of the Anticholinergic Burden in a Nursing Home in Sardinia

2.17.1 S. Sanogo ¹, M. P. Fois¹, O. Dachena¹

2.17.1.1 ¹ARES-Sardegna, Servizio farmaceutico territoriale dell'ASSL di Sassari, Sassari, Italy

Introduction: Some side effects of anticholinergic drugs can be relatively harmless such as dry mouth or constipation, but in some cases, they can manifest themselves in the form of heart arrhythmias or as worsening of dementia or delirium. The elderly are more prone to show anticholinergic effects, due to a progressive decrease in acetylcholine levels, and are often also treated with drug polytherapy with additive effects which leads to an anticholinergic cognitive burden (ACB) [1–4].

Objective: Verify whether it is possible to identify patients who may experience an adverse reaction due to ACB in real clinical practice through a pharmacological investigation, identify which drugs are the possible cause and re-evaluate the therapy to prevent the onset of adverse reactions.

Methods: From October 2021 to May 2022, the drug therapy of 34 patients aged ≥ 65 years admitted to a nursing home in Sardinia was examined. The patients' drug therapy was analyzed using the INTERCheck WEB platform, which makes it possible to calculate the overall ACB value and that associated with each drug. The presence of clinical symptoms was verified for patients with ACB ≥ 5. Clinical analysis was performed by assigning a score of 1 to each adverse event attributable to ACB in the central nervous system, mouth, eyes, heart, gastrointestinal tract, bladder, and skin. Patients with a clinical symptom value (CS) ≥ 4/7 were considered relevant.

Results: In 34 patients, the total number of drugs prescribed was 290 with an average of 8.5 drugs per patient. The main classes of ATC prescribed are N06 (psychoanaleptics) 8%, B03 (antiemetics) 12%, N05 (psycholeptics) 16%. Five patients with a critical ACB score ≥ 5 were identified. In these patients, the major drugs responsible for elevated ACB were quetiapine, chlorpromazine, and paroxetine, all three with a value of 3. The 5 patients also showed clinical signs of ACB. Three patients had CS ≥ 4/7 and two of them experienced clinical improvement following therapy modification.

Conclusion: Computerized determination of CBA was helpful in preventing adverse reactions, identifying which drugs are responsible for adverse reactions and modifying therapy to avoid the occurrence of adverse events. Drug therapy analysis is useful in conjunction with clinical evaluation and can be a valuable tool used in conjunction with tools such as Mini Mental Status.

References/Further Sources of Information

• 1. Kolanowski A, Fick DM, Campbell J, Litaker M, Boustani M. A preliminary study of anticholinergic burden and relationship to a quality of life indicator, engagement in activities, in nursing home residents with dementia. J Am Med Dir Assoc. 2009 May;10(4):252–7. https://doi.org/10.1016/j.jamda.2008.11.005. Epub 2009 Jan 9. PMID: 19426941; PMCID: PMC2735136.

• 2. Oudewortel L, van der Roest HG, Onder G, Wijnen VJM, Liperoti R, Denkinger M, Finne-Soveri H, Topinková E, Henrard JC, van Gool WA. The Association of Anticholinergic Drugs and Delirium in Nursing Home Patients With Dementia: Results From the SHELTER Study. J Am Med Dir Assoc. 2021 Oct;22(10):2087–2092. https://doi.org/10.1016/j.jamda.2021.05.039. Epub 2021 Jun 29. PMID: 34197793.

• 3. Malagaris I, Mehta HB, Li S, Goodwin JS. Decrease of Anticholinergic Drug Use in Nursing Home Residents in the United States, 2009 to 2017. J Am Geriatr Soc. 2020 Dec;68(12):2797–2804. https://doi.org/10.1111/jgs.16776. Epub 2020 Aug 15. PMID: 32798337; PMCID: PMC8285038.

• 4. Aalto UL, Finne-Soveri H, Kautiainen H, Öhman H, Roitto HM, Pitkälä KH. Relationship between Anticholinergic Burden and Health-Related Quality of Life among Residents in Long-Term Care. J Nutr Health Aging. 2021;25(2):224–229. https://doi.org/10.1007/s12603-020-1493-2. PMID: 33491038.

2.18 P019 Measuring the Effectiveness of Electronic Prescription Systems in Reducing Medication Errors in Hospital Setting in Egypt

2.18.1 M. A. Elhawary^1,2, H. Rostom ^3,4

2.18.1.1 ¹Egyptian Ministry of Health and Population-Cairo-Egypt, Preventive Medicine, Cairo, Egypt; ²Faculty of Pharmacy-Ain Shams University, Clinical Pharmacy Dep, Cairo, Egypt; ³Faculty of Pharmacy-MSA University, Clinical Pharmacy Dep, Cairo, Egypt; ⁴International Society of Pharmacovigilance ISoP, Egypt Chapter, Cairo, Egypt

Introduction: Presence of a strong medication safety system can prevent many potential medication errors (MEs) by enforcing safety monitoring on the ordering, prescription, preparation, and administration of medicines [1]. Furthermore, a well established medication safety system can solve many causes of communication problems which account for over half of all causes associated with medication errors through its electronic based system. Unfortunately, many of the existing electronic health records (EHRs) were designed for purposes of medical billing rather than for medical care, resulting in challenges for using the recorded data for safety data capturing. Moreover, commercially available electronic prescribing and computerized physician order entry systems are cost-prohibitive for many health organization, especially non-profit ones. In a previous research project, Egypt Chapter of International Society of Pharmacovigilance (ISoP) was engaged in developing such system in the hospital of Palestine Red Crescent Society (PRCS) in Cairo to support identifying MEs that were experienced by refugees through remodeling and adding new features to the existing hospital management system. The developed system was used as the “intervention” in this research.

Objective: The objective of this study was to assess the effectiveness of introducing internally low-cost electronic prescription system in reducing the frequency of MEs of different types.

Methods: A pre- and post-intervention study was conducted to compare the frequency of MEs before and after replacing the traditionally used paper-based system with an internal electronic-based system in hospital setting. MEs were collected by reviewing randomized medical records at base line and after one year of introducing this electronic-based system. More focus was given to medical records of elderly patients and emergency ward. The prescribing errors, transcribing errors, dispensing errors, administration errors were investigated.

Results: We analyzed 314 paper-based prescriptions at baseline and 416 paper-based and electronic prescriptions at one year of follow-up. The total prescribing errors (before–after %) in elderly were (66–16%) while in the emergency wards they were (71–33%). The errors were (86.9–13.8%) due to a wrong or incomplete transfer of the information from the prescription. Regarding dispensing errors, it was shown that the content errors were (78–33%) and the labeling errors were (68–28%). There were (65–12%) dosing errors during administration.

Conclusion: The adoption of internal electronic prescription systems was effective in markedly reducing the frequency of MEs compared to the paper-based system in a low-resource setting where the expense on complex commercial electronic solutions are burden for institutions.

References/Further Sources of Information

• 1. Elhawary, M.A., Rostom, H., Edwards, B. et al. Medication Errors Special Interest Group of the International Society of Pharmacovigilance and the Trends in International Collaboration for Patient Safety. Drug Saf 45, 97–99 (2022). https://doi.org/10.1007/s40264-021-01145-0.

2.19 P020 Paracetamol, a New Awareness on an Old Drug: A Survey Report on its Clinical Use in a Cancer Institute

2.19.1 C. Calabro ¹, M. Laforgia¹, S. Ferraiuolo¹, V. Ungaro¹, P. Nardulli¹

2.19.1.1 ¹Cancer Institute of Bari, SC Pharmacy and UMaCA, Bari, Italy

Introduction: In spite of its large use, a conspicuous number of paracetamol adverse reaction reports have been recently collected, due to overdosage or posologic mistakes. A recent metanalysis by BMC Med Inform Decis Mak [1] has inserted paracetamol in the list of the six drugs causing severe ototoxicity and a pharmacovigilance retrospective study [2] has highlighted that it induced 1.4% of all severe drug-induced adverse reactions. Another recent review on the analgesic standard doses of paracetamol has demonstrated its grade of toxicity, at the maximum prescribed dose [3].

Objective: A knowledge assessment on paracetamol management among health professionals can rise new inputs for the risk/benefit ratio of this old molecule [4,5].

Methods: A survey of 7 questions on standard dosage, dose adjustment and antidotes to paracetamol overdose was submitted to 36 health professionals (nurses, pharmacists, oncologists, hematologists, surgeons) in the Cancer Institute of Bari. The answers were collected and charted in diagrams, in order to soon identify critical evidences.

Results: The correct answers to the 7 questions were distributed as follows: up to 30–33% to 4, 70% to 2 and 89% to 1 questions, respectively. The lowest value of correct answers (11%) was reported for the question on the minimum time interval among successive administrations, while the highest (89%) was related to the volume of drug solution per administration.

About 30–33% of correct responses were given to both questions on the maximum doses in patients with or without additional risks (kidney and/or liver comorbility), respectively, highlighting the lack of knowledge on the need to personalize therapy. The 70% value of correct answers regards the maximum consented daily doses and the antidote N-acetilcysteine.

Conclusion: The collecting data have demonstrated the clinical need to manage accurately old and apparently well-known drugs to grant a controlled clinical risk in hospitals. The implementation of Recommendation n° 7 by Italian Ministry of Health and precise indications on medical reports of doses and timing in therapy are possible solutions to avoid bad interpretation on prescription and accidental paracetamol overdoses. Pharmacovigilance is a duty for health professionals and the awareness that also old drugs can be causes of toxicity is a substantial starting point for safety of care.

References/Further Sources of Information

• 1. Hyunah Shin, Suehyun Lee. An OMOP-CDM based pharmacovigilance data-processing pipeline (PDP) providing active surveillance for ADR signal detection from real-world data sources. BMC Med Inform Decis Mak. 2021 May 17;21(1):159.

• 2. Nora Bin Yousef, Nagarajkumar Yenugadhati, Nasser Alqahtani, Ali Alshahrani, Mubarak Alshahrani, Majed Al Jeraisy, Motasim Badri. Patterns of adverse drug reactions (ADRs) in Saudi Arabia. Saudi Pharm. 2022 Jan;30(1):8–13.

• 3. Emmert Roberts, Vanessa Delgado Nunes, Sara Buckner, Susan Latchem, Margaret Constanti, Paul Miller, Michael Doherty, Weiya Zhang, Fraser Birrell, Mark Porcheret, KrysiaDziedzic, Ian Bernstein, Elspeth Wise, Philip G Conaghan. Paracetamol: not as safe as we thought? A systematic literature review of observational studies. Ann Rheum Dis 2016 Mar;75(3):552–9.

• 4. Marta Jóźwiak-Bebenista, Jerzy Z Nowak. Paracetamol: mechanism of action, applications and safety concern. Acta Pol Pharm. Jan–Feb 2014;71(1):11–23.

• 5. K Brune, B Renner, G Tiegs. Acetaminophen/paracetamol: A history of errors, failures and false decisions. Eur J Pain. 2015 Aug;19(7):953–65.

2.20 P021 Assessment of the Quality of MedDRA Coding in a Sample of COVID-19 Vaccine Medication Error Data

2.20.1 C. A. Wilson¹, K. Kralova², N. Richebourg³, J. D'souza ⁴

2.20.1.1 ¹MD, Medical Coding Consultant, Berlin, Germany; ²Sanofi, Global Pharmacovigilance & Epidemiology, Chilly-Mazarin, France; ³Sanofi, Fellow at Global Pharmacovigilance & Epidemiology, Chilly-Mazarin, France; ⁴Institute of Pharmacovigilance, Regulatory Intelligence, Praha 4-Nusle, Czech Republic

Introduction: High interest in the last two years was globally put by Health Authorities on the recording, coding, and reporting of medication errors to ensure the safety and effectiveness of the use of medicines and to provide reliable information to healthcare professionals and patients. Medical coding is a prerequisite for efficient, effective, and reproducible data outputs.

Objective: Not applicable.

Methods: A sample of medication error coding results was assessed for accuracy and consistency of MedDRA coding and identification of main types of coding errors. It included 1500 coded reported terms for COVID-19 vaccines medication errors, assigned to MedDRA codes by national regulatory authorities or pharmacovigilance centers and drawn from the Uppsala Monitoring Centre (UMC) VigiBase through August 25, 2021.

Results: One-third of the records could not be assessed due to incomplete or unclear verbatims. In one-third, code assignments were correct, but another third of the sample was not adequately coded. Most frequent coding errors corresponded to vague PT assignments, while more detailed information was available for a more precise coding. This observation is similar to the EudraVigilance database, where some of the most assigned MedDRA terms for medication errors also represent vague concepts.

Conclusion: These findings indicate that understanding of medication error documentation and assessment and of MedDRA content and coding guidelines need to be reinforced. The MedDRA Maintenance and Support Services Organization (MSSO) offers several MedDRA coding trainings, including coding of medication errors. The authors provide valuable references to the latter, to the applicable ICH-Endorsed Guides for MedDRA Users, and to relevant EMA guidance.

References/Further Sources of Information

Not applicable.

2.21 P022 Intoxications in a Pediatric Population: A Regional Retrospective Analysis

2.21.1 G. Baiardi ^1,2, F. Sacco^1,2, G. Calvini^1,2, S. Pasquariello^1,2, I. Negro³, F. Mattioli^1,2, C. Debbia³

2.21.1.1 ¹University of Genoa, Di.M.I. Department of Internal Medicine and Medical Specialties, Genoa, Italy; ²E.O. Ospedali Galliera, Clinical Pharmacology Unit, Genoa, Italy; ³IRCCS Istituto Giannina Gaslini, Emergency Department and Pediatric Emergency Unit, Genoa, Italy

Introduction: Pediatric intoxications represent one of the most common causes of harm to children under the age of six and the fourth leading cause of death in developing countries [1–2]. In Italy 56% of intoxications affect the age group between 0 and 19 years, 39% of which are consequent to drug exposure [3]. Data collection and systematic analysis of intoxication cases is of fundamental importance to gain a greater knowledge of toxic domestic, environmental and pharmacological agents [4–5].

Objective: To analyze pediatric intoxication cases managed by Liguria’s major pediatric Hospital in the absence of a regional Poison Center.

Methods: We performed a retrospective observational study of the intoxication cases managed by the Emergency Department of the IRCCS G. Gaslini for the period from January 2017 to December 2019. All poisoning were retrieved from the Hospital Central Database using the International Classification of Disease (ICD 9) classification code system, and subsequently entered into a local database for data management. Records from patients aged > 19 years old and from those whose ICD9 did not match a poisoning diagnosis were excluded. Included records were then categorized into four main types of intoxication: from drugs, alcohol, carbon monoxide (CO) and fumes, food/other substance. Descriptive statistics were undertaken.

Results: Over a 3 year-period 172 intoxication cases, of which 28 with no available data, were treated by the Emergency Department of the IRCCS G. Gaslini. Our analysis included therefore 144 poisoned patient cases, 70 were from females and 74 from males, with a median age of 3 years old. Out of the total of accesses, 38.9% of cases were attributed to drug intoxication in which the agents most involved were analgesics and sedative-hypnotic drugs, 29.9% to carbon monoxide (CO) and fumes poisoning, 24.3% to food/other substance intoxication and 6.9% to alcohol intoxication. Poisoning severity and the need for hospitalization have also been investigated.

Conclusion: Implementation of high-performance data collection systems in the Emergency Department could be decisive in guiding clinical choices. This study has gathered data on pediatric poisonings in a regional reality in the absence of a Poison Center. Although preliminary, these findings may guide for the improvement of the surveillance system of intoxications in pediatrics.

References/Further Sources of Information

• 1. Shannon M. Ingestion of toxic substances by children. N Engl J Med. 2000 Jan 20;342(3):186–91.

• 2. Hyder AA, Wali S, Fishman S, Schenk E. The burden of unintentional injuries among the under-five population in South Asia. Acta Paediatr. 2008 Mar;97(3):267–75.

• 3. Settimi L, Davanzo F, Bacis G, Luciana Cossa L, Moretti S. Sistema informativo nazionale per la sorveglianza delle esposizioni pericolose e delle intossicazioni: casi rilevati nel 2015. Decimo rapporto annuale. Roma: Istituto Superiore di Sanità; 2019.

• 4. Settimi L, Davanzo F, Carbone P, Sesana F, Locatelli C, Farina ML, et al. Surveillance of toxic exposures: the pilot experience of the Poison Control Centers of Milan, Pavia and Bergamo in 2006. Ann Ist Super Sanita. 2007;43(3):287–94.

• 5. Wolkin AF, Patel M, Watson W, Belson M, Rubin C, Schier J, et al. Early detection of illness associated with poisonings of public health significance. Ann Emerg Med. 2006 Feb;47(2):170–6.

2.22 P023 Identifying Adverse Drug Reactions from Free-Text Dutch EHR in Hospitalized Patients with the Development of an Algorithm (IADRESS)

2.22.1 B. V. D. Burgt ¹, B. Dullemond², A. Wasylewicz¹, R. Grouls³, A. Bouwman⁴, T. Egberts⁵, E. Korsten¹

2.22.1.1 ¹Catharina Hospital Eindhoven, Health Care Intelligence, Eindhoven, Netherlands; ²Technical University Eindhoven, Computer Science and Engineering, Eindhoven, Netherlands; ³Catharina Hospital Eindhoven, Clinical Pharmacy-, Eindhoven, Netherlands; ⁴Catharina Hospital Eindhoven, Anesthesiology, Eindhoven, Netherlands; ⁵University of Utrecht, Pharmacoepidemiology and Clinical Pharmacology, Utrecht, Netherlands

Introduction: While electronic health record (EHR) is a potentially valuable resource of adverse drug reactions (ADRs) [1,2], these ADRs are frequently not registered, registered in the wrong place or only registered using free-text entry [3,4]. Free text data cannot be managed and analyzed with mainstream software tools, but this is possible with text mining (TM) tools.

Objective: To develop an algorithm to identify possible ADRs in free text of Dutch hospital EHR with a TM tool.

Methods: In phase I, the previous rule-based algorithm was translated to a R-algorithm and improved it with the help of previous mentioned issues. In phase II, the terms of MedDRA and SNOMED-CT were added to identify ADRs and in phase III R-scripts were used to improve the R-algorithm.

Results: In phase I, the R-algorithm identified 97% (n = 174) of the EHR notes containing possible ADRs identified by the rule-based algorithm. Five ADRs were missed compared to the rule-based algorithm, because of typo’s and a EHR conversion. The last PDCA cycle compared to the golden standard achieved a sensitivity of 93%, a PPV of 11% and an F-measure of 0.2. For the potentially serious ADRs a sensitivity of 95% was achieved. There were 64 more EHR notes containing possible ADRs identified, by the R-algorithm. In phase II, there were 105 ADRs identified with the R-algorithm using MedDRA, SNOMED-CT and synonyms. In phase III, the R-algorithm improved the PPV, sensitivity and F-measure.

Conclusion: The developed R-algorithm identified ADRs, however further research is required to extrapolate the algorithm and to combine it with clinical decision support systems to bring the data back to the physician to increase ADR registration.

References/Further Sources of Information

• 1. Sun W, Cai Z, Li Y, Liu F, Fang S, Wang G. Data processing and text mining technologies on electronic medical records: A review. J Healthc Eng. 2018;(5):1–9.

• 2. Pereira L, Rijo R, Silva C, Martinho R. Text mining applied to electronic medical records: A literature review. Int J E-Health Med Commun. 2015 Jul 1;6(3):1–18.

• 3. van der Linden C, Jansen P, van Geerenstein E, van Marum R, Grouls R, Egberts T. Reasons for discontinuation of medication during hospitalization and documentation thereof: a descriptive study of 400 geriatric and internal medicine patients. Arch Intern Med. 2010;170(12):1085–7.

• 4. Van Der Linden CMJ, Jansen PAF, Van Marum RJ, Grouls RJE, Korsten EHM, Egberts ACG. Recurrence of adverse drug reactions following inappropriate re-prescription: Better documentation, availability of information and monitoring are needed. Drug Saf. 2010;33(7):535–8.

2.23 P024 Are Monitored Dosage Systems Causing Drug Related Problems? A Retrospective Analysis of Hospital Admissions

2.23.1 L. Stewart ^1,2, P. Crawford², M. Mushipe², Z. Jalal¹, A. R. Cox¹

2.23.1.1 ¹University of Birmingham, School of Pharmacy-College of Medical and Dental Sciences, Belfast, United Kingdom; ²Belfast Health and Social Care Trust, n/a, Belfast, United Kingdom

Introduction: Monitored Dosage Systems (MDS) are used by millions of patients in the UK. Also know as multicompartment compliance aids, they are devices that allow for medicines to be dispensed into compartments which are separated by days of the week and times of the day. Published research has highlighted that between 5 and 15% (1) of hospital admissions are due to Drug Related Problems (DRPs). Studies which highlight the risks of MDS and DRPs appear to be limited (2), whereas research into MDS as the cause for hospital admission are scarce.

Objective: To analyse hospital admissions due to DRPs and association with MDS.

Methods: A retrospective analysis was conducted on four hundred and eighty-seven adult patients' hospital admission episodes. The retrospective analysis took place at the Royal Victoria Hospital, a large general teaching hospital in the Belfast Health and Social Care Trust (BHSCT), over a four month period from July 1st to October 31st, 2021. Each episode was analysed for DRPs and MDS causation using the Pharmaceutical Care Network Europe (PCNE)-DRP classification validation V 9.1 system (3) and the Anatomical Therapeutic Chemical code classification system (4).

Results: Of the four hundred and eighty-seven admissions included, 155 patients (32%) were using MDS, 43 admissions (9%) related to DRPs, out of these 43 admissions with DRPs; 26 patients (60.5%) were using MDS with DRPs, and three patients (7%) had an MDS related DRP. Medications most frequently implicated were antidepressants, ACE inhibitors, analgesics, and antipsychotics.

Conclusion: From this study, MDS have been identified as a cause of hospital admissions due to DRPs. The study highlights that inline with published evidence (5), the cohort of patients more at risk of DRPs are the older population. Older patients frequently use MDS and are already at risk of DRPs as they frequently have multi-morbidities and polypharmacy (6). This study has highlighted that ongoing measures should be considered to reduce DRPs such as deprescribing and regular medication reviews. It also highlights the importance of engaging with patients and carers to increase medication education and awareness.

References/Further Sources of Information

• 1. Beijer HJM, de Blaey CJ. Hospitalisations caused by adverse drug reactions (ADR): a meta-analysis of observational studies. Pharmacy World and Science. 2002;24(2):46–54.

• 2. Oswald K. Pill organisers could put older patients at risk of adverse events. The Pharmaceutical Journal. 2016;297(7891).

• 3. Pharmaceutical Care Network Europe (PCNE) Classification for Drug-Related Problems 2020.

• 4. WHO Collaborating Centre for Drug Statistics Methodology.https://www.whocc.no/.

• 5. Salvi F, Marchetti A, D’Angelo F, Boemi M, Lattanzio F, Cherubini A. Adverse Drug Events as a Cause of Hospitalization in Older Adults. Drug safety. 2013;35(Suppl 1):29–45.

• 6. Zia A, Kamaruzzaman SB, Tan MP. Polypharmacy and falls in older people: Balancing evidence-based medicine against falls risk. Postgrad Med. 2015;127(3):330–7.

2.24 P027 Clinical Pharmacist Interventions in Critically Ill Patients with COVID-19

2.24.1 A. Hida ^1,2, M. Faroudy^1,3, M. A. E. Cadi^1,2, A. Chaibi^1,2

2.24.1.1 ¹Faculty of Medicine and Pharmacy of Rabat, Mohamed V Souissi University, Rabat, Morocco; ²Pharmacy Department, Ibn Sina University Hospital, Rabat, Morocco; ³Intensive Care Unit of Emergency Trauma Department, Ibn Sina University Hospital, Rabat, Morocco

Introduction: Amid the recent outbreak, the quality of medical care provided to COVID-19 (Coronavirus Disease 2019) patients has been deeply impacted as a result of organizational limitations and insufficient medical resources. This complex situation was amplified by additional factors that include the widespread use of experimental drugs, the lack of detailed guidelines and recommendations, and workload increase. Consequently, COVID-19 patients became more vulnerable to medication errors and adverse drug events, especially in the intensive care units (ICUs) [1,2].

Objective: To describe the pharmaceutical interventions (PIs) carried out by a clinical pharmacist and to evaluate their clinical impact.

Methods: A prospective observational study was performed in a 16-bed, university-affiliated, COVID-19 ICU in Morocco. Drugs were classified according to the Anatomical Therapeutic Chemical (ATC) classification code system. PIs were registered by the pharmacist using the French Society of Clinical Pharmacy's PI sheet, and their clinical impact was assessed using Hatoum scale (0-to-3). Data of a two-month period, from October 2020 to December 2020, were analyzed using Excel.

Results: 201 PIs were generated by the clinical pharmacist and concerned 58 COVID-19 patients with respiratory failure. A median age of 64.5 years [IQR 58.25–69.75] was found and 83% of patients were male. The main drug-related problems were dosage error (37%), non-conformity to guidelines (24%), drug omission (18%), and drug interactions (7%). 58% of the interventions were performed after the medical prescription and consisted mainly of dosage adjustment (47%), followed by drug discontinuation (16%) and treatment reminder (13%). Drugs that belong to J, B, and P ATC groups accounted for 32%, 16% and 15% of PIs, respectively. Study results show an acceptance rate of 89%. 88% of the PIs had a clinical impact of 1 and 12% had a clinical impact of 2.

Conclusion: The active role of clinical pharmacists in the ICU is well established in the literature. Our study underlines the necessity of clinical pharmacy services in the COVID-19 ICU, which helps in preventing drug errors and providing optimal care to this sensitive population.

References/Further Sources of Information

• 1. Yusefi AR, Sharifi M, Nasabi NS, Rezabeigi Davarani E, Bastani P, Cheung JC. Health human resources challenges during COVID-19 pandemic; evidence of a qualitative study in a developing country. PLOS ONE 2022; 1: e0262887

• 2. Wang R, Kong L, Xu Q, Yang P, Wang X. On-ward participation of clinical pharmacists in a Chinese intensive care unit for patients with COVID-19: A retrospective, observational study. Research in Social and Administrative Pharmacy 2021; 1: 1853–1858

2.25 P028 A Survey of Medication Errors Reported Due to Look-Alike Antiretroviral Therapy Amongst Adult Clients at Mbagathi Hospital in Nairobi, Kenya

2.25.1 C. Wambura ¹

2.25.1.1 ¹Mbagathi Hospital, Comprehensive Care Centre, Nairobi, Kenya

Introduction: Antiretroviral Therapy is recommended for all persons living with HIV to reduce morbidity and mortality and to prevent the transmission of the virus to others. Medications are offered by health services throughout the world, but their use comes with a substantial growing risk of harm [1]. This includes Medication Errors which is any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the healthcare professional, patient, or consumer [2]. They are among the most common medical errors, harming at least 1.5 million people every year. The extra medical costs of treating drug-related injuries occurring in hospitals alone is at least $3.5 billion a year in addition to lost wages, loss in productivity and additional health care costs [3].

Objective: To establish the number of medication errors reported due to look-alike Antiretroviral Therapy amongst adult clients over a 12month period at Mbagathi Hospital Comprehensive Care Center Pharmacy.

Methods: A survey was carried out over a 12month period between January 2021 and January 2022 to establish the number of medication errors reported due to look-alike Antiretroviral Therapy amongst Adult clients. The results of the study were captured in the medication error reporting forms at the Comprehensive Care Center Pharmacy and in a table indicating the error.

Results: Over the 12month period, 2 medication errors were reported due to look-alike Antiretroviral Therapy. The medication errors reported occurred after two adult clients were dispensed with the wrong medication due to look-alike medications that were stored next to each other on the dispensing shelf. The medications were Abacavir/Lamivudine (120/60 mg) instead of Tenofovir/Emtricitabine (300/200 mg) and Abacavir/Lamivudine (600/300 mg) instead of Zidovudine/Lamivudine (300/150 mg) respectively.

Conclusion: Medication errors were found to have occurred over the 12month survey period. The study was able to confirm that medication errors can occur when staff lack proper training on how to store and dispense look-alike medications. It is therefore important to continuously train staff on appropriate storage and dispensing practices to avoid these medication errors and to have standard operating procedures on how to store and dispense look-alike medications. After the medication error incident we proceeded to rearranged all the look-alike medications ensuring that they were not stored in close proximity to each other and we also printed bold labels for all the medications on the shelves.

References/Further Sources of Information

• 1. Duerden M, Avery T, Payne R. Polypharmacy and medicines optimisation. Making it safe and sound. London: The King’s Fund. 2013 Nov.

• 2. https://www.nccmerp.org/about-medication-errors. About Medication Errors. Accessed on 09.05.2022

• 3. http://elibrary.pcu.edu.ph:9000/digi/NA02/2007/11623.pdf. Preventing Medication Errors: Quality chasm series. The National Academies Press; 2007: 124&132. Accessed on 09.05.2002

2.26 P029 Acute Liver Failure Following Therapeutic Doses of Paracetamol in Patients with Neuromuscular Diseases: A Preventable Medication Error

2.26.1 H. James ¹, G. Kwatra¹

2.26.1.1 ¹Christian Medical College & Hospital, Pharmacology, Ludhiana, India

Introduction: Neuromuscular diseases (NMDs) involve injury or dysfunction of peripheral nerves or muscles, with pain being a significant problem [1]. Paracetamol is used in patients with NMDs. The maximum recommended daily dose is 4 g or 60 mg/kg. In any 24-hour period: toxicity is very unlikely with daily doses consistently less than 75 mg/kg; toxicity rarely occurs with 75-150 mg/kg; and there is risk of serious toxicity with more than 150 mg/kg. Ingestion of a licensed dose is not considered an overdose [2]. However, this may not be true in some patients of NMDs with their different pharmacogenetics and phenotypes [3].

Objective: To collate evidence that in patients with NMDs, therapeutic dose of paracetamol might be an overdose leading to toxicity.

Methods: We performed a literature search on PubMed and EMBASE, from inception till May 2022, to identify cases of NMDs where paracetamol was associated with liver injury. Exclusion criteria were overdose, risk factors, and liver disease. Case reports were critically appraised [4]. Association was assessed using Bradford Hill criteria [5]. Case definition, severity grading and causality assessment were done using the RUCAM scale and criteria set by the Council for International Organizations of Medical Sciences [6].

Results: Eight case reports qualified: 6 males, 2 females; 6 had muscular dystrophies, 2 spinal muscular atrophies; median (Q₁–Q₃) age 18.5 years (13–29); weight 47.5 kg (43–55). Paracetamol consumption was 3 g/day (2.1–3.5), or 50 mg/kg/day (42.9–72.5) for 4 days (4–5.8). Time to onset of clinical manifestations and abnormal liver function tests (LFT) was 4.5 days (4–5.8). LFT values, compared to upper limits or baseline, were: AST 161.7 times (66.6–243.5), ALT 49 times (30.3–167), total bilirubin 5 times (1.9–8) and INR 4.5 times (3.6–6). Paracetamol serum level was 273.3 µmol/L (140.6–505.2). After stopping paracetamol 6 patients recovered (5 with N-acetylcysteine (NAC), 1 without). Two patients died, both had been treated with NAC. Liver injury in all cases was severe and direct (intrinsic). Association was causal and probable. Though we cannot exclude a possible role of concomitant drugs, the causality between paracetamol and liver injury appears probable.

Conclusion: Patients with NMDs are at increased risk of toxic serum levels and severe liver injury following therapeutic doses of paracetamol. Vigilance and personalised medicine based on pharmacogenomics can prevent this medication error. Therapeutic recommendations need to be revised.

References/Further Sources of Information

• 1. Morrison B. Neuromuscular Diseases. Semin Neurol. 2016 Sep 23;36(05):409–18.

• 2. Joint Formulary Committee. Paracetamol. In: BNF 82: September 2021–March 2022. London: BMJ Group and Pharmaceutical Press; 2021. p. 1432–4.

• 3. Lao YE, Molden E, Kringen MK, Annexstad EJ, Sæverud HA, Jacobsen D, et al. Fatal liver failure after therapeutic doses of paracetamol in a patient with Duchenne muscular dystrophy and atypical pharmacogenetic profile of drug‐metabolizing enzymes. Basic Clin Pharmacol Toxicol. 2020 Jul;127(1):47–51.

• 4. Munn Z, Barker TH, Moola S, Tufanaru C, Stern C, McArthur A, et al. Methodological quality of case series studies: an introduction to the JBI critical appraisal tool. JBI Evid Synth. 2020 Oct;18(10):2127–33.

• 5. Hill AB. The Environment and Disease: Association or Causation? Proc R Soc Med. 1965 May;58(5):295–300.

• 6. Council for International Organizations of Medical Sciences. Drug-induced liver injury (DILI): current status and future directions for drug development and the post-market setting. Switzerland; 2020.

2.27 P030 Children Voluntary Intoxications: Cases of Attempted Suicide

2.27.1 S. Mousannif ¹, A. Meftah², A. Cheikh³, L. K. Pediatrician⁴, M. Bouatia¹

2.27.1.1 ¹Mohammed V University-Faculty of Medicine and Pharmacy of Rabat, Pharmacy Department-Pediatric Hospital Rabat, Rabat, Morocco; ²Pediatric Hospital Rabat, Pharmacy Department, Rabat, Morocco; ³Cheikh Zaid Hospital, Pharmacy Department, Rabat, Morocco; ⁴Pediatric Hospital Rabat, Emergency departement, Rabat, Morocco

Introduction: Intoxications by ingestion is the second most common domestic accident in children after traumas. They constitute a serious problem in pediatrics, because of their frequency and difficulties of management.

Objective: The aim of our study is to determine the incidence of voluntary intoxications in children, as well as the different toxic agents involved and the morbidity and mortality related to these intoxications.

Methods: This is a descriptive cross-sectional study of voluntary intoxications (suicide attempts) admitted to the emergency department and managed at the Rabat Children's Hospital over a period of 5 months, from November 1, 2020 to April 1, 2021.

An operating sheet have been established and filled using the epidemiological data and the elements of management of these types of intoxications based on the diagnostic, therapeutic and prognostic levels, contained in the patient’s files.

Results: During the study period, 79 children were admitted to the emergency department for ingestion of toxic products, 18.9% of recorded intoxications were voluntary (suicide attempts), while 81.1% were accidental.

A female predominance was noted with a percentage of 80% while 20% were male.

All patients belonged to the age group between 12 and 16 years.

73.3% of the children had no medical history, however, 26.7% had a depression.

Concerning the period between the accident and the admission, 40% came to the service within 2 hours, 20% came between 3 to 4 hours, 20% arrived over 18 hours while 20% of the cases the period was unknown.

The use of drugs was reported in 73.3% of the suicide attempts, pesticides represent 6.6% and finally 20% of the attempts whose cause was unknown.

The distribution according to the nature of the toxic agent used in the suicide attempt is as follows 13.3% concerned both anxiolytic drugs and oral antidiabetics with the same percentage, 6.6% by the following toxic agents: antidepressants, anti-inflammatories, antidiarrheals, anti-anemics, orexigenic drugs, hallucinogenic drugs and organophosphate pesticides and finally the nature of the toxic agent was unknown in 26.6% of cases.

In 13.3% of the cases the evolution was favorable, while the attempted suicides caused 13.3% of death with principally oral antidiabetic. 73.3% of patients files were not followed up in our study.

Conclusion: Pediatric toxicology is a particular entity because of the frequently accidental intoxication character and which can become voluntary in children between 12 and 15 years old by using commonly used drugs and other toxic agents. The best measure will be prevention, which has proved to be effective on a large level.

References/Further Sources of Information

• 1. Bourrillon A. Intoxications accidentelles par les médicaments et les produits domestiques. In: Pédiatrie pour le praticien3e édition, Paris: Masson; 2000. p. 618.

• 2. Rkain S. El Kettani, N. Rhalem, BSD. Benjelloun. Profil épidémiologique des incidents et intoxications aiguës accidentelles chez l’enfant, Espérance Médicale • Septembre 2011 • Tome 18 • N° 181.

2.28 P031 Is Preventability a Good Criterion for Medication Errors? A Proposal to Assess Continuous versus Binary Faultiness, Seriousness, Contribution to ADRs

2.28.1 J. Beckmann ¹

2.28.1.1 ¹Former Head of the PV Division of the German Drug Regulatory Authority BfArM, Pharmacovigilance, Berlin, Germany

Introduction: Medication Errors (MEs) have been assessed by the criterion of whether they caused adverse drug reactions (ADR) which could have been prevented [1-5]. Typically, several questions are asked like “interaction involved?” and in case of any “yes”, the ADR is considered preventable, and an ME identified. There are problems with this approach. ADRs are assessed when many parameters of the preceding medication are known. In retrospect, it is always possible to conclude that the ADR could have been prevented had certain actions been different. Also, questions about “preventability” are used with a binary meaning, i.e., a “yes-” or “no-” answer is expected instead of a sensibly graded assessment.

Objective: To explore how the ME-criterion preventability could be replaced by a more appropriate criterion and which additional aspects of MEs should be assessed.

Methods: Literature review and proposal of a new approach with relevant examples of ADR cases.

Results: “Faulty” regarding the medication was considered as alternative to “preventable” with respect to an ADR, since it moves the assessor to the time of medication before the ADR occurred. Also, “faultiness” can be graded. Some more suggestions were made: First, to distinguish errors in deciding about a medication from errors in implementing the decision. Second, to distinguish between extent and seriousness of an ME: Aspects of ME-seriousness are how severe an ADR following the ME was, how much more severe or likely—compared to the typical severity or expected frequency—the ADR became, how far the medication deviated from established standards and which options were available to anticipate and minimise the risk. Third, to classify MEs according to whether their faultiness is continuous or binary. Fourth, if an ME preceded an ADR, to ask if—and to what extent—the ME caused or contributed to the ADR. A scheme to classify MEs and cases are presented.

Conclusion: In assessing possible MEs as causes of ADRs it is recommended a) to replace the binary hindsight-criterion “preventable” for ADRs by the term “faulty” for medications, b) to distinguish errors in deciding about a medication from errors in implementing the decision, c) to distinguish between the extent of a deviation from standard and the seriousness of the error, d) to distinguish between MEs by type of faultiness which is either binary or continuous, e) to grade the latter on a scale, and f) to assess the extent to which an ME actually caused the ADR.

References/Further Sources of Information

• 1. Schumock GT, Thornton JP. Focusing on the preventability of adverse drug reactions. Hosp Pharm. 1992; 27(6): 538

• 2. Olivier P, Boulbés O, Tubery M, Lauque D, Montastruc J-L, Lapeyre-Mestre M. Assessing the Feasibility of Using an Adverse Drug Reaction Preventability Scale in Clinical Practice A Study in a French Emergency Department. Drug Saf 2002; 25(14): 1035–1044

• 3. Ferner RE, Aronson JK. Preventability of Drug-Related Harms—Part I A Systematic Review. Drug Saf 2010; 33(11): 985–994

• 4. European Medicines Agency. Good practice guide medication error recording coding reporting assessment (europa.eu). (accessed May 2022)

• 5. National Coordination Council for Medical Error Reporting and Prevention (US NCCMERP). About Medication Errors | NCC MERP (accessed May 2022)

2.29 P032 COVID-19 Vaccination Errors During Tunisian Vaccination Campaign Collected from March 13, 2021 to September 29, 2021

2.29.1 W. Kaabi¹, A. Zaiem¹, G. Lakhoua¹, I. Aouinti¹, R. Daghfous¹, S. E. Aidli ¹

2.29.1.1 ¹University of Tunis El Manar Faculty of Medecine of Tunis -UR17ES12, National Centre of Pharmacovigilance of Tunisia, Tunis, Tunisia

Introduction: Since March 13, 2021, Tunisia has started its vaccination campaign. In addition, the Ministry of Health has organized national mass vaccination days to accelerate the vaccination process. The National Centre of Pharmacovigilance, in collaboration with the Primary Health Care Direction, is charged with monitoring and managing adverse events following immunization (AEFI) that included vaccination errors.

Objective: Our work aims to describe the type and the frequency of these errors in order to prevent their occurrence.

Methods: We conducted an observational study from the onset of the vaccination campaign on March 13, 2021, to September 29, 2021. We collected vaccine errors through the different notification sources used by the National Centre of Pharmacovigilance in Tunisia. We have listed vaccine errors through Vigibase national reports. We categorized the error reports on the basis of the vaccine error type described by the Centres for Disease Control and Prevention (CDC).

Results: During this period, a total of 8.031297 doses were administered. We counted 153 COVID-19 vaccine errors out of 2609 AEFI (5.86%). Reports were related to wrong doses in 70% (Table 1).

Conclusion: Most vaccination misuses are related to technical errors. The enhanced pharmacovigilance reporting system is important for detecting and managing these errors to prevent recurrence during further vaccination campaigns [1]. Moreover, health care providers involved in the COVID-19 vaccine supply chain should anticipate and report COVID-19 vaccine-related errors to promote shared learning opportunities and make every dose of vaccine count.

References/Further Sources of Information

• 1. Hampton LM. Vaccine handling and administration errors should be addressed to improve vaccine program safety. Vaccine. 2020 Jul 6;38(32):4933–4934.

2.30 P034 Pre-Registration Evaluation of Proposed Invented Names for Human Medicinal Products: Saudi Food and Drug Authority Experience

2.30.1 G. Banasser¹, A. A. Draihm ¹, A. A. Zahrani¹, M. Alanzi¹

2.30.1.1 ¹Saudi Food and Drug Authority, Medication Errors Department, Riyadh, Saudi Arabia

Introduction: Several medication error incidents are attributed to name-related issues.¹ Targeting this concern at an early stage through name appropriateness evaluation by regulatory authority as part of the registration process with the intention to prevent medication errors is one of the core duties of Medication Errors Department at the Saudi Food and Drug Authority.²

Objective: To identify common safety concerns associated with proposed invented names rejection.

Methods: A retrospective observational study of the proposed invented names submitted to the Saudi Food and Drug Authority from January to December 2021 was performed. All received requests are entered into a Microsoft excel spreadsheet and classified accordingly: new request, variation request, and objection request. For the purpose of this study only new requests are being evaluated for proposed invented names’ appropriateness.

Results: Submitted new requests throughout the study period counted for 739, while unique proposed invented names for evaluation made up 57% (n = 421 of 739) due to duplication in proposed intended names submission for medications available with various strengths and/or dosage forms. Among the proposed invented names, almost one-third (28.7%, n = 121) were rejected due to several reasons. Further analysis of the rejected proposed invented names revealed that name similarity is the most common reason (47.7% %, n = 73). Other rejection reasons included incorporation of International Nonproprietary Names (INN) stem in proposed names (15.7%, n = 24), followed by use of promotional and/or misleading names (9.8%, n = 15), inappropriate use of qualifiers, inappropriate use of company name, inclusion of dosage form, frequency, or strength, use of abbreviations, name discrepancies across submitted files, indication derived names, as well as use of ambiguous numbers as part of the proposed names.

Conclusion: Pre-registration evaluation of proposed invented names is an essential process to prevent medication errors. Identifying the most common reasons for invented names rejection can be utilized by pharmaceutical companies to enhance the submission process efficiency. Pharmaceutical companies and regulatory authorities should join forces to promote medication safety and prevent medication errors.

References/Further Sources of Information

• 1. Lambert BL, Lin SJ, Tan H. Designing safe drug names. Drug Saf. 2005;28(6):495–512.

• 2. Saudi Food and Drug Authority. Guidance for Naming of Medicinal Products. Available from: https://www.sfda.gov.sa/sites/default/files/2021-04/Guidance%20for%20Naming%20of%20Medicinal%20Products%20V2.1_0.pdf [last accessed May 25, 2022]

2.31 P035 Overview of Paediatric Opioid Overdose Cases in France

2.31.1 L. Diaz¹, D. H. Hanawy ², L. Girod¹, M. A. Taam¹

2.31.1.1 ¹Agence Nationale de Sécurité du Médicament et des Produits de Santé, Pain control-aneastheticsrheumatology-addiction drugs, Saint-Denis, France; ²Agence Nationale de Sécurité du Médicament et des Produits de Santé, Pain control-aneasthetics rheumatology-addiction drugs, Saint Denis, France

Introduction: The use of opioids has increased in the general population by 150% from 2006 to 2017 in France. At the same time, an increasing number of intoxications and deaths related to opioid use have been documented [1]. In addition, cases of fatal paediatric accidental intoxication have recently been reported to the National Agency for the safety of Health Products (ANSM) [2].

Objective: In this study, we will analyse pharmacovigilance cases of opioid overdose in children.

Methods: A search for French cases of overdose in children aged 0-15 years with opioid drugs, of all galenic forms, was carried out on the European pharmacovigilance database "Eudravigilance", from 2001 to April 2022. The substances selected were: morphine, tramadol, fentanyl, methadone, codeine, oxycodone, loperamide, buprenorphine and hydromorphone. The preferred terms associated with the adverse drug reactions (ADRs) identified with the MedDRA 25.0 dictionary were: “accidental overdose”, “extra dose administered”, “incorrect dosage administered” and “incorrect dose administered”.

Results: Over the 17-year period, 63 cases of paediatric overdose were collected. The average age of the children was 4 years (median: 3 years, range: 1; 15 years). 91% (n = 57) of the cases were medically confirmed and 65% are related to oral administration (60% capsules/tablets and 5% syrup).

97% (n = 61) of the cases were serious including 6% (n = 4) death, 38% (n = 24) life-threatening, 30% (n = 19) hospitalisation and 20% (n = 12) unspecified criteria.

Of the 63 cases 129 ADRs were reported with mainly neurological (32%, n = 41), respiratory (26%, n = 33), and gastrointestinal (12%, n = 15) ones.

In 46% of cases (n = 28), it was a medication error. Naloxone was administered in 57% of cases and the outcome, when indicated (n = 21), was favourable in 100% of cases.

Of the 63 cases, 22% (n = 14) were due to accidental exposure at home, of which 29% (n = 4) resulted in death. Naloxone was administered in only 29% (n = 4) with favourable outcome.

Conclusion: This analysis confirms the seriousness of opioid overdose in the paediatric population. ANSM raised awareness to the general public and the healthcare professionals about the rules of proper use, the need of the availability of the emergency therapy for opioid overdose, naloxone [3, 4] and moreover the absolute need to keep the treatment out of the reach and sight of children following the two recent cases of death while taking methadone [2].

References/Further Sources of Information

• 1. Antalgiques opioïdes : l’ANSM publie un état des lieux de la consommation en France. 2020. https://ansm.sante.fr/actualites/antalgiques-opioides-lansm-publie-un-etat-des-lieux-de-la-consommation-en-france.

• 2. Décès d’enfants suite à l’ingestion accidentelle de méthadone—Rappels des règles de bon usage. 2021. https://ansm.sante.fr/actualites/deces-denfants-suite-a-lingestion-accidentelle-de-methadone-rappel-des-regles-de-bon-usage.

• 3. Bon usage des médicaments opioïdes : antalgie, prévention et prise en charge du trouble de l’usage et des surdose. 2022.https://www.has-sante.fr/jcms/p_3215131/fr/bon-usage-des-medicaments-opioides-antalgie-prevention-et-prise-en-charge-du-trouble-de-l-usage-et-des-surdoses.

• 4. Surdosage-et-overdose-dopioides-point-sur-loffre-therapeutique-de-la-naloxone-en-france https://ansm.sante.fr/actualites/surdosage-et-overdose-dopioides-point-sur-loffre-therapeutique-de-la-naloxone-en-france.

2.32 P036 Types and Frequency of Errors in the Preparation and Administration of Drugs in Pediatric Inpatient

2.32.1 S. Mousannif ¹, A. Meftah², M. Bouatia¹

2.32.1.1 ¹Mohammed V University-Faculty of Medicine and Pharmacy of Rabat, Pharmacy Department-Pediatric Hospital Rabat, Rabat, Morocco; ²Pediatric Hospital Rabat, Pharmacy Department, Rabat, Morocco

Introduction: Medication errors are defined as any avoidable happening that may result in improper use of medications or hazards for the patient for which the responsible person may be the health care professional, patient or consumer.

They can happen during different stages of the drug delivery process, which have been classified as prescribing, transcribing, dispensing and administrating.

Objective: The aim of this study was to identify compatibility, types and frequency of errors in preparation and administration of drugs at 5 departments of children hospital of rabat Morocco.

Methods: This study was designed as prospective cross-sectional evaluations, extended over a period of 2 months from March 12, 2022 to May 12, 2022.

It was performed at five departments of children hospital of rabat in Morocco: Neonatal intensive care, General intensive care, Hemato-oncology, Respiratory and Infectious Diseases, endocrinology and metabolic diseases departments.

The sample consisted of 45 observations of the preparation and administration of 27 drugs by external pharmacists.

The following variables were collected: reconstitution and dilution errors, presence of physico-chemical incompatibility, administration errors and the conservation and stability anomalies.

Results: In this study 45 observations of 27 drugs were evaluated in the preparation and administration stages. 81.5% of drugs were injectable, 14.8% belonged to the oral route and 3.7% for respiratory route.

The most frequent drugs administrated were: ceftazidime 18.5%,14.8% each for ceftriaxone and aciclovir and 11% each for vancomycin and metronidazole.

We observed 56 errors in the preparation and administration of drugs, 50% were associated to administration errors, 34% related to reconstitution and dilution errors and 16% had storage anomalies.

According to the Anatomical Therapeutic Chemical Classification System ATCCS, the class J (Anti-infective for systemic use) was the most common class involved in errors (50%).

In the preparation stage 42.3% of errors were using inappropriate diluents for solving while 57.7% were compliant.

During the administration of medications, the following errors were identified:24.4% each for incorrect time of administration and physico-chemical incompatibility between the medications, 8.8% wrong route of administration, 4.4% underdosing drugs. 37.7% of administrations were compliant.

Conclusion: In the pediatric field, the administration of drugs involves a great responsibility, as it directly affects the safety and health of the assisted children.

Involvement of a clinical pharmacist can be a solution to reduce the rate of errors by training the health care professionals and establishing a system of reporting medication errors to encourage documenting the information.

Acknowledgment: The authors would like to thank all pharmacists assigned to each department for their contribution to this study.

References/Further Sources of Information

• 1. Ross LM, Wallace J and Paton JY. Medication errors in a pediatric teaching hospital in the UK: five years operational experience. Arch. Dis. Child. (2000) 83: 492–7.

• 2. Allard J, Carthey J, Cope J, Pitt M and Woodward S. Medication errors: causes, prevention and reduction. Br. J. Haematol. (2002) 116: 255–65

2.33 P038 Need of Drugs and Supplements Recognition in Oncological Patients: Role of the Clinical Pharmacologist

2.33.1 V. Conti¹, B. Stefanelli ¹, E. D. Bellis¹, C. Sellitto¹, N. Bertini¹, V. Manzo¹, D. D. Pascale¹, F. Sabbatino², S. Pepe², G. Corbi³, A. Filippelli¹

2.33.1.1 ¹Clinical Pharmacology Unit-University Hospital of Salerno-Italy., n/a, Salerno, Italy; ²Oncology Unit-University Hospital of Salerno-Italy, n/a, Salerno, Italy; ³Federico II University of Naples, Department of Translational Medical Sciences, Naples, Italy

Introduction: Fluoropyrimidines (FP), including 5-FU and capecitabine, are antimetabolites commonly used to treat solid tumours. Several toxicities limit FPs treatments, including myelosuppression, Hand-Foot Syndrome (HFS) and diarrhoea. Drug-drug and supplement-drug interactions can cause or worsen FP-related toxicity but they are often overlooked.

Objective: To perform a systematic recognition of drugs and other compounds used in patients receiving FP-based therapy to identify potential adverse events associated to drug-drug and supplement-drug interactions.

Methods: Pharmacological anamnesis was recorded in 43 patients receiving FP-based therapy. This recognition was performed besides pharmacogenetic testing, routinely performed to identify congenital dihydropyrimidine dehydrogenase (DPD) deficit associated to severe FP-related toxicity. All drugs and supplements were recorded and several drug-interaction checkers were consulted (Drugs.com, Drugbank, Medscape, WEBMD and Lexicomp. Last access 23 05th, 2022).

Results: A careful recognition of oncological and non-oncological drugs and supplements was carried out by analyzing the records related to 43 patients submitted to clinical monitoring for at least 4 cycles of therapy. Of them, 35 were treated with 5-FU (4 were carriers of DPYD polymorphisms) and 8 with capecitabine. Patients carrying DPYD polymorphisms associated with DPD deficit were excluded from the analysis. Two out of 7 patients received a dosage of capecitabine of more than 2000 mg/m2 per day, which represents the maximum tolerated dose in case of a concomitant folate-based supplementation. Both patients experienced severe HFS and diarrhoea. In one case, capecitabine dosage reduction was executed and statin/ezetimibe treatment was discontinued, while the folate supplementation was not suspended. In the other case, capecitabine and folate supplements were stopped and capecitabine was restarted after a month. Following these changes, severe toxicities were resolved. All the consulted drug interaction checkers could have foreseen the risk of worsening toxicity of capecitabine associated with capecitabine/folates co-administration.

Conclusion: To identify all factors involved in drug toxicity, a pharmacological analysis should be performed, without overlooking drug-supplement interactions. A systematic recognition of drugs and supplements used by oncological patients allows verifying prescription appropriateness and avoiding adverse events, including life-threatening ones. The role of the Clinical Pharmacologist in this field is crucial.

References/Further Sources of Information

• 1. Miranda, V., Fede, A., Nobuo, M., Ayres, V., Giglio, A., Miranda, M., et al. Adverse drug reactions and drug interactions as causes of hospital admission in oncology. J Pain Symptom Manage. 2011;42(3):342–353. https://doi.org/10.1016/j.jpainsymman.2010.11.014.

• 2. Chan, S.L., Chan, A.W.H., Mo, F., Ma, B.B.Y., Wong, K.C.W., Lam, D., et al. Association Between Serum Folate Level and Toxicity of Capecitabine During Treatment for Colorectal Cancer. Oncologist. 2018;23(12):1436–1445. https://doi.org/10.1634/theoncologist.2017-0637.

• 3. Yap, Y.-S., Kwok, L.-L., Syn, N., Chay, W.Y., Chia, J.W.K., Tham, C.K., et al. Predictors of Hand-Foot Syndrome and Pyridoxine for Prevention of Capecitabine-Induced Hand-Foot Syndrome: A Randomized Clinical Trial. JAMA Oncol. 2017;3(11):1538–1545. https://doi.org/10.1001/jamaoncol.2017.1269.

• 4. Fluoropyrimidines, folic acid, toxicity, worsen toxicity, Drug interaction checkers, Hand Foot Syndrome, diarrhea

2.34 P040 The Risk of Acute Kidney Injury in Bladder Cancer Patients Who Have Undergone Radical Cystectomy

2.34.1 X. Pan ¹, V. Kulkarni², Y. Zhang¹, S. Goldstein³

2.34.1.1 ¹Bristol-Myers Squibb, Department of Pharmacoepidemiology, Princeton, USA; ²Mu Sigma-Inc., WWPS Epidemiology Team, Bengaluru, India; ³Bristol-Myers Squibb, Medical Safety Assessment, Princeton, USA

Introduction: Radical cystectomy (RC) is the standard of care for certain stages of bladder cancer (BC) [1]. Acute kidney injury (AKI), a complication of RC, is associated with increased mortality, largely due to chronic kidney disease and disease recurrence [2, 3]. In one study, 38.2% of BC patients developed AKI after RC [4]. Furthermore, AKI may preclude patients from anti-cancer therapy, potentially accelerating the rate of recurrence [5].

Objective: In this retrospective cohort analysis, two large US-based claims databases were used to assess the risk of AKI in BC patients who underwent RC.

Methods: IBM MarketScan and IQVIA PharMetrics Plus claims data from January 1, 2015 to December 31, 2020 were used to examine the occurrence of AKI in BC patients who had undergone RC. ICD-9-CM and ICD-10-CM codes were used to identify diagnoses and procedures. Patients were included if they: (1) had BC; (2) had a RC after their BC diagnosis; (3) were at least 18 years of age, and (4) had continuous enrollment (medical and pharmacy claims) of 12 months before the index date. The index date was defined as the date of RC. AKI occurrence after RC was identified from all inpatient claim records. Panalgo’s Instant Health Data (IHD) healthcare analytics software was used to conduct the analysis.

Results: In the analysis using the PharMetrics Plus database, 1,988 patients were identified as being diagnosed with BC and who also underwent RC. Of those 1,988 patients, 950 were also diagnosed with AKI (351 of these patients received their AKI diagnosis before the index date, i.e., before their RC). AKI prevalence was 47.8% and the incidence rate was 45.5 per 100 person years.

In the analysis using the MarketScan database, 1,263 patients were identified as being diagnosed with BC and who also underwent RC. Of those 1,263 patients, 574 were also diagnosed with AKI (214 of these patients received their AKI diagnosis before the index date). AKI prevalence was 45.4% and the incidence rate was 46.4 per 100 person years.

Conclusion: In this retrospective study, both incidence and prevalence rates generated from the two databases were similar. The risk of AKI among BC patients after RC treatment was higher than in the previously published study [4]. Further analyses are needed to identify possible risk factors associated with AKI and its potential impact on treatment options.

References/Further Sources of Information

• 1. Medscape [Internet]. Radical Cystectomy. [updated July 23, 2020; cited April 29, 2022]; Available from: https://emedicine.medscape.com/article/448623-overview.

• 2. Kwon T, Jeong IG, Lee C, You D, Hong B, Hong JH, et al. Acute Kidney Injury After Radical Cystectomy for Bladder Cancer is Associated with Chronic Kidney Disease and Mortality. Ann Surg Oncol. 2016 Feb;23(2):686–93

• 3. Osman Y, Harraz AM, El-Halwagy S, Laymon M, Mosbah A, Abol-Enein H, et al. Acute Kidney Injury Following Radical Cystectomy and Urinary Diversion: Predictors and Associated Morbidity. Int Braz J Urol. 2018 Jul–Aug;44(4):726–733

• 4. Joung KW, Choi SS, Kong YG, Yu J, Lim J, Hwang JH, et al. Incidence and Risk Factors of Acute Kidney Injury after Radical Cystectomy: Importance of Preoperative Serum Uric Acid Level. Int J Med Sci. 2015 Jul;12(7):599–604

• 5. Birtle A, Johnson M, Chester J, Jones R, Dolling D, Bryan RT, et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomized, controlled trial. Lancet. 2020 Apr 18;395(10232):1268–77

2.35 P041 Safety Assessment of Biologics for Immune-Mediated Inflammatory Diseases Using Italian VALORE Healthcare Database Network and National Spontaneous Reporting System

2.35.1 R. Benoni ¹, Y. Ingrasciotta², C. Ferrajolo³, V. Ientile², E. S. Fiore¹, E. Arzenton¹, A. Cavazzana⁴, V. Biasi⁴, P. Rossi⁵, L. Ejlli⁵, V. Belleudi⁶, F. R. Poggi⁶, V. Solfrini⁷, A. Puccini⁷, G. Trifirò¹

2.35.1.1 ¹University of Verona, Department of Diagnostics and Public Health, Verona, Italy; ²University of Messina, Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Messina, Italy; ³Italian Medicines Agency, Italian Medicines Agency, Rome, Italy; ⁴Regione Veneto, Azienda Zero, Padua, Italy; ⁵Regione Friuli Venezia Giulia, Direzione Centrale Salute, Trieste, Italy; ⁶Lazio Regional Health Service, Department of Epidemiology, Rome, Italy; ⁷Emilia Romagna Health Department, Territorial Assistance Service-Drug and Medical Device Area, Bologna, Italy

Introduction: Pre-marketing randomized clinical trials (RCTs) are designed to show efficacy but have limitations regarding safety [1]. Post-marketing surveillance plays a key role in exploring biologics safety issues, especially for long-term treatments of chronic diseases like immune-mediated inflammatory diseases (IMIDs) [2,3]. Several data sources are available to investigate the biologics safety in the post-marketing setting, such as drug registries, spontaneous reporting system (SRS) or claims databases, including a larger and heterogeneous population than RCTs and integrating evidence from pre-marketing [4].

Objective: To assess the post-marketing safety profile of biological drugs approved in IMIDs using the Italian VALORE database network [5] and the national SRS database.

Methods: Suspected adverse drug reactions (ADRs) related to biologics approved in IMIDs from four Italian regions (Veneto, Lazio, Emilia-Romagna, Friuli-Venezia-Giulia) were retrieved from the SRS database between 2010–2020. Safety Outcomes of Interest (SOI) related to the same biologics and person-years (py) of exposure were identified from the VALORE database in the same period and regions. Suspected ADRs were analysed at High Level Term (HLT) of MedDRA^® and stratified by drug class [TNF-α-inhibitors, interleukin (IL) inhibitors, and selective immunosuppressants]. ADR Spontaneous Reporting Rates (SRR) and SOI incidence rate (IR) were estimated using the total number of suspected ADRs and SOI as numerator and the exposure to biologics as denominator (among 100,000py).

Results: A total of 2,675 ADRs reports were identified in the SRS database: 2,042 involved TNF-α-inhibitors (76%), 478 IL-inhibitors (18%) and 155 immunosuppressants (6%). Biologics users from the VALORE database were 74,046: 176,039py for TNF-α-inhibitors (72%), 35,666py for IL-inhibitors (20%), 13,039py for immunosuppressants (8%).

The ADRs associated with the highest SRRs belonged to Therapeutic and nontherapeutic responses HLT category in TNF-α-inhibitors, IL-inhibitors and immunosuppressants (195, 53, and 752/100,000py, respectively); followed by skin disorders, included Urticarias (87/100,000py), Erythema (73), Rashes, eruptions and exanthems (70) and Pruritus (65) for TNF-α-inhibitors; Lower respiratory tract and lung infections (20) for IL-inhibitors; and Neutropenia (207) for immunosuppressants.

As regards to SOI, the highest IRs in the three cohorts were: neoplasm (567, 723, and 972/100,000py), ischemic heart failure (524, 745, and 810/100,000py), and pneumonia (522, 742, and 807/100,000py).

Conclusion: Among ADR reports, the highest rates were related to treatment inefficacy and immune system disorders while among healthcare data, were neoplasm, ischemic heart disease and pneumonia. These results showed the need of pooling data from healthcare databases and active surveillance as a comprehensive approach to detect different potential safety signals related to biologics.

References/Further Sources of Information

• 1. Doran MF, Crowson CS, Pond GR, O'Fallon WM, Gabriel SE. Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis Rheum. 2002;46(9):2287–2293.

• 2. Cutroneo PM, Isgrò V, Russo A, et al. Safety profile of biological medicines as compared with non-biologicals: an analysis of the Italian spontaneous reporting system database. Drug Saf. 2014;37(11):961–970.

• 3. Giezen TJ, Mantel-Teeuwisse AK, Leufkens HG. Pharmacovigilance of biopharmaceuticals: challenges remain. Drug Saf. 2009;32(10):811–817.

• 4. Montilla S, Xoxi E, Russo P, Cicchetti A, Pani L. Monitoring registries at ITALIAN medicines agency: fostering access, guaranteeing sustainability. Int J Technol Assess Health Care. 2015;31(4):210–213.

• 5. Trifirò G, Isgrò V, Ingrasciotta Y, et al. Large-Scale Postmarketing Surveillance of Biological Drugs for Immune-Mediated Inflammatory Diseases Through an Italian Distributed Multi-Database Healthcare Network: The VALORE Project. BioDrugs. 2021;35(6):749–764.

2.36 P042 An Overview of the Pharmacovigilance System in Ghana

2.36.1 S. Onasanya ¹, P. Yamoah¹, F. Oosthuizen¹

2.36.1.1 ¹University of KwaZulu-Natal-Westville Campus, School of Health-Science-Department of Pharmacology, Durban, South Africa

Introduction: The goals of Pharmacovigilance (PV) includes early detection of adverse events (AE) and interactions with other drugs/food, detection of frequency of a known adverse effect, Identification of risk factors and mechanisms behind adverse events, continuous monitoring for risk-benefit ratio of investigational product (IP) and distribution of information about discovered AEs and interactions(1) Ghana joined the WHO PV program as the 65^th member in 2001 and as the first country in West-Africa. The use of pharmaceuticals preparations has become one of the fast growing components of global health care expenditure in Ghana (2).

Objective: To study the PV system in Ghana using World Health Organization (WHO) indicators

Methods: This study was directed towards the Ghana Food and Drugs Authority (FDA) which is the National Pharmacovigilance Coordination Center that also house the National Pharmacovigilance Centre in Ghana. A review of the government’s National Policy on Pharmacovigilance and Implementation Framework was carried out using the WHO core and complimentary indicators as the basis. The Indicator-based Assessment Tool (IPAT), developed by WHO was used to assess Ghana’s PV system

Results: Regulatory framework for PV activities was present in Ghana. Quality Control (QC) laboratory with a clear mandate and functioning, but the QC laboratory is yet to be prequalified by WHO. The budget for PV is available with a medicine safety advisory committee present and functioning. The system for co-ordination of PV data and adverse drugs reactions (ADR) reports collation is available but majorly online. Consumer reporting forms and suspected ADR reporting forms are available and being put to use but no product quality reporting form, medication error form and treatment failure form

Conclusion: Ghana FDA is mandated to regulate the development, manufacturing, importation and marketing of medicinal products in Ghana, with remarkable improvement since inception. The provision of national policy on PV and the recognition of Ghana FDA as WHO Global Benchmark Tool (GBT) performance maturity level 3 is a positive step in the right direction and with the continuous support from the government, the PV system in Ghana can only get better despite some shortcomings as identified by the WHO indicators

References/Further Sources of Information

• 1. CCRPS. (2021). Pharmacovigilance Online training Online. pp. 4–7

• 2. Nwokike, K., & Eghan, K. (2010). Pharmacovigilance in Ghana: A systems analysis: Strengthening pharmaceutical systems center for pharmaceutical management. Management Sciences for Health

2.37 P043 An Overview of the Pharmacovigilance System in Nigeria

2.37.1 S. Onasanya ¹, F. Oosthuizen¹, P. Yamoah¹

2.37.1.1 ¹University of KwaZulu-Natal-Westville Campus, School of Health-Science-Department of Pharmacology, Durban, South Africa

Introduction: The primary purpose of pharmaceutical regulation is to safeguard the public from unsafe medical products and the menace that may ensue from its administration. In many low and medium -income countries (LMIC), like Nigeria, Pharmacovigilance (PV) activities are fragmented, weak, and unable to protect the public adequately (1-3).

Objective: To study the PV system in Nigeria using World Health Organization (WHO) indicators

Methods: This study was directed towards the National Agency for Food, Drugs Administration and Control (NAFDAC), which is the National Pharmacovigilance Coordination Center in Nigeria. A review of the government’s National Policy on Pharmacovigilance and Implementation Framework was carried out using the WHO core and complimentary indicators as the basis. The Indicator-based Assessment Tool (IPAT), developed by WHO was used to assess Nigeria’s PV system.

Results: There is a presence of regulatory framework for PV in Nigeria. There is a Quality Control (QC) laboratory with a clear mandate, structure, and function, but the QC laboratory is not prequalified by WHO. The budget for PV is limited but a medicine safety advisory committee is present and functioning. There is a system for co-ordination and collation of PV data from all sources in the country, as well as a system for collation of adverse drugs reactions (ADR) reports. There is a presence of consumer reporting forms and suspected ADR reporting forms, but no product quality reporting form, medication error form and treatment failure form

Conclusion: The National Agency for Drugs Administration and control (NAFDAC) is mandated to regulate the development, manufacturing, importation and marketing of medicinal products and medical appliances in Nigeria, with considerable improvement since inception. The provision of national policy on PV is a positive step in the right direction and with the prompt and continuous support from the government, the PV system in Nigeria can only get better despite some weakness highlighted by the WHO indicators

References/Further Sources of Information

• 1. WHO (2015) WHO Pharmacological indicators. A Practical manual for the assessment of pharmacovigilance systems. pp. 9–15.

• 2. WHO (2015) The WHO essential Medicines and Health Products information Portals p 1.

• 3. World Bank datahttps://data.worldbank.org/indicator/SP.POP.TOTL?locations/ng. Accessed April 28th, 2021

2.38 P044 Adverse Drug Effects Related to Biotherapy Used in the Treatment of Chronic Inflammatory Rheumatism at El Ayachi-Sale Hospital, Morocco

2.38.1 R. Lakhmiri ¹, S. A. Samir^1,2, F. Allali³, R. Bahiri⁴, Y. Cherrah¹, S. Serragui¹

2.38.1.1 ¹Faculty of Medicine and Pharmacy Rabat-Morocco, Pharmaco-economics and pharmaco-epidemiology research team -Laboratory of Pharmacology and Toxicology, Rabat, Morocco; ²El Ayachi hospital. CHU Ibn Sina, Pharmacy Department, Rabat-Salé-Morocco., Morocco; ³El Ayachi hospital. CHU Ibn Sina, Department of Rheumatology B, Rabat-Salé-Morocco., Morocco; ⁴El Ayachi hospital. CHU Ibn Sina, Department of Rheumatology A, Rabat-Salé-Morocco., Morocco

Introduction: The biological treatment which is the most effective type of therapy for inflammatory rheumatic diseases, has become part of a standard clinical rheumatology practice in recent years. Thousands of patients with rheumatoid arthritis, different forms of spondyloarthritides and with psoriatic arthritis are now successfully treated in this way (1), however they may be associated with a new spectrum of adverse drug effects (ADEs).

Objective: identify the ADEs related to the use of biological drugs for inflammatory rheumatic diseases and also the impact of these ADEs on the treatment.

Methods: This was a prospective descriptive, monocentric study of patients suffering from chronic inflammatory rheumatism, receiving biotherapy treatment and collected in the rheumatology departments. The data collection included the socio-demographic characteristics, the pathological profile of the patients, the treatment of the biotherapy received and the study of the adverse effects that appeared during or after administration of the biotherapy.

Results: In total, 321 patients were identified between June 1 and August 31 2021, most of these received infliximab (27.4%), rituximab (17.4%), secukinumab (15.5%), golimumab (14.3%), adalimumab (12.4%), etanercept (7.1%), tocilizumab (3.4%). Of the 268 patients, 16 (4.3%) experienced one or more adverse effects related to biological agents. A total of 62.5% of the cases corresponded to women. Most of the adverse effects were classified as type B (58.2%) and A (18.7%), and 37.5% were serious cases. The most frequently reported ADEs were administration site reactions and skin effects (31.5%), nervous and gastro-intestinal system were also affected (25%), followed by cardiovascular disorders (12.5%). The drugs related to the significant number of ADEs were infliximab (37.5%) and rituximab (25%). Half of the patients who suffered from adverse effects switched to another biologic (50%), 43.75% of patients maintained the previous treatment, and 6.25% discontinued treatment.

Conclusion: The adverse effects observed in this study had no impact on the functional or vital prognosis of the patient. This type of study can support decision makers in ways that benefit patient safety and interaction with health systems (2).

References/Further Sources of Information

• 1. Adverse effects of biological therapy in rheumatology. Olejárová, Marta. 7–8, January 2016, Internal Medicine, Vol. 62, pp. 605–612.

• 2. Adverse drug reactions associated with the use of biological agents. Machado-Alba JE, Jime´nez-Morales AL, Moran-Yela YC, Parrado-Fajardo IY, ValladalesRestrepo LF. s.l.: PLOS ONE, 2020, Vol. 15(12). e0240276.

2.39 P045 Does Omalizumab Increase the Risk of Malignancy? A Retrospective Case-Control Study in a Single Tertiary Hospital

2.39.1 H. J. Kim ¹, H. H. Kim¹, H. W. Park², C. S. Heon², K. H. Ryun¹, L. S. Young¹

2.39.1.1 ¹Seoul National University Hospital, Drug Safety Center, Seoul, Korea Republic of; ²Seoul National University Hospital, Department of Internal Medicine, Seoul, Korea Republic of

Introduction: Omalizumab is a humanized anti-IgE monoclonal antibody indicated for the treatment of chronic idiopathic urticaria, IgE-mediated allergic asthma, and nasal polyps¹. Despite its overall safety, a disproportionate analysis (case/non-case study) within VigiBase indicated that omalizumab might be associated with a significantly higher risk of malignancies (3) from 1,380 reports of neoplasms associated with omalizumab.² The disproportionality signal was significant and positive, with a reporting odds ratio (ROR) of 1.65 which was particularly strong in breast and lung cancers.

Objective: Therefore, we aimed to analyze the frequency of primary malignancy in omalizumab-treated patients in a real-world clinical setting through propensity score matching (PSM).

Methods: We performed a retrospective case-control study in a single tertiary hospital to identify patients diagnosed with cancer after omalizumab treatment and a matching ratio of 1:4 was used to select omalizumab-untreated controls.

Results: A total of 2,340 patients (468 patients in the omalizumab group and 1,872 in the omalizumab-untreated control group) were included in our study. Baseline serum IgE before starting omalizumab treatment was significantly higher in the omalizumab group than in the control group (Table 1). The morbidity rates of malignancy did not differ between the omalizumab group and the control group (2.35% and 2.94%, respectively). This difference remained insignificant after dividing the number of patients with malignancy by observation time to calculate cases per 1,000 person-years. Omalizumab treatment did not show any association with any type of primary malignancy. The clinical characteristics of patients who were newly diagnosed as primary malignancy did not differ according to omalizumab treatment. The serum IgE levels did not differ between patients with and without malignancy as well.

Conclusion: Using real-world clinical data from a single tertiary hospital in Korea for the first time, we reported that omalizumab was not associated with a significantly higher risk of primary malignancy. The mean observation time per person was longer at 7.29 years (7.58 years in the omalizumab-untreated group and 6.14 years in the omalizumab-treated group) compared to the data from a previous clinical trial.³ This enabled us to observe slow-growing malignancies with long latency periods. Further studies with larger numbers of patients and longer observation times are required to confirm the results of our study.

References/Further Sources of Information

• 1. EMA. Omalizumab (XOLAIR). Summary of product characteristics. 2015. https://www.ema.europa.eu/en/documents/product-information/xolair-epar-product-information_en.pdf. Accessed 24 Jan, 2022.

• 2. Mota D, Rama TA, Severo M, Moreira A. Potential cancer risk with omalizumab? A disproportionality analysis of the WHO's VigiBase pharmacovigilance database. Allergy 2021;76:10.1.

• 3. Long A, Rahmaoui A, Rothman KJ, Guinan E, Eisner M, Bradley MS, et al. Incidence of malignancy in patients with moderate-to-severe asthma treated with or without omalizumab. J Allergy Clin Immunol 2014;134:3.

2.40 P046 Safety Profile of PCSK9 Inhibitors in Clinical Practice: An Italian Prospective Pharmacovigilance Study

2.40.1 A. Gagliardi¹, C. Palleria², M. D. Naturale², A. E. De Francesco², C. Leporini³, L. Muraca², V. Rania¹, M. Tallarico¹, M. Pisano², C. D. Sarro ², A. Leo¹, R. Citraro¹, L. Gallelli¹, G. D. Sarro¹

2.40.1.1 ¹University Magna Græcia of Catanzaro, Department of Health Sciences, Catanzaro, Italy; ²Mater Domini University Hospital Catanzaro, Department of Health Sciences, Catanzaro, Italy; ³Hospital of Rutigliano-Bari, Territorial Pharmacy of Rutigliano/Mola-Local Health Unit of Bari, Catanzaro, Italy

Introduction: Primary hypercholesterolemia, which is not adequately controlled with the continued use of statins at the maximum allowed dose is a serious problem in patients at high risk of cardiovascular events¹. The new monoclonal antibodies alirocumab (Praluent ©) and evolocumab (Repatha ©) represent a further therapeutic option with demonstrated superiority over placebo and/or ezetimibe, in reducing LDL levels. Considering the potential chronicity of the treatment, dedicated pharmacovigilance studies are essential to define the long-term safety profile of these drugs.

Objective: The aim of the study was to collect safety data, track adherence to therapy and identify specific drug interactions by paying closer attention to adverse reactions (ADRs) detection.

Methods: The study included a 3-month enrollment phase, followed by a 6-month follow-up/monitoring period. Specifically, the Authorized Prescribing Centers identified the patients with prior informed consent, which were contacted by telephone within 15 days and then contacted again in the first month and at 3 and 6 months. All observed ADRs were included in the National Pharmacovigilance Network. In addition, the Morisky questionnaire was used to assess adherence to the therapy of the patients and the data were compared with the analysis of the therapeutic plans. The DIPS questionnaire was used to identify the interactions.

Results: Overall, 79 patients (48 males and 31 females, mean age of 65.4 years) with a diagnosis of familial mixed hyperlipidemia (3.8%, 3), familial hyperlipidemia (29.1%, 23) and pure or common hyperlipidemia (67%, 53) have been enrolled. In terms of comorbidities, most of the patients were affected by cardiac pathologies such as arterial hypertension (77.2%; 61) coronary heart disease (44.3%; 35), followed by diabetes (30.4%; 24); the 25.3% of patients had both diabetes and arterial hypertension. Moreover, the 40.5% of patients started the therapy with alirocumab while 59.5% with evolocumab. All patients have received previous statin therapy, in particular 73.4% atorvastatin, 15.2% rosuvastatin and 11.4% simvastatin. In the majority of patients, statin therapy was suspended due to intolerance, while in a minority the switch occurred due to failure to reach target values. The most common ADRs described so far have been 2 cases of injection site pain (redness, itching) and 1 case of rhinorrhea by patients treated with alirocumab.

Conclusion: In conclusion, although few ADRs were detected, the awareness of health personnel led to greater consciousness of the importance of pharmacovigilance. Furthermore, the complete adherence to therapy by all enrolled patients confirms the tolerability and safety of these drugs.

References/Further Sources of Information

• 1. Mampuya WM, et al. Treatment strategies in patients with statin intolerance: The Cleveland clinic experience. Am J 2013; 166: 597-603

2.41 P047 Regorafenib-Related Myocardial Injury in Patient with HepatoCellular Carcinoma (HCC) Post Orthotopic Liver Transplant (OLT): Prevention and Management

2.41.1 C. D. Giorgio¹, G. Pascale ¹, F. Corrù¹, C. C. Cimarusti¹, D. Drago¹, F. Ruggiero¹, L. Cervi¹

2.41.1.1 ¹Niguarda Hospital, Hospital Pharmacy, Milan, Italy

Introduction: The incidence of cardiac adverse events, specifically heart attack and myocardial ischaemia, related to the use of regorafenib is uncommon (≥ 1/1.000 to < 1/100).

Regorafenib is an oral tumor blocking agent that effectively blocks several protein kinases (PTKs) involved in tumour angiogenesis (VEGFR1, VEGFR2, VEGFR3, TIE2), oncogenesis (KIT, RET, RAF1, BRAF, BRAFV600E) and in the tumour microenvironment (PDGFR, FGFR) [1].

It is used as monotherapy for the treatment of adult patients with metastatic colorectal cancer, gastrointestinal stromal tumours, HCC after treatment with sorafenib.

Objective: To identify risk factors associated with using of regorafenib.

Methods: AS (56 years), weight 90 kg and height 170 cm, smoker for 30 years until 2015 (1 pack per day) diagnostic of moderately differentiated HCC not infiltrating the glissian cassock in the absence of neoplastic vascular infiltration, class C (advanced) [2], class Child-Pugh A [3], ECOG 1 [4], HCV and HBV infection, adequate renal function, subjected to OLT from a male donor organ (60 years) weighing 1.9 kg, steatosis in 0-20 %, staging 1 for the presence of fibrosis [5].

Immunosuppression therapy with FK506 (tacrolimus), basiliximab and steroid.

Regular perioperative course: no interventional radiological procedure, endoscopic, nor major infections or critical complications.

Subsequently emergence of post-transplant clinical problems: active relapse of HCC.

Initially on sorafenib therapy, discontinued due to disease progression, and subsequently with regorafenib.

In november 2020 the patient reported moderate chest pain that subsides with the rest for which echocardiography and stress testing were indicated.

After pharmacological stimulation, the diagnosis was of drug induced myocardial ischaemia.

The patient started cabozantinib and optimization of cardiac control therapy.

Drug-related Adverse Drug Reaction (ADR) Onset: cardiotoxicity (protocol n° 721581 in National Pharmacovigilance Network).

Results: The shift to a Tyrosine Kynase Inhibitor (TKI) with a lower cardiovascular impact (cabozantinib) and an optimization of cardiac therapy allowed a better control of the patient's clinical course, avoiding serious ADRs that could further compromise the antineoplastic therapy choice.

Conclusion: The joint work of multidisciplinary teams (in the specific case oncology and cardiology teams), the physical examination of the patient, the necessary instrumental and biochemical tests, the adequate training of health professionals on the management of ADRs reports and the therapeutic optimization, represent the key points, useful and effective, and the “unmeet need” for the correct management of other patients, allowing to adopt of all the necessary precautions aimed at having a minimum impact on the patient's clinical condition.

References/Further Sources of Information

• 1. European Medicines Agency [Internet]. Regorafenib Product information [cited 2022 May 11]. Available from: https://www.ema.europa.eu/en/documents/product-information/stivarga-epar-product-information_it.pdf.

• 2. Cancer Research UK [Internet]. Barcellona Clinic Liver Cancer Calssification [cited 2022 May 11]. Available from: https://www.cancerresearchuk.org/about-cancer/liver-cancer/stages/bclc-staging-system-child-pugh-system.

• 3. Healthline [Internet]. Child Pugh Score [cited 2022 May 11]. Available from: https://www.healthline.com/health/child-pugh-classification.

• 4. ECOG-acrin cancer research group [Internet]. ECOG Performance Status Scale [cited 2022 May 11]. Available from: https://ecog-acrin.org/resources/ecog-performance-status/.

• 5. Hepatitis C online [Internet]. Staging of Liver Fibrosis [cited 2022 May 11]. Available from: https://www.hepatitisc.uw.edu/go/evaluation-staging-monitoring/evaluation-staging/core-concept/all.

2.42 P048 Meeting the Need: A Training Course for Data Safety Monitoring Board (DSMB) Members in LMIC

2.42.1 S. Black¹, M. Sturkenboom ²

2.42.1.1 ¹SPEAC Project, Taskforce for Global Health, Atlanta-Georgia, USA; ²University of Utrecht, SPEAC Project, Rotterdam, Netherlands

Introduction: Increasingly, vaccine clinical trials are being conducted in LMIC, especially for vaccines that target diseases that are endemic there. Having members of Data Safety Monitoring Boards for these trials who are from the geographic area where trials are conducted is critical to assure adequate safety assessment and to consider events observed in an appropriate context. However, the number of vaccine safety-experienced individuals to fulfill this role is currently limited.

Objective: To describe the next for trained DSMB members from low and middle income countries and a program developed to meet this need.

Methods: A DSMB training course combining online modules and facilitated live interactive sessions was developed with support from the Coalition for Epidemic Preparedness Innovations (CEPI). The initial two sessions targeted trainees in Africa while the third session includes individuals in Asia. The course runs over 8 weeks and contains eight modules which describe the role of the DSMB, rare events epidemiology, the phases and purposes of vaccine clinical trials, and regulatory issues. Pre-recorded lectures are provided by leaders in the field of vaccinology while the weekly one-hour virtual discussion sessions are led by a trained facilitator.

Results: Two sessions of the course have been successfully completed and a third is now in progress. Almost all enrollees have successfully completed the course with 29 graduates thus far and 15 enrolled in the current session. Surveys of participants have rated the course very highly in terms of content and relevance to their future work. Participants have also stated the course has provided them with increased confidence in becoming future DSMB members.

Conclusion: It is possible to develop and conduct a hybrid virtual and live interactive course to train future DSMB members for vaccine trials conducted in LMIC.

References/Further Sources of Information

Further information can be obtained at https://brightoncollaboration.us/speac/.

2.43 P050 Biological Medicines in Accidents with Poisonous Animals: Integrating Data from Various Sources

2.43.1 G. A. Keller ¹, A. R. d. Roodt¹, G. Temprano¹, C. Bonel¹, J. C. Dokmetjian¹

2.43.1.1 ¹Administración Nacional de Laboratorios e Institutos de Salud ANLIS Malbran, Instituto Nacional de Produccion de Biologicos, Ciudad Autonoma de Buenos Aires, Argentina

Introduction: In Argentina, a public institute produces and distributes biological substances that include different antivenoms based on equine F(ab')2 fragments for the treatment of accidents with snakes (bothrops, chrotalus, elapids) and arthropods (Loxosceles, Latrodectus, Phoneutria and Tityus). Currently, it has implemented a pharmacovigilance program that uses different sources of information and integrates them into a database to improve product safety analysis.

Objective: To describe the particular methodology of the integration of information sources in a public producer of biological medicines.

Methods: The institute integrates information from notifications of adverse reactions made directly to the institute (from patients, professionals, health coordinators and local health ministries), and forms of epidemiological report of accidents with poisonous animals. The different sources, available data fields and results of data integration are described.

Results: Through the use of relational tables, concordance can be found between the epidemiological reports and the adverse reactions reports (using geographical area, date and type of accident reported). The integration of the databases makes it possible to quantify the frequency of adverse reactions and their individual case analysis allows the classification of reactions by seriousness, preventability, and to compare these data between regions. The cases of adverse reactions show a prevalence of 7.05 ± 1.3 (6.1–8.3)% over the total of patients treated with antisera, with slight variations between years and geographical areas. The description of the type of event allows classifying them as early reactions in 85% (nausea, vomiting, local reactions), and late reactions in 15% (serum sickness). Non-serious adverse reactions counted for 89%, being predictable in 87%, preventable in 94% and requiring medical treatment in 15% of cases. All of them evolved with ad-integrum restitution.

Conclusion: Joining data using relational databases can allow the collection of additional information that allows not only to quantify the frequency of adverse reactions more reliably, but also to describe other factors that may be associated with changes in effectiveness and/or safety. The correlation with geographic areas and times between the occurrence of the accident and the administration of the product could serve to optimize the distribution process. This strategy helps to generate new information that is superior to the mere sum of the individual data.

References/Further Sources of Information

Beninger P. Pharmacovigilance: An Overview. Clin Ther. 2018 Dec;40(12):1991–2004.

2.44 P051 Use of Biological Drugs for Psoriasis: A Drug-utilization Study Using Tuscan Administrative Databanks

2.44.1 S. Giometto ¹, S. Tillati¹, L. Baglietto¹, N.D. Bortoli², M. Mosca³, M. Conte⁴, M. Tuccori^5,6, R. Gini⁷, E. Lucenteforte¹

2.44.1.1 ¹University of Pisa, Unit of Medical Statistics-Department of Clinical and Experimental Medicine, Pisa, Italy; ²University of Pisa, Unit of Gastroenterology-Department of Clinical and Experimental Medicine, Pisa, Italy; ³University of Pisa, Unit of Rheumatology-Department of Clinical and Experimental Medicine, Pisa, Italy; ⁴Université Paris-Saclay, UVSQ-Inserm, Villejuif, France; ⁵University of Pisa, Unit of Pharmacology and Pharmacovigilance-Department of Clinical and Experimental Medicine, Pisa, Italy; ⁶University Hospital of Pisa, Unit of Adverse Drug Reactions Monitoring, Pisa, Italy; ⁷Tuscan Regional Healthcare Agency, Unit of Pharmacoepidemiology, Firenze, Italy

Introduction: Psoriasis is an inflammatory skin disease that encompasses several clinical phenotypes and for which there has been much progress over the past 30 years in understanding the pathogenesis but for which there is currently no curative treatment [1]. Despite the frequency of switches in clinical practice, it is unclear which drugs are most frequently switched to and no clinical recommendations are available in this regard.

Objective: Our study aims at providing evidence on patterns of biologic drugs use for psoriasis in Tuscany, Italy.

Methods: We conducted a drug-utilization study based on administrative databanks of Tuscany (EUPAS45365). We selected new-users of etanercept, infliximab, adalimumab, ustekinumab, or secukinumab between January 1st, 2011 and December 31st, 2016. We considered subjects with psoriasis and followed subjects until end of study period (three years), or patient’s death, whichever came first. We censored subjects for pregnancy or neoplasia. For each subject, we defined the state as the weekly coverage of one of biologic drugs of interest. We then defined the switch as the change from a state to another one.

Results: A total of 7062 subjects with a first dispensation of PSObio drug in the inclusion period was identified. We included 1839 psoriatic patients (52.9% females, 51.6 mean age), resident in Tuscany, with one year of observation before the first biologic dispensation, and three years of observation after the first biologic dispensation. Among new users of adalimumab (N = 770, 41.9%), one third showed a continuous behaviour, the others moved to etanercept and ustekinumab. New-users of etanercept (N = 758, 41.2%), had the highest proportion of switchers, with adalimumab most often being the second choice. New users of infliximab (N = 159, 8.6%) experienced the highest proportion of treatment discontinuation, and of those who changed medication drug, most switched to adalimumab or, to a lesser extent, to etanercept. New users of ustekinumab (N = 115, 6.3%) had the highest percentage of subjects on continuous therapy, and a small percentage of switchers.

Conclusion: The present study suggests that the majority of patients treated with PSObio drugs do not switch from one active ingredient to another. However, patients who started biological therapy with etanercept had the highest frequency of switch to other PSObio drugs. Instead, patients with ustekinumab as index drug had the lowest frequency of switch to other PSObio drugs. Those who started treatment with infliximab had the highest discontinuation rate.

References/Further Sources of Information

• 1. Griffiths, C.E.M.; Armstrong, A.W.; Gudjonsson, J.E.; Barker, J.N.W.N. Psoriasis. The Lancet 2021, 397, 1301–1315, https://doi.org/10.1016/S0140-6736(20)32549-6.

2.45 P052 Local Experience on Adalimumab and Etanercept Biosimilar Drugs: Safety and Efficacy Confirmation Encourages Rheumatologist Biosimilar Prescription

2.45.1 G. Babaglioni ¹, D. Paganotti¹, E. Festa¹, T. E. Testa¹, F. Franceschini²

2.45.1.1 ¹ASST Spedali Civili Brescia, Hospital Pharmacy, Brescia, Italy; ²ASST Spedali Civili Brescia and University of Brescia, Department of Clinical and Experimental Sciences-Rheumatology and Clinical Immunology Unit, Brescia, Italy

Introduction: Biosimilars are biological medicines of rigorous pharmaceutical standard quality, that can provide benefits for patients in terms of safety, efficacy and quality, for healthcare systems as well in increasing treatment alternatives, access and cost competitiveness [1].

Objective: To evaluate the safety reports of subcutaneous biosimilars of adalimumab (ADA) and etanercept (ETN), the two biological pillars of rheumatology, by considering the patients therapies and safety signals collected in the local center.

Methods: A three years period analysis was considered after the introduction of the first biosimilar of ADA (2019) and ETN (2017): the safety reports occurred in this period were analyzed after being reported in the AIFA National Pharmacovigilance Network (RNF) database [2]. Patients biological scheme assessments were defined by using an internal accounting system of provided drugs to outpatient and home regimen patients.

Results: Etanercept was the first biosimilar subcutaneous anti-TNFα introduced in the rheumatological center: the switching practice was embraced for the 23.1% of patients (n = 93) and the biosimilar prescription was adopted for the 26.2% naïve patients (n = 105). The safety signal rate of ETN biosimilar/originator (0.6) was in favor of the biosimilar; 25% of the events were considered serious, with no difference between biosimilar and originator. Drug ineffectiveness was recorded both for originator and biosimilar with different rate (60% and 41.7% respectively), proving that the poor control of the disease should be independent by the drug formulation itself. The second generation biosimilars of adalimumab were introduced into the clinical practice much more incisively, thanks to the raising physician confidence acquired with ETN. The 37.7% of patients (n = 283) in ADA originator were switched to biosimilar and the 47.7% (n = 358) received biosimilars as first-line therapy. Although in this case there was a 38.5% of reports for perceived ineffectiveness of the biosimilars (n = 13), they were all classified as not serious and signaling rate was still favoring the biosimilars (0.76).

Conclusion: From what emerges from the quantitative and qualitative analysis of the adverse reactions reported in the RNF, there are no specific safety concerns or clinically meaningful differences in the use of biosimilars [3]. Indeed, doctors are increasingly supporting biosimilarity/interchangeability, combined with an appropriate level of communication with patients, that can enhance the biosimilars contribution to sustainability and patient therapy access [4].

References/Further Sources of Information

• 1. ICMRA. ICMRA statement about confidence in biosimilar products (for healthcare professionals). (2019).

• 2. https://www.aifa.gov.it/rete-nazionale-di-farmacovigilanza. Accessed May 04, 2022.

• 3. Italian Medicines Agency. Biosimilar medicines—Safety analysis. Available from:https://www.aifa.gov.it/documents/20142/0/190712_MedBio19.pdf. Accessed May 10, 2022.

• 4. de Mora, F. et al. Biosimilar and interchangeable: Inseparable scientific concepts? Br. J. Clin. Pharmacol. 85, 2460–2463 (2019).

2.46 P053 Clinicians’ and Patients’ Involvement in Reporting Adverse Drug Reactions and Adherence to Treatment of Biological Drugs in Rheumatology, Dermatology, Gastroenterology

2.46.1 E. Sapigni¹, R. Ricciardelli ¹, C. Ajolfi², S. Croce¹, N. Mogheiseh¹, V. Nikitina¹, A. M. Potenza¹, E. Pasi³, N. Viani⁴, M. Rolli⁵

2.46.1.1 ¹Regional Pharmacovigilance Centre of Emilia-Romagna, Hospital Care Sector-General Directorate for Personal Care-Health and Welfare, Bologna, Italy; ²Local health units of Modena, Pharmacovigilance, Modena, Italy; ³Scientific secretary of the Regional Commission of the drug, Hospital Care Sector-General Directorate for Personal Care-Health and Welfare, Bologna, Italy; ⁴Local health units of Modena, Pharmaceutical Directorate, Modena, Italy; ⁵Hospital Care Sector, General Directorate for Personal Care-Health and Welfare, Bologna, Italy

Introduction: Biological/biotechnological drugs play a key role in the treatment of immune-mediated inflammatory diseases, such as rheumatoid arthritis, chronic inflammatory diseases of the intestines and psoriasis.

The involvement of clinicians and patients in the reporting of suspected adverse drug reactions (ADRs) is essential, and a more effective interaction aimed at the correct and safe use of medicines should be promoted. It is a regional Pharmacovigilance project funded by the Italian Medicines Agency.

Objective: To promote the collection of ADRs to biological drugs used in rheumatology/dermatology/gastroenterology, through an active interaction with clinicians, paying attention to the reports’ quality, lack of efficacy and therapeutic switches; to produce information cards that improve adherence to therapy, promote proper methods of home intake and reporting of ADRs. To encourage the use of biosimilar drugs in clinical practice.

Methods: A multidisciplinary regional group composed by clinicians and pharmacists of Local Health Units and Hospital Trusts of Modena, Reggio-Emilia, Bologna, Ferrara, Romagna, Pharmacovigilance Regional Centre and Scientific secretary of the Regional Commission of the drug (CRF) was involved. They deepened the topic of the quality of ADRs’ reports and shared methods of collection and analysis of ADRs. This collaboration led to definition of information cards regarding each medicinal product and its medical devices, which were developed for patients and distributed for its use in health practice.

Results: During the period 02/01/2020–28/02/2022 a total of 232 reports were collected: 72.4% submitted online; 98.7% filled out by clinicians; 37.1% with at least one follow-up; 56.5% with outcome; 94.4% with de-rechallenge; 14,1% with lack of efficacy; 44% with therapeutic switches; > 90% use of biosimilars. The total of 51 patient information cards was produced, combining 25 cards related to active ingredients and 40 cards for medical devices. The contents included: methods of conservation; aspects to be addressed; expected behaviors in case of missed intake; side effects of clinical relevance.

Conclusion: The discussion among healthcare professionals has allowed a dialogue on pharmacovigilance, with insights on reports of ineffectiveness and therapeutic switches. A multidisciplinary approach has allowed patients to identify clinical relevance of ADRs and correct use of these drugs.

The collaboration between healthcare professionals is necessary to increase the quality of ADRs’ reports aiming at the comprehension of potential risks of the medicines’ use.

The development of information cards addressed to patients was a moment of sharing a collaborative multidisciplinary approach in creation of documents useful to promote a conscious and safe use of medicines.

References/Further Sources of Information

• 1. Singh JA, Wells GA, Christensen R, Tanjong Ghogomu E, Maxwell L, Macdonald JK, Filippini G, Skoetz N, Francis D, Lopes LC, Guyatt GH, Schmitt J, La Mantia L, Weberschock T, Roos JF, Siebert H, Hershan S, Lunn MP, Tugwell P, Buchbinder R. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev. 2011 Feb 16;2011(2):CD008794. https://doi.org/10.1002/14651858.CD008794.pub2. PMID: 21328309; PMCID: PMC7173749.

• 2. Strand V, Balsa A, Al-Saleh J, Barile-Fabris L, Horiuchi T, Takeuchi T, Lula S, Hawes C, Kola B, Marshall L. Immunogenicity of Biologics in Chronic Inflammatory Diseases: A Systematic Review. BioDrugs. 2017 Aug;31(4):299–316. https://doi.org/10.1007/s40259-017-0231-8. PMID: 28612180; PMCID: PMC5548814.

• 3. Bai F, Li GG, Liu Q, Niu X, Li R, Ma H. Short-Term Efficacy and Safety of IL-17, IL-12/23, and IL-23 Inhibitors Brodalumab, Secukinumab, Ixekizumab, Ustekinumab, Guselkumab, Tildrakizumab, and Risankizumab for the Treatment of Moderate to Severe Plaque Psoriasis: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials. J Immunol Res. 2019 Sep 10; 2019:2546161. https://doi.org/10.1155/2019/2546161. PMID: 31583255; PMCID: PMC6754904.

• 4. Sedger M, Ranasinghe C, McDermott M, Asvadi P. Therapeutic Antibody‐Based Drugs in the Treatment of Human Inflammatory Disorders. In: Metodiev, K., editor. Immunotherapy–Myths, Reality, Ideas, Future [Internet]. London: IntechOpen; 2017. Available from: https://www.intechopen.com/chapters/54286https://doi.org/10.5772/67478.

2.47 P054 A Rare Case of Polydactyly in a Newborn from Mother Affected by Multiple Sclerosis

2.47.1 C. Galuppi ¹, D. Paganotti¹, I. Restivo¹, A. Pozzi¹, L. Silva¹, D. Bettoni¹, T. E. Testa¹, C. Cordioli², N. D. Rossi²

2.47.1.1 ¹ASST Spedali Civili of Brescia, Hospital Pharmacy, Brescia, Italy; ²ASST Spedali Civili of Brescia, Multiple Sclerosis Centre, Brescia, Italy

Introduction: Polydactyly is the most common congenital anomaly of hand and foot. It is characterized by extra fingers or toes and it can occur as part of a syndrome or as a separate event [1].

Objective: To report a case of congenital polydactyly in a baby born from a mother affected by multiple sclerosis (MS) in therapy with ocrelizumab.

Methods: We performed a prospective analysis of the relationship between the use of drugs modifying the course of MS, and the risk of serious adverse drug reactions (ADRs). The case was reported in the Italian National Pharmacovigilance Network (RNF) as serious event [2]. We performed an analysis of the number of ADRs occurred to pregnant women receiving ocrelizumab, through a comparison between the RNF and the Eudravigilance database [3].

Results: The mother is a 42-years-old Senegalese woman, affected by MS since 2014. She also suffers from bronchial asthma, atopic eczematous dermatitis, allergic rhinitis, obesity. On 2016 the woman delivered a healthy baby; during her first pregnancy she didn’t receive any SM therapy. After 2 years of treatment with fingolimod, on January 2019 doctors switched to ocrelizumab (intravenous infusion, 600 mg every 6 months). The last infusion was in November 2020, and in January 2021 she got pregnant again. Therapy was discontinued and the baby was born in good health by vaginal birth on Oct. 2021 but had polydactyly in his hands and feet. Doctors are now considering amputation surgery. From the year of ocrelizumab authorization (2018) to date (30/04/2022), 5 other ADRs regarding "congenital, family and genetic diseases" and "pregnancy, puerperium and perinatal disorders" have been reported in the RNF [2] and 57 ADR in Eudravigilance [3]. According to an EMA Assessment report, 46 patients receiving ocrelizumab became pregnant during clinical study participation. Among these, 11 cases reported a spontaneous fetal loss and 9 cases reported premature delivery and/or an abnormal finding in a live born baby [4].

Conclusion: Pre-clinical studies do not indicate teratogenic effects of ocrelizumab, but there is some evidence of these effects in humans. Ocrelizumab Summary of Product Characteristics (SmPC) indicates to adopt a contraceptive method during the treatment and for 12 months after the end of therapy. Naranjo's algorithm did not exclude the causal relationship between the adverse event reported in this abstract and the therapy with ocrelizumab, defining it as "doubt".

References/Further Sources of Information

• 1. Al Amin ASM, Carter KR. Polydactyly. 2021 Nov 7. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan. PMID: 32965966. Available from: https://www.ncbi.nlm.nih.gov/books/NBK562295/.

• 2. https://www.agenziafarmaco.gov.it/Farmacovigilanza/.

• 3. https://www.adrreports.eu/.

• 4. Assessment report EMA/790835/2017

2.48 P056 Safety of Biologic Therapy for Crohn’s Disease: An Active Pharmacovigilance Study

2.48.1 L. Ruffolo ¹, C. Palleria¹, R. Citraro², A. Leo², M. Tallarico¹, C. D. Sarro¹, C. Leporini³, I. Caccavo⁴, G. Marcianò¹, C. Vocca¹, A. Casarella¹, R. Spagnuolo⁵, P. Doldo⁵, L. Gallelli¹, G. D. Sarro¹

2.48.1.1 ¹University of Catanzaro-Operative Unit of ClinicalPharmacology-Mater Domini University Hospital, Department of Health Science-School of Medicine-, Catanzaro, Italy; ²System and Applied Pharmacology@University Magna Grecia FAS@UMG Research Center-Science of Health, Department-School of Medicine-Magna Graecia University of Catanzaro, Catanzaro, Italy; ³Local Health Unit of Bari, Territorial Pharmacy of Rutigliano/Mola-Hospital of Rutigliano, Bari, Italy; ⁴Local Health Unit of Matera, Pharmaceutical Territorial Service-Pharmaceutical Department, Matera, Italy; ⁵"Magna Graecia" University of Catanzaro, Department of Clinical and Experimental Medicine, Catanzaro, Italy

Introduction: The rising incidence of Crohn’s Disease (CD) led to a significant increase in biologics therapy. Due to their recent development, the long-term risk/benefit profile of these therapies is still not completely defined. Therefore, pharmacovigilance activities become essential to monitor their safety.

Objective: The purpose of this prospective pharmacovigilance study was to evaluate safety of biologics for the treatment of CD.

Methods: All patients treated with at least one biologic drug in gastroenterology centers located in Calabria between January 2019 to April 2021, were enrolled, including both bionaïve and previous biologics exposed patients. Demographic and clinical characteristics including age, sex, diagnosis, comorbidities, type of drugs used, discontinuation or switch/swap to another biologic and AEs were collected. Each patient was monitored for 6 months at least, since the date of enrollment (follow-up period). AEs were analyzed through mapping with the PT (Preferred Term) and SOC (System Organ Class) codes of MedDRA dictionary. The most common AEs were detected and reported.

Results: A total of 163 patients were enrolled, of which 116 (71.2%) were bionaïve: mean age (± SD) was 39.7 (± 13.6) years; 58.3% were males. At the index data, infliximab (IFX) was the most and widely used in study population (44.8% of patients), followed by: adalimumab (ADA) (38.7%), vedolizumab (VED) (11.0%), ustekinumab (UST) (5.5%). During the follow-up, the 15.3% of patients reported at least one AEs related to biologics administration (Total AEs reported: 35). The most common AEs were “general disorders and administration site conditions” (34.3% of total AEs); mainly, asthenia in patients treated with IFX (7 patients) and ADA (1). Injection site reaction (1), flushing (2), oedema (1) were also reported in patients treated with IFX. “Nervous system disorders” occurred in 17.1% of cases, which included: 3 reports of headache (2 IFX, 1 ADA), 2 of somnolence (1 IFX, 1 UST) and 1 of confusional state (IFX). We also detected 5“musculoskeletal and connective tissue disorders”, such as arthralgia, in patients treated with IFX. In all cases, the most common AEs, belonging to three different SOC, occurred in the hours immediately after administration and resolved within 24/48 hours. Only one patient treated with IFX reported persistent headache that requires further neurological examination.

Conclusion: Results showed that the highest incidence of AEs was related to infusion reactions. Indeed, the majority of AEs resolved within a maximum of 2 days after administration of biologics. However, further studies are needed to address the questions about the long-term safety of biologics.

References/Further Sources of Information

Not applicable.

2.49 P057 Safety of Biological Drugs in Naïve Patients in Dermatological Field: Real Life Data from an Active Pharmacovigilance Project in Calabria Region

2.49.1 C. Verduci ¹, C. Palleria¹, R. Citraro², A. Leo², M. Tallarico¹, C. D. Sarro¹, C. Leporini³, I. Caccavo⁴, L. Catarisano¹, E. Basile¹, S. Dastoli⁵, L. Bennardo⁵, M. Passante⁵, L. Gallelli¹, G. D. Sarro¹

2.49.1.1 ¹University of Catanzaro-Operative Unit of Clinical Pharmacology-Mater Domini University Hospital, Department of Health Science-School of Medicine, 88100-Catanzaro, Italy; ²System and Applied Pharmacology@University Magna Grecia FAS@UMG Research Center-Science of Health, Department of Health Science-School of Medicine, Catanzaro, Italy; ³Local health unit of Bari, Territorial Pharmacy of Rutigliano/Mola-Hospital of Rutigliano, Bari, Italy; ⁴Local health unit of Matera, Pharmaceutical Territorial Service-Pharmaceutical Department, Matera, Italy; ⁵Mater Domini University Hospital, Department of Health Science-School of Medicine-University of Catanzaro-Operative Unit of Dermatology, Catanzaro, Italy

Introduction: Biological drugs have made important advances in the treatment of many inflammatory diseases. With their increasing use in real life, post-marketing activities became crucial for evidence on their long-term safety.

Objective: Aim of this active pharmacovigilance study was to evaluate the safety of biologics in bio-naïve patients affected by psoriasis (Pso), psoriatic arthritis (PsA) and atopic dermatitis (AD).

Methods: A prospective analysis of patients with dermatological diseases, naïve to biologics, in the period 2019–2022 was carried out. All bio-naïve patients treated with at least one biologic drug in dermatology centers located in Calabria were enrolled. Demographic and clinical data have been collected for each enrolled patient: age, sex, diagnosis, disease duration, current biologic drugs, biosimilar drugs, other treatments, relevant comorbidities, switch/swap, potential failure, and adverse events (AEs) onset.

Results: The study sample consisted of 521 patients: 47% with PsA, 49.5% with Ps, and 3.5% with an AD. Mean age (± SD) was 54.5 ± 13.4 years and 59.1% were male. Mean age at diagnosis was 45.6 ±15.4 and the mean disease duration was 11.8 ± 9.1 years. The most prescribed drug was Adalimumab (ADA) 36.6% of which the 6% were biosimilar drugs, followed by etanercept (ETN) 22.3% which the 12.8% were biosimilar drugs, ustekinumab (UST) 15.9%, secukinumab (SEC) 10.7%, golimumab (GOL) 4%, dupilumab (DPL) 2.6%, infliximab (IFX) 2.5%, ixekizumab (IXE) 2.4%, tildrakizumab (TIL) 0.9%, guselkumab (GUS) 0.7%, risankizumab (RZE) 0.7%, brodalumab (BRO) 0.5%, tocilizumab (TCZ) 0.1%, and abatacept (ABT) 0.1%. Regarding safety, overall, 417 patients (80%) not reported AEs, whereas patients 20% experienced at least one AE, mostly due to ADA (39.4%). The most frequent identified AEs were general disorders, in particular: asthenia (26%), injection site reactions (14.4%), headache (13.4%), skin disorders and gastrointestinal disorders (6.7%); all the AEs observed were expected.

Conclusion: Considering the low rate of AEs reported, our data seems to confirm a good safety profile of biologics. The reported AEs have been generally mild to moderate and mostly related to general disorders and administration. Nevertheless, the acquisition of data from clinical practice should be endorsed to better define the safety and efficacy profile of new biologic agents.

References/Further Sources of Information

Not applicable.

2.50 P058 Venetoclax and Tumor Lysis Syndrome (TLS): Data Mining of the FDA Adverse Event Reporting System (FAERS) Database

2.50.1 C. D. Giorgio¹, G. Pascale ¹, C. C. Cimarusti¹, F. Corrù¹, D. Drago¹, L. Napoli¹, S. Ingrillì¹, F. Ruggiero¹, L. Cervi¹

2.50.1.1 ¹Niguarda Hospital, Hospital Pharmacy, Milan, Italy

Introduction: Venetoclax is a BH3-mimetic compound that selectively antagonizes BCL-2 (B-cell lymphoma 2) and induces apoptosis of CLL (Chronic Lymphocytic Leukemia) cells [1].

This oral treatment has demonstrated significant clinical advantages, but rapid tumor debulking can lead to a treatment-related risk of the acute condition known as tumor lysis syndrome (TLS), caused by the abrupt release of cellular components into the bloodstream [2].

A warning has been issued by the European Medicine Agency (EMA) and Italian Medicine Agency (AIFA) regarding the risk of TLS in patients treated with venetoclax [3].

Objective: The objective of this study was to investigate whether a disproportionally elevated signal of developing TLS may be detected in patients treated with venetoclax as compared to those treated with other drugs.

Methods: A retrospective analysis of spontaneously reported cases of TLS contained in the free and publicly available FDA Adverse Event Reporting System (FAERS) database was conducted in the period January 2015–December 2020 [4].

We calculated, as a signal of disproportionality, the reporting odds ratio (ROR), and the relative 95% confidence interval (CI), of TLS in patients treated with venetoclax. The signal was considered significant when the ROR lower limit of the 95% CI was > 1.

Results: A total of 11.800.647 FAERS reports were identified during the study period; 15.933 (0.13%) reports mentioned venetocalx. There were 2.978 (0.02%) reports of TLS of which 353 (11.8%) attributed to venetoclax treatment.

The majority of these reports referred to patients aged 65–85 years (41%) and male (61.18%) (OR = 87.89, 95% CI 78.53–98.14, z = 78.72 P <0.0001) as compared to other drugs.

Conclusion: With this study we demonstrated that in patients treated with venetoclax exists a higher risk to develop TLS.

It would be of interest to further analyze reports of TLS associated with this drug, comparing signals deriving from FAERS and those deriving from the European pharmacovigilance database EudraVigilance [5].

EMA and AIFA has recommended a continuous and constant updating of information on venetoclax to reflect current knowledge on this issue and address it in the best possible way and in the shortest possible time.

References/Further Sources of Information

• 1. European Medicines Agency [Internet]. Ventoclax Product information [cited 2022 May 11]. Available from: https://www.ema.europa.eu/en/documents/product-information/venclyxto-epar-product-information_it.pdf.

• 2. Venclexta hcp [Internet]. Venetoclax and Tumor Lysis Syndrome (TLS) [cited 2022 May 11]. Available from: https://www.venclextahcp.com/cll/dosing/risk-assessment.html.

• 3. Italian Medicines Agency [Internet].Important AIFA alert note about Tumor Lysis Syndrome (TLS) caused by Venetoclax [cited 2022 May 11]. Available from: https://www.aifa.gov.it/-/nota-informativa-importante-su-venclyxto-venetoclax-compresse-rivestite-con-film.

• 4. US Food and Drug Administration [Internet].FDA Adverse Event Reporting Systems (FAERS) Public Dashboard [cited 2022 May 11]. Available from: https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard.

• 5. European Medicines Agency [Internet]. European Pharmacovigilance database EudraVigilance [cited 2022 May 11]. Available from: https://www.ema.europa.eu/en/human-regulatory/research development/pharmacovigilance/eudravigilance

2.51 P060 Secondary Depression Associated to TNF-α Inhibitors

2.51.1 F. E. Jabri ¹, S. Kastalli¹, W. Kaabi¹, S. Dabbeche¹, R. Daghfous¹, S. E. Aidi¹

2.51.1.1 ¹Tunis El Manar University Medical school of Tunis/research unit UR17ES12, Chalbi Belkahia national centrer of de pharmacovigilance/ adverse effects collection and analysis departement, tunis, Tunisia

Introduction: A number of adverse drug reactions are known to be associated with Anti TNF alpha drugs; they include infections, injection site reactions, liver function abnormalities, hematological, and solid organ malignancies. Potential psychiatric adverse events have been described only in few cases.

Objective: To investigate the relationship between the onset of neuropsychiatric symptoms and the use of anti-TNF alpha drugs.

Methods: We describe the case of a patient with no history of psychiatric disorders that experienced secondary depression on anti-TNF alpha with positive rechallenge.

Results: A 57-year-old woman was diagnosed with axial ankylosing spondylitis associated with psoriasis and started on etanercept, which was stopped for paradoxical uveitis and substituted with adalimumab, one injection every 15 days. She presented 15 days after the fourth adalimumab infusion, mood disorders with black ideas, negative thoughts, neglect of her appearance and insomnia. These symptoms resolved within 20 days of stopping treatment. She was put under infliximab, and had presented from the first day a recurrence of the depressive syndrome with auditory hallucinations that have disappeared 15 days after stopping this drug.

Conclusion: The results suggest that psychiatric disorders may be associated with TNF-α inhibitors. Thus, we draw the attention of clinicians to the possibility of this type of adverse event occurring with this therapeutic class

References/Further Sources of Information

Keywords: tumor necrosis factor alpha, depression.

2.52 P061 Safety Profile of Dupilumab Approved for Chronic Rhinosinusitis with Nasal Polyposis: Analysis from the European Spontaneous Adverse Event Reporting System

2.52.1 M. A. Barbieri ¹, C. Galletti², E. E. Sorbara¹, G. Cicala¹, P. M. Cutroneo³, F. Ciodaro², B. Galletti², E. Spina¹

2.52.1.1 ¹University of Messina, Department of Clinical and Experimental Medicine, Messina, Italy; ²University of Messina, Department of Adult and Developmental Human Pathology "Gaetano Barresi", Messina, Italy; ³University Hospital of Messina, Sicilian Regional Pharmacovigilance Centre, Messina, Italy

Introduction: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is characterized by a type 2 pattern of inflammation resulting in the production of some cytokines such as interleukin (IL)-4, IL5, and IL13. Options for treatment-resistant CRSwNP include aspirin desensitization, recurrent topic and systemic corticosteroid use, and functional endoscopic sinus surgery (FESS). However, frequent relapses after medical and surgical treatment have been observed. Thus, dupilumab, a human recombinant monoclonal IgG4 antibody, changes radically the treatment of CRSwNP because of its binding effects on major drivers of human type 2 inflammatory processes [1-3]. Considering its recent approval, it may be useful to evaluate its safety profile.

Objective: The aim of this study was to describe better adverse drug reactions (ADRs) related to dupilumab in the treatment of CRSwNP analyzing all individual case safety reports (ICSRs) collected into the European Spontaneous Reporting System (SRS) database.

Methods: All ICSRs recorded starting from the drug approval up to 31 December 2021 with dupilumab reported as suspected and having the specific indication of CRSwNP were considered. A descriptive analysis was conducted to assess demographic characteristics and dupilumab-related variables.

Results: Out of 10,400 ICSRs related to dupilumab, only 481 (4.6%) had CRSwNP indication, of which 68.2% were related to adults and 54.3% to females. The 68.4% were serious; however, ICSRs mainly led to a completely or partial recovering (25.4%) and 8 cases were fatal (1.7%). The time to onset (TTO) of ADRs was 25 (1–84.75) days while the time to resolution (TTR) was 5 (1.75–15.75) days. Analyzing ADRs by System Organ Classes (SOCs), the most reported were general and administration site conditions (36.4%) followed by injuries (21.6%), infections (21.2%), respiratory (19.1%), skin (16.6%), and nervous system disorders (16.4%). Looking at Preferred Terms (PTs), arthralgia (7.3%), eosinophilia (6.9%), COVID-19 (6.0%), pyrexia (5.8%), asthenia (5.6%), rash (5.4%), and dyspnoea (5.2%) were the most reported. The 7.5% of ICSRs described an aggravated condition with persistent nasal polyps: in 4 cases (0.8%) a nasal polypectomy was required. Considering fatal ICSRs, two cases were related to progression of COVID-19, one to road traffic accident, one to accidental death and the others were not fully specified.

Conclusion: These results showed that dupilumab-related ICSRs are not commonly reported in CRSwNP. However, given the good treatment response and the minimal adverse effects observed, clinicians should consider treating CRSwNP with dupilumab. Moreover, additional analyses are necessary to better outline the safety profile of dupilumab in this particular setting.

References/Further Sources of Information

• 1. Hoy, SM. Dupilumab: A Review in Chronic Rhinosinusitis with Nasal Polyps. Drugs 2020; 80, 711–717

• 2. Kim J, Naclerio R. Therapeutic Potential of Dupilumab in the Treatment of Chronic Rhinosinusitis with Nasal Polyps: Evidence to Date. Ther Clin Risk Manag. 2020; 16, 31–37

• 3. Agache I, Song Y, Alonso-Coello P, et al. Efficacy and safety of treatment with biologicals for severe chronic rhinosinusitis with nasal polyps: A systematic review for the EAACI guidelines. Allergy. 2021;76(8):2337–2353

2.53 P062 Safety Profile of Tyrosine Kinase Inhibitors Approved for Gastrointestinal Stromal Tumors: Analysis from the European Spontaneous Adverse Event Reporting System

2.53.1 M. A. Barbieri ¹, E. E. Sorbara¹, V. Santoro¹, G. Cicala¹, P. M. Cutroneo², M. Santarpia³, T. Franchina³, N. Silvestris³, E. Spina¹

2.53.1.1 ¹University of Messina, Department of Clinical and Experimental Medicine, Messina, Italy; ²University Hospital of Messina, Sicilian Regional Pharmacovigilance Centre, Messina, Italy; ³University of Messina, Department of Adult and Developmental Human Pathology "Gaetano Barresi", Messina, Italy

Introduction: Gastrointestinal stromal tumors (GISTs), soft tissue sarcomas of the digestive tract, are associated with oncogenic mutations that led to the approval of tyrosine kinase inhibitors (TKIs) [1-2]. Considering the increased use of TKIs in clinical practice, it may be useful to identify unexpected adverse drug reactions (ADRs).

Objective: The aim of this study was to describe better ADRs and to identify unexpected potential safety signals through the analysis of individual case safety reports (ICSRs) among TKIs approved for GIST collected into the European Spontaneous Reporting System (SRS) database.

Methods: All ICSRs recorded starting from the drug approval up to 31 December 2021 with one of the following TKIs reported as suspected drug were included: imatinib (IM), sunitinib (SU), avapritinib (AVA), regorafenib (REG), and ripretinib (RIP). A descriptive analysis was conducted to assess all demographic characteristics. Moreover, a disproportionality analysis was performed using the Reporting Odds Ratio (ROR) with the corresponding 95% Confidence Interval (CI) to evaluate the frequency of ADRs for each TKI compared to all other TKIs.

Results

The number of analyzed ICSRs was 8,512 (Figure 1 Flowchart of ICSRs selection process): the 57.9% were related to IM, followed by SU (24.2%), AVA (13.1%), REG (2.7%), and RIP (2.1%). ICSRs were mainly serious (87.5%), related to males (51.7%), and to adults (44.7%); moreover, the 25.5% were fatal. The disproportionality analysis showed a higher reporting frequency of some unexpected ADRs for each TKI: gait disturbance (ROR 2.86; 95% CI 1.90–4.29), hyperhidrosis (2.57; 1.06–6.20), and hyperammonemia (3.92; 1.05–14.60) for SU; cerebrovascular accident (6.23; 2.18–17.84), hemoglobin decreased (2.23; 1.08–4.61), and internal haemorrhage (14.44; 3.94–52.92) for RIP; gastrointestinal ulcer (10.88; 2.98–39.81) for REG; hepatic and lung cancer for IM (12.79; 8.04–20.37 and 7.71; 3.33–17.84, respectively); hallucination (24.33; 9.02–65.68), mood swings (8.02; 2.44–26.33), and stress (6.68; 1.93–23.11), nephrolithiasis (6.69; 2.15–20.77), pollakiuria (3.08; 1.17–8.13), and dialysis (6.68; 1.67–26.73), sinusitis (3.34; 1.14–9.78), cellulitis (4.17; 1.36–12.78), and COVID–19 (7.25; 3.40–15.45), chills (2.36; 1.22–4.58), limb fracture (3.53; 1.63–7.60), hernia (9.23; 3.71–23.00), diabetes mellitus (5.02; 2.11–11.95), hyposideraemia (5.02; 2.11–11.95), tinnitus (3.64; 1.34–9.87), parosmia (5.00; 1.12–22.38), Raynaud's phenomenon (5.00; 1.12–22.38), and thyroid function test abnormal (8.90; 1.99–39.83) for AVA.

Conclusion: This study is largely consistent with results from literature but some unexpected ADRs were shown. Further studies are necessary to increase the awareness about the safety profiles of new TKIs approved for GISTs.

References/Further Sources of Information

• 1. Corless CL, Barnett CM, and Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat. Rev. Cancer. 2011; 11, 865–878

• 2. Li GZ, and Raut CP. Targeted therapy and personalized medicine in gastrointestinal stromal tumors: drug resistance, mechanisms, and treatment strategies. Onco. Targets. Ther. 2019; 12, 5123–5133

2.54 P063 Safety Profile of Tyrosine Kinase Inhibitors Used in Non-Small-Cell Lung Cancer: An Analysis from The Italian Pharmacovigilance Database

2.54.1 M. A. Barbieri¹, E. E. Sorbara ¹, G. Cicala¹, V. Santoro¹, P. M. Cutroneo², T. Franchina³, M. Santarpia³, N. Silvestris³, E. Spina¹

2.54.1.1 ¹University of Messina, Department of Clinical and Experimental Medicine, Messina, Italy; ²University of Messina, Sicilian Regional Pharmacovigilance Centre, Messina, Italy; ³University of Messina, Department of Adult and Developmental Human Pathology "Gaetano Barresi", Messina, Italy

Introduction: Non-small cell lung cancer (NSCLC) is often caused by molecular alterations that led to the approval of new tyrosine kinase inhibitors (TKIs) [1-2]. Given the clinical relevance of some TKI-related adverse drug reactions (ADRs) not yet fully characterized it may be useful to evaluate the safety profile of TKIs in NSCLC.

Objective: The aim was to highlight all Italian open data-related ADRs associated with TKIs approved for NSCLC and, consequently, to focus on all regional Sicilian reports.

Methods: All national publicly-available aggregated ADR reports recorded from 2002 to 2021 into the Reports of Adverse Reactions of Medicines (RAM) system and all complete Sicilian data reported into the Italian spontaneous reporting system (SRS) database having as suspected drugs the following TKIs approved for NSCLC were consulted: afatinib, alectinib, brigatinib, ceritinib, crizotinib, erlotinib, gefitinib, lorlatinib, nintedanib, and osimertinib. Descriptive analyses of national publicly-available aggregated data and full-access regional data were performed to assess demographic and drug-related variables followed by a more in-depth analysis of all Sicilian ADRs.

Results: Out of 3,048 collected reports, the 47.5% were related to erlotinib, followed by afatinib, gefitinib, and crizotinib. ADRs were mainly not serious (n = 2,192; 71.9%), related to females (n = 1,592; 52.2%) and to the age group > 65 years (n = 1,617; 53.1%). The most reported ADRs were skin and gastrointestinal disorders (n = 1,766; 57.9% and n = 1,024; 33.6%, respectively) followed by general disorders and infections (n = 536; 17.6% and n = 483; 15.8%, respectively). The case-by-case assessment of Sicilian reports showed 68 serious ADRs (28.8%) with a median time-to-onset of 45 (21-134) days that mainly involved rash (n = 13; 19.1%), diarrhea (n = 10; 14.7%), respiratory failure (n = 7; 10.3%), hypertransaminasemia and dermatitis (both with n = 6; 8.8%), asthenia, folliculitis and nail conditions (n = 4; 5.9%). Four cases of death related to erlotinib were associated with the onset of epilepsy and cerebral ischemia, the occurrence of pneumonia with neutropenia and leukopenia, the onset of respiratory failure and cardiogenic shock, and the occurrence of intestinal lung disease; two cases of death, associated with osimertinib, concerned a case of neoplasm progression and a case of sudden death.

Conclusion: The reporting of drugs-related ADRs in NSCLC were mostly reported in the literature and not unexpected ADRs were shown. However, further studies are necessary to increase the awareness about the safety profiles of new TKIs onto the market.

References/Further Sources of Information

• 1. Hirsch FR, Varella-Garcia M, Franklin WA, Veve R, Chen L, Helfrich B, et al. Evaluation of HER-2/neu gene amplification and protein expression in non-small cell lung carcinomas. Br. J. Cancer. 2002; 86, 1449–1456

• 2. Mishra R, Hanker AB, and Garrett JT. Genomic alterations of ERBB receptors in cancer: clinical implications. Oncotarget. 2017; 8, 114371–114392

2.55 P064 Focus on the Management of Reporting for Drug Ineffectiveness

2.55.1 A. Giannandrea ¹, M. Blonda¹, S. Antonacci ¹, D. Sivo²

2.55.1.1 ¹ASL Bari, Area Farmaceutica Territoriale, Bari, Italy; ²ASL Bari, Direzione Sanitaria, Bari, Italy

Introduction: About "MANAGEMENT OF REPORTS OF LACK OF EFFECTIVENESS IN THE NATIONAL PHARMACOVIGILANCE NETWORK", the AIFA Post-Marketing Supervision Area highlighted that, for therapeutic ineffectiveness reports, it’s important to establish if there is a drug therapeutic ineffectiveness or a disease progression, not attributable to the drug itself, but related to the natural course of the disease. AIFA ha sottolineato che, per una corretta valutazione clinica,i quattro requisiti minimi (un segnalatore identificabile, un paziente, una reazione avversa e un farmaco sospetto) non sono sempre sufficienti per considerare valida una segnalazione. Pertanto, per le segnalazioni di inefficacia del farmaco biologico, particolare attenzione deve essere pagato per ottenere informazioni relative a: anamnesi, durata della terapia, lotto, azioni intraprese, test di laboratorio, obiettività, indici di valutazione della malattia pre e post trattamento.

Objective: È stata effettuata un'analisi comparativa delle segnalazioni di mancata efficacia terapeutica pervenute prima e dopo il 10 maggio 2021 (data di pubblicazione nota AIFA). L'obiettivo dello studio era verificare l'efficacia delle informazioni aggiuntive richieste.

Methods: The data relating to drug ineffectiveness reports about the most populous ASL (1.221.857, ¼ regional population) were extrapolated from the National Pharmacovigilance Network (NPN), filtered by ASL of interest, from 01/01/2017 to04/30/2022.

Results: In the analyzed period, 39/2046 (1.9%) reports were received for ineffectiveness. In 2017, 2/269 (5% of 39), records were related to therapeutic ineffectiveness (1 originator Adalimumab; 1 equivalent Formoterol). In 2018, 2/217 (5% of 39), related to biosimilar Eritropoietin. In 2019, 1/249 (3%), related to measles, mumps, rubella vaccine. In 2020, of 13/288 (33%), 6 related to Adalimumab (2 originators,4 biosimilars); 2 Etanercept (1 originator, 1 biosimilar); 1 Certolizumab; 1 Tofacitinib; 1 Secukinumab; 1 Dimethyl Fumarate. In 2021, of 19/793 (46%), 11 were received before the AIF Anote (5 biosimilar Adalimumab; 1 biosimilar Infliximab; 1 cyclosporine;1 Tocilizumab; 1 Methotrexate;1 Fingolimod; 1 Carbomer), while 8 after the AIF Anote (3 biosimilar Adalimumab; 1 Sarilumab; 1 Vedolizumab; 1 Secukinumab; 1 Certolizumab; 1 Apremilast). As suggested by AIFA, for the last 8 reports, additional information was requested. In 5/8 cases, through additional information, 4/5 reports were evaluated like disease progression attributable to the drug itself. For Apremilast, by the clinical information, the progression of the disease was not attributable to the drug, rather to its physiological progression. Therefore, the report was sent to the AIC Holder, and not recorded in the RNF, like AIFA document. In 2022, up to 30 April, 3 reports were received for ineffectiveness (2 biosimilar Adalimumab;1 Guselkumab),supported by the reporters information.

Conclusion: The analysis of the therapeutic ineffectiveness reports has shown an increase over time. After the AIFA note publication, however, was recorded a reports decrease, from which it is possible to deduce a different approach by the reporters.

References/Further Sources of Information

AIFA, Area Vigilanza Post-Marketing, UFFICIO GESTIONE DEI SEGNALI, “GESTIONE DELLE SEGNALAZIONI DI MANCANZA DI EFFICACIA NELLA RETE NAZIONALE DI FARMACOVIGILANZA”, 10/05/2021

2.56 P065 Real-World Pharmacovigilance Analysis of Lenvatinib Use in Qatar

2.56.1 N. E. Omar ¹, S. Elazzazy²

2.56.1.1 ¹National Centre for Cancer Care and Research-Hamad Medical Corporation, Pharmacy Department, Doha-Qatar, Egypt; ²National Centre for Cancer Care and Research-Hamad Medical Corporation, Pharmacy Department, Doha-Qatar, Egypt

Introduction: Lenvatinib is a Tyrosine Kinase Inhibitor (TKI) that has been approved for different solid tumors including hepatocellular carcinoma (HCC), renal cell carcinoma, endometrial and thyroid cancer (1–4).

Objective: A Medication use evaluation (MUE) was performed for Lenvatinib. MUE is a systematic and interdisciplinary performance improvement method with an overarching goal of optimizing patient outcomes via ongoing evaluation and improvement of medication utilization (5).

Methods: The electronic health record identified of patients who received Lenvatinib between January 2020 and November 2021 were reviewed.

Results: A total of 28 patients were identified. Most of the patients used the Lenvatinib as a first or second line. Lenvatinib was used as monotherapy in 10 cases while as combination therapy in 18 cases: with pembrolizumab, everolimus or nivolumab. Lenvatinib was used as first line in 9 cases, second line in 8 cases, third line in 6 cases, fourth line in 3 cases and as fifth line in 2 cases. Three patients received Lenvatinib for non-FDA/non-EMA approved indications, including cholangiocarcinoma and metastatic melanoma (in combination with Nivolumab). Oncologists chose to start with lower doses than approved ones in 57 % of patients. Despite that, nearly 90 % of patients had multiple-dose reductions due to adverse drug reactions (ADRs) development. 60% of the patients were still alive during the review period; 82 % of them (14 out of 17) still receiving Lenvatinib while 18 % (3 out of 17) progressed. Unfortunately, 22% (6 out of 28) deceased while 18 % lost follow-up. Mortality was within less than or equal to 30 days post Lenvatinib initiation in one patient with HCC. A total number of 26 ADRs were identified. All ADRs were documented by Clinical pharmacists. The most-reported ADRs were cardiovascular and dermatological followed by endocrine ADRs. A list of reported ADRs is summarized in table 1. In more than 50 % of cases; monitoring parameters were not done as baseline or follow up (especially ECG, ECHO, dental clearance, and protein urine dipstick), which in some cases leads to toxicities and ADRs development.

Conclusion: Lenvatinib is a vital oncology medication but it has been badly tolerated in our center. Utilizing this medication as indicated with performing the appropriate monitoring parameters as recommended can benefit patients. Encouraging all health care providers to document ADRs will lead to a better patient experience. A monitoring plan sheet will be implemented in our center.

References/Further Sources of Information

• 1. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet (London, England) [Internet]. 2018 Mar 24 [cited 2022 May 21];391(10126):1163–73. Available from: https://pubmed.ncbi.nlm.nih.gov/29433850/.

• 2. Motzer R, Alekseev B, Rha S-Y, Porta C, Eto M, Powles T, et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med [Internet]. 2021 Apr 8 [cited 2022 May 21];384(14):1289–300. Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa2035716.

• 3. Makker V, Colombo N, Casado Herráez A, Santin AD, Colomba E, Miller DS, et al. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. N Engl J Med [Internet]. 2022 Feb 3 [cited 2022 May 21];386(5):437–48. Available from: https://pubmed.ncbi.nlm.nih.gov/35045221/.

• 4. Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med [Internet]. 2015 Feb 12 [cited 2022 May 21];372(7):621–30. Available from: https://pubmed.ncbi.nlm.nih.gov/25671254/.

• 5. Davis S, Rungruangphol PD, Gibson CM. Maximizing Benefits With the Medication Use Evaluation Process [Internet]. Vol. 53, Hospital Pharmacy. 2018. p. 284–5. Available from: https://doi.org/10.1177/0018578718775330.

2.57 P066 Psoriasis Associated with Interferon Bêta-1b in a Multiple Sclerosis Patient with Positive Rechallenge

2.57.1 M. Daldoul¹, W. Kaabi¹, M. B. Belgacem¹, Y. Mahjoubi¹, R. Daghfous¹, S. E. Aidli ¹

2.57.1.1 ¹University of Tunis El Manar Faculty of Medecine of Tunis-UR17ES12, National Centre of Pharmacovigilance of Tunisia, Tunis, Tunisia

Introduction: Several drugs such as lithium, beta-blockers, adrenergic antagonists, and interferons can aggravate pre-existing psoriasis or cause de novo psoriasis. Few cases of psoriasis were described with interferon bêta-1b.

Objective: Herein we report a rare case of interferon bêta-1b induced nummular psoriasis that occurred in a multiple sclerosis patient with positive rechallenge.

Methods: This case was reported in August 2020 and evaluated according to the French imputation method of causality assessment.

Results: A 39‐year‐old woman with no medical history of skin diseases has started interferon bêta-1b for her multiple sclerosis. After one month of daily use, she presented a generalized erythroderma and secondary diffuse erythemato-squamous coin-sized lesions evocative of nummular psoriasis. The patient denied any recent infection or stress. The evolution was favorable 20 days after drug withdrawal with corticosteroids treatment. After full recovery the rechallenge was attempted and the same symptomatology recurred one month later after the onset.

Conclusion: We suspected that interferon was the causative agent in the induction of psoriasis. The imputation score was likely due to the evocative delay of psoriasis occurrence, the favorable outcome after drug withdrawal, and the positive rechallenge.

Activation of psoriasis is an uncommon side effect of drugs and could mimic other cutaneous diseases in its rare features [1]. Physicians taking care of sclerosis patients should be aware of this affection which need careful evaluation of an added morbidity.

References/Further Sources of Information

• 1. Kolb-Mäurer A, Goebeler M, Mäurer M. Cutaneous Adverse Events Associated with Interferon-β Treatment of Multiple Sclerosis. Int J Mol Sci. 2015 Jul 2;16(7):14951-60.

2.58 P067 Optic Neuritis: A Serious Adverse Effect of Etanercept

2.58.1 I. Dahmani¹, S. Kastalli¹, O. Charfi¹, I. Aouinti¹, A. Zaiem¹, G. Lakhoua¹, R. Daghfous ¹, S. E. Aidli¹

2.58.1.1 ¹Chalbi Belkahia National Center of pharmacovigilance of Tunisia, Analyse et recueil des effets indésirables, Tunis, Tunisia

Introduction: Etanercept is a TNF-alpha inhibitor with proven efficacy in both rheumatic diseases and psoriasis. In contrast to uveitis and scleritis, which are the most reported ocular adverse reactions with etanercept, optic neuritis has been rarely described.

Objective: We hereby report a rare case of optic neuritis secondary to etanercept treatment.

Methods: This case was notified to the department of collection and analysis of adverse reactions of the Chalbi BELKAHIA national centre of pharmacovigilance of Tunis, and analysed according to the updated French method of imputability [1]

Results: A 34-year-old female patient with type 1 diabetes is followed for 18 years for pustular psoriasis with psoriatic arthritis. She was initially put on ciclosporin and methotrexate without improvement. Treatment with etanercept at a dose of 50 mg/week was then initiated with good cutaneous and articular evolution. After 15 months of treatment, the patient presented an amputation of the left temporal visual field with, on ophthalmological examination, a visual acuity of 8/10, a fundus examination without abnormality with no signs of papillary edema on angiography and a present and symmetrical photomotor reflex. The visual evoked potential, cerebral-medullary MRI, lumbar puncture and the immunological and infectious work-up were without abnormalities.

The diagnosis of optic neuritis was retained, etanercept was stopped and evolution was marked by the recurrence of the cutaneous and articular symptomatology with resolution of the visual disorders (visual acuity at 10/10). Later reintroduction of etanercept was marked by reappearance of visual disorders.

Conclusion: Optic neuritis remains a serious visual complication. Therefore, a visual field test before and during etanercept treatment is recommended.

References/Further Sources of Information

• 1. Théophile H, Dutertre JP, Gérardin M, Valnet-Rabier MB, Bidault I, Guy C, Haramburu F, Hillaire-Buys D, Méglio C, Arimone Y. Validation and Reproducibility of the Updated French Causality Assessment Method: an Evaluation by Pharmacovigilance Centres & Pharmaceutical Companies. Therapie. 2015 Sep–Oct;70(5):465–76. https://doi.org/10.2515/therapie/2015028. Epub 2015 Jun 26. PMID: 26423144.

2.59 P068 Safety of Biologic Therapies for Severe Asthma: An Analysis of Adverse Reactions Reported in the WHO Pharmacovigilance Database

2.59.1 P. M. Cutroneo ¹, E. Arzenton², F. Furci³, M. Bulzomi¹, M. Caminati4, G. Senna³, U. Moretti², G. Trifirò²

2.59.1.1 ¹Sicily Pharmacovigilance Regional Centre-University Hospital of Messina, Unit of Clinical Pharmacology, Messina, Italy; ²Section of Pharmacology, Department of Diagnostics and Public Health-University of Verona, Verona, Italy; ³Asthma Centre and Allergy Unit, University of Verona and Verona University Hospital, Verona, Italy; ⁴Department of Medicine, University of Verona and Verona University Hospital, Verona, Italy

Introduction: Biologics for severe asthma, targeting specific steps of the TH2 immune inflammation, represent a revolutionary treatment option for asthma therapy. Five biologics are approved for type 2 asthma phenotype: anti-IgE (omalizumab), anti-IL5 (mepolizumab, reslizumab, benralizumab), and anti-IL4 (dupilumab) [1]. These drugs are generally well tolerated, though information on long-term safety is limited and some adverse effects have not yet been fully characterized [2]. Spontaneous reporting systems represent the cornerstone for the detection of potential signals and exploration of the safety profile of all marketed drugs.

Objective: To provide an overview of safety data regarding biologics for severe asthma using VigiBase, the WHO global pharmacovigilance database.

Methods: We selected all Individual Case Safety Reports (ICSRs) attributed to biologics for severe asthma in VigiBase, up to May 8th, 2022. Study drugs included omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab. Descriptive frequency analyses of ICSRs as a whole class, as well as by individual products have been conducted. Reporting odds ratio (ROR) and the Information Component (IC) with 95% confidence intervals (CIs) were used as measures of disproportionality for adverse drug reactions (ADRs) associated with the study drugs compared with all other suspected drugs (reference group).

Results: Out of a total of 30,620,801 ICSRs collected in VigiBase up to May 8th, 2022, 147,467 (0.5%) were related to all biologics for severe asthma. Dupilumab was indicated as a suspected drug in 58.3% reports, followed by omalizumab (27.9%), mepolizumab (8.8%), benralizumab (4.8%), and reslizumab (0.3%). Most ICSRs concerned adult patients (39.4%) and mainly involved women (54.8%). Biologics for asthma were associated with a lower frequency of serious ADR reporting than for the reference group (24.5% vs 32%; p < 0.001). The most reported ADRs included in the important medical events (IME) list were pneumonia (n = 2,706), anaphylactic reaction (n = 2,102) and angioedema (n = 794). The frequencies of ocular, general, immune, cutaneous and respiratory disorders, injury, poisoning and procedural complications and infections were significantly higher for study drugs than for reference group (p < 0.001). Focusing on serious ADRs of IME list, selected biologics were disproportionally associated with unexpected adverse reactions, such as malignancies, pulmonary embolism, sarcoidosis, and acquired haemophilia A, in particular with omalizumab, herpes infections with dupilumab and mepolizumab, and eosinophilic granulomatosis with polyangiitis related to benralizumab.

Conclusion: The analysis of ADR reports related to biologics for severe asthma showed that the most frequently reported events concerned general, cutaneous and respiratory disorders. Potential safety signals, including malignancies, herpes infections, pulmonary embolism were detected, requiring further investigation.

References/Further Sources of Information

• 1. Caminati M, Bagnasco D, Rosenwasser L,et al. Biologics for the Treatments of Allergic Conditions: Severe Asthma. Immunol Allergy Clin North Am. 2020 Nov; 40(4): 549–564.

• 2. Jackson K, Bahna SL. Hypersensitivity and adverse reactions to biologics for asthma and allergic diseases. Expert Rev Clin Immunol. 2020 Mar; 16(3): 311–319.

VigiBase, the WHO global database of individual case safety reports (ICSRs) is the source of the information; the information comes from a variety of sources, and the probability that the suspected adverse effect is drug-related is not the same in all cases; the information does not represent the opinion of the UMC or the World Health Organization.

2.60 P069 Tofacitinib-Induced Acute Pancreatitis

2.60.1 M. B. Belgacem¹, A. Zaiem¹, O. Charfi ¹, Y. Mahjoubi¹, M. Daldoul¹, S. E. Aidli¹, R. Daghfous¹

2.60.1.1 ¹Tunis el Manar University Faculty of Medicine of Tunis/Research Unit UR17ES12., Chalbi Belkahia National Centre for Pharmacovigilance/Service for the collection and analysis of adverse reactions, Tunis, Tunisia

Introduction: Tofacitinib is an oral active immunosuppressant drug mainly indicated in rheumatoid arthritis (RA), inflammatory bowel disease¹. It is generally well tolerated. However, some adverse reactions (ADR) were reported. The most common ADR are severe infection, malign and benign tumors and thrombotic events. Pancreatitis has never been reported.

Objective: We report an exceptional case of pancreatitis associated with tofacitinib.

Methods: A 57-year-old female was treated since 2017 with captopril 50mg/day for hypertension and by several immunosuppressive treatment for rheumatoid arthritis (RA). On February, 14th 2022, for RA therapeutic failure, the patient started a new treatment based on tofacitinib 10mg daily. On February 20th, the patient presented acute abdominal pain with vomiting. Abdominal CT scan was performed in spite of a sub-normal biological tests (including the serum amylase and lipase level) showing a grade C pancreatitis. Etiologic investigations were normal including metabolic and lithiasic origin. The newly introduced drug (tofacitinib) was withdrawn. The patient presented a rapid clinical improvement with no recurrence of pancreatitis episode after 3 months of follow-up.

Results: The responsibility of tofacitinib was retained with an imputation score of I4 (C2, S2)³ mainly because of a compatible delay, the favorable outcome following its withdrawal (tofacitinib was the only drug stopped), and the negative investigations.

Pancreatitis is reported with immunosuppressive drugs. However, this ADR is not associated with the new anti-JAK, especially tofacitinib.

The mechanism is generally either toxic or immunologic. In this case, the mechanism seems to be toxic since the short delay of occurrence and the absence of immunologic symptoms.

Conclusion: This observation reported an exceptional case of pancreatitis induced by tofacitinib. The probable mechanism is toxic.

References/Further Sources of Information

• 1. Dhillon, S. Tofacitinib: A Review in Rheumatoid Arthritis. Drugs 77, 1987–2001 (2017).

• 2. Wolfe D, Kanji S, Yazdi F, Barbeau P, Rice D, Beck A, Butler C, Esmaeilisaraji L, Skidmore B, Moher D, Hutton B. Drug induced pancreatitis: A systematic review of case reports to determine potential drug associations. PLoS One. 2020 Apr 17;15(4):e0231883.

• 3. Miremont-Salamé, G., Théophile, H., Haramburu, F., & Bégaud, B. (2016). Imputabilité en pharmacovigilance: de la méthode française originelle aux méthodes réactualisées. Therapies, 71(2), 171–178.

2.61 P070 Collection of Data for Detecting Adverse Drug Events in Smart Hospitals via Electronic Health Records, the GTT, Sensors and IoMT

2.61.1 F. D. Pretis ^1,2, M. Kervinen³, K. Haatainen⁴, M. Tiihonen⁵, A. M. Tolppanen⁵, M. M. Forsberg^2,5

2.61.1.1 ¹University of Modena and Reggio Emilia, Department of Communication and Economics, Reggio Emilia, Italy; ²VTT Technical Research Centre of Finland, Kuopio Unit, Kuopio, Finland; ³Kuopio University Hospital, Centre of Medicine, Kuopio, Finland; ⁴Kuopio University Hospital, Patient Safety Manager, Kuopio, Finland; ⁵University of Eastern Finland, School of Pharmacy, Kuopio, Finland

Introduction: There is a need for a more comprehensive adverse drug event (ADE) surveillance system that would be capable of handling all of more extensive information sources [1]. This goal can be advanced by positioning hospitals in the centre of research work, and by exploiting the growing role of the secondary use of healthcare data laws such as a recent Finnish legislation fostering a broader and easier collection and exploitation of healthcare data for secondary use [2].

Objective: An improved detection of ADEs requires smart solutions for the collection of data, which has to occur in a more effective and comprehensive way at the hospital level [3].

Methods: Based on previous literature and experiences, we suggest a more efficacious integration of electronic health records with the employment of the Global Trigger Tool (GTT, developed by the Institute for Healthcare Improvement) [4] as the main backbone of a data collection system to be deployed in combination with monitoring technology [5] and Internet of Things for healthcare purposes, known as Internet of Medical Things (IoMT) [6].

Results: This ensemble of methods can help building a secondary surveillance network for adverse drug events. This network is an important step in improved detection of ADEs and development of traditional pharmacovigilance networks.

Conclusion: Enabling legislation with smart hospital concept can facilitate development of pharmacovigilance towards more precise direction and service individual patient [1].

References/Further Sources of Information

• 1. De Pretis F, van Gils M, Forsberg M M. A smart hospital-driven approach to precision pharmacovigilance. Trends Pharmacol. Sci. 2022; 43(6): 473–481

• 2. Aula V. Institutions, infrastructures, and data friction—reforming secondary use of health data in Finland. Big Data Soc 2019; 6205395171987598

• 3. Amalberti R, Benhamou D, Auroy Y, Degos L. Adverse events in medicine: easy to count, complicated to understand, and complex to prevent. J. Biomed. Inform. 2011; 44: 390–394

• 4. Sharek PJ, Parry G, Goldmann D, Bones K, Hackbarth A, Resar RK, et al. Performance Characteristics of a Methodology to Quantify Adverse Events over Time in Hospitalized Patients. Health Serv Res 2010; 46(2): 654–678

• 5. Triantafyllidis AK, Koutkias VG, Chouvarda I, Adami I, Kouroubali A, Maglaveras N. Framework of sensor-based monitoring for pervasive patient care. Healthc Technol Lett 2016; 3: 153–158

• 6. Yu L, Lu Y, Zhu X. Smart hospital based on Internet of Things. J Netw 2012; 7: 1654–1661

2.62 P071 Voriconazole-Induced Junctional Tachycardia: A Case Report

2.62.1 I. Bouaziz¹, K. Ksouda¹, M. Ksentini 3¹, H. Affes¹, R. Athyemen¹, R. Sahnoun¹, S. Hammami¹, K. Zghal ¹

2.62.1.1 ¹Regional Pharmacovigilance Service of Sfax-Pharmacology Laboratory, Faculty of Medicine-University of Sfax, Sfax, Tunisia

Introduction: The antifungal voriconazole is effective for the treatment of invasive fungal infections in immunocompromised patients. A serious adverse reaction to other triazoles is QT interval prolongation, which may precede life-threatening arrhythmias, such as twisted tips. Although ventricular arrhythmias are mentioned as a possible adverse effect of treatment with voriconazole (1).

Objective: We report a case report of Voriconazole-induced junctional tachycardia notified in the Regional Pharmacovigilance Service of Sfax.

Methods: The imputability study was performed according to the French Bégaud method.

Results: A 15-year-old patient with acute lymphoblastic leukemia and candidiasis infection was treated with Voriconazole. He developed 15 days later junctional tachycardia. Laboratory examinations showed a white blood cell count of 8140/mm³, absolute neutrophil count of 300/mm³, hemoglobin level of 4.4 g/dL, platelet count of 54,000/mm³, sodium level of 133/mm³ and potassium level of 3.5/mm³. Voriconazole was continued and the patient was treated with Flecainide with slight improvement.

The imputability score of voriconazole for junctional tachycardia was rated as doubtful C1S2I1B2

Conclusion: Voriconazole can induce QT prolongation and ventricular arrhythmia in the absence of other arrhythmogenic factors. It is recommended, as a precautionary measure, to monitor the heart rate and QT interval in patients receiving long-term treatment with voriconazole and, possibly, in patients receiving treatment with other antifungal azoles (1). The mechanism may be dependent or independent of dose and concentration

References/Further Sources of Information

• 1. Voriconazole-Induced QT Interval Prolongation and Ventricular Tachycardia: A Non–Concentration Dependent Adverse Effect. Y. Alkan et al; 2004 by the Infectious Diseases Society of America.

2.63 P072 Safety of Linagliptin in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis

2.63.1 H. Aljohani¹, F.S. Alrubaish¹, W. Alghamdi¹, F. Al-Harbi¹, N. Al-Fadel ¹

2.63.1.1 ¹Saudi Food and Drug Authority-Riyadh-Saudi Arabia., Drug Safety and Risk Management department, Riyadh, Saudi Arabia

Introduction: Linagliptin is an oral dipeptidyl peptidase (DPP) ‐4 inhibitor, which is indicated for the treatment of Type 2 diabetes mellitus (T2DM) as monotherapy or add-on therapy with other hypoglycemic drugs.¹

Objective: We aimed to summarize the evidence from randomized controlled trials (RCTs) to assess the safety of linagliptin focusing on cardiovascular risks among subjects with type 2 diabetes mellitus.

Methods: We performed a systematic search in the following databases: Medline, Embase, Cochrane Central, and Register of Controlled Trials from inception to November 2021. Randomized controlled trials (RCTs) of linagliptin compared to placebo in patients with Type 2 diabetes were included. The primary safety points were: cardiovascular (CV) adverse events including nonfatal stroke, nonfatal myocardial infarction (MI), CV death, MI, stroke, and hospitalization for unstable angina. While, secondary safety points were included 17 reported adverse events such as infections, hypoglycemia, and abdominal pain. Three reviewers independently screened and reviewed each study to extract relevant information. Any discrepancies were resolved by consensus. We performed meta-analyses using the random-effects model. Pooled risk ratios (RRs) of targeted adverse events with linagliptin compared to placebo were estimated using Mantel Haenszel.

Results: 24 studies with 19,981 adults patients were included. There was no difference in the incidence of all CV adverse events or individual CV adverse events between linagliptin and placebo arms. The pooled estimate of the risk of upper respiratory tract infection was reported in twelve trials, and a 32% risk reduction was shown among patients treated with the linagliptin group compared to the placebo group (RR = 0.68, 95% CI 0.51–0.90, and I² = 0%), while no difference was found in other infections. For gastrointestinal disorders, only the risk of abdominal pain showed a 5% risk reduction among patients treated with the linagliptin group compared to the placebo group (RR = 0.35, 95% CI 0.16–0.77, and I² = 0%).

Conclusion: Our meta-analysis study shows that there is no difference in CV. risks between linagliptin and placebo groups. Moreover, our study shows that there is a 32% risk reduction of upper respiratory tract infection and a 5% risk reduction for abdominal pain when using linagliptin compared to placebo.

References/Further Sources of Information

• 1. W; WYDYTYZ. Risk factors contributing to type 2 diabetes and recent advances in the treatment and prevention [Internet]. International journal of medical sciences. U.S. National Library of Medicine; [cited 2022 Jan 12]. Available from: https://pubmed.ncbi.nlm.nih.gov/25249787/.

2.64 P075 Drug Related-Problems in Hospitalised Patients with Chronic Kidney Disease

2.64.1 W.S. Alruqayb ^1,2, V. Paudyal¹, M. Price^3,4, A. Sarwar⁵, J. Aston⁵, R.S. Ahmed⁶, M. Hausien⁷, A.R. Cox¹

2.64.1.1 ¹Institute of Clinical Sciences-University of Birmingham, School of Pharmacy, Birmingham, United Kingdom; ²Taif University, College of Pharmacy, Saudi Arabia, Saudi Arabia; ³Institute of Applied Health Research-University of Birmingham, Test Evaluation Research Group, Birmingham, United Kingdom; ⁴University Hospitals Birmingham NHS Foundation Trust and University of Birmingham-, NIHR Birmingham Biomedical Research Centre, Birmingham, United Kingdom; ⁵University Hospitals Birmingham NHS Foundation Trust-Birmingham, Pharmacy Department, Birmingham, United Kingdom; ⁶University Hospitals Birmingham NHS Foundation Trust-Queen Elizabeth Hospital Birmingham, Renal, Birmingham, United Kingdom; ⁷Bedfordshire Hospitals NHS trust and Putnoe Medical Centre Partnership, Pharmacy, Bedford, United Kingdom

Introduction: A drug-related problem (DRP) is defined as "an event or circumstance involving drug therapy that actually or potentially interferes with desired health outcomes".^[1] Patients with chronic kidney disease (CKD) are more susceptible to DRPs due to comorbidities and polypharmacy.^[2,3]

Objective: This study aimed to investigate the types, characteristics, severity, causes, most common involved drug classes, and risk factors for DRPs in hospitalised patients with CKD.

Methods: A prospective follow up study was conducted in one of the largest teaching hospital trusts in England examining adults ≥ 18 years with a diagnosis of CKD (stage 1–4) hospitalised in medical and renal wards from November 2021 to April 2022. This study reviewed patients’ records, prescriptions, laboratory tests' results to identify DRPs. Identified DRPs were classified according to Pharmaceutical Care Network Europe (PCNE) v 9.0 classification system and assessed by an expert panel for severity and preventability. Potential risk factors of DRPs were tested using logistic regression statistical analysis.

Results: Three hundred and seventy-eight patients were included in this study with a mean age of 74.1 and a median of 78 (IQR 67–87). Females represented 54% of the sample, with polypharmacy present in 86% of patients. A total of 375 DRPs were identified in 240 patients (64%) with an average prevalence of 1.56 per patient. Prevalence of DRPs was 0.4% in stage-1 CKD, 1.7% in stage-2 CKD, 55% in stage-3 CKD, and 42.9% in stage-4 CKD. Number of DRPs per patients ranged from 1 to 4 (IQR 1–2). Treatment effectiveness was the most frequent DRP type (215–57.3%), followed by treatment safety (157–41.9%), and other (3–0.8%). The severity of DRPs was minor (n = 56, 14.9%), moderate (n = 315, 84%), and severe (n = 4, 1.1%). Most DRPs were definitely preventable (n = 268–71.5%). Common drugs groups involved were: Blood and blood forming organs (n = 88, 19.8%), Alimentary tract and metabolism with (n = 78, 17.6%), and Cardiovascular system with (n = 61, 13.7%). Hospital stays over 5 days and using ≥ 6 drugs were independent factors for DRPs in CKD hospitalised patients with (OR 6.5, 95% CI 3.2–13.2; P = < 0.001) and (OR 6.3, 95% CI 2.9–13.5; P = < 0.001), respectively.

Conclusion: The majority of hospitalised CKD patients experienced a DRP, with polypharmacy and co-morbidities as significant risk factors. Awareness of this increased risk should inform prescribing decisions. Future work should focus on interventions to reduce DRPs in patients with CKD.

References/Further Sources of Information

• 2. 1 Pharmaceutical Care Network Europe (PCNE). Classification for Drug Related Problems V9. 1.

• 3. 2 Abunahlah N, Elawaisi A, Velibeyoglu FM, Sancar M. Drug related problems identified by clinical pharmacist at the Internal Medicine Ward in Turkey. International Journal of Clinical Pharmacy. 2018 Apr;40(2):360–7.

• 4. 3 Adibe MO, Igboeli NU, Ukwe CV. Evaluation of drug therapy problems among renal patients receiving care in some tertiary hospitals in Nigeria. Tropical Journal of Pharmaceutical Research. 2017 Apr 5;16(3):697–704.

2.65 P076 Factors Associated with Patient-Experienced Burden of Adverse Drug Reactions of Non-Vitamin K Oral Anticoagulants

2.65.1 G. von Kreijfelt ¹, J. B. Zhang¹, L. Rolfes¹

2.65.1.1 ¹The Netherlands Pharmacovigilance Centre Lareb, Signal Detection, 's-Hertogenbosch, Netherlands

Introduction: Experiencing adverse drug reactions (ADRs) may impact the patient's well-being and attitude towards their therapy with medicines. It has been demonstrated that the majority of patients who discontinued drugs reported a very high burden of ADRs [1]. How patients experience the burden of ADRs may be explained by several factors. Insight in these factors can help healthcare professionals (HCPs) to optimize the guidance of patients through their drug therapy.

Objective: To explore factors that are associated with a high, or low to moderate patient-experienced burden of ADRs.

Methods: A web-based prospective cohort design was used to collect information on patient characteristics and their experienced ADRs on non-vitamin K oral anticoagulants (NOACs) through four questionnaires. The experienced burden of ADRs was asked using a 5-point Likert scale ranging from 1 (not burdensome) to 5 (extremely burdensome). Burden scores 1 to 3 were considered as low to moderate burden, and burden scores 4 and 5 as high burden. To identify associated factors for the burden of ADRs, we performed backward stepwise selection to create a logistic regression model. Factors included in the analysis were: gender, age (< 70 or ≥ 70 years), type of NOAC, previous vitamin K antagonist use, self-managing NOAC use, consulting a HCP, (considering) withdrawing the NOAC, hospitalisation, haemorrhagic ADRs, the amount of ADRs (< 4 or ≥ 4), and outcome of the ADR. RStudio with R version 4.1.3 was used for the statistical analysis, with a significance level of < 0.05.

Results: A total of 1076 ADRs reported by 627 participants were included. Factors associated with a high burden are demonstrated in Table 1. Hospitalisation (OR 6.07), (considering) withdrawing the NOAC (ORs 6.10 and 6.34 respectively), and worsening of the ADR (OR 6.17) had the strongest association with a high burden. Consulting a HCP and experiencing four or more ADRs increased the odds by respectively 4.18 and 2.57. Furthermore, women had a 1.55 increased odds for a high burden compared to men.

Conclusion: This study demonstrates that multiple factors are associated with the patient-experienced burden of ADRs of NOACs. Worsening of the ADR, hospitalisation and (considering) NOAC withdrawal were mostly associated with a high burden of ADRs. Other factors associated with a high burden were female gender, consulting a HCP, and experiencing ≥ 4 ADRs. More studies are needed to explore how these factors influence drug therapy.

References/Further Sources of Information

• 1. Rolfes L, Haaksman M, van Hunsel F, van Puijenbroek E. Insight into the Severity of Adverse Drug Reactions as Experienced by Patients. Drug Saf. 2020 Mar;43(3):291–293.

2.66 P077 Factors Affecting Clopidogrel Cafety in the Montenegrin Population

2.66.1 V. Vukicevic ¹, S. Mugosa^1,2

2.66.1.1 ¹Institute for Medicines and Medical Devices, Pharmacovigilance Department, Podgorica, Montenegro; ²Faculty of Medicine-University of Montenegro, Lecturer, Podgorica, Montenegro

Introduction: Clopidogrel is an antiplatelet drug that inhibits platelet activation and aggregation by blocking adenosine diphosphate (ADP) P2Y12 receptor [1]. Along with aspirin, it represents the mainstay in the management of patients suffering from myocardial infarction, ischemic stroke, acute coronary syndrome, and atrial fibrillation [2]. However, clopidogrel therapy is not always efficient or safe since the possible outcomes range from complete resistance to treatment to major bleeding events [3].

Objective: The aim of this study was to provide the analysis of genetic and non-genetic factors that influence clopidogrel efficacy and safety in cardiology patients.

Methods: We have conducted a prospective study in 200 hospitalized patients. CYP2C19 genetic testing was conducted, and the PREDICT score was calculated in 102 out of 200 patients treated with clopidogrel in order to determine the influence of genetic and non-genetic factors on outcomes of interest. Adverse cardiovascular events and adverse reactions to clopidogrel were assessed during 12 months follow up period.

Results: In univariate logistic regression model, statistically significant predictors of the outcome of interest are: the PREDICT score (p < 0.001), enzymatic activity [slow metabolizers (p < 0.001) compared to the rapid, extensive and intermediate metabolizers as a reference category] and concomitant use of other drugs that are also metabolized through CYP2C19 (p = 0.030). In multivariate logistic regression model, predictors from the model of univariate logistic regression which were statistically significant at the significance level of 0.05 were included. The model contains three predictors—PREDICT score, enzymatic activity and concomitant administration of other drugs that are metabolized via the same CYP enzyme. The whole model was statistically significant (p < 0.001). There is no significant multicollinearity or interaction between the predictors (p = 0.002 and 0.009, respectively).

Conclusion: In assessing the clopidogrel resistance in cardiology patients the stepwise approach could be used, combining the PREDICT score, platelet aggregation test, and genetic testing for CYP2C19 polymorphism [4].

References/Further Sources of Information

• 1. Schror K. The basic pharmacology of ticlopidine and clopidogrel. Platelets 1993; 4: 252–261.

• 2. Zhang Q, Wang C, Zheng M et al. Aspirin plus clopidogrel as secondary prevention after stroke or transient ischemic attack: a systematic review and meta-analysis. Cerebrovasc Dis 2015; 39: 13–22.

• 3. Bowry AD, Brookhart MA, Choudhry NK. Meta-analysis of the efficacy and safety of clopidogrel plus aspirin as compared to antiplatelet monotherapy for the prevention of vascular events. Am J Cardiol 2008; 101: 960–966.

• 4. Su J, Xu J, Li X et al. ABCB1 C3435T polymorphism and response to clopidogrel treatment in coronary artery disease (CAD) patients: a meta-analysis. PLoS One 2012; 7: e46366.

2.67 P078 Urinary MicroRNAs as Possible Biomarkers of Cisplatin-Induced Nephrotoxicity in Patients with Head and Neck Cancer

2.67.1 N. d. G. Torso¹, J. C. F. Quintanilha¹, M. A. Cursino¹, J. B. Borges², E. d. C. Pincinato¹, C. S. P. Lima¹, L. A. S. Navarrete³, P. Moriel ⁴

2.67.1.1 ¹University of Campinas, School of Medical science, Campinas, Brazil; ²Instituto Dante Pazzanese de Cardiologia, Instituto Dante Pazzanese de Cardiologia, São Paulo, Brazil; ³Universidade de La Frontera, Facultad de Medicina, Temuco, Chile; ⁴University of Campinas, Faculty of Pharmaceutical Science, Campinas, Brazil

Introduction: The treatment of head and neck cancer (HNC) currently recommended consists of chemotherapy with cisplatin concomitant with radiotherapy. However, cisplatin treatment is frequently associated with renal adverse drug reactions (ADRs) (1), impacting patients' quality of life; besides, as traditional biomarkers have low sensitivity and specificity (2,3), there is currently a search for new ones.

Objective: This study aimed to evaluate miRNAs as possible biomarkers of cisplatin-induced renal ADRs in HNC patients.

Methods: Massive sequencing was performed using urinary miRNAs from HNC patients, collected 5 days after cisplatin chemotherapy. To assess the expression of miRNAs, a comparison was made between the case and control groups (6 patients with nephrotoxicity and 6 without nephrotoxicity, respectively); differential expression was analyzed by GeneGlobe (Qiagen) and normalized by DESeq2. Based on the results of sequencing and analysis of the current literature, 6 miRNAs were selected (hsa-miR-6729-5p, hsa-miR-1238-5p, hsa-miR-4706, hsa-miR-6805-5p, hsa-miR-4322 and hsa-miR-21-5p) to have their expression evaluated by qPCR, before and 5 days after chemotherapy (D5), also in urine samples. In this validation stage, the expression profile of these miRNAs was compared between the case and control groups (composed, respectively, of 24 participants with renal ADRs and 25 participants without); the relative expressions were evaluated by the 2^-∆CT method.

Results: The results obtained in the validation stage showed that, except hsa-miR-6729-5p, all other miRNAs showed a tendency to be upregulated in the control group before and after chemotherapy when compared to the case group. Some miRNAs resulted in remarkably high fold regulation (FR) values (1. hsa-miR-6729-5p—baseline: FR = 11.8, p = 0.5958; D5: FR = 4.1, p = 0.6306; 2. hsa-miR-4706—baseline: FR = − 1.3, p = 0.4843; D5: FR = − 26.7, p = 0.8623) and others were smaller but still relevant (3. hsa-miR-1238-5p—baseline: FR = − 2.4, p = 0.1170). However, although a difference in expression was found between the groups for all miRNAs, this difference was not significant.

Conclusion: Renal ADRs are still an obstacle to the effective therapy and quality of life of patients treated with cisplatin. The preliminary results of this work show that some miRNAs tend to be elevated in patients without ADRs, therefore they could be protecting against the induction of renal injury; however, in order to possibly help the clinician in the evaluation/choice of chemotherapy treatment for these patients, further studies are still needed and in a larger number of patients.

References/Further Sources of Information

• 1. Weykamp F, Seidensaal K, Rieken S, Green K, Mende S, Zaoui K, et al. Age-dependent hemato- and nephrotoxicity in patients with head and neck cancer receiving chemoradiotherapy with weekly cisplatin. Strahlentherapie und Onkol. 2020 Jun 1;196(6):515–21.

• 2. Waikar SS, Betensky RA, Emerson SC, Bonventre J V. Imperfect gold standards for kidney injury biomarker evaluation. J Am Soc Nephrol. 2012;23(1):13–21.

• 3. Van Meer L, Moerland M, Cohen AF, Burggraaf J. Urinary kidney biomarkers for early detection of nephrotoxicity in clinical drug development. Br J Clin Pharmacol. 2014;77(6):947–57.

Financial support: Fapesp–Processo nº: 2019/20010-7 e 2019/13250-1; CNPq and CAPES.

2.68 P079 ABCC2 Gene Polymorphism and Adverse Reactions to Carboplatin and Paclitaxel Treatment in Non-small Cell Carcinoma Patients

2.68.1 C. S. Sequin¹, P. E. N. S. Vasconcelos¹, G. F. S. Fidelis², M. V. Morau¹, A. S. Barbeiro¹, L. Zambon¹, M. W. Perroud Jr¹, E. C. Pincinato¹, P. Moriel ²

2.68.1.1 ¹University of Campinas, School of Medical Science, Campinas, Brazil; ²University of Campinas, Faculty of Pharmaceutical Science, Campinas, Brazil

Introduction: The estimate for each year of the triennium 2020-2022 that will occur 30 thousand lung cancer new cases in Brazil¹, which can be classified as: small cell lung cancer (SCLC) and non-small cell lung cancer cells (NSCLC), that corresponds the 85% of the cases². The main NSCLC treatments are platinum-derived chemotherapeutics, highlighting carboplatin and paclitaxel³, adverse drug reaction (ADRs) may compromise the treatment. ABCC2 gene is involved in molecules of transport, polymorphs in this gene may be related wit ADRs and response compromising the effectiveness of treatment⁴.

Objective: Investigate the prevalence the main ADRs after the first cycle of chemotherapy with Carboplatin and Paclitaxel in patients with NSCLC. Analyze the frequency of polymorphism in the gene ABCC2 (rs717620) in those who had hematological and renal ADRs.

Methods: Hematological and biochemical tests were performed before and after 21 days of the first chemotherapy session. Hematological, renal, hepatic and gastrointestinal ADRs was determined using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, criteria. Genomic DNA was extracted and purified from peripheral blood using a Wizard^® Genomic DNA Purification Kit (Promega, USA) according to the manufacturer's protocol. The ABCC2 (rs717620) the polymorphisms were studied with Taqman^® (Applied Biosystems, CA, USA), determined by rt-PCR.

Results: A total of 85 patients with NSCLC, treated at Clinics of Hospital Unicamp, the most with an average age of 63 years, men (55%), Caucasians (85%), accentuated smokers (35%), abstainer (35%), with performance status (KPS) at 100% (88%) and with adenocarcinoma (63%). Observed that 72% of patients had an hematological ADRs, grade 1 anemia was the most prevalent. 61% had a grade 1 gastrointestinal ADRs: nausea (25%), vomit (8%) and diarrhea (18%). Hepatic ADRs (59%) grade 1 hepatic ADRs was observed in 59%. Renal ADRs grade 1 was observed in 74%, the most prevalent were: reduced creatinine clearance (28%), Hyponatremia (24%), and Hypocalcemia (18%). In the gene ABCC2, was observed heterozygosity (CT) in 56%, 28% homozygous CC and 15% homozygous TT in the population studied, those with genotype CC had more hematological (54%) and renal (44%) ADRs when compared to the others genotypes, the polymorphism were in the Hardy-Weinberg equilibrium.

Conclusion: Patients in this study has a high prevalence of hematological and renal ADRs. The finding suggests that patients who are homozygous (CC) for the gene ABCC2 (rs717620) are at increased risk for hematologic and renal ADRs if compared to the other genotypes (CT + TT).

References/Further Sources of Information

• 1. INCA—Instituto Nacional de Câncer [Internet]. Síntese de Resultados e Comentários [cited 2022 April 27]. Available from: https://www.inca.gov.br/estimativa/sintese-de-resultados-e-comentarios#:~:text=C%C3%A2ncer%20de%20pulm%C3%A3o-.

• 2. Araújo A, Magalhães M, Febra J, Coutinho F, Rosendo E, Castro A, et. al. Terapêutica após progressão do carcinoma do pulmão de não pequenas células precoce ou localmente avançado tratado com quimioterapia. Revista GECP 2014; 2: 17–22.

• 3. Oliveira PI, Pereira CAC, Belasco AGS, Bettencourt ARC. Comparison of the quality of life among persons with lung cancer, before and after the chemotherapy treatment. Rev. Latino-Am. Enfermagem 2013; 21(3): 787–794.

• 4. Peethambaram P, Fridley BL, Vierkant RA, Larson MC, Kalli KR, et. al. Polymorphisms in ABCB1 and ERCC2 associated with ovarian cancer outcome. Int J Mol Epidemiol Genet 2011; 2(2):185–195.

Financial support: CAPES; CNPq and FAPESP.

2.69 P080 Development of a Clinical Focus Pharmacovigilance System

2.69.1 J. A. Maza ¹, P. G. K. Michel², R. H. Franchesca³, C. J. J. Guadalupe¹, G. V. Ingrid¹, M. Z. Daniela¹, F. R. Susana¹

2.69.1.1 ¹Instituto Nacional de Cardiología Ignacio Chávez, Clinical Pharmacology, Mexico, Mexico; ²Instituto Nacional de Cardiología Ignacio Chávez, Clinial Pharmacology, Mexico, Mexico; ³Instituto Nacional de Cardiología Ignacio Chávez, Clincial Pharmacology, Mexico, Mexico

Introduction: Now more than ever the pharmacovigilance has demonstrated great relevance in making medication safer by evaluating the benefit-risk ratio in the treatment used in COVID-19 patients [1]; nevertheless, pharmacovigilance has always aimed to help clinicians and patients make wiser therapeutical decisions as Dra. Marie Lindquist’s once said. Therefore, we have developed at the Instituto Nacional de Cardiología Ignacio Chávez the Pharmacovigilance Institutional Center, establishing as our goals to manage a pharmacovigilance’s system that aims to take the World Health Organization Challenge Medication Without Harm by promoting the rational use of medication, and identifying risks related to drugs before they impact the patients.

Objective: Exemplify the impact that a clinical focus pharmacovigilance system has had in the patients at the Instituto Nacional de Cardiología Ignacio Chávez.

Methods: With the Pharmacovigilance Institutional Center databases of Drug Adverse Reactions (DAR) and Event Supposedly Attributed to Vaccination or Immunization (ESAVI) identify the most important cases in which a clinical decision has been made and exemplify the process of the decision making.

Results: From the opening of the Institutional Center in 2020 at the start of the COVID-19 pandemic, we have identified and reported 292 DAR in VigiFlow and 421 ESAVI to the General Direction of Epidemiology. From these reports we can identify several different pharmaceutical interventions related to the pharmacovigilance evaluations, that have given as a result the modification of the clinical approach:

• Corticosteroids used in COVID-19 patients: we modified the dosage given to patients reducing the severity of the DAR.

• Drug Induced Liver Injury: we alerted in early moment the elevation of hepatic markers making changes in the prescriptions.

• · Dapagliflozin use in heart failure patients that produced ketoacidosis: after alerting the surgical team there was no more patients presenting this DAR.

• · Tocilizumab used in COVID-19 patients, there was a concern to use this monoclonal medication: with this intervention we established the safety parameters to use this medication.

• · RNA COVID-19 vaccines producing myocarditis: with this intervention we have been able to establish a fast identification of these cases.

Exemplifying the process in the next table.

Conclusion: Pharmacovigilance now a day require to explore a more patient focus and clinical approach in where there are pharmacovigilants working hand by hand next to the clinicians and understanding the needs of the patients. For that we require assemble teams that can identify, evaluate and give feedback on the best way to treat DAR.

References/Further Sources of Information

• 1. A New Era of Pharmacovigilance: Future Challenges and Opportunities; Frontier in Drug Safety and Regulation; Gianluca Trifirò and Salvatore Crisafulli; 25 February 2022

2.70 P081 Falling for Amiodarone—A Safety Analysis in Patients 60 Years and Older

2.70.1 A. Rudolph ¹, C. Wikner¹, Q. Y. Yue¹

2.70.1.1 ¹WHO Collaborating Centre for International Drug Monitoring-Uppsala Monitoring Center, WHO CC-Signal Management Team, Uppsala, Sweden

Introduction: Older patients, representing a frail population, are at a high risk of falling because of age-related changes in multiple physiological systems. Falls are the leading cause of injury-related deaths in elderly individuals [1]. Cardiac arrhythmias affect a large proportion of the world’s population and are frequent within the older population [2]. Amiodarone is one of the most effective and commonly prescribed antiarrhythmic drugs. It has a very long plasma half-life and undergoes extensive hepatic metabolism via several CYP enzymes [3]. Its toxicity profile is broad, potentially affecting various organs. Amiodarone may interact with other clinically important drugs. The mechanisms of its drug interactions could be the change of pharmacokinetics (mainly by inhibition of hepatic metabolism), or pharmacodynamics of co-administered drugs [4].

Objective: To review the risk of falling with amiodarone in older patients.

Methods: A quantitative analysis of data in VigiBase, the WHO global database of suspected adverse reactions of medicinal products.

Results: As of 3 May 2022, VigiBase included 378 cases reporting the MedDRA preferred term “Fall” and the substance amiodarone as suspected or interacting agent. After de-duplication and removal of irrelevant reports, 279 reports remained for analysis. Most reports (n = 270; 97%) concerned patients aged 60 years or older. The patients’ median age was 81 years, ranging from 60 to 96. In 108 cases (39%), amiodarone was reported as the only suspected drug. Most patients received more than one drug with a median of two drugs being administered concomitantly, ranging from one to fifteen medicinal products.

The event “Fall” was reported to occur in median six months after start with amiodarone treatment, with a wide range between days to years. However, information about the time-to-onset was reported only in a limited number of cases. A subgroup analysis comparing patients with and without polypharmacy was performed (see Table 1). Median time-to-onset was remarkably shorter and fatality was higher in patients receiving more than five drugs.

In 20 cases (38%), a drug-drug-interaction between amiodarone and one or more other substances was identified and flagged by the reporter.

Conclusion: Prescribers should be aware that adding drugs—especially drugs able to cause extensive toxicity and drug-drug-interactions, such as amiodarone—to a pre-established multi-drug therapy regime in an older patient population, may significantly increase the risk for experiencing falling and potentially severe adverse outcomes.

References/Further Sources of Information

• 1. US Centers for Disease Control and Prevention. Deaths from Older Adult Falls., https://www.cdc.gov/falls/data/fall-deaths.html (2020, accessed 27 October 2021).

• 2. Gupta AK, Maheshwari A, Tresch DD, et al. Cardiac arrhythmias in the elderly. Card Electrophysiol Rev 2002; 6: 120–128.

• 3. Latini R, Tognoni G, Kates RE. Clinical Pharmacokinetics of Amiodarone: Clin Pharmacokinet 1984; 9: 136–156.

• 4. Lesko LJ. Pharmacokinetic Drug Interactions with Amiodarone: Clin Pharmacokinet 1989; 17: 130–140.

2.71 P082 Pharmacogenomics (PGx) as a New Special Interest Group (SIG) at ISOP

2.71.1 Q. Y. Yue ¹, B. Edwards², G. Furlan³, A. Agarwal⁴, P. Zuluaga⁵, M. Wadelius⁶

2.71.1.1 ¹Uppsala Monitoring Centre, WHO Collaborating Centre, Uppsala, Sweden; ²Managing Director Husoteria ltd, Pharmacovigilance & Drug Safety, London, United Kingdom; ³Pfizer S.r.I, Worldwide Safety, Milano, Italy; ⁴Zogenix, Drug Safety & Pharmacovigilance, Emeryville, USA; ⁵President-Colombian Association of Pharmacovigilance, Consultant, Bogota, Colombia; ⁶Uppsala University, Department of Medical Sciences, Uppsala, Sweden

Introduction: The risk of certain adverse drug reactions (ADRs) is known to be associated with variation in so called pharmacogenes [1]. Pharmacogenomic information has been included in the labels of a number of medicines to provide guidance on appropriate dose or to advise patients carrying risk alleles to carefully monitor for ADR symptoms or to not take the medicine [2].

Pharmacogenomic information in the product label takes into consideration the overall benefit-risk balance, magnitude of the genomic biomarker effect, strength of evidence as well as other aspects such as seriousness of the ADRs, underlying diseases, therapeutic alternatives, and interactions with other medicines. The label regarding pharmacogenomic testing may be classified into three categories as mandatory, recommended, or for information [3].

Objective: A global Special Interest Group (SIG) has been established in 2020 within the International Society of Pharmacovigilance (ISoP) to provide an opportunity for members interested in pharmacogenomics to expand knowledge of how medicines cause ADRs in genomic subpopulations; and to support Pharmacovigilance relevant to medicines with pharmacogenomic associations.

Methods: The SIG is open to all ISoP members and is made up of clinical and academic members from medicines regulatory bodies, non-governmental organizations and the pharmaceutical industry. SIG members regularly share news amongst the members and exchange experiences to support the coordination, evaluation and training on pharmacogenomics in pharmacovigilance, this with the purpose of improving knowledge and contributing to the safety of those patients who must use medications.

Results: Examples of the activities of the SIG will be shared.

Conclusion: The pharmacogenomics SIG at ISoP will contribute to the goal of identifying patients at risk and to improve the benefit/risk balance of drug treatment in genomic subpopulations.

References/Further Sources of Information

• 1. Carr DF, Pirmohamed M. Biomarkers of adverse drug reactions. Exp Biol Med (Maywood) 2018; 243: 291–299.

• 2. Drug Label Annotations. PharmGKB, https://www.pharmgkb.org/labelAnnotations (accessed 28 April 2022).

• 3. Guideline on key aspects for the use of pharmacogenomics in the pharmacovigilance of medicinal products. 19.

2.72 P085 Influence of the CYP450 Genetic Variation in Lipid Abnormalities with Clozapine Treatment: A Pilot Study in Patients with Psychiatric Disorder

2.72.1 J. K. N. Pereira ¹, E. d. C. Pincinato¹, P. Dalgalarrondo¹, A. S. Júnior¹, P. Moriel², O. H. D. T. Torre¹

2.72.1.1 ¹UNICAMP, School of Medical Science, Campinas, Brazil; ²UNICAMP, Faculty of Pharmaceutical Science, Campinas, Brazil

Introduction: Clozapine (CLZ) is one of the antipsychotics considered the gold standard for treatment-resistant schizophrenia (ERT); despite its effectiveness, it is related to adverse drug reactions (ADRs), which can be caused by several factors, including genetic variability [1-3]. Despite the significant benefits involved in the treatment of CLZ, its use may be associated with an increased prevalence of metabolic disorders such as diabetes, obesity, metabolic syndrome, and dyslipidemia [4-5].

Objective: This study aimed to verify whether CYP450 Genetic Variation related to Clozapine metabolism can influence the presence of ADRs related to lipids metabolism in patients with psychiatric disorders

Methods: This prospective and observational study was conducted at the Psychiatry Outpatient Clinic of HC/UNICAMP. Lipids ADRs was determined using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Genomic DNA was extracted and purified from peripheral blood using a Wizard^® Genomic DNA Purification Kit (Promega, USA) according to the manufacturer's protocol. The CYP genetic variation were studied with Taqman^® (Applied Biosystems, CA, USA), determined by rt-PCR. The project was approved by the Research Ethics Committee (83192918.9.0000.5404).

Results: Thirty-nine patients aged 29.7 ± 10.0 years were enrolled in the study, mostly men (64.1%), Caucasians (82.1%), and single (64.0%). Observing the ADRs for hypertriglyceridemia, 29.7% had grade 1 severity, 8.1% had grade 2, 2.3% had grade 3, and 2.3% had grade 4. No patient had hypercholesterolemia. For the CYP2D6 Gene (rs1065852), CYP3A4 (rs2740574) and CYP1A2 (rs762551) we observed a prevalence of 62.0% for the homozygote GG, 79.0% homozygote TT and 89.2% for the heterozygote (CA), respectively. The allelic variant rs762551 (CYP1A2) can be related to the occurrence of hypertriglyceridemia, where patients with homozygous CC had more probability in this ADR (75.0%) than in the group of heterozygous (CA) (39.4%).

Conclusion: Most of the patients in the study are young male adults and singles. Hypertriglyceridemia was observed in 43.2% of patients to some degree. This increase in triglycerides is related to increased body weight, a necessary ADR of clozapine can lead to other metabolic disorders such as diabetes and hypertension. Preliminary data also suggest that patients homozygous (GG) for the CYP1A2 gene (rs762551) have a higher risk of having hypertriglyceridemia when compared to the other genotypes.

References/Further Sources of Information

• 1. Mak M, Samochowiec J, Frydecka D, Pelka-Wysiecka J, Szmida E, Karpinski P, et al. First-episode schizophrenia is associated with a reduction of HERV-K methylation in peripheral blood. Psychiatry Res. 2019; 271: 459–63

• 2. Uher R. Gene-environment interactions in severe mental illness. Front Psychiatry. 2014; 5: 48

• 3. Dick DM, Adkins A, Aliev F, Kendler KS, Agrawal A, Hewitt JK, et al. Candidate Gene-Environment Interaction Research: Reflections and Recommendations. Perspectives on Psychological Science. 2015; 10: 37–59

• 4. 4.Citrome L, McEvoy JP, Saklad SR. Guide to the Management of Clozapine-Related Tolerability and Safety Concerns. Clin Schizophr Relat Psychoses. 10: 163–77

• 5. Pato CMF, Rodriguez VM, Valverde JIF. Metabolic syndrome and atypical antipsychotics. Possibility of prediction and control. Rev Psiquiatr Salud Ment. 2017; 10: 38–44

Funding: Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES); Conselho Nacional de Desenvolvimento Científico e Tecnológico CNPQ).

2.73 P086 Clinical Pharmacokinetics and Pharmacodynamics of Moxifloxacin in Human Tuberculosis

2.73.1 S. Onasanya ¹, O. Onasanya², A. G. Onasanya³

2.73.1.1 ¹University of KwaZulu-Natal-Westville Campus, School of Health-Science-Department of Pharmacology, Durban, South Africa; ²Olabisi Onabanjo University Teaching Hospital, Pharmacy, Sagamu, Nigeria; ³Olabisi Onabanjo University, Pharmacy, Sagamu, Nigeria

Introduction: Clinicians treating patients with tuberculosis have recommended that the current regimen requires improvement and /or a less cumbersome and easy to adhere to therapeutic medicine/regimen. In the current therapeutic treatment, the duration of the treatment is overly long and patients unable to tolerate the combination The current 6 months regimen was introduced in early 80’s and there is a growing threat of multidrug resistant (MDR) and extremely drug-resistant (XDR0-TB. One of the best approaches to TB drug development that can yield results rapidly is to repurpose drugs that also have activity against TB. Moxifloxacin is an example of this drug. Moxifloxacin has been reported to play an important role in the management of patients who are unable to tolerate multidrug resistance TB regimen

Objective: To assess the pharmacokinetic and Pharmacodynamics of Moxifloxacin in human tuberculosis.

Methods: A narrative review of Moxifloxacin pharmacokinetics and pharmacodynamics in adults with TB was carried out across a range of doses and various variables that influence its pharmacokinetics/pharmacodynamics. Several factors including malnutrition, fasting, HIV infection, diabetes mellitus, dose size, pharmacogenetic polymorphisms, hepatic cirrhosis, and substandard medicinal products alter Moxifloxacin exposure and/or efficacy

Results: Renal impairment has no significant influence on Moxifloxacin pharmacokinetics when dosed at 800 mg/day. The mean maximum concentration of drug in serum and the area under the concentration–time curve from 0 to 24 h (AUC_0–24 h) is 3.2 mg·L⁻¹ and 29.2 mg h·L⁻¹ maximum (peak) concentration is an independent predictor of sterilizing activity and therapeutic drug monitoring at 6, 12, and 18 h post-dose may aid in optimizing dosing to achieve the recommended moxifloxacin concentration of ≥ 29 mg/L. A higher Moxifloxacin C_max is required for severe forms TB such as TB meningitis, with C_max ≥ 35 mg/L and area under the concentration–time curve (AUC) from time zero to 6 h (AUC₆) ≥ 7 mg·h/L associated with reduced mortality.

Conclusion: Further studies are needed to confirm whether doses achieving exposures higher than the current standard dosage could translate into faster sputum conversion, higher cure rates, lower relapse rates, and less mortality. It is interesting to discover that daily Moxifloxacin dose of up to 800 mg/ 70kg were found to be safe and well-tolerated over a period of 3 months. Higher -dose Moxifloxacin may be considered in future studies when examining potentially and shorter regimens and markers of efficacy like AUC/MIC (Minimum inhibitory Concentration) and AUC/MIC should equally be examined.

References/Further Sources of Information

• 1. Fox, W., Ellard, G.A., Mitchison, D.A (1999). Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946–1986, with relevant subsequent publications. Int J Tuberc Lung Dis 1999; 3.

• 2. Irwin, S.M., Converse, P.J., (2015). Evaluation of moxifloxacin-containing regimens in pathologically distinct murine tuberculosis models. Antimicrob Agents Chemother 2015; 59: 4026–4030

• 3. Te Brake, L., Dian, S., Ganiem, A.R., (2015). Pharmacokinetic/pharmacodynamic analysis of an intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis. Int J Antimicrob Agents. 2015;45:496–503

2.74 P087 Evaluation of Circulating MicroRNAs as Biomarkers of Hematological Adverse Reactions in Lung Cancer Patients Treated with Carboplatin and Paclitaxel

2.74.1 P. Moriel ¹, P. E. N. S. Vasconcelos², C. S. Seguin², M. V. Geraldo³, A. d. S. Barbeiro², L. Zambon², E. d. C. Pincinato², M. W. P. Junior²

2.74.1.1 ¹University of Campinas, Faculty of Pharmaceutical Science, Campinas, Brazil; ²University of Campinas, School of Medical Science, Campinas, Brazil; ³University of Campinas, Biology Institute, Campinas, Brazil

Introduction: Lung cancer is the leading cause of cancer-related morbidity and mortality worldwide [1]. The treatment of lung cancer initially depend on the definition of the type of tumor and its staging [2]. The most common treatment is chemotherapy and the first line of treatment is the combination of carboplatin and paclitaxel. The effectiveness of this treatment is low and presents a high prevalence of adverse reactions, especially hematological [3]. Studies of new biomarkers, such as circulating miRNAs, related to these adverse reactions are very important to optimize the quality of life of patients.

Objective: To verify a relation between circulating miRNAs and hematologic adverse reactions caused by treatment with carboplatin and paclitaxel in lung cancer patients.

Methods: This study was approved by the ethics committee no. 83196318.8.0000.5404. Blood was collected from patients before and 15 days after chemotherapy, for hematological adverse reactions analysis, for MicroArray and for qPCR validation. Adverse reactions were classified according to the Common Terminology Criteria for Adverse Events v4.0 [4]. The MicroArray was performed with plasma from 6 patients without and 6 patients with hematological adverse reactions. Three miRNAs identified by MicroArray were validated via qPCR using 20 patients without and 26 with hematological adverse reactions. Bioinformatics analyses were performed by miRwalk, DAVID and GeneMani.

Results: Patients with lung cancer treated with carboplatin and paclitaxel are mostly white, with a mean age of 63.50 years, retired, with low schooling, heavy smokers, not eligible for surgical resection, with histopathological diagnosis of adenocarcinoma and stage 4. We observed a high prevalence of grades above 0 for anemia (44%). The MicroArray of patients with and without hematological toxicity verified 9 differently expressed plasma miRNAs among these patients. Of these 3 were chosen for validation being miR-1273g-3p, miR-3613-5p and miR-455-3p. Only miR-455-3p showed a significant expression reduction (p = 0.04) between the groups, before chemotherapy with carboplatin and paclitaxel. The bioinformatics analysis of hsa-miR-455-3p showed an important relationship of this miRNA with the hematopoiesis pathway, especially with action on the RUNX1 and TAL1 genes.

Conclusion: The most prevalent adverse reactions in lung cancer patients treated with carboplatin and paclitaxel were hematological, especially anemia. This adverse reaction, caused by a dysfunction of the hematopoietic system, can be explained by a possible relation between important genes in this system, RUNX1 and TAL1, and hsa-miR-455-3p.

References/Further Sources of Information

• 1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71: 209–49.

• 2. García-Campelo R, Bernabé R, Cobo M, Corral J, Coves J, Dómine M, et al. SEOM clinical guidelines for the treatment of non-small cell lung cancer (NSCLC) 2015. Clin Transl Oncol. 2015; 17:1020–9.

• 3. Protocolos clínicos e diretrizes terapêuticas em Oncologia/Ministério da Saúde, Secretaria de Atenção à Saúde. Brasília: Ministério da Saúde; 2014.

• 4. NCI, NIH, D. Common Terminology Criteria for Adverse Events version 4.03. Bethesda: NIH Publication vol. 4; 200.

Financial Support: CNPq; CAPES and FAPESP.

2.75 P088 ABCB1 Transporter Allelic Variants and Dermatologic Adverse Reactions Related to Gefitinib Therapy in Lung Cancer Patients: A Pilot Study

2.75.1 P. Moriel ¹, M. V. Morau², C. S. Seguin², A. d. S. Barbeiro², L. Zambon², E. d. C. Pincinato², M. W. P. Junior², M. B. Visacri³

2.75.1.1 ¹University of Campinas, Faculty of Pharmaceutical Sciences, Campinas, Brazil; ²University of Campinas, School of Medical Sciences, Campinas, Brazil; ³University of São Paulo, Faculty of Pharmaceutical Sciences, São Paulo, Brazil

Introduction: Lung cancer is the leading cause of cancer related death worldwide [1]. Gefitinib is a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that has consistent clinical benefit in non-small cell lung cancer (NSCLC) patients with the activating mutations of the EGFR gene. However, dermatological adverse drug reactions (ADRs) are common in patients receiving gefitinib [2,3]. ABCB1 gene variants may be associated with skin rashes [3,4].

Objective: To investigate associations between ABCB1 transporter allelic variants with dermatological ADRs in patients treated with gefitinib.

Methods: This is a cohort study that included patients with NSCLC receiving oral geftinib (250 mg/day). DNA was isolated from whole blood samples. Genotyping was performed by TaqMan^® using real-time PCR. For the ABCB1 gene, dbSNP-ID rs1045642 (C3435T) and rs1128503 (1236T>C) were studied. Dermatological ADRs (cutaneous rash, maculopapular rash, and hyperpigmentation) were evaluated after 8 weeks of TKI use and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

Results: Eighteen patients were included with a mean age of 63.0 ± 11.0 years, mostly women (55.5%), Caucasian (83.2%), and non-smokers (66.6%). Stage IVA (50.0%) was the most observed. Moreover, 72.2% had EGFR exon 19 deletion and 27.7% had EGFR exon 21 mutation. The two ABCB1 variants studied were in Hardy-Weinberg equilibrium. For rs1045642, AG heterozygous was observed in most patients (41.1%); 29.4% of patients showed GG and AA homozygous genotypes. For rs1128503, AG alleles were also predominant (64.7%); AA and GG homozygous genotypes were observed in 17.6% of patients. The most observed ADR was hyperpigmentation (grade 1: 44.4%; grade 2: 11.1%). Also, 33.3% and 11.1% of patients showed grade 1 and grade 2 cutaneous rash, respectively. For rs1045642, AA homozygous individuals showed a higher prevalence of cutaneous rash (80%) when compared to AG + GG genotypes (25%), similar to that observed for rs1128503. For rs1045642, maculopapular rash was more frequent in AA homozygous individuals (60%) than in AG + GG group (33.3%), similar to that observed for rs1128503. Only for rs1128503, it was possible to observe a higher prevalence of hyperpigmentation in the AG + GG group (57.1%) when compared to the AA homozygous patients (33.33%).

Conclusion: This study suggests the possibility of a association between AA genotype and the presence of rashes, for both dbSNP-ID in ABCB1 gene.

References/Further Sources of Information

• 1. Bade BC, Dela Cruz CS. Lung Cancer 2020: Epidemiology, Etiology, and Prevention. Clin Chest Med. 2020;41:1–24.

• 2. Kobayashi H, Sato K, Niioka T, Miura H, Ito H, Miura M. Relationship Among Gefitinib Exposure, Polymorphisms of Its Metabolizing Enzymes and Transporters, and Side Effects in Japanese Patients With Non-Small-Cell Lung Cancer. Clin Lung Cancer. 2015;16:274–81.

• 3. Ma Y, Xin S, Huang M, Yang Y, Zhu C, Zhao H, et al. Determinants of Gefitinib toxicity in advanced non-small cell lung cancer (NSCLC): a pharmacogenomic study of metabolic enzymes and transporters. Pharmacogenomics J. 2017;17:325–30.

• 4. 4.Tamura M, Kondo M, Horio M, Ando M, Saito H, Yamamoto M, et al. Genetic polymorphisms of the adenosine triphosphate-binding cassette transporters (ABCG2, ABCB1) and gefitinib toxicity. Nagoya J Med Sci. 2012;74:133–40.

Financial support: CNPq, CAPES, and FAPESP.

2.76 P089 Prescribing Patterns in Hospitalised Chronic Kidney Disease Patients: An Observational Study

2.76.1 W. S. Alruqayb ^1,2, V. Paudyal¹, P. Malcolm^3,4, A. Sarwar⁵, J. Aston⁵, A. R. Cox¹

2.76.1.1 ¹Institute of Clinical Sciences, School of Pharmacy-University of Birmingham, Birmingham, United Kingdom; ²College of Pharmacy, Taif University, Taif, Saudi Arabia; ³Institute of Applied Health Research, Test Evaluation Research Group-University of Birmingham, Birmingham, United Kingdom; ⁴NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Bimingham, United Kingdom; ⁵University Hospitals Birmingham NHS Foundation Trust-Heritage Building Queen Elizabeth Hospital-Queen Elizabeth Medical Centre, Pharmacy, Birmingham, United Kingdom

Introduction: Multiple comorbidities and altered pharmacokinetics are common in patients with CKD, which can have long-lasting consequences on quality of life.^[1,2] Understanding the nature of medication prescribed for co-morbidities, and the monitoring they require, is essential for safe prescribing practice and to avoid drug-related problems (DRPs) in CKD.

Objective: This study aims to describe the drug utilisation patterns of in-hospital CKD patients, with reference to the World Health Organisation (WHO) drug use indicators.^[3]

Methods: An observational follow up study on the drug utilisation pattern was conducted in hospitalised CKD patients over five months (November 2021 to April 2022) in a large teaching hospital in England. The study included hospitalised patients ≥ 18 years with CKD and followed them until discharge. WHO core drug use indicators were evaluated. Prescribed drugs for each patient were recorded on a data collection tool prepared for the purpose of this study and all drugs were classified according to the Anatomical Therapeutic Chemical (ATC) Classification System. Polypharmacy (≥ 6 drugs) risk factors were assessed with univariable and multivariable logistic regression using STATA 17 Software.

Results: During the study period, 387 patients were included in this study, with mean (SD) age of 75 (± 15.5). Over half were female (n = 208 54%). The mean (SD) number of drugs per patient was 11 (± 4.9), the percentage of patients requiring a prescription of an antibiotic was 61.8%, the percentage of patients requiring a prescription of an injection was 93.5%, the percentage of drugs prescribed by generic name was 90.2%, and the percentage of drugs prescribed from essential drugs list or formulary was 88.9%. The most frequent drug groups prescribed were: Alimentary tract and metabolism (22%), Cardiovascular system (18.7%), and Blood and blood forming organs (17%). Longer hospital stay (P < 0.001), admission to a renal ward (P = 0.02) and number of comorbidities (P < 0.001) were independently associated with polypharmacy.

Conclusion: In this cohort of CKD patients, we found mixed compliance with the WHO drug use indicators. There was relatively good compliance with drug formulary use and with generic prescribing, but a high number of drugs prescribed. As might be expected more complex patients with longer stays, and multiple co-morbidities had a higher chance of polypharmacy with the potential for increased DRPs. Further work should investigate prescribers’ views on prescribing in CKD patients.

References/Further Sources of Information

• 1. Velenosi TJ, Urquhart BL. Pharmacokinetic considerations in chronic kidney disease and patients requiring dialysis. Expert opinion on drug metabolism & toxicology. 2014 Aug 1;10(8):1131–43.

• 2. Papotti B, Marchi C, Adorni MP, Potì F. Drug-drug interactions in polypharmacy patients: the impact of renal impairment. Current Research in Pharmacology and Drug Discovery. 2021 Jan 1;2:100020.

• 3. World Health Organization. How to investigate drug use in health facilities: selected drug use indicators—EDM research series No. 007. WHO/DAP/93.1. Geneva: World Health Organization; 1993. Available at https://apps.who.int/iris/bitstream/handle/10665/60519/WHO_DAP_93.1.pdf.

2.77 P090 Associations of Genetic Polymorphisms of the Transporters with Cisplatin-Induced Renal Adverse Reactions in Patients with Head and Neck Cancer

2.77.1 P. Moriel ¹, M. A. Cursino², J. C. F. Quintanilha², L. B. Bastos¹, J. M. d. Oliveira¹, N. d. G. Torso², C. S. P. Lima², M. B. Visacri³

2.77.1.1 ¹University of Campinas, Faculty of Pharmaceutical Sciences, Campinas, Brazil; ²University of Campinas, School of Medical Sciences, Campinas, Brazil; ³University of São Paulo, Faculty of Pharmaceutical Sciences, São Paulo, Brazil

Introduction: Head and neck cancer (HNC) is the set of malignant tumors located in the upper aerodigestive tract [1]. Treatment of locally advanced HNC is based on radiotherapy concomitant with high-dose cisplatin chemotherapy, which is limited by the occurrence of severe toxicities [1,2]. Regarding cisplatin-induced adverse reactions, mainly in the kidney, there are considerable interindividual differences. Several aspects are considered to explain the different grades of adverse reactions and outcomes of the same treatment, and in this scenario, pharmacogenetics stands out. Genetic factors may include polymorphisms that affect the pharmacokinetics of cisplatin [3,4].

Objective: To evaluate the association of genetic polymorphisms of the transporter genes (ABCB1, ABCC2, OCT2, and MATE1) with cisplatin-induced renal adverse reactions in patients with HNC.

Methods: This is a prospective cohort study with consecutive sampling. Blood samples were collected from patients with HNC treated at the Clinical Oncology Outpatient Clinic of a tertiary teaching hospital in Brazil, before (baseline) and after cisplatin administration (80–100 mg/m²). Ten single-nucleotide polymorphisms (SNPs) in four transporter genes ABCB1 (rs1045642, rs1128503, rs2032582 C>A, and rs2032582 C>T), ABCC2 (rs717620, rs2273697, and rs3740066), OCT2 (rs316003 and rs316019), and MATE1 (rs2289669) were selected to investigate their associations with renal adverse reactions. Genotyping was conducted by quantitative PCR using TaqMan probes. Renal adverse reactions were graded according to Common Terminology Criteria for Adverse Events v4.0. Multivariate Logistic Regression analyses were performed with SPSS v.27 and a P value less than 0.05 was considered statistically significant. This study was approved by the Research Ethics Committee (number 69402017.1.0000.5404).

Results: Ninety-five patients were enrolled in this study, with a mean age of 58.00 ± 7.71 years; most patients were male (90.5%). A low creatinine clearance was observed after the first cycle of cisplatin, affecting 40.0% of patients in grades ≥ 2 (4.44% with grades 3 and 4), accompanied by ionic imbalances, even after prophylactic intravenous hydration. Associations were observed between the SNPs of the ABCB1 (rs2032582 C>A) and ABCC2 (rs3740066) genes with cisplatin-mediated renal adverse reactions. ABCB1 rs2032582 C>A wild type allele was significantly associated with hyponatremia in grades > 1 (P = 0.045, OR = 3.398). ABCC2 rs3740066 wild type allele was significantly associated with increase in serum creatinine in grades > 1 (P = 0.010, OR = 31.18). The other SNPs were not associated with renal adverse drug events.

Conclusion: ABCB1 rs2032582 C>A and ABCC2 rs3740066 might be potential clinical markers for predicting cisplatin-induced renal adverse reactions.

References/Further Sources of Information

• 1. Chow LQM. Head and Neck Cancer. N Engl J Med. 2020;382:60–72.

• 2. Visacri MB, Pincinato EC, Ferrari GB, Quintanilha JCF, Mazzola PG, Lima CSP, et al. Adverse drug reactions and kinetics of cisplatin excretion in urine of patients undergoing cisplatin chemotherapy and radiotherapy for head and neck cancer: a prospective study. Daru. 2017;25:12.

• 3. Zazuli Z, Vijverberg S, Slob E, Liu G, Carleton B, Veltman J, et al. Genetic Variations and Cisplatin Nephrotoxicity: A Systematic Review. Front Pharmacol. 2018;9:1111.

• 4. Pincinato EC, Costa EFD, Lopes-Aguiar L, Nogueira GAS, Lima TRP, Visacri MB, et al. GSTM1, GSTT1 and GSTP1 Ile105Val polymorphisms in outcomes of head and neck squamous cell carcinoma patients treated with cisplatin chemoradiation. Sci Rep. 2019;9:9312.

Financial support: CNPq, CAPES, and FAPESP (number 2017/11329-4)

2.78 P099 COVID-19 Vaccine Safety Surveillance and Causality Assessment of Adverse Events Following Immunisation: Lessons from South Africa

2.78.1 J. Meyer ^1,2, M. Schönfeldt³, L. J. Bamford³, H. Dawood⁴, S. K. Dlamini⁵, C. M. Gray⁶, M. F. Matlala⁷, F.C. Mabena⁸, M. P. B. Mawela⁹, L. Mubaiwa¹⁰, K. M. McCarthy¹¹, J. G. Peter¹², V. M. Sekiti⁷, B. S. Makokotlela¹³

2.78.1.1 ¹Sefako Makgatho Health Sciences University, Public Health Pharmacy and Management, Pretoria, South Africa; ²Sefako Makgatho Health Sciences University, South African Vaccination and Immunisation Centre, Pretoria, South Africa; ³National Department of Health, Directorate: Child-Youth and School Health, Pretoria, South Africa; ⁴Greys Hospital, Department of Medicine, Pietermaritzburg, South Africa; ⁵University of Cape Town, Division of Infectious Diseases and HIV Medicine-Groote Schuur Hospital, Cape Town, South Africa; ⁶Stellenbosch University, Department of Biomedical Science, Cape Town, South Africa; ⁷South African Health Products Regulatory Authority, Pharmacovigilance, Pretoria, South Africa; ⁸University of the Witwatersrand, Respiratory and Meningeal Pathogens Research Unit, Johannesburg, South Africa; ⁹Sefako Makgatho Health Sciences University, Paediatrics and Child Health, Pretoria, South Africa; ¹⁰University of KwaZulu-Natal, Department of Paediatrics & Child Health, Durban, South Africa; ¹¹National Institute for Communicable Diseases, Division of Public Health-Surveillance and Response, Johannesburg, South Africa; ¹²University of Cape Town, Division of Allergology and Clinical Immunology-Department of Medicine, Cape Town, South Africa. ¹³South African Health Products Regulatory Authority, Chief Executive Officer, Pretoria, South Africa

Introduction: The South African Health Products Regulatory Authority (SAHPRA) utilises various AEFI reporting tools to monitor vaccine safety in the country. In 2020, SAHPRA in collaboration with the National Department of Health’s (NDoH) Expanded Programme on Immunisation (EPI), joined the African Union Smart Safety Surveillance programme, as one of four pilot countries, to introduce an electronic adverse event following immunisation (AEFI) reporting system (Med Safety App) for healthcare professionals and consumers [1]. On 17/05/2021, the NDoH introduced its national COVID-19 vaccination programme. SAHPRA launched a microsite during 2021, to provide feedback to the public on AEFI with the COVID-19 vaccines.

Objective: To provide an overview of COVID-19 vaccine safety surveillance and describe causality assessment outcomes for serious AEFI reported during the first year of COVID-19 vaccine administration.

Methods: All severe and/or serious AEFI are investigated by provincial EPI surveillance teams, followed by causality assessment conducted by the National Immunisation Safety Expert Committee (NISEC), using the World Health Organization (WHO) methodology [2]. Causality assessment outcomes are classified based on the final diagnoses determined during the assessment by NISEC according to WHO categories, seriousness, Medical Dictionary for Regulatory Activities (MedDRA) system organ class and patient demographics. Data were collected retrospectively from the SAHPRA COVID-19 AEFI microsite and the EPI national AEFI database.

Results: By 01/04/2022, 33,063,221 COVID-19 vaccine doses had been administered, with 5 815 spontaneous AEFI reports (0.0173%) submitted. Of these, 2,571 (0.008%) were reported as serious. Spontaneous reporting of AEFI increased significantly compared to pre-COVID-19 vaccine introduction. The most frequently reported AEFIs were side effects already listed in the product information. No safety concerns were raised based on causality assessment outcomes for 273 serious cases analysed by 01/04/2022. Over two thirds of these cases were classified as coincidental (70.7%) as cardiac-, respiratory- or vascular disorders (MedDRA system organ class), with 12.1% classified as vaccine product related (see table below).

The presentation will include all causality assessments conducted up to 31/08/2022, and more detailed information about causality assessed cases will be available in the public domain at the time of the conference and will be included in the presentation.

Conclusion: Vaccine safety surveillance and monitoring trends of reported AEFI are vital measures to ensure that the benefits of immunisation are maintained in the interest of public health and efficient vaccination programmes. Transparent communication with the public is important to maintain public confidence in vaccines and prevent all AEFI being misinterpreted as caused by the vaccine.

References/Further Sources of Information

• 1. Med Safety App download and instructions available at: http://medsafety.sahpra.org.za/.

• 2. World Health Organization. Causality assessment of an adverse event following immunization (AEFI). User manual for the revised WHO classification. 2nd Edition. 2019.

2.79 P100 mRNA COVID-19 Vaccines Induced-Sudden Sensorineural Hearing Loss (SSNHL): Descriptive Analysis of French Pharmacovigilance Database (FPDB)

2.79.1 M. A. Resident¹, M. B. V. Rabier², T. V. Hung³, H. Bagheri ⁴

2.79.1.1 ¹Lyon University Hospital, Department of Audiology and otoneurological Evaluation, Lyon, France; ²Besançon University Hospital, Department of Medical Pharmacology-Center of Pharmacovigilance, Besançon, France; ³Lyon University Hospital, Department of Audiology and Otoneurological Evaluation-INSERM U1120, Lyon, France; ⁴Faculty of Medicine, Pharmacology, Toulouse, France

Introduction: Several case reports and pharmacoepidemiological studies suggested a potential association between the mRNA) COVID-19 vaccine, tozinameran (Comirnaty) and elasomeran (Spikevax) and SSNHL. However, data remain controversed because of scarcity of this adverse effect (1,2).

Objective: To assess an descriptive analysis of all spontaneous reporting of mRNA COVID-19 vaccines induced-Sudden Sensorineural Hearing Loss (SSNHL) to the French Pharmacovigilance system and to estimate the incidence of SSNHL reported cases.

Methods: All cases of mRNA COVID-19 vaccines induced-SSNHL recorded in the FPDB from the beginning of the campaign of COVID-19 vaccination in France until 2 February 2022 were included. Following data were collected: demographic data (age, gender), risk factors, history of immunologic disease, other factors leading to SSNHL (trauma, infections,…), the range and the month of vaccination, the delay of onset of SSNHL, associated symptoms (dizziness and tinnitus), the degree of hearing loss and the outcome. Audiogramm and/or medical reports were requested in order to guarantee a better informativeness of data. All cases were reviewed by a staff including two pharmacologists and two otorhinolaryngologists. All cases with a delay onset>30 days were excluded. Cases were split in “well completed” and (non completed) based on the availability of audiogram and medical reports.

Results: A total of 250 cases were recorded during this period for the 2 vaccines (60 Spikevax/190) (23 cases excluded because of other reasons or missed data). 226 cases were analyzed and will described according to over mentioned criteria, corresponding to 151 cases classed as “well completed” (31 Spikevax/120 Comirnaty). The estimated incidence of SSNHL was estimated as 0.18/100000 for serious cases for Comirnaty and 0.27/100000 for both serious and non serious cases for Spikevax. For Spikevax, the median age was 50 years with a sex ratio of 0.9, the half of cases occurred after D1, 5 cases of positive rechallenge and hearing loss was associated with tinnitus in 50% and dizziness in 21.6%. For Comirnaty, the median age was 56 years with a sex ratio of 0.8, 76% of cases occurred after D1, 1 case of positive rechallenge, associated with tinnitus in 84% and dizziness in 39% of cases.

Conclusion: In our knowledge, it is the first study analysing all cases of mRNA vaccines-induced SSNHL supporting by audiogram analysis. This adverse effect remains rare but should be considered in patients with audio-vestibular risk factors. Other studies would be necessary in order to understand the mechanism which remains unclear.

References/Further Sources of Information

• 1. Wishova H, Miller ME, Derebery MJ. Otol and Neurotol. 2021; 42:e1213–e1218

• 2. Formeister EJ, et al. JAMA Otolaryngol Head Neck Surg,. 2022; 148(4): 07–315

2.80 P102 Upgrade of Croatian ADR e-Reporting System for COVID-19 Prospective Cohort Event Monitoring (ACCESS Project)

2.80.1 B. Kovačić¹, S. D. Blažok ¹, Ž. M. Koletić¹, N. M. Skvrce¹, S. Tomić²

2.80.1.1 ¹HALMED, Department of Pharmacovigilance and Rational Pharmacotherapy, Zagreb, Croatia; ²HALMED, Directorate, Zagreb, Croatia

Introduction: Building on the lessons learnt from 2009 H1N1 pandemic, in order to prepare EU network for monitoring of COVID-19 vaccines, ACCESS project (vACcine Covid-19 monitoring readinESS, VAC4eu.org) was funded in May 2020 by the European Medicines Agency (EMA). It was designed to ensure infrastructure for effective monitoring of COVID-19 vaccines. The Croatian Agency for Medicinal Products and Medical Devices (HALMED) saw this as an opportunity to upgrade existing ADR e-reporting system (OPeN) and set up post-marketing active surveillance of adverse drug reactions (ADRs).

Objective: To upgrade existing OPeN system to prospectively collect data about Adverse Events Following Immunisation (AEFIs) against COVID-19 in near real-time.

Methods: For the purpose of data collection defined by the ACCESS protocol, OPeN system has been upgraded to incorporate an informed consent, survey tool, survey data report, direct reporting of AEFI reports, when applicable, and their transmission to EudraVigilance.To participate in the study an user account needs to created and consent given. Study participants access the system via the appropriate link. The system is protected by a firewall and Secure Sockets Layer (SSL) protocol. Data protection has been established for both internal and external users.

Results: The first phase of the OPeN upgrade started in November 2020 and finished in February 2021. The inclusion of participants in the Croatian study began on 12 February 2021. In the first phase, only healthcare professionals could participate, but the variation in protocol allowed that from April 2021 all vaccinated people could be included. With second phase of upgrade, we were able to include additional questions on relevant medical history, pregnancy, 3rd and booster vaccine dose. 374 vaccinees were recruited in the period from start until the end of April 2022. Almost all vaccinees were adults. Majority were female (77%), and average age was 38 years-old (SD 10, CI ± 1). Total of 303 AEFI reports were collected, of which 97% were non-serious.

Conclusion: The OPeN system has shown a wide upgradeability and HALMED was able to establish a system of post-marketing active surveillance in very short time frame as addition to our routine pharmacovigilance activities. However, throughout this process we have identified several issues: time consuming multi-step registration process, not enough user friendly interface and insufficient promotion of the OPeN system. Nevertheless, since this was the first time HALMED performed prospective safety monitoring by using a web-based tool we find results encouraging for future activities.

References/Further Sources of Information

Not applicable.

2.81 P103 Psoriasis Induced by COVID 19 Vaccine

2.81.1 M. Daldoul¹, A. Zaiem¹, W. Kaabi¹, M. B. Belgacem¹, I. Aouinti¹, I. Dahmani¹, S. E. Aidli ¹

2.81.1.1 ¹Université Tunis el Manar Faculté de médecine de Tunis/Unité de recherche UR17ES12., Centre national Chalbi Belkahia de pharmacovigilance/ Service de recueil et d'analyse des effets indésirables, Tunis, Tunisia

Introduction: Psoriasis is a chronic, immunologically mediated, inflammatory skin condition. It is characterized by well-defined, erythematous, indurated scaly plaques, with predilection of extensor surfaces, the scalp and the nails. It may be caused by drug, infection, stress, physical trauma, and vaccination. COVID 19 vaccines have recently been linked to worsening of pre-existing psoriasis.

Objective: We report an exceptional case of new onset of psoriasis following COVID-19 vaccine.

Methods: This case was reported in February 2022 to The National Centre of Pharmacovigilance and evaluated according to the updated French method of causality assessment.

Results: A 58-year-old female patient with a past medical history of hypothyroidism treated by sodiclevothyroxin received on 07 August 2021 her first dose of VAXZEVERIA COVID-19vaccine. On 17 August 2021, she presented to the emergency department because of anerythematous and febrile eruption on her limbs. Dermatological examination, revealed, erythematous skin with yellow crusts on the limbs and desquamation over the upper and lower limbs. No mucosal membrane or palmo-plantar involvement was noted. The bacterial skin swab was negative. Histological findings confirmed the Psoriasis. Based on the history and clinical findings, she was diagnosed with psoriasis onset with the vaccine. The patient was started on betametasone an calcipotriol resulting in a significant resolution of the skin eruption one month later.

Conclusion: In this case, the responsibility of the COVID-19 vaccine in inducing Psoriasis was evaluated as I4 (C2S2) according to the updated French method of imputation in front of: a suggestive delay (10 days after starting the treatment), mainly the favorable outcome after the vaccination and the finding of skin biopsy. The responsibility of sodic levothyroxin was non retained because of the favorable outcome despite his pursuit. Psoriasis associated with COVID-19 vaccine is a rare condition.

References/Further Sources of Information

Huang YW, Tsai TF. Exacerbation of Psoriasis Following COVID-19 Vaccination: Report From a Single Center. Front Med (Lausanne). 2021 Dec 23;8:812010.

2.82 P104 Incidence of ischaemic Stroke Following Comirnaty™ Administration: Comparison of Data from ASST GOM Niguarda and FAERS

2.82.1 G. Pascale ¹, C. C. Cimarusti¹, C. D. Giorgio¹, L. Napoli¹, D. Drago¹, S. Ingrillì¹, F. Ruggiero¹, L. Cervi¹

2.82.1.1 ¹ASST GOM Niguarda, Pharmacy, Milan, Italy

Introduction: Although the mechanism of neurological complications after COVID-19 vaccination has not been precisely explained, it could be attributed to the inflammatory state triggered by COVID-19 vaccine as in the course of COVID-19 viral infection. This condition induces disseminated intravascular coagulation (DIC) in combination with vascular endothelial dysfunction, leading to stroke of the large vessels. This hypothesis may be the main cause of DIC, especially in mRNA-based vaccines, whose mechanism involves delivery of the mRNA code of the spike protein to human cells. Cellular synthesis of the spike protein stimulates the immune system to recognize and store it for future attack. Based on this hypothesis, the inflammatory state triggered by the vaccine can be considered the main pathway for neurological complications of COVID-19 vaccine.

Objective: The aim of this work is to analyse the incidence of ischaemic stroke risk following administration of the Comirnaty™ vaccine in ASST GOM Niguarda, an Italian hospital based in Milan, and to compare it with data from FAERS database.

Methods: The Reporting Odds Ratio (ROR) was calculated in order to evaluate a possible correlation between the risk of ischaemic stroke and Comirnaty™ vaccine administration in the period of January-December 2021. For this purpose, we consulted FAERS public domain database that allows you to search information relating to adverse events reported to the FDA.

Results: From reports of adverse events of Comirnaty™ vaccinated patients at ASST GOM Niguarda hospital, it was observed that after administration of this vaccine there is a correlation with the risk of developing ischaemic stroke mainly in over 65 years old patients (OR = 1.26; 95% CI 0.17–9.13; z = 0.230; p value = 0.8182) when comparing the data with other vaccines. These data match the data obtained from FAERS (OR: 1.29; 95% CI 0.85–1.96; z = 1.205; p value = 0.228), confirming the data collected in ASST GOM Niguarda.

Conclusion: The data extrapolated from this analysis conducted at ASST GOM Niguarda mirror those obtained from the FAERS database with a comparable significance index (p value).

In conclusion, the possible correlation between Comirnaty™ vaccine administration and the development of ischaemic stroke as an adverse event was confirmed.

References/Further Sources of Information

• 1. Assiri SA, Althaqafi RMM, Alswat K, Alghamdi AA, Alomairi NE, Nemenqani DM, Ibrahim ZS, Elkady A. Post COVID-19 Vaccination-Associated Neurological Complications. Neuropsychiatr Dis Treat. 2022 Feb 2; 18:137–154.

• 2. FAERS: https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard.

2.83 P105 COVID Vaccines AEFI Monitoring in Tunisia: March 2021 to May 2022

2.83.1 I. Aouitni ^1,2, S. Debbeche¹, G. Lakhoua^1,2, W. Kaabi², H. Zayani¹, S. Kastalli^1,2, R. Daghfous^1,2, S. E. Aidli^1,2

2.83.1.1 ¹Centre national de pharmacovigilance, Service d’analyse et de recueil des données, Tunis, Tunisia; ²University Tunis El Manar, Research Unit UR17ES12 Faculty of Medicine, Tunis, Tunisia

Introduction: As part of vaccines surveillance, a reinforced surveillance strategy for Covid-19 vaccines adverse events following immunization (AEFI) was set up in Tunisia. This strategy was conducted since the Covid-19 vaccination campaign has been started in March 2021. The safety profile of available vaccines was monitored in real time to ensure security of the population and to be able to anticipate coincidental events that might be attributed to the vaccine.

Objective: to analyze the reported AEFI associated with different types of COVID-19 vaccines.

Methods: A descriptive study on AEFI from Covid-19 vaccines collected at the National Chalbi Belkahia Center for Pharmacovigilance (CNPV) from March 13th 2021 to May 22, 2022. During this period, vaccines used were Pfizer BioNTech^®, Vaxzevria^®, Spikevax^®, Janssen^®, Sputnik V^®, Coronavac^®, and Sinopharm^®.

Results: We collected 3116 AEFI on 13 173 137 COVID-19 vaccines administered doses (0.02%).

The mean age was 48.8 years [13–98]. The sex ratio M/F was 0.59. The vaccines mainly used were the Pfizer BioNTech^® vaccine in 51.6%, Vaxzevria^® in 16.1%, Spikevax^® in 10.9% and Janssen^® in 7.6% of cases.

AEFI SOCs were general manifestations and injection site reactions (44%), nervous system disorders (27.4%), musculoskeletal and connective tissue disorders (16.4%), Skin and subcutaneous tissue disorders (16.2%), gastrointestinal disorders (12.1%), respiratory, thoracic and mediastinal disorders (6.7%), immune system disorders (5.9%), vascular disorders (5.8%), infections and infestations (5.7%), Injury, poisoning and procedural complications (5.5%), Ear and labyrinth disorders (4.9%), cardiac disorders (4.6%), and others (9.2%).

The most reported MedDRA terms were fever (20.2%), asthenia (16.9%), headache (13.8%), injection site pain (9.4%), and muscle pain (8.9%).

Serious AEFI were noted in 7% of AEFI. SOCs were Nervous system disorders (38.7%), Cardiac disorders (17.5%), General disorders and administration site conditions (15.2%), vascular disorders (12.9%), Infections and infestations (12.4%), Respiratory, thoracic and mediastinal disorders (7.8%), Skin and subcutaneous tissue disorders (6.5%), and others (21.2%).

The most used vaccines in serious AEFI Pfizer BioNTech^® in 47%, Vaxzevria^® in 21.2% and Coronavac^® in 11.1%.

Conclusion: This study confirms clinical trials data in which the most frequent AEFIs were general and injection site disorders. Serious adverse event were rare. These results show that the benefit of vaccination outweighs the risk and encourage vaccination

References/Further Sources of Information

Not applicable.

2.84 P106 Maternal, Fetal, and Neonatal Outcomes among Pregnant Women Receiving COVID-19 Vaccination: the Preg-Co-Vax Study

2.84.1 F. Fraenza ¹, S. Cristina¹, G. d. Mauro¹, R. Rosanna¹, R. Concetta¹, S. M. Giuseppa¹, R. Francesco¹, S. Liberata¹, C. Annalisa¹

2.84.1.1 ¹Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine-Section of Pharmacology “L. Donatelli”-University of Campania “Luigi Vanvitelli”, Naples, Italy

Introduction: Although the International and National Regulatory Authorities encourage COVID-19 vaccination in pregnant women [1-2], the scientific evidence supporting maternal exposure to COVID-19 vaccines during pregnancy is still limited and further studies are needed to monitor their safety profile in order to evaluate the potential consequences in both mother and child.

Objective: We aimed to investigate Adverse Events Following Immunization (AEFI) with COVID-19 vaccines that occurred after maternal exposure during pregnancy.

Methods: We retrieved Individual Case Safety Reports (ICSRs) following maternal exposure to COVID-19 vaccines during pregnancy from the EudraVigilance database of the European Medicines Agency during the year 2021. We investigated outcomes related to the mother and child age groups (defined as fetus, infant, and neonate). The Reporting Odds Ratio (ROR) was computed to compare the reporting probability of spontaneous abortion between each COVID-19 vaccine and all other COVID-19 vaccines.

Results: During the study period (1 January 2021–31 December 2021), among 1,315,315 ICSRs related to COVID-19 vaccines, we retrieved 3,252 (0.25%) reports of AEFI that occurred after maternal exposure during pregnancy. More than half (58.24%) of ICSRs were submitted by non-healthcare professionals. The majority (87.82%) of ICSRs concerned serious AEFI. More cases of AEFI occurred in pregnant women (n = 2,764; 85.0%) than in child age groups (n = 258; 7.9%). Moreover, 55.16% ICSRs related to pregnant women exposed to COVID-19 vaccines involved non pregnancy-specific adverse events, mostly headache, pyrexia, fatigue, myalgia, and pain in extremities. The 17.92% were pregnancy-, neonatal-, or fetal-specific adverse events. Moderna and Oxford-AstraZeneca vaccines had a higher reporting probability of spontaneous abortion (ROR 1.2, 95% CI 1.05–1.38, P = 0.009; and ROR 1.26, 95% CI 1.08–1.47, respectively), while a lower reporting probability was found for Pfizer-BioNTech vaccine compared with all other Covid-19 vaccines (ROR 0.73, 95% CI 0.64–0.84). We also observed that 5.8% (n = 188) of cases reported a fatal outcome, 17 of them were clearly associated with the mother, while 171 with the child.

Conclusion: We did not observe any strong insight into any unknown adverse events associated with COVID-19 vaccination. However, we analyzed data related to only one year of the vaccination program. Therefore, our experience also highlights the need for continuing to monitor the safety profile of COVID-19 vaccines and to identify long-term adverse events following immunization. In conclusion, in the European context, the analysis of real-world evidence suggests that the benefits of COVID-19 vaccines during pregnancy outweigh the possible risks for pregnant women and children.

References/Further Sources of Information

• 1. European Medicines Agency (EMA). COVID-19 vaccines. Available at the website: https://www.ema.europa.eu/en/human-regulatory/overview/public-health-threats/coronavirus-disease-covid-19/treatments-vaccines/covid-19-vaccines.

• 2. Shimabukuro TT, Kim SY, et al. Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons. N Engl J Med. 2021;384(24):2273–2282.

2.85 P107 COVID-19 Vaccines and Reproductive Disorders: An Analysis of the European Database EudraVigilance

2.85.1 C. Riccardi ¹, A. Zinzi¹, M. Gaio¹, N. Balzano¹, C. Pentella¹, V. Liguori¹, R. D. Napoli¹, C. Rafaniello¹, F. Rossi¹, A. Capuano¹

2.85.1.1 ¹Center of Pharmacovigilance and Pharmacoepidemiology-Campania Region-Naples-Italy, Department of Experimental Medicine-University of Campania “L. Vanvitelli”, Naples, Italy

Introduction: Rare or serious Adverse Events (AEs) in the reproductive sphere have been reported following the administration of the COVID-19 vaccine, especially mRNA vaccines. Although several fertility Societies have announced that COVID-19 mRNA vaccines are unlikely to affect fertility, pregnancy, or breastfeeding, there is no denying that the current evidence is very limited [1].

Objective: Aim of this study was a post-marketing assessment of the safety profile of COVID-19 vaccines, through the analysis of the Individual Case Safety Reports (ICSRs) collected in EudraVigilance in 2021 year, by focusing on reproductive disorders.

Methods: We analyzed all ICSRs that contained at least one COVID-19 vaccine as suspected and at least one AE belonging to the Standardized MedDRA Query (SMQ) level 1 “Fertility disorders” or “Pregnancy and neonatal conditions”. We performed a descriptive analysis and all AEs have been coded as Preferred Term (PT) according to MedDRA. Finally, we used the Reporting Odds Ratio (ROR) with a 95% of Confidence Interval (95% CI) to investigate disproportional reporting of AEs belonging to the SMQs of interest among the vaccines included in the analysis.

Results: During the study period, 27,089 ICSR were collected and the total number of AEs was found to be 31,337; of these, 62.8% were referred to Comirnaty^®, 20.8% to Spikevax^®, 12.7% to Vaxzevria^®, and 3.7% to Janssen^®. For each of the four COVID-19 vaccines, 96.4% were related to female patients, aged between 18–64 years (88.1%), 71.5% were not serious, 46.0% were not resolved yet and 82.3% were reported by non-healthcare professionals. Regardless of the type of vaccine, the most reported PTs were amenorrhea, irregular menstruation, and delayed menstruation. The ROR showed that the probability to report an AE belonging to the SMQ “Fertility disorders” is greater for Comirnaty^® (ROR: 4.20, 95% CI 4.08–4.32) while no statistically significant difference was observed to the SMQ “Pregnancy and neonatal conditions”.

Conclusion: In this study, no potential signs of reproductive system safety were found regarding fertility, pregnancy or breastfeeding. Most of the reported events were related to changes in the menstrual cycle, although these disorders are temporary and normally common in the female population. At the time, the EMA’s PRAC concluded that the evidence did not support a causal link between these vaccines and menstrual disorders, however, it decided to further studies collecting data from real life contexts are strongly needed to assess their safety profile in relation to reproductive function.

References/Further Sources of Information

• 1. Chen F, Zhu S, Dai Z, Hao L, Luan C, Guo Q, Meng C, Zhang Y. Effects of COVID-19 and mRNA vaccines on human fertility. Hum Reprod. 2021 Dec 27;37(1):5–13.

Correspondences: consiglia.riccardi@unicampania.it.

2.86 P108 Pharmacovigilance Regulatory Actions by National Pharmacovigilance Centres in Fourteen Middle Eastern Countries Following COVID-19 Pandemic

2.86.1 S. A. Zubiedi ¹, M. Younus², S. A. Khalidi³, M. Ekilo⁴, T. Alshammari ⁵

2.86.1.1 ¹School of Pharmacy/ The Univesity of Jordan, Biopharmaceutics and Clinical Pharmacy, Amman, Jordan; ²Iraqi Ministry of Health, Pharmacovigilance Centre, Baghdad, Iraq; ³King Saud University, Medication Safety Research Centre, Riyadh, Saudi Arabia; ⁴Uppsala Monitoring Centre, Uppsala Monitoring Centre, Uppsala, Sweden; ⁵Riyadh Elm University, College of Pharmacy, Riyadh, Saudi Arabia

Introduction: Pharmacovigilance (PV) activities were affected by COVID-19. Therefore, several health authorities around the world have issued guidelines and practices to ensure that PV activities are maintained and continued during the pandemic [1].

Objective: This study aimed to assess the impact of COVID-19 on the preparedness and performance of national PV systems in 14 Arab Countries in the Middle East.

Methods: This was a cross-sectional study that was conducted between July and October 2020. National PV centres in 18 in the Middle East were invited to participate in this study. Descriptive analysis was used to summarize and present the results of this study.

Results: Responses were obtained from 14 (77.8%) countries. Adverse events reporting was the main PV activity that was covered by PV guidelines and practices. National guidelines and practices covered other PV activities in 8 (57.14%) of the participating countries. Performance and practices of national PV centres vary considerably among participating countries during the pandemic.

Conclusion: The findings highlight the differences in preparedness and performance of different national PV centres in participating Middle Eastern countries. Improving digital infrastructure among participating countries could serve as a useful tool to minimize the impact of the pandemic on PV activities.

References/Further Sources of Information

• 1. Chandler RE, McCarthy D, Delumeau JC, et al. The Role of Pharmacovigilance and ISoP During the Global COVID-19 Pandemic. Drug Saf. 2020; 43(6): 511–512.

2.87 P109 The Impact of SARS-CoV-2 on Mental Health. Focus on depression, Antidepressants Consumption and ADRs Signal Detection

2.87.1 G. Zerial ¹

2.87.1.1 ¹Public Health Center of Pharmacovigilance-Friuli-Venezia Giulia Regional Office, Department of Central Health-Social and Disability Policies, Trieste, Italy

Introduction: The SARS-CoV-2 public health emergency is leading to challenges for healthcare professionals, students, patients with COVID-19 and vulnerable persons, blocking the economic development and mental wellbeing. The pandemic containment measures and the fear of infection have caused psychological distress and inflamed underlying diseases

Objective: To analyse the impact of the SARS-CoV-2 on the Mental Health in Friuli-Venezia Giulia Region, Italy, focusing on depression disorder and Antidepressants consumption. Furthermore, to assess the state of adverse event reports, from spontaneous signalling method, in patients taking Antidepressants

Methods: For consumption data extraction I utilized the Regional Social and Health Information System. About reports of ADRs based on the National Pharmacovigilance Network I used the VigiSegn app. I accessed on INTERCheck System to balancing the risks and benefits of therapies. I compared two periods from 11.03.2019 to 10.03.2020 and from 11.03.2020 to 11.03.2021 separated by 11 March 2020, when the Director General of the WHO described the situation as a pandemic [1]. Antidepressants were classified using the ATC code system. Anonymous drug utilization was expressed in DDDs

Results: Since 11 March 2020 I observed a marginal increase in consumption of sertraline, trazodone and vortioxetine. Regarding pharmaceutical spending there has been an increase of sertraline, trazodone, vortioxetine, bupropion, mirtazapine and venlafaxine. In the feminine gender, I observed an increase in AD consumption in the age ranges < 15 yrs, 16–19, 30–34, 55–59, 60–64, 70–74, 80–84, over 85; in the male gender in the ranges < 15 yrs, 20–24, 30–34, 55–59, 70–74, 80–84, over 85 (Picture 1). Concerning ADRs I analysed one tab about AD out of a total of 2146 medicines and vaccines reports in which the “hyponatremia” is reported on the warning label and caused by significant drug interactions

Conclusion: Although the SARS-CoV-2 public health emergency is a rapidly evolving situation, the knowledge about the impact on the Mental Health is still limited. It is likely that the psychosocial demand will increase in the coming months. In the regional context, the thesis has highlighted a very slight rise in AD consumptions and a significant decrease of spontaneous signalling method compared to the previous year. These scenarios also depend on the new balance of health services and the lack of access to care (10% of citizens has given up on care) [13, 14]. The healthcare systems will have to face important challenges and the success of the creation of high-quality healthcare reality will depend on the alliance between healthcare specialists

References/Further Sources of Information

• 1. World Health Organization—www.who.int.

• 13. Salutequità—4° Report. Le cure mancate nel 2020

• 14. Salutequità—3° Report. Trasparenza e accesso ai dati sullo stato dell’assistenza ai pazienti NON Covid-19

2.88 P110 Ivermectin-Induced Liver Injury when Used as Self-Medication in SARS-CoV-2 Infection

2.88.1 T. J. Oscanoa ^1,2, J. A. Tineo¹, J. M. Pérez³, W. T. Huamaní³, A. Carvajal⁴

2.88.1.1 ¹Universidad Nacional Mayor de San Marcos-Facultad de Medicina, Pharmacology, Lima, Peru; ²Universidad de San Martín de Porres-Facultad de Medicina., Drug Safety Research Center. Hospital Almenara ESSALUD., Lima, Peru; ³Hospital Nacional Edgardo Rebagliati Martins-EsSalud, Emergency Department, Lima, Peru; ⁴Universidad de Valladolid, Pharmacology, Valladolid, Spain

Introduction: In the context of the global health emergency due to SARS-CoV-2 pandemic, ivermectin has been repurposed in some Latin American countries to treat COVID-19; in these countries its use as self-medication has been frequent (1). Ivermectin-induced liver injury, though extremely rare(2,3), had been previously described even before the COVID-19 pandemic

Objective: To characterize clinical features of liver injury associated with ivermectin when used as self-medication for treating COVID-19.

Methods: Clinical records of those patients diagnosed with severe COVID-19 at the Emergency Room in Rebagliati Hospital in Lima, Peru, during March 2021, were carefully revised. To establish diagnosis of drug-induced liver injury (DILI) and causality assessment, the criteria of DILI-Expert Working Group and the Council for International Organizations of Medical Sciences/Roussel Uclaf Causality Assessment Method (CIOMS/RUCAM), respectively, were used

Results: Out of 327 patients identified, 38 took ivermectin as self-medication (11%); of those 38, five were diagnosed with liver injury presumably related to that medication (13.2%). The mean age of those patients who developed the condition was 49.3 (12.3) [men, 4; woman, 1]. The mean (standard deviation) of Tomographic Severity Score (TSS), C-reactive protein, ferritin levels, Lymphocyte count and D-dimer were 52.2% (22.6), 13.8 (12.2) mg/dl, 1325.375 (239.7072) ng/ml, 2.0 (2.0) K/μl and 0.9 (0.7) μg/ml. The patients had no identified risk factors, but two; one patient had type I diabetes mellitus, and other, obesity. Mean daily ivermectin dose, duration, and total ivermectin dose were 32.9 (21.8) mg/day, 2.6 (0.6) days, and 89.6 (71.4) mg, respectively. As an average, liver injury occurred 11 (3.8) days after the start of treatment, none developed jaundice. Mean levels of alanine aminotransferase, alkaline phosphatase, gamma-glutamyltransferase were increased 8 (4.4), 1.66 (0.9), 10.9 (5.0) times above the upper limit of normal. Two patients presented a hepatocellular pattern, 2 mixed and 1 cholestatic. All cases were mild and recovered. As for causality assessment, 4 cases were considered as "possible", and one, as "highly probable".

Conclusion: Given its widespread use in some countries, ivermectin-induced liver injury requires further pharmacovigilance studies when used for treating COVID-19.

References/Further Sources of Information

• 1. Quincho-Lopez A, Benites-Ibarra CA, Hilario-Gomez MM, Quijano-Escate R, Taype-Rondan A. Self-medication practices to prevent or manage COVID-19: A systematic review. Aslam MS, editor. PLoS One [Internet]. 2021 Nov 2;16(11):e0259317. Available from: https://dx.plos.org/10.1371/journal.pone.0259317.

• 2. Veit O, Beck B, Steuerwald M, Hatz C. First case of ivermectin-induced severe hepatitis. Trans R Soc Trop Med Hyg [Internet]. 2006 Aug;100(8):795–7. Available from: https://academic.oup.com/trstmh/article-lookup/doi/10.1016/j.trstmh.2006.02.003.

• 3. HIROTA M, TODA T, MORISAWA H, MINESHITA S. A Case Report of Ivermectin-Induced Prolonged Liver Dysfunction in an Elderly Patient with Scabies. Rinsho yakuri/Japanese J Clin Pharmacol Ther [Internet]. 2011;42(5):341–3. Available from: http://joi.jlc.jst.go.jp/JST.JSTAGE/jscpt/42.341?from=CrossRef.

2.89 P111 COVID-19 Vaccine Pharmacovigilance Spontaneous Reporting in a Pandemic—Notes from a Small Country

2.89.1 S. Kenyon ¹, M. Tatley ²

2.89.1.1 ¹Ministry of Health, Medsafe, Wellington, New Zealand; ²University of Otago, New Zealand Pharmacovigilance Centre, Dunedin, New Zealand

Introduction: Medsafe, the New Zealand Pharmacovigilance Centre (NZPhVC) and the Covid Vaccine Immunisation Programme (CVIP) created a vaccine pharmacovigilance strategy. We report pros and cons of the strategy.

Objective: We aimed to use existing systems and expertise but leverage new technologies to manage an expected increase in reporting to support signal detection activities and requests for data. [1]

Methods: A new reporting form was included in the new Covid Immunisation Register (CIR) so events occurring at the vaccination centre could then be easily reported into a database.

A new on-line COVID-19 vaccine reporting form was constructed which populated the database. This form incorporated a list of common vaccine side effects and AESIs that could be selected by the reporter [2].

A new COVID-19 vaccine database for storing reports was built in the same electronic environment as the CIR. This facilitated data linkage, report triaging, dedicated access and analysis. Importantly this database was accessible remotely through secure VPN.

Qlik Sense data visualisation and analytics were used to report on data incorporating daily data transfers to allow tracking of reporting and daily updates to support policy and communications.

Results: From start to 29 April 2022, 62,427 cases of adverse events were received in New Zealand, more than 12 times the normally expected number. The average reporting rate was 5.7 reports per 1000 vaccinations.

The CIR reporting option was used over 15,000 times and the online form was used more than 28,000 times by consumers.

The CIR linkage to the AEFI database allowed duplicate and fake reports to be quickly detected and ensured vaccine administration data was high quality. Rapid processing of the massive increase in reports was possible, but there were issues due to limitations of the database and the volume of reports received.

Event tick boxes in the reporting form had advantages for reporters but impacted the granularity of the data. The AESI event tick boxes were undesirable. These were often selected by vaccinees based on self diagnosis, in error and not supplemented by supporting evidence. This resulted in an increase in work to follow up these reports.

The Qlik app facilitated rapidly identifying trends in the data and AEFI report updates.

Conclusion: The system enabled close to real time data for signal analysis, public reassurance and communication. Data-linkage supported accurate determination of data.

However, an increase in staff was still required and it was impossible to review all reported cases for accuracy or need for further information.

References/Further Sources of Information

• 1. World Health Organization. (2020). COVID-19 vaccines: safety surveillance manual. World Health Organization. https://apps.who.int/iris/handle/10665/338400.

• 2. World Health Organization. (2016). Immunization safety surveillance : guidelines for immunization programme managers on surveillance of adverse events following immunization. 3rd ed. World Health Organization https://www.who.int/publications/i/item/9789290617457.

2.90 P112 Factors Influencing Patient Reporting of Adverse Reactions to Covid-19 Vaccines

2.90.1 C. Anton ¹, A. Cox², R. Ferner³

2.90.1.1 ¹West Midlands Centre for Adverse Drug Reactions, Pharmacy, Birmingham, United Kingdom; ²University of Birmingham, School of Pharmacy, Birmingham, United Kingdom; ³University of Birmingham, School of Clinical and Experimental Medicine, Birmingham, United Kingdom

Introduction: The Covid-19 pandemic and the resultant vaccination programme has seen greatly increased discussion of adverse drug reactions (ADR) and how to report them, and non-healthcare professions have submitted many more ADR reports. Various barriers have been proposed to influence the reporting by patients [1, 2] and patients’ motives to report have also been discussed [3]. We investigated differences in COVID-19 vaccine ADR reporting rates within this region to identify factors that may influence the number of reports received from patients.

Objective: To identify factors which may influence the number of reports received from patients

Methods: The West Midands Centre for ADRs receives data from Yellow Card reports that are generated in the Midlands NHS region (population 6.6 million) in the UK. We compared the rates of ADR reporting by patients with COVID-19 vaccination rates and indices of deprivation [4] in the 12 clinical commissioning groups (CCGs)—areas with populations ranging from 0.13 to 1.38 million. We ranked CCGs by number of patient reports to COVID-19 vaccines and compared these with the rankings of the number of vaccines received and each of the domains of deprivation using Spearman’s rank correlation.

Results: In the period 9/12/20 to 31/12/21 there were 30,874 patient reports from the region (83% of all COVID-19 vaccine reports). Reporting rates per CCG ranged from 167 to 307 (mean 240) per 100,000 vaccinations administered, with a mean of 2.00 (range 1.69 to 2.14) vaccines per person—the UK at this stage was part way through the booster campaign with only adults routinely vaccinated. Table 1 shows the correlation between ADR reporting and the listed factors

Conclusion: ADR reporting rates had, perhaps unsurprisingly, a strong correlation with high vaccination rates. However, higher deprivation, lower education levels, and more unemployment were all negatively correlated with patient ADR reporting to COVID-19 vaccinations, echoing similar findings in professionals ADR reports from deprived areas. [5] The experiences of adverse effects that patients from lower socio-economic groups have are likely to have been less well recorded than those of more wealthy and educated groups. This may have implications for the design and availability of ADR reporting forms and for the assessment of ADRs more generally.

References/Further Sources of Information

• 1. Al Dweik R, Stacey D, Kohen D, et al. Factors affecting patient reporting of adverse drug reactions: a systematic review. Br J Clin Pharmacol 2017;83:875–83.

• 2. Banovac M, Candore G, Slattery J, et al. Patient reporting in the EU: analysis of EudraVigilance data. Drug Saf 2017;40:629–45.

• 3. de Vries ST, Denig P, Andric A, et al. Motives to report adverse drug reaction to the national agency: a survey study among healthcare professionals and patients. Drug Saf 2021;44:1073–83.

• 4. Ministry of Housing, Communities and Local Government. English indices of deprivation 2019. https://www.gov.uk/government/statistics/english-indices-of-deprivation-2019 Accessed on 27/4/22.

• 5. Cox AR, Anton C, McDowell SE, Marriott JF, Ferner RE. Correlates of spontaneous reporting of adverse drug reactions within primary care: the paradox of low prescribers who are high reporters. Br J Clin Pharmacol. 2010;69(5):529–34.

2.91 P113 Digital Media and Pharmacovigilance: The SIMeF Pharmacovigilance Working Group Perspective

2.91.1 L. Stagi ¹, D. Bernardini², I. Bocchi³, S. Bonato³, D. Bottalico⁴, V. Calderazzo⁵, C. Casino⁶, G. N. Castiglione⁷, C. Cottone⁸, S. Dellon⁹, I. Grisoni¹⁰, A. Mattavelli¹¹, G. Pirisino¹², S. Romano¹³, G. Sirizzotti¹⁴

2.91.1.1 ¹Roche spa, Pharmacovigilance, Monza, Italy; ²Novartis Farma, Pharmacovigilance, Origgio, Italy; ³; ³Bayer spa, Pharmacovigilance, Milano, Italy; ⁴Takeda Italia, Customer Excellence & Innovation, Roma, Italy; ⁵Boehringer Ingelheim Italia, Pharmacovigilance, Milano, Italy; ⁶Servier Italia, Pharmacovigilance, Roma, Italy; ⁷Chiesi Farmaceutici, Pharmacovigilance, Parma, Italy; ⁸Teva Italia, Pharmacovigilance, Assago, Italy; ⁹Neopharmamed Gentili, Pharmacovigilance, Milano, Italy; ¹⁰Jazz Pharmaceuticals, Pharmacovigilance, Villa Guardia, Italy; ¹¹Janssen-Cilag, Pharmacovigilance, Cologno Monzese, Italy; ¹²Astellas Pharma, Pharmacovigilance, Milano, Italy; ¹³Sanofi Pasteur Vaccines Italy and Malta, Pharmacovigilance, Milano, Italy; ¹⁴Biogen Idec Italia, Pharmacovigilance, Milano, Italy

Introduction: Digital media are integrated in our daily routine, play a critical role in the dissemination of health information and disease prevention guidelines and are becoming more impacting in pharmacompanies activities, with an increasing trend after the pandemic period. They pose pharmacovigilance challenges for application of PV rules. a structured approach is needed for pharmacovigilance departments in the new digital scenario.

Objective: The SIMeF pharmacovigilance working group worked on digital topic since two years, addressing it in a structured way: from a a specific survey (1), to proposals for addressing the needs underlined, to seminars and events for capability building and discussions among experts. SIMEF group also worked on a proposal guideline for supporting PV departments (6), suggesting a framework for managing sponsored digital activities with potential collection of adverse events, to provide useful operative suggestions on PV requirements management.

Methods: A research on the regulation in force and the current status of digital media was conducted, with a focus on pharmacovigilance, privacy and quality aspects. The guideline was written considering the expertise of the authors in the management of pharmacovigilance activities. Seminars were done to favour discussions among experts.

Results: All healthcare sectors are impacted by digital media: scientific societies, academic institutions, patients’ associations, hospitals and healthcare institutions are increasing their online presence ^2,3. Social media are used by patients to compare health data, collect treatment information and discuss with physicians, with an increasing active role. Digital media should be considered as a potential source of AEs by pharmacompanies, when managing sponsored activities. PV aspects of digital activities are currently described, although not in details, in different regulations by EMA, FDA and MHRA.

Management digital projects by pharmacompanies is complex and require a structured multifunctional process, to guarantee a holistic approach to regulatory and legal requirements. Many aspects should be considered for compliance and efficiency. SIMeF work pose considerations on the importance of crossfunctional work, early pharmacovigilance advice, tracking system, execution of risk-based assessment, escalation to quality, SOPs presence, personnel trainings (including vendors) and a Quality System covering PV. New skills and capability will be crucial for PV departments in future.

Conclusion: Digital media are powerful instrument to increase patients and physicians involvement and to support disease knowledge. The rising amount of safety data generated through digital opens a challenge for pharmacompanies. This work is a starting point to trigger broader discussions around PV quality system for digital activities.

References/Further Sources of Information

• 1. Stagi L, Bocchi I, Bianco S, Sirizzotti G, Bernardini D, Calderazzo V, Pirisino G, Grisoni I, Silvia R. “Pharmacovigilance and the digital world in Italy: presentation of the results of a national survey”. Ther Adv Drug Saf, 2021, Vol. 12: 1–8.

• 2. Convertino I, Ferraro S, Blandizzi C, Tuccori M. 2018. "The usefulness of listening social media for pharmacovigilance purposes: a systematic review." Expert Opin Drug Saf 1081–1093

• 3. Richard Sloane, Orod Osanlou, David Lewis, Danushka Bollegala, Simon Maskell, Munir Pirmohamed. 2015 Oct. "Social media and pharmacovigilance: A review of the opportunities and challenges." Br J Clini Pharmacol 910–20

• 4. De Carli G.2015. “QUALITY ASSURANCE E FARMACOVIGILANZA. PARTE II—Quality Assurance in Pharmacovigilance (ii)” Giornale Italiano di Farmacoeconomia e Farmacoutilizzazione”. 7 (1): 27–35

• 5. Brosch S, de Ferran AM, Newbould V, Farkas D, Lengsavath M, Tregunno P. 2019. "Establishing a Framework for the Use of Social Media in Pharmacovigilance in Europe." Drug Saf 921–930

• 6. Daniela Bernardini, Ilenia Bocchi, Stefano Bonato, Davide Bottalico, Valentina Calderazzo, Carmela Casino,Gian Nicola Castiglione, Carla Cottone, Stefania Dellon, Ilaria Grisoni, Amanda Mattavelli, Giacomo Pirisino, Silvia Romano, Grazia Sirizzotti, Lisa Stagi "Guideline proposal for pharma companies to manage pharmacovigilance activities in digital media" AboutOpen 2022; 9: 21–28

2.92 P114 Previous Use of Proton Pump Inhibitors (PPI) in Hospitalized Patients and COVID-19 Mortality in Peru

2.92.1 T. J. Oscanoa ^1,2, J. A. Tineo³, W. T. Huamaní⁴, J. M. Pérez⁴, A. Carvajal⁵

2.92.1.1 ¹Universidad Nacional Mayor de San Marcos-Facultad de Medicina-Lima-Perú, Pharmacology, Lima-, Peru; ²Universidad de San Martín de Porres-Facultad de Medicina, Drug Safety Research Center. Hospital Almenara ESSALUD, Lima, Peru; ³Universidad Nacional Mayor de San Marcos-Facultad de Medicina-Lima-Perú, Medicine, Lima, Peru; ⁴Hospital Nacional Edgardo Rebagliati Martins-EsSalud, Emergency Department, Lima, Peru; ⁵Universidad de Valladolid, Pharmacology, Valladolid, Spain

Introduction: One of the known adverse reactions among long-term proton pump inhibitor (PPI) users, especially the elderly, is that it increases the risk of community-acquired pneumonia [1]. The probable mechanism is that the increase in gastric pH produces a decrease in elimination or an increase in colonization of bacteria; PPIs promote the proliferation of bacteria in the mouth and oropharynx and would increase in this manner the risk of pneumonia [2]. In COVID-19, lungs are particularly at risk. Currently, there is a great interest in establishing the relationship between the severity and mortality of SARS-CoV-2 infection in patients using PPIs [3].

Objective: To explore the relationship between the previous use of PPIs and mortality due to COVID-19

Methods: A retrospective observational study was carried out in a tertiary care hospital in Lima, Peru. Patients hospitalized in March 2021 for severe SARS-CoV-2 infection, confirmed by molecular tests (reverse transcription polymerase chain reaction), were included. Severe COVID-19 disease was defined as peripheral oxygen saturation on admission less than 93% (without supplemental oxygen) or pulmonary involvement greater than 30% (on the total severity score or TSS) in the lung tomography

Results: A total of 327 patients entered the study (mean age, 61.36 ± 16.0 years; male, 59.95%). PPIs users and non-users were 10 (3.06%) and 317 (96.94%), respectively. The mean age, Charlson score and total severity score (TSS) between PPIs users and non-users were 68.8 ± 17.11 vs. 61.12 ± 15.93 (p = 0.134), 3.6 ± 2.32 vs. 2.25 ± 1.715 (p = 0.019) and 55 ± 25.28 vs. 48.44 ± 24.30 (P = 0.399), respectively. Mortality in those using and not using PPIs were 80.0% (8 out of 10) and 38.49% (122 out of 317), respectively (Crude odds ratio, 6.39; 95% confidence interval 1.34–30.61; p = 0.008). No significant difference was observed in the leukocyte count, mean lactate dehydrogenase concentration, Ferritin, D-dimer and fibrinogen and serum levels of C-Reactive Protein, in those users of PPIs compared to non-users.

Conclusion: Among hospitalized patients for severe SARS-CoV-2 infection, prior use of PPIs was associated with a higher mortality risk. This association does not necessary imply causality. Further research would be required to clarify potential mechanisms.

Keywords: COVID-19, SARS-COV-2, proton pump inhibitor, mortality (Source: DeCS-BIREME).

References/Further Sources of Information

• 1. Xun X, Yin Q, Fu Y, He X, Dong Z. Proton Pump Inhibitors and the Risk of Community-Acquired Pneumonia: An Updated Meta-analysis. Ann Pharmacother. 2022 May;56(5):524–532. https://doi.org/10.1177/10600280211039240. Epub 2021 Aug 23. PMID: 34425689.

• 2. Nguyen PA, Islam M, Galvin CJ, Chang CC, An SY, Yang HC, Huang CW, Li YJ, Iqbal U. Meta-analysis of proton pump inhibitors induced risk of community-acquired pneumonia. Int J Qual Health Care. 2020 Jun 17;32(5):292–299. https://doi.org/10.1093/intqhc/mzaa041. PMID: 32436582.

• 3. Fatima K, Almas T, Lakhani S, Jahangir A, Ahmed A, Siddiqui A, Rahim A, Qureshi SA, Arshad Z, Golani S, Musheer A. The Use of Proton Pump Inhibitors and COVID-19: A Systematic Review and Meta-Analysis. Trop Med Infect Dis. 2022 Feb 28;7(3):37. https://doi.org/10.3390/tropicalmed7030037. PMID: 35324584; PMCID: PMC8950138.

2.93 P115 Utilization WHO Vaccine Hesitancy Tool to Assess the Refusal Rate of Routine Immunization Among Parents in Egypt

2.93.1 M. A. Elhawary^1,2, H. Rostom ^3,4

2.93.1.1 ¹Egyptian Ministry of Health and Population, Preventive Medicine Dep, Cairo, Egypt; ²Faculty of Pharmacy-Ain Shams University, Clinical Pharmacy Dep, Cairo, Egypt; ³Faculty of Pharmacy-MSA University, Clinical Pharmacy Dep, Cairo, Egypt; ⁴International Society of Pharmacovigilance ISoP, Egypt Chapter, Cairo, Egypt

Introduction: Vaccine hesitancy is defined as intentional delay or refusal to vaccinate children despite vaccine availability and it has been considered by the World Health Organization (WHO) as one of the ten major risks to public health globally. In fact, Egypt has achieved several successes in controlling vaccine preventable diseases, including strong national vaccination coverage of over 90%, through an increase of vaccine coverage and continuous surveillance leading to reduced illness, disability and death from diseases such as diphtheria, tetanus, whooping cough, measles and polio [1].

If we want to maintain this vaccine coverage ratio, we must verify whether parents agree to vaccinate their children because they are convinced of the efficacy and safety of vaccines, or because it is mandatory?

Objective: To determine the prevalence of hesitancy among Egyptian parents towards routine immunization for their children by using the WHO Strategic Advisory Group of Experts (SAGE) on Vaccine Hesitancy Survey Tool [2].

Methods: A cross-sectional study was conducted among 410 of parents between December 2021 and April 2022 in Cairo, Egypt. A WHO validated questionnaire was used consists of 13 questions designed to measure parents' hesitation towards vaccinations.

Results: Of 410 families screened, No parent had ever refused a vaccination, and only 4 parents (0.97%) had been reluctant or hesitated to get a vaccination for their children. Parents either with higher or moderate educational levels were strongly agree that childhood vaccination is important for child health (p < 0.001). No doubts or concerns related to vaccine safety have been reported and this has been mainly due to the presidential national immunization initiatives to increase Expanded Program on Immunization (EPI) coverage. Its worth to mention, Egypt announced that it was completely free of polio in 2006, and this was due to these presidential campaigns, which gave greater confidence in the safety and effectiveness of vaccines.

Conclusion: To maintain high levels of immunization, healthcare professionals should be kept on the same level of awareness with vaccine safety and vaccine risk communication to keep the trust of the population with the safety and effectiveness of vaccines. Because when high immunization rates are reached and sustained in the population they generate herd immunity to protect communities. In addition, the mass media played an active role as it has covered the results of these presidential campaigns, which has increased parents' confidence in these vaccinations. Finally, Egypt must continue with this successful approach of encouraging the vaccination.

References/Further Sources of Information

• 1. WHO Expanded Programme on Immunization—Egypt [Internet]. Available from: http://www.emro.who.int/egy/programmes/expanded-programme-on-immunization.html.

• 2. Schuster M, Eskola J, Duclos P; SAGE Working Group on Vaccine Hesitancy. Review of vaccine hesitancy: Rationale, remit and methods. Vaccine. 2015;33(34):4157–4160. https://doi.org/10.1016/j.vaccine.2015.04.035.

2.94 P116 Active Monitoring of Adverse Events in a Closed Population: Contributions from Colombia to COVID-19 Vaccines Safety

2.94.1 C. Vaca ¹, J. Vahos¹, S. P. Moncaleano¹, J. L. Gutierrez¹, J. L. Mendez¹

2.94.1.1 ¹Universidad Nacional de Colombia, Farmacia, Bogota D.C, Colombia

Introduction: Information on the effectiveness and safety of vaccines for COVID-19 is limited as clinical trials did not provide enough evidence about long-term effects and all possible adverse events [1]. Moreover, marketing authorization for these vaccines was conditioned on providing more information about adverse events and effects on populations not included in clinical trials, like pregnant and pediatric population [2,3].

Objective: To evaluate the clinical performance and Adverse Events Following Immunization (AEFIs) of the vaccines against COVID-19 in a closed cohort from a Colombian university.

Methods: This is an observational study of a prospective cohort, with members of the Universidad Nacional de Colombia (UNAL, by its Spanish acronym) followed from June 2021 to April 2022. Data was collected via a telephonic survey and additional clinical information was provided by the health institution Unisalud. Description of the AEFIs in the population and the characteristics of the people with adverse events was analyzed.

Results: A total of 3,764 persons were included, 35.73% reported AEFIs from which around 8.55% (115/1,345) experienced them 5 days after immunization. AEFIs tended to have low or medium intensity (70% on a 5 Likert scale, from very low to very high) and a duration between 1 and 3 days (65.1%). The vaccine with fewer AEFIs was Sinovac and was statistically different from Pfizer and AstraZeneca (using Tukey HSD and 95% confidence).

Conclusion: The percentage of AEFIs is consistent with findings in active monitoring programs. Risk factors coincide with other studies. This study demonstrates high rates of AEFIs in the population differing by brand. Serious events were rare. This study contributes to the knowledge of AEFIs for vaccines only used in middle and low-income countries. The active monitoring program of UNAL gives very relevant and reliable information. Models to study risk factors for AEFIs are needed and are currently in development by the authors.

References/Further Sources of Information

• 1. Vélez M, Vélez V. Vacunas para la COVID-19: evidencia sobre seguridad, inmunogenicidad y eficacia Unidad de Evidencia y Deliberación para la Toma de Decisiones. 2020;1–49.

• 2. Richman DD. COVID-19 vaccines: implementation, limitations, and opportunities. Glob Heal Med [Internet]. 2021 Feb 28 [cited 2022 May 10];3(1):1. Available from: /pmc/articles/PMC7936373/

• 3. DIME Decisiones. Breve recordatorio sobre el significado de las autorizaciones de uso en emergencia [Internet]. 2020 [cited 2022 May 10]. Available from: http://www.proyectodime.info/apex/f?p = 355:21:2021015822819::::P21_ID_PUBLICACION:486

2.95 P118 COVID-19 Pandemic: A Surge in Counterfeit Medicines

2.95.1 S. Ussai ¹

2.95.1.1 ¹University of Cagliari, Clinical Pharmacology and Toxicology, Cagliari, Italy

Introduction: Falsified medical products may contain no active ingredient, the wrong active ingredient, or the wrong amount of the correct active ingredient [1]. The prevalence of falsified medicines spans from 1% in developed settings to 10% in the Global South [2].

Due to broken supply chains, strong demand for medicines and limited capacities of law enforcement, the COVID-19 pandemic created the optimal conditions for the falsified medicines’ market to expand.

Objective: Aim of this abstract is to present evidence about the surge in counterfeit medicines amid the COVID-19 crisis.

Methods: This review examines the existing published scientific literature and peer-to-peer networks, grey literature as well as briefs and policy reports on counterfeit medicines amid COVID-19 pandemic.

Results: According to EOCD, People’s Republic of China and India are the primary producers of counterfeit medicines, with the United Arab Emirates, Singapore and Hong Kong (China) serving as transit economies [3].

The review has identified three areas of impact for counterfeit medicines amid COVID-19. These are: (i) the increased demand for COVID-19-reated medicines, due to the medical supply restrictions related to the pandemic. These restrictions have been introduced by local authorities (e.g. supply restriction for Chloroquine and Azithromycin) or occurred because of air traffic reduction. Over 60 countries have implemented export restrictions and 25% of restricted products were medicines [4]; (ii) E-commerce as a relevant platform for substandard medicines. For instance, advertisements of illicit COVD-19-related medical products have been reported on social media platforms, such as Instagram. According to the industry, online distribution becomes predominant and about 50% of purchases of illicit medicines are done on-line [5]; (iii) weak regulatory frameworks, including insufficient technical capacity, constrained access and ineffective over-sight to address substandard and falsified medical products. WHO reports that 30 per cent of national regulatory authorities do not have full effective capacity to perform their functions [6].

Conclusion: COVID-19 pandemic has increased the vulnerability to counterfeit medicines, leading to serious damage to the health of individuals or failure to treat their medical needs adequately. The abstract identifies three relevant governance gaps (increased demand, E-commerce and weak regulatory frameworks) to be further addressed in dedicated fora.

References/Further Sources of Information

• 1. Newton PN, Bond KC, on behalf of 53 signatories from 20 countries. COVID-19 and risks to the supply and quality of tests, drugs, and vaccines. Lancet Glob Health. 2020 Jun 1;8(6):e754–e755.

• 2. Tesfaye, W., Abrha, S., Sinnollareddy, M., Arnold, B., Brown, A., Matthew, C., Oguoma, V. M., Peterson, G. M., & Thomas, J. (2020). How Do We Combat Bogus Medicines in the Age of the COVID-19 Pandemic?. The American journal of tropical medicine and hygiene, 103(4), 1360–1363.

• 3. Trade in fake medicines at the time of COVID-19 pandemic. Available at: https://www.oecd.org/gov/illicit-trade/oecd-fake-medicines-webinar-june-10-summary-note.pdf.

• 4. USP. Interactive dashboard of COVID-19 drugs in world pharmacopeias. U.S. Pharmacopeia, 2021. https://www.usp. org/covid-19/treatment-and-prevention/world-pharmacopeias-dashboard

• 5. Miller, R., Wafula, F., Onoka, C. A., Saligram, P., Musiega, A., Ogira, D., Okpani, I., Ejughemre, U., Murthy, S., Garimella, S., Sanderson, M., Ettelt, S., Allen, P., Nambiar, D., Salam, A., Kweyu, E., Hanson, K., & Goodman, C. (2021). When technology precedes regulation: the challenges and opportunities of e-pharmacy in low-income and middle-income countries. BMJ Global Health, 6(5), e005405. https://doi.org/10.1136/bmjgh-2021-005405.

• 6. World Health Organization. WHO; 2021. Medical Product Alert N°5/2021: Falsified COVISHIELD vaccine.https://www.who.int/news/item/16-08-2021-medical-product-alert-n-5-2021-falsified-covishield-vaccine.

2.96 P119 Pharmacovigilance in Healthcare Emergency: Lessons Learned from COVID-19: Uganda

2.96.1 J. Atuhaire¹, J. Mayengo¹, H. N. Byomire ¹

2.96.1.1 ¹National Drug Authority, Product Safety, Kampala, Uganda

Introduction: Before the pandemic, reporting of Adverse Drug Reactions had been the preserve of health care professionals and they were the main beneficiaries of sensitizations and trainings. However, with the outbreak of the Covid pandemic, it became necessary to expand pharmacovigilance to the lay person as they were likely to receive the vaccine in a non-hospital setting, making it difficult to monitor them.

Objective: To describe the actions taken to foster pharmacovigilance during the pandemic and the lessons learned.

Methods: Retrospective primary data analysis of reporter details in the individual case safety reports submitted to the National Pharmacovigilance Centre of the Uganda National Drug Authority.

Results: Before the pandemic, patient reports numbered below 10 over the years. After the pandemic, WHO supported the NPC to develop a patient reporting platform using the USSD code which led to a leap in reports up to over 2000, and ultimately enabling the NPC to pass the 10,000 reports mark in Vigiflow since 2004.

Trends of Reporters Showing Patients Overtaking Other Reporter Categories During the Pandemic

Conclusion: Patients had been a long neglected reporting segment. The Covid pandemic showed that given the right tools and knowledge, they are able to report and provide important data components that may be missed when health care providers report on their behalf. The Centre is now including patient engagements among the routine activities to reach out to patients.

References/Further Sources of Information

• 1. Al Dweik R, Stacey D, Kohen D, Yaya S. Factors affecting patient reporting of adverse drug reactions: a systematic review. British journal of clinical pharmacology. 2017 Apr;83(4):875–83.

• 2. Blenkinsopp A, Wilkie P, Wang M, Routledge PA. Patient reporting of suspected adverse drug reactions: a review of published literature and international experience. British journal of clinical pharmacology. 2007 Feb;63(2):148–56.

• 3. Anderson C, Krska J, Murphy E, Avery A, Yellow Card Study Collaboration. The importance of direct patient reporting of suspected adverse drug reactions: a patient perspective. British journal of clinical pharmacology. 2011 Nov;72(5):806–22.

• 4. Jarernsiripornkul N, Krska J, Capps PA, Richards RM, Lee A. Patient reporting of potential adverse drug reactions: a methodological study. British journal of clinical pharmacology. 2002 Mar;53(3):318–25.

• 5. Van Grootheest K, de Jong-van den Berg L. Patients’ role in reporting adverse drug reactions. Expert opinion on drug safety. 2004 Jul 1;3(4):363–8.

2.97 P120 Impact of the Inclusion of Covid-19 Vaccines in the National Pharmacovigilance Database on the Measurement of Disproportionality

2.97.1 I. Talibi ¹, A. Tebaa¹, R. S. Bencheikh¹

2.97.1.1 ¹Centre Antipoison et de Pharmacovigilance du Maroc, Ministry of health and social protection, Rabat, Morocco

Introduction: During the strengthened Covid-19 vaccine safety surveillance, the Moroccan pharmacovigilance center has collected a higher number of adverse events following immunization (AEFI) reports. More than half of the Individual Case Safety Reports (ICSRs) collected in the National pharmacovigilance database since its creation are linked to Covid-19 vaccines [1].

Objective: To assess the impact of the inclusion of the AEFI related to Covid-19 vaccines on the measures of disproportionality in the National pharmacovigilance database.

Methods: Measurement of disproportionality by the calculation of the Reporting odds ratio (ROR) [2] for the "Drug-Effect" pairs collected at the National pharmacovigilance database (data from March 16, 2022) with and without inclusion of Covid-19 vaccines. Using “VigiLyze” (Uppsala Monitoring Center) we calculated the RORs and exported to “Excel” the list of "Drug-Effect" pairs for which the lower limit of the 95% confidence interval of the ROR is greater than 1. Then, on the list obtained, we recalculated by Excel the RORs after excluding the Covid-19 vaccines from the database.

Results: Among the 69,814 cases of adverse effects recorded in the National pharmacovigilance database from March 16, 2022, 36,541 cases (52.6%) concerned Covid-19 vaccines (Table 1). The measurement of the disproportionality showed that 88% of the RORs increased and 5% decreased after inclusion of Covid-19 vaccines in database. The median of the ROR change factor following this inclusion (ROR_{Covid vaccines included}/ROR_{Covid vaccines excluded}) was 2.1 (1.8–2.1); this can be explained by the higher proportion of Covid-19 vaccines cases (half of the database). Also, the degree of this influence depends on the frequency of AEFI to Covid-19 vaccines. Thus, the ROR had decreased with inclusion of cases of covid-19 vaccines for most common reactions and had been multiplied by a factor more than 2 for the low-reported reactions with Covid-19 vaccines.

Conclusion: The inclusion of Covid-19 vaccines in the National pharmacovigilance database has influenced the measures of disproportionality, which would influence signal detection. This bias must be taken into account when a type of drug or vaccine is very represented in a database. The proposed solution is to specify database for these types of products or to improve VigiLyze to be able to perform disproportionality measurements from parts of the national database.

References/Further Sources of Information

• 1. Moroccan Anti Poison and Pharmacovigilance Center (Centre Anti Poison et de Pharmacovigilance du Maroc). National pharmacovigilance database.

• 2. van Puijenbroek EP et al. A comparison of measures of disproportionality for signal detection in spontaneous reporting systems for adverse drug reactions. Pharmacoepidemiol Drug Saf. Jan–Feb 2002;11(1):3–10.

2.98 P121 Evaluation of Suspected Adverse Reactions to COVID-19 Vaccines in Patients with Autism Spectrum Disorder: Analysis of VAERS Database

2.98.1 C. D. Carluccio ¹, R. D. Cas², M. L. Scattoni², F. M. Ippolito²

2.98.1.1 ¹MSD Italy, Pharmacovigilance, Rome, Italy; ²Italian National Institute of Health, Pharmacoepidemiology and Pharmacovigilance, Rome, Italy

Introduction: Several neurobiological mechanisms have been proposed to support the hypothesis of a higher COVID-19 risk in individuals with Autism Spectrum Disorder (ASD) [1]. Since the end of 2020 EMA and FDA, among others Agencies, issued Emergency Use Authorization for COVID-19 vaccines, approved for prevention of COVID-19 disease [2]. Safety of these vaccines are monitored in all countries. In USA, spontaneous reports are collected in the Vaccine Adverse Event Reporting System (VAERS), that is freely accessible [3]. This continuous and intense safety monitoring is needed to enable a timely evaluation of the benefit/risk profile of COVID-19 vaccines to ensure the benefit of vaccination continues to outweigh risks.

Objective: To evaluate suspected adverse reactions following vaccination with COVID-19 vaccines in persons with ASD reported to VAERS.

Methods: This study analyzed VAERS reports of suspected adverse reactions following vaccination with Pfizer-BioNTech, Moderna and Janssen COVID-19 vaccines until 04/Mar/2022 in children, adolescents and adults with ASD. Reports were analysed by age, sex, seriousness, type of vaccine (manufacturer), dose, onset interval, length of hospitalisation and outcome.

Results: Eighty-seven reports have been retrieved from VAERS. The most affected age group is between 18-29 years with a higher percentage distribution in males than in females. Seventy-six (76%) reports were related to non-serious events, thus, he most frequent reactions reported were expected: fever, pain at the injection site and headache. Other adverse reactions are rare and unexpected including febrile seizure and eye rolling. Two cases of amonorrhea were also observed. Among the 11 serious cases, 6 (6.90%) were hospitalized; 2 (2.30%) were reported as life-threatening and 2(2.30%) caused permanent disability. Death was reported in one case, occurrin few hours after the vaccination. At the time of the reporting, the patients presented concomitant medical conditions, treated with various product medications, who contributed, therefore, to the onset of events.

Conclusion: The number of cases reported to VAERS and related to suspected adverse reactions in individuals with ASD does not suggest a safety concern attributable to authorized COVID-19 vaccines at this time in this special population.

References/Further Sources of Information

• 1. A Pilot Study on Covid and Autism: Prevalence, Clinical Presentation and Vaccine Side Effects, Brondino et al.

• 2. Thrombocytopenia including immune thrombocytopenia after receipt of mRNA COVID-19 vaccines reported to the Vaccine Adverse Events Reporting System (VAERS), Kerry J Welsh et al.

• 3. https://vaers.hhs.gov.

2.99 P122 Safety and Pharmacokinetic Profile of an Immunobiological Drug (anti SARS-Cov-2) in the Treatment of CoViD-19

2.99.1 G. A. Keller ¹, G. D. Girolamo², H. E. D. Salvo², D. S. Zotta², R. Salvi², L. Madeo², E. R. García², I. Colaianni², J. Bartolome², S. Miranda³, G. Bramuglia⁴, A. R. d. Roodt⁵, G. Temprano⁶, C. Bonel⁷, J. C. Dokmetjian⁶

2.99.1.1 ¹Administración Nacional de Laboratorios e Institutos de Salud ANLIS Malbran, Instituto Nacional de Produccion de Biologicos, Ciudad Autonoma de Buenos Aires, Argentina; ²Hospital General de Agudos Donación Francisco J. Santojanni, Departamento de Urgencias, Ciudad Autónoma de Buenos Aires, Argentina; ³Universidad de Buenos Aires-Instituo Alberto C. Taquini de Investigaciones en Medicina Traslacional IATIMET, Laboratorio de Glico-Inmuno-Biologia, Ciudad Autónoma de Buenos Aires, Argentina; ⁴Universidad de Buenos Aires-Instituo Alberto C. Taquini de Investigaciones en Medicina Traslacional IATIMET, Laboratorio de Farmacocinética, Ciudad Autónoma de Buenos Aires, Argentina; ⁵Administración Nacional de Laboratorios e Institutos de Salud ANLIS Malbran-Instituto Nacional de Produccion de Biologicos, R&D department, Ciudad Autonoma de Buenos Aires, Argentina; ⁶Administración Nacional de Laboratorios e Institutos de Salud ANLIS Malbran-Instituto Nacional de Produccion de Biologicos, Quality management, Ciudad Autonoma de Buenos Aires, Argentina; ⁷Administración Nacional de Laboratorios e Institutos de Salud ANLIS Malbran-Instituto Nacional de Produccion de Biologicos, Technical deparment, Ciudad Autonoma de Buenos Aires, Argentina

Introduction: Equine hyperimmune serum (F(ab')2 fragments) has been widely used in Argentina in the last 100 years with satisfactory results and an acceptable safety profile in the treatment of accidents with poisonous animals such as snakes (bothrops, chrotalus, elapids) and arthropods (Loxosceles, Latrodectus, Phoneutria and Tityus). These antisera were developed by the National Institute for the production of Biologicals (ANLIS-Malbrán) and distributed free of charge in public hospitals in the country.

Objective: The aims of this study (NCT04913779) is to analyze the efficacy and safety of a passive immunotherapy strategy using hyperimmune equine serum known as Anti-SARS-CoV-2 elaborated by the National Institute for the Production of Biologicals (ANLIS-Malbrán) as an addition to the standard therapeutic approach for hospitalized patients with COVID-19, in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Methods: A randomized, double-blind controlled clinical study is carried out in 200 patients with COVID-19 requiring oxygen therapy in which the safety and efficacy of early use (72 hours from the onset of symptoms) of the research product is evaluated. The present work corresponds to a preliminary result of the safety and pharmacokinetic analysis in the first 20 patients included.

Results: 20 initial patients (1:1 treatment: control ratio) were studied. The post-administration follow-up time was 28 days. The pharmacokinetic analysis shows that the research product presents an extracellular volume of distribution, with a median half-life of distribution was 6.3h (10–90% percentiles: 3.4–8.1 h) and half-life of elimination, 121h (10th–90th percentiles: 83–171 h). Neutralizing activity in plasma was correlated with drug concentration. Daily controls were carried out including physical examination, questioning in relation to symptoms presented, and blood extraction for routine laboratory control. No patient reported symptoms consistent with adverse reactions. Although some patients presented mild laboratory alterations (hepatogram, urea, creatinine), in all cases they were alterations that existed prior to the administration of the research product and that improved after treatment.

Conclusion: Despite the small number of patients studied initially, and the possible masking of an adverse event due to the underlying disease (COVID-19), no significant adverse reactions were evidenced during treatment with the research product. There were no serious reactions and the pharmacokinetic characteristics appear to show a long-acting profile correlated with neutralizing activity in vitro.

References/Further Sources of Information

• 1. Dixit R, Herz J, Dalton R, Booy R. Benefits of using heterologous polyclonal antibodies and potential applications to new and undertreated infectious pathogens. Vaccine. 2016 Feb 24;34(9):1152–61.

2.100 P123 Self-Medication Among Romanian Patients in General and in the Context of the COVID-19 Pandemic

2.100.1 I. Iaru¹, C. Bucsa², C. Rus², C. Mogosan¹, A. Farcas ²

2.100.1.1 ¹Iuliu Hatieganu University of Medicine and Pharmacy, Department of Pharmacology-Physiology and Pathophysiology, Cluj-Napoca, Romania; ²Iuliu Hatieganu University of Medicine and Pharmacy, Pharmacovigilance Research Center, Cluj-Napoca, Romania

Introduction: Self-medication is important for public healthcare as it allows patients to make their own decisions about how to maintain their health and well-being. In the context of COVID-19 healthcare emergency, self-medication is likely to have been increased for prevention or treatment of perceived infection.

Objective: To assess self-medication in general and in the context of COVID-19.

Methods: We conducted a cross-sectional survey among Romanian patients during December 2020-March 2021. Participants were recruited through patients’ associations (email, Facebook groups). Those who agreed to participate to the study were directed to an online questionnaire. The in-house developed questionnaire was anonymous, consisting of 42 questions assessing knowledge, attitudes (using Likert scale) and practice regarding self-medication and it was pretested for adjustments in a community pharmacy in 14 patients.

Results: A total of 398 participants (77.1% female), with most (64.8%) in the age category of 35-64, responded to the survey. The majority were urban residents (84.9%), having under and postgraduate studies (63.1%). More than half (57.3%) reported having chronic disease. In general, 89.7% reported practicing self-medication, with 70.4% of participants taking an average of 1-2 OTC drugs over the course of a month. Among those self-medicated, 12.9% reported using doses higher than recommended in the leaflet. Of those who experienced adverse reactions (15.4%) when self-medicated, 30.9% reported exceeding the doses. Only 25.4% agreed that self-medicated OTC drugs are safe and 42% of respondents disagreed/strongly disagreed. A considerable percentage of participants (71.3%) agreed that it is a good idea to consult a specialist before using OTC drugs. When asked which drugs are OTC, respondents gave mainly correct answers, however, 24.9% considered antivirals being OTC and therefore suitable for self-medication. In the context of COVID-19, only 17.8% reported going to the pharmacy more often than they usually did, with 42.7% and 29.9% taking medicines for preventive and treatment purposes. Medicines/ supplements mostly purchased from the pharmacy during COVID-19 pandemic were vitamin C (61.8%) and D (44.7%), paracetamol (56.0%), zinc (29.4%), ibuprofen (20.1%), and in lower percentages azithromycin (6.0%), oseltamivir (3.3%) and hydroxychloroquine (3.0%). 76.4% respondents stated that they were not influenced by media reports about medicines used to prevent SARS-CoV-2 virus infection and only 6.8% bought medicines online in the context of the COVID-19 pandemic.

Conclusion: Self-medication was commonly reported among our study population; however, it seems that it was not greatly influenced by the COVID-19 pandemic and by media information on drugs to be used for COVID-19 prevention.

References/Further Sources of Information

Not applicable.

2.101 P124 Systemic COVID-19 vaccines Adverse Events Following Immunizations and Their Associated Factors: A Comparative Study Using Iraqi Consumers’ Self-Reported Data

2.101.1 B. A. Shimran ¹, Y. Manal ¹, H. Amer¹

2.101.1.1 ¹Ministry of Health, Pharmacy, Baghdad, Iraq

Introduction: Three types of COVID-19 vaccines were deployed in Iraq; PfizerBioNTech, AstraZeneca, and Sinopharm. Spontaneous self-reported safety data received directly from consumers was an important source of COVID-19 vaccine reporting sources for the first time in Iraq.

Objective: To study the common systemic AEFIs and factors influencing them, using self-reported data by Iraqi consumers vaccinated with different COVID-19 vaccine types.

Methods: As a part of the national plan for COVID-19 vaccines safety surveillance, an online self-assessment form was designed by the national pharmacovigilance center for the public consumers across the country. The form was quadrilingual and captures the necessary information for a valid AEFI report. Demographic data, contact details, vaccination details, adverse event information, and medical history were collected. To facilitate the filling process and standardize the answers, a list of predefined common short-term AEFIs were included as a checklist, in addition to a free text for other unlisted AEFIs.

A retrospective cross-sectional study using the collected responses from April, 2021 until April, 2022 was performed. Data was validated and cleaned. Analyses was performed using SPSS software version 26. Selected common short-term AEFIs were analysed. The incidence of these AEFIs were compared between vaccine types using chi-square test. Moreover, predictors of reporting these AEFIs were explored using binary logistic regression for each vaccine type.

Results: A total of 2843 report were included, 62.0% of them were male. The age mean was 36.33 (SD ± 12.2). The participants were more likely to report after the 1st dose (79.4%). AstraZeneca vaccine was found to produce the highest number of AEFIs per report, 4.31 (SD ± 2.4). AstraZeneca and PfizerBioNTech were significantly associated with a higher incidence of multiple AEFIs as compared with Sinopharm (fatigue, joint pain, headache, fever, and chills). PfizerBioNTech vaccine was associated with 71 out of the 76 reported lymph nodes AEFIs.

Factors that were significant predictors of higher reporting of systemic AEFIs were; for PfizerBioNTech (female gender, increased dose number, and increased likelihood of previous COVID-19 infection); AstraZeneca (younger age, female gender, and increased likelihood of previous COVID-19 infection); and in case of Sinopharm (younger age, and female gender)

Conclusion: The results showed that AstraZeneca and PfizerBioNTech vaccines were associated with more AEFIs than Sinopharm. Predictor factors of AEFIs include; female gender in all vaccines; the presence of previous COVID-19 infection in both PfizerBioNTech and AstraZeneca vaccines; second dose in PfizerBioNTech; and younger age for both AstraZeneca and Sinopharm.

References/Further Sources of Information

• 1- Ban Abdulameer AL-Shimran, Manal M. Younus, Abdul Razzaq Ali Qaragholi. COVID-19 Vaccines Adverse Events Following Immunization Surveillance Report: A Year of Vaccinovigilance. Iraqi New Medical Journal. January 2022;8(15). http://iraqinmj.com/upload/upfile/en/283.pdf.

• 2- Attash, H.M.; Al-Obaidy, L.M.; Al-Qazaz, H.K. Which Type of the Promising COVID-19 Vaccines Produces Minimal Adverse Effects? A Retrospective Cross-Sectional Study. Vaccines 2022, 10, 186. https://doi.org/10.3390/vaccines10020186.

• 3- Hind B. Almufty, Shinah A. Mohammed, Arshad M. Abdullah, Muayad A. Merza, Potential adverse effects of COVID19 vaccines among Iraqi population; a comparison between the three available vaccines in Iraq; a retrospective cross-sectional study, Diabetes & Metabolic Syndrome: Clinical Research & Reviews, Volume 15, Issue 5, 2021, 102207, ISSN 1871-4021, https://doi.org/10.1016/j.dsx.2021.102207.

2.102 P125 How Covid-19 Pandemic Affected the National Pharmacovigilance System in the Czech Republic

2.102.1 J. Kopecká ¹, V. Deščíková¹

2.102.1.1 ¹State Institute for Drug Control, Pharmacovigilance department, Prague, Czech Republic

Introduction: Covid-19 pandemic has impacted all areas of human society worldwide, including drug regulatory authorities. Enormous public interest and seriousness of the disease resulted in boom of new medicines for treatment and prevention of Covid-19. Patients and healthcare professionals (HCP) concerns on safety of these new medicines resulted in the highest increase in the reporting rate of adverse drug reactions (ADRs) in the history of the Czech Republic (CZ).

Objective: To present how the PV processes were affected by Covid-19 pandemic. To present the impact of increased reporting rate and related workload on the national PV system in Czech regulatory authority (SUKL) and the influence on awareness of ADRs reporting in the Czech public.

Methods: In 2020, the total number of ADRs (n = 2904) reported to SUKL was the lowest in the past 5 years (2016-2020). The probable cause may be the Covid-19 pandemic, including the lack of time for HCP to report ADRs.

Results: On the contrary, in 2021 (1) with the entry of the treatment and prevention of Covid-19 into the clinical practice, there was a massive increase in reported ADRs in CZ. Of the total number of reported cases (n = 13 759), 81.10 % (n = 11 159) were vaccine-related (all types of vaccines). Of these vaccine-related ADRs 95.27 % (n = 10 631) were reported for Covid-19 vaccines only. Considerable interest in vaccine safety in CZ is evident, resulting in high number of suspected ADRs reported following vaccine administration.

Conclusion: Due to the significant increase in the ADRs reported, the national PV system had to be adapted. A system of triage of case reports was set including pre-assessment of seriousness by PV assessors. More staff had to be hired and trained to assist with the case processing, including receipt of the report, HCP confirmation of patient reports, follow-up and hospital records requests. To satisfy an extensive media attention and to increase transparency of vaccine safety, SUKL published an overview of reported ADRs on weekly basis (2) and communicated the most serious concerns online, together with EMA recommendations. Czech PV assessors were deeply involved in all European procedures related to Covid-19 treatment (e.g., remdesivir) and prevention (vaccines). The Czech public became more aware of the possibility of reporting ADRs, the number of reports will be presented. Based on reporters ´ suggestions the online reporting form for ADRs was re-designed. This experience has been challenging and brought new approaches and improvements to the national PV system.

References/Further Sources of Information

• 1. State Institute for Drug Control [Internet]. Information Bulletin on ADRs. Prague, The Institute, 2022. [cited 2022 May 04]; Available from: https://www.sukl.cz/sukl/informacni-zpravodaj-nezadouci-ucinky-leciv-1-2022 [in Czech]

• 2. State Institute for Drug Control [Internet]. Weekly reports of ADRs reported from the whole territory of the Czech Republic. Prague, The Institute, 2022. [cited 2022 May 04]; Available from: https://www.sukl.cz/tydenni-zpravy-o-prijatych-hlasenich-podezreni-na-nezadouci [in Czech]

2.103 P126 Active Surveillance for Safety Monitoring of COVID-19 Vaccines in Saudi Arabia

2.103.1 S. Alhabardi ¹, L. Alhusayni¹, M. Aljebreen¹, A. Alzamil², M. AlSwead³, M. Alrohaimi¹, A. Fawaz¹

2.103.1.1 ¹Saudi Food and Drug Authority, Drug Safety and Risk Management Department-Executive Directorate of Pharmacovigilance-Drug Sector-Saudi Food and Drug Authority, RIYADH, Saudi Arabia; ²Al Maarefa University, Al Maarefa University-College of Pharmacy, Riyadh, Saudi Arabia; ³Prince Nourah bint Abdulrahman University, Prince Nourah bint Abdulrahman University-College of Pharmacy, Riyadh, Saudi Arabia

Introduction: At the end of 2019, a novel coronavirus was identified as the cause of a cluster of pneumonia cases in Wuhan, China [1, 2]. It is generally accepted that the world will not return to the pre-pandemic normally situation until safe and effective vaccines become available. However, the rare and unknown adverse events following immunization (AEFIs) are not usually detected in the clinical trials. Thus, monitoring the safety of COVID-19 vaccines in real-world population is essential.

Objective: To perform a post-marketing safety surveillance of AEFIs of COVID-19 vaccines.

Methods: A prospective cohort study conducted and followed subjects who received COVID-19 vaccines from the first day of vaccination for seven days after the first and second doses, then biweekly for three months. All vaccinee demographic information, vaccine type, co-morbidities, concomitant medications and AEFIs were collected by phone through a standardized online questionnaire. Baseline characteristics and AEFIs were analyzed descriptively by SPSS software. AEFIs were classified according to medical Dictionary for Regulatory Activities (MedDRA).

Results: 544 subjects of 8867 agreed to be part of the study. Among them 218 subjects completed the study, of them 110 individual were male (50.5%) and 108 (49.5%) were female; the median age was 33 year. Out of 218, 87 (39.91%) individual received Pfizer-BioNTech vaccine, 45(20.64%) individual received Oxford/AstraZeneca vaccine, 5(2.3%) individual received Moderna vaccine, and 81 (37.2%) received two different COVID-19 vaccines. The reported events were categorized to system organ class (SOC) according to MedDRA. The most reported SOCs were respiratory, thoracic and mediastinal disorders (n = 8 with Pfizer-BioNTech vaccine, n = 4 with Oxford/AstraZeneca vaccine, n = 1 with Moderna vaccine), Injection site reactions (n = 66 with Pfizer-BioNTech vaccine, n = 34 with Oxford/AstraZeneca vaccine, n = 5 with Moderna vaccine), nervous system disorder (n = 20 with Pfizer-BioNTech vaccine, n = 18 with Oxford/AstraZeneca vaccine, n = 3 with Moderna vaccine),infections and infestations (n = 23 with Pfizer-BioNTech vaccine, n = 33 with Oxford/AstraZeneca vaccine, n = 4 with Moderna vaccine), musculoskeletal disorders (n = 53 with Pfizer-BioNTech vaccine, n = 46 with Oxford/AstraZeneca vaccine, n = 7 with Moderna vaccine). Only 10 (4.6%) cases were serious and required medical intervention to overcome the harm.

Conclusion: The preliminary results of the study shows the short-term safety profiles of included COVID-19 vaccines are acceptable in Saudi Arabia.

References/Further Sources of Information

• 1. Sonali Kochhar, Daniel A. Salmonc. Planning for COVID-19 vaccines safety surveillance. Vaccine. 2020; 38: 6194–6198.

• 2. Roger Chou, Tracy Dana, David I. Buckley, Shelley Selph. Epidemiology of and Risk Factors for Coronavirus Infection in Health Care Workers. A Living Rapid Review. Annals of Internal Medicine. 2020.

2.104 P127 RESPIR’Nantes Study: What About the Safety ?

2.104.1 P. Violleau¹, G. Veyrac¹, V. Guardiolle², F. Raffi³, J. Duconseil⁴, J.F. Huon⁴, A. L. Ruellan ¹

2.104.1.1 ¹University Hospital Center, Clinic Pharmacology, Nantes, France; ²University Hospital Center, Data Clinic, Nantes, France; ³University Hospital Center, Infectious and Tropical Diseases, Nantes, France; ⁴University Hospital Center, Clinic Pharmacy, Nantes, France

Introduction: Remdesivir, has been evaluated in the treatment of SARS-CoV-2 pneumonia in several clinical trials, then it has been used in routine care since the European approval in this indication.

Objective: The main objective of the RESPIR'Nantes study was to describe the clinical outcome and safety of patients treated with remdesivir in real life. We chose here to focus on safety outcomes.

Methods: To describe the safety, we considered adverse events (AEs), based on those reported to date in the Summary of Product Characteristics and potential post-marketing signals from the international pharmacovigilance database Vigilyze^®. AEs were classified according to the System Organ Class (SOC) of the Medical Dictionary of Adverse Events terminology. The AEs of SOC "hepatobiliary disorders" and "renal and urinary disorders" being the most reported to date, a detailed analysis was performed

Results: A total of 76 patients were included in the study from March 13 to December 31, 2020. The most common AEs were metabolism and nutrition disorders, hepatobiliary disorders, gastrointestinal disorders and renal and urinary disorders.

Patients with hepatobiliary disorders had mainly include transaminases increases and 60% had pre-existing hepatobiliary disease that worsened during treatment. The median time to onset or worsening of hepatobiliary disease was one day [1-2]. It led to discontinuation of treatment in one case. Among patients with renal and urinary disorders, 50% had increased blood creatinine levels prior therapy initiation. The median time to onset or worsening of renal and urinary disorders was one day [0–16]. It led to discontinuation of treatment in two cases.

Conclusion: A potential signal of pharmacovigilance has been identified for liver and renal disorders in Vigilyze^® and we have reported the expected remdesivir Aes. However, it is difficult to suspect remdesivir only without considering the pathology itself, but remdesevir appears to have favorable safety profile in patients who require minimal supplemental oxygen.

References/Further Sources of Information

Not applicable.

2.105 P128 Covid-19 Vaccines: Is the Seriousness Criterion “Medically Important” Applied Correctly in Reports and Are There Differences between HCPs and Non-HCPs?

2.105.1 I. Scholz ¹, S. Banholzer², M. Haschke², T. Stammschulte¹

2.105.1.1 ¹Swissmedic, Pharmacovigilance Unit, Bern, Switzerland; ²Clinical Pharmacology and Toxicology, Department of General Internal Medicine Inselspital University Hospital, Bern, Switzerland

Introduction: During the Covid-19 vaccination campaign, Swissmedic received approximately 50% of the spontaneous reports from health care professionals (HCP) and 50% directly from patients/consumers. The rate of adverse drug reactions (ADRs) following Covid-19 vaccination categorized as “serious” by the reporters is approximately 35% in Switzerland and thus significantly higher than e.g. in the US (6.6%), while rates of reports with fatal outcome are comparable (1.4% vs. 1.3%) (1).

A high proportion of the cases labelled as “serious” in Switzerland was classified based on the category “medically important”. Since this criterion is used very commonly but is less distinct than the other seriousness criteria, we aimed to analyze whether it is used correctly by the reporters and whether differences between healthcare professionals and patients/consumer can be identified.

Objective: To evaluate the appropriate usage of the seriousness criterion “medically important” in spontaneous ADR reports submitted by health care professionals compared to non-health care professionals following immunization with a Covid-19 vaccine.

Methods: All serious ADR reports received between the 1^st of January 2021 and 31^st of December 2021 following immunization with a Covid-19 vaccine were extracted from the Swiss database. Cases categorized as “medically important” were further analyzed. We extracted the preferred terms (PT) according to the medical dictionary for regulatory activities (MedDRA) (2) of the reported ADRs and matched them with the important medical event terms list (IME list) (3).

Results: From a total of 11,115 ADR reports, 4,125 (37.1%) were classified as “serious”. 2,773 (67.2%) of the serious cases were reported by HCPs and 1,352 (32.8%) by non-HCPs. In 2,260 (55%) reports, the seriousness was based solely on the criterion “medically important”. 755 (33.4%) of these reports would also be classified as “serious” according to the IME List. 498 (39%) reports by HCP and 257 (26%) by non-HCP match with the IME list. The proportion of correctly categorized ADRs is significantly higher (p < 0.0001) in reports from HCPs compared to non-HCPs.

Conclusion: Only approximately one third of the cases, which were classified as “medically important” and thus reported as “serious”, would also be classified as such according to the IME list. The proportion of correctly categorized ADRs is significantly higher in reports from HCPs. Additional information and training for HCPs appears necessary to achieve a higher rate of appropriate seriousness categorization in ADR reports. The usage of the category “medically important” in reports by patients/consumers requires general revision.

References/Further Sources of Information

• 1. Rosenblum HG, Gee J, Liu R, Marquez PL, Zhang B, Strid P, et al. Safety of mRNA vaccines administered during the initial 6 months of the US COVID-19 vaccination programme: an observational study of reports to the Vaccine Adverse Event Reporting System and v-safe. The Lancet Infectious Diseases. 2022.

• 2. MedDRA Medical Dictionary for Regulatory Activities

• 3. European Medicine Agency: Important medical event terms list (MedDRA version 25.0)

2.106 P129 Hepatic Disorders in Adults Associated with the Use of Ivermectin for SARS-CoV-2 Infection: A Pharmacovigilance Study in VigiBase

2.106.1 T. J. Oscanoa ^1,2, J. A. Tineo³, R. R. Ortuno⁴, A. Carvajal⁵

2.106.1.1 ¹Universidad de San Martín de Porres-Facultad de Medicina Humana, Drug Safety Research Center. Hospital Almenara ESSALUD., Lima-, Peru; ²Universidad Nacional Mayor de San Marcos. Facultad de Medicina, Pharmacology, Lima, Peru; ³Universidad Nacional Mayor de San Marcos-Facultad de Medicina., Medicine, Lima, Peru; ⁴Trinity College Dublin, Mercer's Institute for Successful Ageing-St James's Hospital, Dublin, Ireland; ⁵Universidad de Valladolid, Pharmacology, Valladolid, Spain

Introduction: In the face of the global health emergency due to SARS-CoV-2, Ivermectin has been, among other drugs, repurposed in some Latin American countries to treat COVID-19 [1]. Studies are needed on the safety of Ivermectin for this new indication. VigiBase is the WHO pharmacovigilance database that registers all Individual Case Safety Reports (ICSRs) from more than 130 countries.

Objective: To review in VigiBase the reports of serious hepatic disorders in adults associated with the use of Ivermectin for COVID-19.

Methods: We extracted, in men or women aged ≥ 18 years between 1 January 2020 and 7 march 2021, all ICSRs registered as "serious" associated with the use of ivermectin, and established the prevalence of serious hepatic disorders when Ivermectin was indicated for COVID-19

Results: During the study period, there were 1,393 ICSRs in VigiBase associated with Ivermectin, of which 60 (4.3%) were registered as "serious"; in 25 of those, Ivermectin had been used for COVID-19. Out of those 25, five reported serious cases of hepatic disorders (hepatitis, hepatocellular injury, cholestasis, increased alanine aminotransferase and aspartate aminotransferase, abnormal liver function test). Three patients were male and overall mean age was 59.2 ± 9.7 years. Ivermectin was administered during a mean of 2.5 ± 2.4 days, and the mean daily dose was 14.3 ± 2.9 mg. Two patients simultaneously received other drugs (Remdesivir, Hydroxychloroquine, Azithromycin). Two patients had concurrent conditions (strongyloidiasis, diabetes mellitus). Only in 2 patients liver enzyme data were reported. In all patients the evolution was favorable after stopping the drug (de-challenge), and no patient was re-exposed (re-challenge). Causality analysis was reported in 3 cases, qualifying as possible or probable.

Conclusion: The safety of the use of Ivermectin should be studied more exhaustively, especially as regards the probability of hepatic disorders when used for COVID-19

References/Further Sources of Information

• 1. Quincho-Lopez A, Benites-Ibarra CA, Hilario-Gomez MM, Quijano-Escate R, Taype-Rondan A. Self-medication practices to prevent or manage COVID-19: A systematic review. Aslam MS, editor. PLoS One [Internet]. 2021 Nov 2;16(11):e0259317. Available from: https://dx.plos.org/10.1371/journal.pone.0259317.

2.107 P130 Strengthened Pharmacovigilance in France for Monitoring COVID-19 Vaccines and Therapeutics Toward a New Surveillance Era?

2.107.1 A. Page ¹, M. Levraut¹, C. Férard¹, B. Mehdi¹, I. Bidault¹, E. Pierron¹, B. Jacquot¹, C. Mounier¹, French Network regional pharmacovigilance centers Crpv²

2.107.1.1 ¹French National Agency for the Safety of Medicines and Health Products, Surveillance, Saint-Denis, France; ²French Network of regional pharmacovigilance centers, Pharmacovigilance, Saint-Denis, France

Introduction: Following the emergence of SARS-CoV-2, a range of measures have been put in place in France: strengthened surveillance of COVID-19 therapeutics and vaccines, using tools and methods developed to detect promptly any safety issues in order to take appropriate risk minimisation measures [1].

For COVID-19 therapeutics, ANSM has mobilized the French Network of regional pharmacovigilance centers (CRPV) to ensure continuous monitoring and assessment of adverse reaction reports through a specific survey. The results were discussed at an experts’ monitoring committee which involves several scientific experts. The members assess collegially the potential safety signals. Then, a specific communication associated with the investigation reports are published on the ANSM website.

For COVID-19 vaccines, a similar organization was put in place with additional components.

Artificial intelligence and an information system have been used to optimize reports processing and improve specific data collection. Information sheets on adverse events have been made available to patients and healthcare professionals.

Finally, pharmaco-epidemiological studies have been conducted in case of a potential signal for confirmation or to quantify the risk.

Objective: To evaluate the implementation of strengthened monitoring of vaccines and therapeutics used in COVID-19.

Methods: Potential signals detected on vaccines and drugs used in COVID-19 following the implementation of new pharmacovigilance tools and methods were analysed.

Results: As of March 31th, 2022, more than 140 million doses of COVID-19 vaccines administered with more than 150,000 adverse reactions reports, 45 monitoring committees held and 43 potential signals of COVID-19 vaccines have been transmitted by ANSM to European authorities to reinforce or initiate a signal.

As of January 26, 2022, more than 2 300 adverse reactions reports collected for treatment used for patients with COVID-19, 21 monitoring committees held and 3 signals were identified.

Conclusion: The use of tools and methods in COVID-19 vaccines and medicines monitoring have allowed for early detection of signals and implementation of appropriate risk minimisation measures. This has been made possible thanks to the whole organization of strengthened surveillance which remains agile along the pandemic crisis. Furthermore, facilitation was given to accelerate evaluation, methods to prioritize a large volume of spontaneous reports, and different channels to communicate transparently in order to build trust among stakeholders.

There are still challenges to build a new era of surveillance concerning the management of a large number of adverse drug reports, expertise and communication in a daily routine.

References/Further Sources of Information

• 1. Benkebil M, Gautier S, Gras-Champel V, Massy N, Micallef J, Valnet Rabier MB. COVID-19 vaccines surveillance in France: a global response to a major national challenge. Anaesth Crit Care Pain Med. 2021 Jun;40(3):100866.

2.108 P131 Background Incidence in Spontaneous Reporting: Observed/Expected analysis of Myocarditis and Pericarditis with COVID-19 Vaccines in the Netherlands

2.108.1 R. Eekeren-Van ¹, F. Hunsel-van², A. Kant³

2.108.1.1 ¹Netherlands Pharmacovigilance Centre Lareb, Vaccines, 's-Hertogenbosch, Netherlands; ²Netherlands Pharmacovigilance Centre Lareb, Signal detection, 's-Hertogenbosch, Netherlands; ³Netherlands Pharmacovigilance Centre Lareb, Director, 's-Hertogenbosch, Netherlands

Introduction: Pericarditis and myocarditis have been recognized as rare adverse drug reactions of the mRNA COVID-19 vaccines of Pfizer and Moderna [1,2]. Most cases are observed in young males within 5 days following the 2nd dose and the course is often mild. The estimated excess risk is about 1-3 per 100,000 vaccinated persons, whereas the risk ratios following Sars-CoV-2 infection are 5-18 for myocarditis and pericarditis respectively [3]. Few studies indicate an increased risk of myocarditis with the 1st dose of the vector vaccine of AstraZeneca [4]. General incidence of myocarditis is 10-20 per 100,000 personyears and young men are at increased risk. Incidence-rates of pericarditis are not exactly known, since the condition is often self-limiting and underdiagnosed [5].

Objective: We evaluated the use of Standardised Morbidity Rates (SMR) to compare spontaneously reported cases of myocarditis and pericarditis with COVID-19 vaccines with stratified Dutch background incidence rates from 2019 in the vaccine exposed population.

Methods: SMRs are calculated by dividing the reported as observed (O) cases by the expected (E) number within risk windows of 5/14 days following each dose and vaccine. SMR > 1 indicates that more cases were reported than expected [6].

Results: Until January 2022, 373 reports of myocarditis and pericarditis were received. The majority of the cases was reported following an mRNA vaccination (85%), mostly following the second dose (47%). The mean age for men and women was 34.7–45.1 years for myocarditis and 45.2–46.6 years for pericarditis. The mean times to onset (TTO) for myocarditis and pericarditis with the 1st and 2nd doses are about three weeks, with a wide range. Median TTO show a latency of 5 days for myocarditis and 9–14 days for pericarditis. Six patients died following myocarditis or pericarditis. In the table, SMRs for myocarditis within 5 days are summarized, stratified for vaccine, dose, sex and age. For pericarditis, SMRs show a similar pattern, and more reports were received than expected in men and women < 40 years with all doses of Pfizer, in men < 40 with Moderna, in men < 40 and women > 40 with the first dose of AstraZeneca and in men who received the Janssen vaccine.

Conclusion: Myocarditis and pericarditis were reported more frequently than expected in various patient groups with both mRNA and vector vaccines. However, spontaneous reporting is signal generating and epidemiological studies are needed to confirm the potential signal with vector vaccines.

References/Further Sources of Information

• 2. EMA. SmPC Comirnaty. Via: https://www.ema.europa.eu/en/documents/product-information/comirnaty-epar-product-information_en.pdf (accessed at 1-10-2021)

• 3. EMA. SmPC Spikevax. Via: https://www.ema.europa.eu/en/documents/overview/spikevax-previously-covid-19-vaccine-moderna-epar-medicine-overview_en.pdf (accessed at 1-10-2021)

• 4. Barda N, Dagan N, Ben-Shlomo Y, Kepten E, Waxman J, Ohana R, Hernán MA, Lipsitch M, Kohane I, Netzer D, Reis BY, Balicer RD. Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting. N Engl J Med. 2021 Sep 16;385(12):1078–1090. https://doi.org/10.1056/NEJMoa2110475. Epub 2021 Aug 25. PMID: 34432976; PMCID: PMC8427535.

• 5. Patone M, Mei XW, Handunnetthi L, Dixon S, Zaccardi F, Shankar-Hari M, Watkinson P, Khunti K, Harnden A, Coupland CAC, Channon KM, Mills NL, Sheikh A, Hippisley-Cox J. Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection. Nat Med. 2022 Feb;28(2):410–422. https://doi.org/10.1038/s41591-021-01630-0. Epub 2021 Dec 14. PMID: 34907393; PMCID: PMC8863574.

• 6. Imazio M. Noninfectious pericarditis: management challenges for cardiologists. Kardiol Pol. 2020 May 25;78(5):396–403. https://doi.org/10.33963/KP.15353. Epub 2020 May 11. PMID: 32394692. https://pubmed.ncbi.nlm.nih.gov/32394692/.

• 7. Mahaux, O., Bauchau, V., & Van Holle, L. (2016). Pharmacoepidemiological considerations in observed-to-expected analyses for vaccines. Pharmacoepidemiology and drug safety, 25(2), 215–222.

2.109 P133 Role of the Hospital Pharmacist in the Evaluation of the Anti-COVID-19 Vaccine Safety Profile in the Post-Marketing Phase

2.109.1 C. Argirò¹, L. Costantino ², S. Valentina³, S. Francesca³, M. Rita³

2.109.1.1 ¹Università degli Studi "Magna Graecia" di Catanzaro, Scuola di Specializzazione in Farmacia Ospedaliera, Catanzaro, Italy; ²Università degli Studi "Magna Graecia" di Catanzaro, Scuola di Specializzazione in Farmacologia e Tossicologia Clinica, Catanzaro, Italy; ³Azienda Ospedaliera Pugliese Ciaccio, UOC Farmacia Ospedaliera, Catanzaro, Italy

Introduction: The European Medicines Agency, following positive evaluation regarding the safety, quality, and efficacy of anti-COVID-19 vaccines, granted conditional marketing authorization (CMA) for these drugs on the condition that the developers would continuously provide additional data on their safety and efficacy even after marketing authorization in order to confirm the risk-benefit ratio. Following the start of the vaccination campaign in December 2020, special attention was paid to the occurrence of possible adverse reactions (ADRs). The pharmacist staff of Pugliese-Ciaccio Hospital, in order to monitor the safety of the new vaccine and to promptly report suspected vaccine ADRs, prepared a short questionnaire to be administered to the employees of the hospital at the time of administration of the second dose of vaccine.

Objective: Monitoring vaccine safety & promptly reporting side effects.

Methods: The survey was conducted between January and April 2021. All employees were administered mRNA vaccine and, at the time of the administration of the second dose, were asked to answer the above questionnaire specifying the following information: biographical data, gender, date of administration of the two doses of vaccine, occurrence of any ADRs resulting from the first dose of vaccine, type of resolution, presence of concomitant diseases and related medication intake in the days before/following the vaccination.

Results: The questionnaire was administered to 1,656 health care workers and all of them answered the questions comprehensively. Among them, 51.6 percent experienced adverse reactions after administration of the first dose of vaccine, and the predominantly noted symptoms included systemic diseases and conditions related to the site of administration, musculoskeletal and connective tissue disorders, nervous system disorders and gastrointestinal disorders. The frequency of reporting was higher among the young than the elderly population (58% vs. 38.67%). ADRs occurred approximately 1,7 times more frequently among women than men.

Conclusion: The intense pharmacovigilance activity carried out by the Hospital Pharmacist was a pivotal moment during the pandemic emergency, as it allowed the safety profile of anti-COVID-19 vaccines to be readily confirmed with real-life data. Infact, it was found that the main symptoms detected were in line with what was reported in the safety data from the pre-registration studies [1], from which it was also found that the frequency of ADRs was higher among the young than the elderly, a finding that was also confirmed by our study. So, the questionnaire survey was able to substantiate the safety of vaccines, confirming that the benefits of vaccination outweigh the risks.

References/Further Sources of Information

• 1. https://www.ema.europa.eu/en/documents/assessment-report/comirnaty-epar-public-assessment-report_en.pdf.

2.110 P134 Sotrovimab—Flashes of Safety in COVID-19 Patients

2.110.1 F. A. Braik ¹, M. Y. Hasan¹

2.110.1.1 ¹UAE University-UAE, College of Medicine & Health Silences-, Al Ain, United Arab Emirates

Introduction: Sotrovimab is a monoclonal therapy authorized for emergency use (EUA) on May 26, 2021, by the US (FDA) for treatment of mild-to-moderate coronavirus disease (COVID-19) in adults and children ≥ 12 years old). The drug showed positive viral testing in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and, reduced risk for progressing to severe COVID-19, including hospitalization or death¹.

Objective: This paper reviewed published data on safety of Sotrovimab 500mg in COVID-19 patients.

Methods: The study based on reviewing published literature. Pubmed and FDA web was searched for data on Safety of Sotrovimab use in COVID-19 patients (May2021-May2022).

Results: Gupta A et al² reported among (n = 291 Sotrovimab group, n = 292 placebo group) mild diarrhea occurred in 5 cases (1%) in Sotrovimab group, compared to 1 case of moderate diarrhea, while diarrhea occurred in 3 patients in placebo group. One patient who received Sotrovimab had moderate dyspnea, an infusion-related reaction that was related to Sotrovimab. Hospitalization adverse events occurred in 2% of Sotrovimab group and in 6% in placebo group. No death or serious adverse events e.g., hematological disorders or liver damage were related to Sotrovimab. Further study by Gupta A et al³ for Sotrovimab (n = 528) or placebo (n = 529) reported that adverse events were infrequent and are similar between two groups (22% for Sotrovimab vs 23% for placebo); the most common events were diarrhea with Sotrovimab (n = 8; 2%) and COVID-19 pneumonia with placebo (n = 22; 4%).

Kreuzberger N et al⁴ reported treatment with Sotrovimab may reduce the number of participants with oxygen requirement weaned in 3 days and risk of all-cause hospitalization or death without exhibiting significant adverse reaction.

Fernandes G et al⁵ observed that following administration of Sotrovimab to kidney transplant recipients infected with Omicron variant, two patients required hospitalization for oxygen therapy. None were admitted to the intensive care unit or died.

Conclusion: This review found limited number of safety studies of Sotrovimab in COVID-19, which reflects low numbers of publications. This is probably because of the Emergency utilization of drug and limitation of use in many countries. Lately, FDA US announced Sotrovimab is no longer authorized to treat COVID-19 in US due to increases in the proportion of COVID-19 cases caused by the Omicron variants⁶. Further data is needed to evaluate Sotrovimab safety in COVID-19 patients and examine risk-benefit, adverse events, and risk correlation to disease severity in patients with various risk factors.

References/Further Sources of Information

• 1. Coronavirus (COVID-19) Update: FDA Authorizes Additional Monoclonal Antibody for Treatment of COVID-19 | FDA; https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-additional-monoclonal-antibody-treatment-covid-19.

• 2. Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab. N Engl J Med. 2021 Nov 18;385(21):1941–1950.

• 3. Anil Gupta, Yaneicy Gonzalez-Rojas, Erick Juarez, et al. Effect of Sotrovimab on Hospitalization or Death Among High-risk Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial. JAMA.2022 Apr 5;327(13).

• 4. Nina Kreuzberger, Caroline Hirsch, Khai Li Chai et al. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev.2021 Sep 2;9(9):CD013825.

• 5. Guillaume Fernandes, Arnaud Devresse, Anais Scohy et al. Monoclonal Antibody Therapy in Kidney Transplant Recipients with Delta and Omicron Variants of SARS-CoV-2: A Single-Center Case Series. Kidney Med. 2022 Apr 27;100470.

• 6. FDA updates Sotrovimab emergency use authorization | FDA; https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-sotrovimab-emergency-use-authorization.

2.111 P136 Characteristics of Spontaneous Reports of Thrombosis with Thrombocytopenia Syndrome after COVID-19 Vaccines in the Netherlands

2.111.1 R. Eekeren-Van ¹, S. Middeldorp², M. Kruip³, F. Hunsel-van⁴, A. Kant⁵

2.111.1.1 ¹Netherlands Pharmacovigilance Centre Lareb, Vaccines, 's-Hertogenbosch, Netherlands; ²Radboud University Medical Centre, Head Department of Internal Medicine, Nijmegen, Netherlands;³Erasmus MC-Erasmus University Medical Centre, Haematology, Rotterdam, Netherlands;⁴Netherlands Pharmacovigilance Centre Lareb, Head of Signal Detection, 's-Hertogenbosch, Netherlands;⁵Netherlands Pharmacovigilance Centre Lareb, Director, 's-Hertogenbosch, Netherlands

Introduction: In March 2021 first cases of thrombosis with thrombocytopenia syndrome (TTS), also called vaccine induced thrombosis with thrombocytopenia (VITT), were published and reported, raising a concern with the adenovector vaccine of AstraZeneca [1, 2]. One month later, TTS was also associated with the Janssen vaccine [3]. No conclusive evidence of VITT with mRNA vaccines is found [4]. In Europe, vaccination programmes were put on hold and the indications for use restricted. The role of pharmacovigilance was to monitor the events closely and estimate its frequency of occurrence. While mass vaccination campaigns were ongoing, information on case criteria and definitions was limited. In the Netherlands, internists wrote guidelines, organised centralised diagnostics for PF4 ELISA and HIPA tests and encouraged expert physicians to report suspected cases to The Netherlands Pharmacovigilance Centre Lareb [5]. Lareb managed to monitor TTS cases closely by a fast triage of relevant reports and strong collaboration with external specialists.

Objective: Spontaneously reported cases of TTS in The Netherlands are described.

Methods: We used CDC classification criteria combined with Dutch guidelines to determine confirmed and strongly suspected cases. CDC classification recognizes ‘tier 1’ with thrombosis at unusual sites not requiring tests and ‘tier 2’ with common types of thrombosis and requiring confirmatory tests [6].

Results: In total, 75 cases of thrombocytopenia with any kind of thrombosis were reported. Only 26 reports met criteria of TTS, concerning 19 AstraZeneca, 5 Janssen and 2 mRNA vaccines. The majority (23; 89%) of the cases was reported following the first dose. Reporting rates for AstraZeneca and Janssen were 7.7 and 5.7 per million vaccinations in total, respectively, and 13.4 per million vaccinations of the first dose with AstraZeneca. Patient and report characteristics are described in table 1. ‘Tier 1’ criteria were met in 15 cases. ‘Tier 2’ criteria were met in 6 cases and in 5 cases TTS was strongly suspected based on the Dutch guidelines. A functional HIPA test was performed in 20 cases of which 17 were positive and 3 negative. Also, two reports were received with mRNA vaccines, one well documented with positive PF4-ELISA and HIPA-tests (Moderna, 3rd dose) and the other poorly documented but meeting ‘tier 1’ criteria (Pfizer, 1st dose).

Conclusion: In The Netherlands, TTS was predominantly reported after the first dose of the AstraZeneca vaccine, similar to other countries [1]. Intensive collaboration between clinical practice and pharmacovigilance resulted in good monitoring of TTS cases with spontaneous reporting.

References/Further Sources of Information

• 1. Greinacher, A., Thiele, T., Warkentin, T. E., Weisser, K., Kyrle, P. A., & Eichinger, S. (2021). Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. The New England journal of medicine, 384(22), 2092–2101. Via: https://doi.org/10.1056/NEJMoa2104840.

• 2. European Medicines Agency. COVID-19 Vaccine AstraZeneca: benefits still outweigh the risks despite possible link to rare blood clots with low blood platelets. Publication date: 18-3-2021. Via: https://www.ema.europa.eu/en/news/covid-19-vaccine-astrazeneca-benefits-still-outweigh-risks-despite-possible-link-rare-blood-clots.

• 3. European Medicines Agency. COVID-19 Vaccine Janssen: EMA finds possible link to very rare cases of unusual blood clots with low blood platelets. Publication date: 20-4-2021. Via: https://www.ema.europa.eu/en/news/covid-19-vaccine-janssen-ema-finds-possible-link-very-rare-cases-unusual-blood-clots-low-blood.

• 4. See I, Allison Lale, Paige Marquez, et al. Case Series of Thrombosis With Thrombocytopenia Syndrome After COVID-19 Vaccination—United States, December 2020 to August 2021. Ann Intern Med. [Epub ahead of print 18 January 2022]. https://doi.org/10.7326/M21-4502 Via: https://www.acpjournals.org/doi/full/10.7326/M21-4502?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org.

• 5. Nederlandse Vereniging voor Hematologie. Diagnostiek en behandeling van patiënten met trombocytopenie met of zonder trombose na COVID-19 vaccinatie. Version date 15-4-2021. Accessed at 10-5-2022. Via: https://internisten.nl/sites/internisten.nl/files/berichten/leidraad_trombopenie_met-zonder_trombose_vaccinatie_.final_def%20_1.pdf.

• 6. See I. Updates on Thrombosis with Thrombocytopenia Syndrome (TTS), 16-12-2021. Via: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-12-16/02-COVID-See-508.pdf.

2.112 P137 How a Community Approach Can Drive Pharmacovigilance Activities in Low-Resource Settings during a Public Health Emergency: Lessons from COVID-19

2.112.1 R. Walker ¹, E. Allen², T. Lang¹

2.112.1.1 ¹University of Oxford, Oxford Centre for Global Health Research, Oxford, United Kingdom; ²University of Cape Town, Division of Clinical Pharmacology, Cape Town, South Africa

Introduction: Undertaking effective drug safety monitoring can be particularly challenging in low-resource settings due to a lack of infrastructure, weak regulatory systems and poor access to training and education [1]. Given the continued impact the COVID-19 pandemic is having upon health systems globally, it is essential to ensure that pharmacovigilance systems in these vulnerable settings have the capacity to address both the exacerbated pre-existing and novel challenges that they now face [2]. This project seeks to harness the membership of an online pharmacovigilance platform, globalpharmacovigilance.org (GPV) to work together in a ‘community of practice’ (CoP) on specific challenges facing pharmacovigilance during the pandemic [3, 4].

Objective: To gather consensus on pharmacovigilance priorities in low-resource settings during the COVID-19 pandemic and provide resources to address them using a CoP model.

Methods: This project has built on a consensus-gathering methodology developed by The Global Health Network that has been implemented successfully during the pandemic to address wider COVID-19 research priorities. An online survey of GPV members was used to identify highly-ranked areas for pharmacovigilance improvement in low-resource settings during the pandemic. A virtual workshop was then hosted to invite further discussion on the survey results and reach consensus on the highest priorities. Members of the CoP were next invited to form virtual working groups, each focussing on one of the top 3 priorities identified. These groups are being supported by GPV to work together and facilitate the development (or provision, if pre-existing) of pharmacovigilance resources to address the priorities identified.

Results: Of the 43 pharmacovigilance ‘themes’ that were presented to the CoP membership in the initial survey, 3 topics were identified as the highest priorities at that point in the COVID-19 pandemic, where support, training and guidance are needed; ‘The safety of COVID-19 vaccination in pregnancy’, ‘The safety of COVID-19 vaccination in children/adolescents’ and ‘Analysis of COVID-19 vaccine safety data’. As of May 2022, the number of GPV members interested in involvement in working groups addressing these themes are 207, 206, and 284 respectively. Initial group meetings took place in April 2022 and discussions are ongoing as to how to take group activities forward and address the priorities identified.

Conclusion: A CoP model represents an effective method of consensus gathering amongst pharmacovigilance stakeholders at a global level, and allows rapid identification of healthcare priorities during public health emergencies. It is anticipated that working groups outputs will include the provision of resources designed to address the priorities identified.

References/Further Sources of Information

• 1. Olsson, S., S.N. Pal, and A. Dodoo, Pharmacovigilance in resource-limited countries. Expert Rev Clin Pharmacol, 2015. 8(4): p. 449–60.

• 2. Chandler, R.E., et al., The Role of Pharmacovigilance and ISoP During the Global COVID-19 Pandemic. Drug Saf, 2020. 43(6): p. 511–512.

• 3. TGHN-GPV. Global Pharmacovigilance. 2022 [cited 2022 10th May]; Available from: https://globalpharmacovigilance.tghn.org/.

• 4. Wenger, E., R.A. McDermott, and W. Snyder, Cultivating communities of practice: A guide to managing knowledge. 2002: Harvard Business Press.

2.113 P140 Pharmacists' Engagement in the Adverse Drug Reactions Reporting Process During the COVID-19 Pandemic

2.113.1 E. Gavazova ¹, R. Staynova¹, D.G. Kafalova¹

2.113.1.1 ¹Medical university of Plovdiv-Faculty of Pharmacy, Department of Pharmaceutical Sciences, Plovdiv, Bulgaria

Introduction: The COVID-19 pandemic put a burden on healthcare systems worldwide [1]. Pharmacists have shown their significant role as a part of the frontline workers in many countries [2-3]. Pharmacists have a suitable position in the process of adverse drug reactions (ADRs) reporting of COVID-19 treatments and vaccines.

Objective: To assess the engagement of pharmacists in the pharmacovigilance process related to the treatment of COVID-19.

Methods: A systematic search of the electronic databases PubMed, Scopus, ScienceDirect and Google Scholar was carried out for relevant articles published between December 2020– April 2022, reporting the engagement of community, clinical and hospital pharmacists in the ADRs reporting process during the COVID-19 pandemic. In this systematic review the following keywords were used: “COVID-19”, “pharmacists”, ”drug safety”, “pharmacovigilance” "ADRs". The inclusion criteria were full text articles.

Results: A total of 18 articles matched our inclusion criteria. In the beginning of the COVID-19 pandemic drug-repurposing was used as a treatment strategy. Chinese clinical pharmacists were involved in close monitoring, documentation and reporting of ADRs. Some European countries (Italy, Belgium, Switzerland and Serbia) actively involved hospital pharmacists in the safety monitoring of COVID-19 vaccines. In Australia a national vaccine safety surveillance program (AusVaxSafety) was launched with the active engagement of community pharmacists. The goal of this new pharmacists-led pharmacovigilance system is to provide critically significant safety data regarding potential ADRs following vaccination.

Conclusion: Pharmacists may play a key role in maintaining the rational and safe use of medicines. Effective reporting of ADRs by the pharmacists is an essential aspect of the pharmacovigilance system during COVID-19 pandemic. Enhanced collaboration, and availability of resources, tools and methods will add to the lessons learned from previous experiences.

References/Further Sources of Information

• 1. Palacios Cruz M, Santos E, Velázquez Cervantes MA, León Juárez M. COVID-19, a worldwide public health emergency. Rev Clin Esp (Barc). 2021;221(1):55–61.

• 2. Watson KE, Schindel TJ, Barsoum ME, Kung JY. COVID the Catalyst for Evolving Professional RoleIdentity? A Scoping Review of Global Pharmacists’ Roles and Services as a Response to the COVID-19 Pandemic. Pharmacy. 2021; 9(2):99.

• 3. Visacri MB, Figueiredo IV, Lima TM. Role of pharmacist during the COVID-19 pandemic: A scoping review. Res Social Adm Pharm. 2021;17(1):1799–1806.

2.114 P141 How to Handle a Sudden Tenfold Increase in ICSRs—Lessons Learned During the SARS-Cov-2 Pandemic

2.114.1 H. Samdal ¹, M. G. Dale¹, A. Einhaug², G. Evensen², B. Grundmark¹, L. C. Hagen¹, A. Luong¹, P. Harg¹

2.114.1.1 ¹Norwegian Medicines Agency, Department for Safe Use, Oslo, Norway; ²Norwegian Institute of Public Health, Infectious Disease Registries, Oslo, Norway

Introduction: The unprecedented vaccination efforts related to COVID-19 have strained PV systems and resources of stakeholders globally.

Objective: The Norwegian Medicines Agency (NoMA) wishes to present lessons learned from changes implemented nationally before and during the vaccination campaign.

Methods: Anticipating a large increase in spontaneous reporting, improved tools and procedures simplifying reporting, case processing, and analysis were implemented. Resources for hiring additional temporary staff was made available. The overall aim was that of an agile preparedness with ability to replan and reprioritize activities to fulfil pharmacovigilance obligations of a national competent authority, while continuing NoMAs tradition of transparency towards the public.

Results: NoMA experienced a tenfold increase in ICSRs from healthcare professionals and consumers during COVID-19 vaccination. Compared to normal vaccine reporting the increase was even higher. Case processing, signal detection and signal management procedures were stretched thin. Still, several international signals were detected and managed early. Despite additional resources supplied, a backlog in handling of non-serious reports accumulated while serious reporting was unaffected. Communication to the public was radically increased.

Among measures put in place by NoMA before and during the vaccination campaign, the following were useful:

• Electronic reporting forms.

• Collection of unique patient identification number.

• Daily status meetings, both internally and externally (i.e. Norwegian Institute of Public Health).

• Daily triage of incoming ICSRs.

• A clear order of priority for case processing.

• Simplified processing of non-serious ICSRs.

• Automated report generation to monitor special groups, events or outcomes, e.g. children, Adverse Events of Special Interest, fatal cases.

• Weekly overviews of suspected adverse reactions associated with COVID-19 vaccination in Norway was made available to the public, both in Norwegian and English.

Conclusion: By implementing various measures NOMA managed to prioritise processing of the ICSRs that added most value to detecting signals of possible new safety issues.

References/Further Sources of Information

Norwegian Medicines Agency. Reported suspected adverse reactions of covid-19 vaccines. Available at https://legemiddelverket.no/english/covid-19-and-medicines/vaccines-against-covid-19/reported-suspected-adverse-reactions-of-covid-19-vaccines.

2.115 P142 Nocebo Responses in Relation to COVID-19 Vaccine Safety

2.115.1 J. Jose ¹

2.115.1.1 ¹University of Nizwa, School of Pharmacy, Nizwa, Oman

Introduction: Nocebo effect is the negative counterpart of the placebo phenomenon.¹ It refers to the adverse effects that occur in clinical or laboratory medical contexts, respectively, after administration of an inert treatment or as part of active treatments, due to mechanisms such as expectancies of the patient.² The nocebo responses are extremely common in medical practice and multiple factors contribute to it including risk communication statergies.³

Objective: To summarize the existing literature on nocebo responses reported in relation to COVID-19 safety, factors which might contribute to the same and its implications.

Methods: Concerns on the safety of the COVID-19 vaccines contributed by various sources including social and mass media, and other members in the public have contributed to the significant minority of people who were hesitant to receive the vaccine.^3,4 Here lies the importance of appropriate modes and process of risk communication. Nocebo responses observed by COVID-19 vaccine recipients by virtue of expectations on the potential adverse effects might have had an impact of public’s decision on receiving the vaccine. In a systematic review carried out by Amazio et al, rates of solicited adverse events in the active and placebo groups of SARSCoV-2 vaccines were compared. ⁵ It was reported that a substantial proportion of solicited AEs are not a result of the vaccine per se but are, in fact, nocebo effects. A meta-analysis was performed to evaluate the frequency and magnitude of nocebo responses in COVID-19 vaccine trials based on the data from four RCTs with a total of 119,110 participants. The frequency and magnitude of nocebo responses were 16.4% and 0.3%, respectively.⁶

Results: It is important to understand the factors which contribute to the nocebo responses noticed by the recipients of the COVID-19 vaccines. Methods to prevent or tackle these responses should be identified and discussed to reduce the vaccine hesitancy. For the present and future vaccination campaigns, there should be prevention strategies for nocebo effects to promote a possible greater adherence to the vaccination campaign. Raising awareness of nocebo effects by media and health care professionals and positive framing of the side effect information can help to reduce nocebo effects.⁵.

Conclusion: The role and responsibilities of various stake holders including patients, patient organisations, health professionals, media, pharmaceutical companies and regulatory agencies in this regard should be identified and delineated. Risk communication strategies should be tailored to the need of the situation and focused on avoiding any negative impact.

References/Further Sources of Information

• 1. Pharmacol Res Perspect. 2016;4(2):e00208.

• 2. Psychother Psychosom. 2018;87(4):204–210.

• 3. Sever P. Nocebo affects after COVID-19 vaccination. Lancet Regional Health Europe 2022; 12:100273

• 4. Amanzio M, Cipriani GE, Bartoli M. How do nocebo effects in placebo groups of randomized controlled trials provide a possible explicative framework for the COVID-19 pandemic? Expert Rev Clin Pharmacol. 2021 Apr;14(4):439–444. https://doi.org/10.1080/17512433.2021.1900728. Epub 2021 Mar 12. PMID: 33682603.

• 5. Lancet Reg Health Eur. 2022;12:100253. https://doi.org/10.1016/j.lanepe.2021.100253.

• 6. Lee YH, Song GG. Nocebo responses in randomized controlled trials of COVID-19 vaccines. Int J Clin Pharmacol Ther. 2022 Jan;60(1):5–12. https://doi.org/10.5414/CP204028. PMID: 34622766.

2.116 P143 PharmaCovigilance: Role of the Pharmacist During COVID-19 Vaccination Campaign

2.116.1 I. Martignoni ¹, D. Bragantini², P. Cicco², G. Gianfilippi², M. Gambera³

2.116.1.1 ¹Università degli studi di Milano, Hospital Pharmacy, Milano, Italy; ²Ospedale P. Pederzoli, Health Department, Peschiera del Garda, Italy; ³Ospedale P. Pederzoli, Pharmacy, Peschiera del Garda, Italy

Introduction: COVID-19 vaccination campaign at Pederzoli Hospital (Veneto, Italy) started in January 2021 using the two approved m-RNA vaccines. The vaccination schedule included 2 doses and one booster.

Objective: The Pharmacy unit created a digital form in order to collect information on the incidence of the adverse events after the anti-covid vaccination.

Methods: The Pharmacy Unit created a simplified digital form including a set of questions about the occurrence of adverse events. To improve the adherence to this pharmacovigilance program, the digital form was uploaded on the hospital website and all the employees received a remainder about this vaccine adverse event reporting system via e-email regularly. The data collected from the electronic spreadsheet were analyzed by the Health Department in order to produce a report in the dedicated national website (Vigifarmaco).

Results: From January 2021 to April 2022 1076 employees received the first dose, 965 received the second dose, and 1019 received the third dose. 323 adverse events reporting forms have been collected after the first dose (30% of those who received it). 291 forms (30%) were collected after the second dose. 12 forms (1.2%) were collected after the third dose. The most reported adverse events after the first dose were: local pain (38% of reported adverse events), muscle pain 15%; asthenia 12%, headache 11%. Moreover, 6 employees reported fever above 38.5 °C and 19 employees reported fever between 37.5 °C and 38.5 °C. The most reported adverse events after the second dose were: local pain 19%, muscle pain 18%; asthenia 15%, headache 13%. An employee reported a syncope. In addition,35 reported fever above 38.5 ° C and in 70 fever between 37.5 °C and 38.5 °C. After the third dose, 10 reported headache, 9 local pain, and 8 asthenia and muscle aches. Only 2 employees reported fever above 38.5 °C and 5 fever between 37.5 °C and 38.5 °C.

Conclusion: The active role of the Hospital Pharmacy Unit during the vaccination campaign of the health care workers of our hospital permitted to collect data regarding the side effects of these new vaccines and nonetheless made the health care workers about more aware about the importance of vaccine adverse event reporting system. The use of this digital form supported the pharmacovigilance program creating a useful and “user friendly” tool which may be tailored to new future projects.

References/Further Sources of Information

https://www.vigifarmaco.it/.

2.117 P144 Covid-19 Vaccines and Menstrual Disorders: Reports from Sardinian Regional Centre of Pharmacovigilance

2.117.1 M. E. Stochino¹, G. Ambu², L. Anania², A. Boccalini², E. E. Cau², A. Congiu², A. Ferrari², D. Pala², E. M. Puddu ², G. Rapallo², S. Ussai², M. Pistis², C. Chillotti¹, A. Deidda¹

2.117.1.1 ¹Sardinia Regional Center of Pharmacovigilance, Unit of Clinical Pharmacology-University Hospital Agency of Cagliari AOUCA, Cagliari, Italy; ²University of Cagliari, Department of Biomedical Sciences-Section of Neurosciences and Clinical Pharmacology, Cagliari, Italy

Introduction: The anti-Covid vaccines approved in Italy are: Comirnaty, Spikevax, Vaxzevria, Janssen, Nuvaxovid. As of March 26th, 2022, 134,361 adverse events following immunization have been collected in the National Pharmacovigilance Database, 69% of them concern women [1]. Regarding the Sardinian region, as of May 12th, 2022, there are 3043 total reports, 63.4% involve women. In July 2021, the French Drug Agency issued an alert about reports concerning menstrual alterations [2]. PRAC, since new studies have been published, recently decided to further investigate [3]. A cohort study conducted in the US comparing cycle length in a vaccinated cohort vs. an unvaccinated cohort, showed a statistically significant difference [4]. A British case-control study found that 20% of the population included reported menstrual changes, with a higher incidence in individuals with a history of Covid infection [5]. A Norwegian study showed similar results [6].

Objective: To describe the adverse events regarding menstrual disorders in the Sardinian population vaccinated against Covid-19.

Methods: We analyzed reports of suspected adverse reactions in the National Pharmacovigilance Database regarding the region of Sardinia, from December 27th, 2020 to April 30th, 2022, we extracted those concerning menstrual cycle alterations after Covid-19 vaccine administration.

Results: A total of 78 reports referring to all three scheduled administrations were collected. The majority concerned Comirnaty, with 56 reports: 51 were non-serious, concerning abnormal menstrual cycles in lenght and flow, amenorrhea, dysmenorrhea; five cases were considered serious, but there were other adverse events associated (hypersensitivity reactions, autoimmune disorders, myocarditis in one case). Six reports were related to Vaxevria, with similar manifestations as for Comirnaty; in one case the patient was treated with Tamoxifen. Sixteen cases were reported for Spikevax, with one reporting an episode of bleeding in a three-year menopausal patient. In one case, the patient (IUD carrier) reported menstrual disturbances following all three vaccine administrations (two Comirnaty, one Spikevax).

Conclusion: The different distribution of reports among the vaccines can be explained by the increased administration of Comirnaty in the general population and the phasing out of Vaxzevria. Menstrual disorders are common and can be related to several conditions, although a link with Covid vaccines is plausible, as highlighted by recent studies [4-6] and as already observed for other vaccines. In particular, the strong immune system response created by mRNA vaccines may affect the hypothalamic-pituitary-ovarian axis, which regulate the menstrual cycle.

References/Further Sources of Information

• 1. https://www.aifa.gov.it/documents/20142/1315190/Rapporto_sorveglianza_vaccini_COVID-19_11.pdf.

• 2. https://ansm.sante.fr/actualites/point-de-situation-sur-la-surveillance-des-vaccins-contre-la-covid-19-periode-du-23-07-2021-au-29-07-2021.

• 3. https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-7-10-february-2022.

• 4. Edelman A, Boniface ER, Benhar E, Han L, Matteson KA, Favaro C, Pearson JT, Darney BG. Association Between Menstrual Cycle Length and Coronavirus Disease 2019 (COVID-19) Vaccination: A U.S. Cohort. Obstet Gynecol. 2022; 139: 481-9.

• 5. https://doi.org/10.1101/2021.11.23.21266709.

• 6. https://ssrn.com/abstract=3998180 or https://doi.org/10.2139/ssrn.3998180.

2.118 P145 Lessons Learned from COVID19: Enhancing the Discipline of Communications in Pharmacovigilance

2.118.1 D. Abatemarco ¹, K. Schmidt¹, T. Veizovic¹, F. Mujeebuddin¹, E. Mingle¹

2.118.1.1 ¹BeiGene, Global Patient Safety, Ridgefield Park, USA

Introduction: Pharmacovigilance (PV) organizations are traditionally structured to address and comply with global regulations. However, PV organizations are well poised to contribute beyond legislation, by sharing insights across communities in a digestible, accessible way.

Examining communication needs following the height of the COVID-19 pandemic may elucidate opportunities for PV to play a more central role in public health, particularly in generating and disseminating timely, credible and accurate communications.

The need for safety to play a larger role in combating vaccine hesitancy is well documented and is fundamental to building trust in patient populations. ¹ While previous initiatives have focused on meeting the needs of legislation, research has indicated new approaches that incorporate a listening mechanism for public feedback are needed to provide tailored communications.^1-2

PV organizations carry a responsibility to communicate directly to patients, due to their central positioning as a ‘source of truth’ for emerging safety information. The challenge is the level of uncertainty as a product’s benefit/risk profile is characterized over time.

Objective: We aim to identify safety-related communication needs across the healthcare ecosystem and propose an enhanced safety communication framework.

Methods: A three-part approach was taken to design a safety communications framework, addressing internal and external information needs. We performed a literature search to identify trends in PV innovation (2009–2022). Interviews were conducted with the BeiGene Global Patient Safety (GPS) organization to evaluate needs and communication opportunities within PV. Results were compared with lessons learned from the COVID-19 crisis.

Results: Literature results demonstrated that PV innovation publications increased over the past decade, with a peak in 2015 and marked rise in 2021–2022, spanning numerous concepts. Publications relating to safety communications increased yearly since 2010, with over 300 articles published this year to date.

Results from BeiGene interviews (N = 5) demonstrated the following opportunities: (1) Building awareness and understanding of PV externally, (2) Building networks of relevant stakeholders, (3) Demonstrating transparency with the public, (4) Generating accessible safety communications for patient populations by drawing on the discipline of communications in other industries.

Qualitative research across 19 EU countries demonstrated critical gaps in addressing information needs throughout the pandemic relating to under-resourced public health services and lack of interoperative health IT systems.³

Conclusion: GPS has implemented a safety communications framework focused on internal and external communications, research and publications and ongoing intelligence monitoring. Its focus is to increase transparency, visibility and understanding of PV, with the aim to establish trust and credibility in healthcare communities.

References/Further Sources of Information

• 1. Bahri P, Castillon Melero M. Listen to the public and fulfil their information interests—translating vaccine communication research findings into guidance for regulators. Br J Clin Pharmacol. 2018 Aug;84(8):1696–1705. https://doi.org/10.1111/bcp.13587. Epub 2018 May 31. PMID: 29573274; PMCID: PMC6046478.

• 2. Radecka, A., Loughlin, L., Foy, M. et al. Enhancing Pharmacovigilance Capabilities in the EU Regulatory Network: The SCOPE Joint Action. Drug Saf 41, 1285–1302 (2019). https://doi.org/10.1007/s40264-018-0708-5.

• 3. Negro-Calduch E, Azzopardi-Muscat N, Nitzan D, Pebody R, Jorgensen P, Novillo-Ortiz D. Health Information Systems in the COVID-19 Pandemic: A Short Survey of Experiences and Lessons Learned From the European Region. Front Public Health. 2021;9:676838. Published 2021 Sep 28. https://doi.org/10.3389/fpubh.2021.676838.

2.119 P146 Cross-Reactivity between Pfizer/BioNTech and Johnsson Vaccines: A Case Report

2.119.1 M. Ksentini¹, L. B. Mahmoud¹, R. Sahnoun¹, R. Atheymen¹, I. Bouaziz¹, A. Hakim¹, Z. Sahnoun¹, K. Zghal ¹

2.119.1.1 ¹University of Sfax-Faculty of medecine of Sfax, Pharmacology Department, sfax, Tunisia

Introduction: Polyethylene glycol (PEG) is one of the ingredients in the Pfizer/BioNTech COVID 19 vaccine (mRNA vaccine) and has been known to cause hypersensitivity [1-3]. Polysorbate is an ingredient in the Johnson vaccine (adenovirus vaccine) which may cross-react with PEG.

Objective: We report a case of cross-reactivity between Pfizer/BioNTech and Johnsson vaccines.

Methods: This observation was notified in the pharmacovigilance center of Sfax, Tunisia (faculty of medicine of Sfax). The study of drug imputability was carried out according to the WHO method.

Results: We report the case of a 32-year-old Tunisian woman with a history of atopy and intolerance to non-steroidal anti-inflammatory drugs (NSAIDs) but no history of SARS-CoV-2 infection.

On August 15, 2021 (at 08:30), she developed sweating, vomiting and dizziness immediately after receiving the initial dose of Johnson COVID-19 vaccine. Her blood pressure became lower (less than 90/60 mmHg). She had to stay at the vaccination centre for one hour, and the clinical signs improved spontaneously after one hour. In the evening of the same day, the patient presented a febrile maculopapular eruption in the abdomen, trunk, and face. The rash resolved spontaneously over a week. The patient was referred to the pharmacovigilance center of Sfax (Tunisia). The messenger RNA vaccine was advocated for the second vaccine.

On December 2021, she was received the second dose of the Pfizer/BioNTech COVID 19 vaccine (mRNA vaccine). Six hours later, she experienced a pruritic maculopapular rash on the abdomen, trunk, neck, and face. These clinical signs improved spontaneously after two days. the diagnosis of cross-allergy between these two vaccines was retained for this patient

Conclusion: To our knowledge, this is the first cross-allergy between mRNA and adenovirus COVID-19 vaccines notified in Tunisian population. Healthcare professionals should be aware that hypersensitivity can occur with COVID-19 vaccines containing macrogols/PEGs and those containing polysorbates. Its recognition may be challenging and often require skin testing. Per CDC guidance, consultation with an allergist-pharmacologist should be considered to help determine if the patient can safely receive vaccination [4].

References/Further Sources of Information

• 1. Lukaszuk K, Podolak A, Malinowska P, Lukaszuk J, Jakiel G. Cross-Reactivity between Half Doses of Pfizer and AstraZeneca Vaccines—A Preliminary Study. Vaccines. avr 2022;10(4):521.

• 2. Greenhawt M, Abrams EM, Shaker M, Chu DK, Khan D, Akin C, et al. The Risk of Allergic Reaction to SARS-CoV-2 Vaccines and Recommended Evaluation and Management: A Systematic Review, Meta-Analysis, GRADE Assessment, and International Consensus Approach. J Allergy Clin Immunol Pract. oct 2021;9(10):3546–67.

• 3. Ieven T, Van Weyenbergh T, Vandebotermet M, Devolder D, Breynaert C, Schrijvers R. Tolerability of polysorbate 80-containing COVID-19 vaccines in confirmed polyethylene glycol-allergic patients. J Allergy Clin Immunol Pract. déc 2021;9(12):4470–4472.e1.

• 4. CDC. COVID-19 Vaccination. Centers for Disease Control and Prevention. 2021 [cité 13 mai 2022].

2.120 P148 Cerebro-Vascular Accident after Covid-19 Vaccination

2.120.1 S. Debbeche¹, O. Charfi¹, I. Aouinti¹, Y. Mahjoubi¹, I. Hamza¹, R. Daghfous¹, S. E. Aidli ¹

2.120.1.1 ¹Université Tunis El Manar/ Faculté de Médecine de Tunis/ Unité de recherche UR17ES12, Centre National Chalbi Belkahia de Pharmacovigilance/ Service de recueil et d'analyse des effets indésirables, Tunis, Tunisia

Introduction: Stroke is the second cause of death and a major cause of disability worldwide. Its incidence is increasing related to the increase in the age of the population [1]. Younger people can be affected especially when they have risk factors (hypertension, diabetes, dyslipidemia, smoking or obesity) [2].

Objective: The aim of this study was to describe all the cases of Cerebral Vascular accident that occurred after Covid-19 immunization.

Methods: We conducted a retrospective study involving all cases of cerebral vascular accident that occurred after Covid-19 vaccination, from the beginning of the campaign of immunization in March 2021 to May 2022. These cases were notified to the National Center of Pharmacovigilance, Tunisia.

Results: There were 36 cases of Cerebral Vascular accident over 12 million doses of vaccine. These cases represented 1.2% of all the Adverse Effects following Immunization (AEFI) notified to the pharmacovigilance center.

These cases were notified by attending physicians in 45.6% of cases. The sex ratio M/F was 3.2. The mean age was 73.4 years [51–87 years].

The onset of neurological symptoms ranged between 1 and 34 days with an average of 6,18 days following immunization.

The cerebral vascular accident occurred after the 1st shot in 19 patients and after the 2nd shot for 7 patients. This data was not available for 10 patients.

The involved vaccines were Pfizer/BioNTech (mRNA vaccine) in 63.8% cases, an adenovirus viral vector in 22.2% (AstraZeneca COVID-19 vaccine in 19.4% and Sputnik V in 2.8%), an inactivated Covid 19 vaccine in 11.1% cases (Coronavac 8.3% and Sinopharm 2.7%)

Investigations revealed that 25 patients (69.4%) had at least one cardiovascular risk factors, 11 patients had at least 2 and 6 patients had 3 or more factors.

Four patients had a cerebral vascular accident history. Hypertension was noticed in 15 patients, diabetes in 12 patients, dyslipidemia in 3 patients, cardiac rhythm disorders in 4 patients and a concomitant Covid-19 infection in 2 patients. For the other 11 patients, this data was not provided.

There were no cases of Thrombosis with Thrombocytopenia Syndrome in our survey.

Conclusion: Despite a temporal relationship, the vaccine responsibility cannot be retained given the patient’s medical histories and the existence of several risk factors.

References/Further Sources of Information

• 1. Katan M, Luft A. Global Burden of stroke. Semin Neurol. 2018; 38: 208–211.

• 2. Merel SE, Esther MB, Aneesh BS, et al. Epidemiology, aetiology, and management of ischaemic stroke in young adults. Lancet Neurol. 2018; 17: 790–801.

2.121 P149 Myocarditis Related to SARS-CoV-2 Vaccines: Comparing Spontaneous Adverse Drug Reaction Reports with Intensive Monitoring of Nationwide Health-Registers in Sweden

2.121.1 A. Sundström ¹, N. Pihlström², M. L. C. Handler¹, M. L. Nurminen¹, R. Ljung³

2.121.1.1 ¹Swedish Medical Products Agency, Department of Drug Safety, Uppsala, Sweden; ²Swedish Medical Products Agency, Department of Efficacy and Safety 2, Uppsala, Sweden; ³Swedish Medical Products Agency, Division of Use and Information, Uppsala, Sweden

Introduction: In spontaneous reporting, it is normal is to presuppose a more or less pronounced under-reporting to Adverse Drug Reaction (ADR) databases. During 2021, the Swedish Medical Products Agency (MPA) received a record total of more than 100.000 ICSRs on SARS-CoV-2 vaccines. At the same time, MPA implemented a record-linkage study using data from several nation-wide health registers to monitor the safety of said vaccinations [1].

Objective: To estimate the degree of under-reporting of myocarditis to the MPA ADR-database in 2021 through January 2022.

Methods: We compared the number of ICSRs on suspected myocarditis submitted to the MPA with the number of cases of the same condition identified in the Swedish National Patient Register (SNPR).

Dates of vaccination(s) were collected from the National Vaccination Register. A main diagnosis in SNPR within 28 days of any SARS-CoV-2 vaccination was considered an exposed case. This association has been thoroughly studied and established in another study [2].

Cases of myocarditis in the SNPR were incident since 2017; such status in the ICSRs was however unknown.

Results: Until September 2021, the number of submitted ICSRs was less than the number of patients identified in the SNPR. However, the accumulated number of ICSRs surpassed the number of cases in the SNPR in October 2021 and remained higher thereafter.

By the end of follow-up, a suspected myocarditis had been reported in 322 ICSRs, while 254 such cases had been identified in the SNPR.

However, if only ICSRs from health care professionals are considered, the apparent under-reporting prevailed throughout the period: 220 ICSRs v 254 SNPR cases.

Conclusion: This is a special observation where the number of submitted ICSRs exceeds the number of cases in an intensive monitoring of health-care registers.

This can be explained by (1) the case-definition in the SNPR where only admissions within 28 days after a vaccination was considered; this limitation was not applied to the ICSRs; and (2) ICSR of misdiagnosed or only suspected myocarditis.

On October 5, the month during which ICSR reporting surpassed register cases, the Public Health Agency of Sweden declared that individuals under the age of 30 would not be given the Moderna mRNA-1273 vaccine due to the risk for myocarditis.

This was probably a strong motivation for the increased reporting that followed, especially from consumers.

References/Further Sources of Information

• 1. Ljung R, Sundström A, Grünewald M, Backman C, Feltelius N, Gedeborg R, et al. The profile of the COvid-19 VACcination register SAFEty study in Sweden (CoVacSafe-SE). Ups J Med Sci. 2021 Dec 10;126.

• 2. Karlstad Ø, Hovi P, Husby A, Härkänen T, Selmer RM, Pihlström N, et al. SARS-CoV-2 Vaccination and Myocarditis in a Nordic Cohort Study of 23 Million Residents. JAMA Cardiol. 2022 Apr 20:e220583.

2.122 P150 Bell’s Palsy and Covid-19 Vaccination

2.122.1 D. Sana¹, O. Charfi ¹, K. Rania¹, K. Widd¹, D. Riadh², E. A. Sihem¹

2.122.1.1 ¹Université Tunis el Manar Faculté de médecine de Tunis/Unité de recherche UR17ES12., Centre national Chalbi Belkahia de pharmacovigilance/ Service de recueil et d'analyse des effets indésirables, Tunis, Tunisia; ²Université Tunis el Manar Faculté de médecine de Tunis/Unité de recherche UR17ES12., Département : Centre national Chalbi Belkahia de pharmacovigilance/ Service de recueil et d'analyse des effets indésirables, Tunis, Tunisia

Introduction: Bell’s palsy incidence varies from 15 to 30 cases/100,000 persons/year in general population. Various etiologies are identified such as viral infection, neoplasic or traumatic causes. Otherwise, Bell’s palsy has been also reported after vaccines such as influenza vaccine, anti-diphteria, anti-viral B hepatitis and others. Several cases of Bell’s palsy were reported since phase 3 of clinical trials of Covid-19 vaccines.

Objective: The aim of this study was to describe all the cases of Bell’s palsy that occurred after Covid-19 immunization.

Methods: We conducted a retrospective study involving all cases of Bell’s Palsy that occurred after Covid-19 vaccination, from the beginning of the campaign of immunization in March 2021 to May 2022.These cases were notified to the National Center of Pharmacovigilance of Tunisia.

Results: We collected 13 cases of Bell’s palsy over 12 million doses of vaccine. These cases represented 0.4 % of all the Adverse Event following Immunization (AEFI) notified to the National Pharmacovigilance Centre.

The sex ratio M/F was 1.6. The mean age was 49.7 years [29–77 years].

The onset of symptoms following immunization ranged between 1 and 13 days with an average of 6 days. Evolution was favorable in 5 cases and unknown in the other cases.

Bell’s palsy occurred after the 1st shot in six patients and after the 2nd shot in 5 patients. This data was not available for 2 patients.

The involved vaccines were m RNA vaccines in 84.6% cases (Pfizer/BioNTech vaccine in 76.9% cases and Spikevax Covid-19 vaccine-Moderna in 7.6%), an adenovirus viral vector in 7.6% (AstraZeneca COVID-19 vaccine), and an inactivated Covid 19 vaccine in 7.6% cases (Corona-vac).

Conclusion: Bell’s palsy following Covid-19 vaccination are rare, benign and generally resolve in few days.

References/Further Sources of Information

• 1. PatoneM; Handunnetthi L; Saatci D and al. Neurological complications after first dose of COVID-19 vaccines and SARS-CoV-2 infection. Nature Medicine (27); December 2021: 2144–2153

• 2. Kharoubi S. Paralysie faciale périphérique post vaccination COVID-19: à propos d’un cas. The Pan African Medical Journal. 2021; 40:244.

• 3. Garg RK., Paliwal VK. Spectrum of neurological complications following Covid-19 vaccination. Neurological sciences; 2022; 43:3–40

2.123 P151 Rates of ADR Reports by Number of Administered SARS-CoV-2 Vaccination Doses in Sweden: Large Temporal Variations Especially in Consumer Reporting

2.123.1 A. Sundström ¹, M. Larsson ¹, M. L. Nurminen¹

2.123.1.1 ¹Swedish Medical Products Agency, Deptartment of Drug Safety, Uppsala, Sweden

Introduction: During the SARS-CoV-2 vaccinations in 2021, a record number of Individual Case Safety Reports (ICSR) were submitted to the Swedish Medical Products Agency (MPA).

MPA further initiated a record-linkage study [1] by which vaccination data from the National Vaccination Register (NVR) was made accessible.

Objective: We aimed at identifying temporal variations in reporting rates of ICSRs by number of administered vaccine doses, and if found, seek plausible explanations to them.

Methods: The weekly number of ICSRs submitted to the MPA was divided by the weekly number of administered doses between December 27, 2001, and May 1st, 2022, resulting in the reporting rate per 1,000 doses and week.

Results: A total of 102,798 submitted ICSRs and 21.9 million administered doses resulted in an overall reporting rate of 4.7 ICSRs per 1000 doses, range: 0.9/1000 (April 2022) to 21.3/1000 (March 2021). Eighty-two percent of the reports were submitted by consumers.

A four-fold increase in reporting rate was observed between weeks 5 and 11, 2021. This coincided with the start of vaccination of prioritized health-care personnel and ensuing mass media activity on e.g. whole hospital wards having to close due to the personnel’s flu-like symptoms (fever, headache, fatigue, chills, etc.) following vaccination.

On March 16, the Public Health Agency of Sweden decided that only individuals aged 65 or older would receive the Astra Zeneca AZD1222 vaccine. This was followed by a steep seven-fold decline in reporting in three weeks.

Reporting rates from both health-care professionals and consumers increased and decreased in a similar fashion.

During the summer of 2021, additional peaks in reporting rates were observed. At the same time, menstruation disorders following vaccination were debated in both social and traditional media.

The most recent decline in reporting rates, which has yet to turn to an increase, occurred after the Russian invasion of Ukraine in the end of February 2022.

The fluctuating reporting rates observed since April 2021 and onwards were almost exclusively seen in consumer reports.

Conclusion: Rates of submitted spontaneous reports per 1.000 vaccinations in Sweden varied markedly during the studied period, the most pronounced of which originated from changes in consumer reporting.

Many peaks in reporting rates can be—at least temporally—associated to various media or world events, even if a causal relationship can’t be proven.

References/Further Sources of Information

• 1. Ljung R, Sundström A, Grünewald M, Backman C, Feltelius N, Gedeborg R, et al. The profile of the COvid-19 VACcination register SAFEty study in Sweden (CoVacSafe-SE). Ups J Med Sci. 2021 Dec 10;126.

2.124 P152 Fixed Drug Eruption after ChAdOx1 nCoV‐19 Vaccine

2.124.1 F. E. Jabri ¹, S. Kastalli¹, K. Ferchichi¹, S. Dabbeche¹, R. Daghfous¹, S. E. Aidli¹

2.124.1.1 ¹Tunis El Manar University Medical school of Tunis/ research unit UR17ES12., Chalbi Belkahia national centrer of de pharmacovigilance/ adverse effects collection and analysis departement, tunis, Tunisia

Introduction: ChAdOx1 nCoV‐19 vaccine is an adenoviral‐vectored COVID‐19 vaccine. The most common side effects are headache, muscle pain, redness, swelling, and tenderness at the injection site. Cutaneous reactions have been rarely reported.

Objective: To discuss the association between a fixed drug eruption (FDE) and ChAdOx1 nCoV‐19 vaccine.

Methods: We report one case of (FDE) following administration of the ChAdOx1 nCoV‐19.

Results: A 60‐year‐old man with no medical history and no regular medication presented with a rash that had appeared 24 hours after he had received his first dose of the ChAdOx1 nCoV‐19 vaccine (Oxford–AstraZeneca). The lesions had appeared abruptly without any accompanying symptoms. Physical examination revealed three, well‐defined, round to oval, erythematous to violaceous plaques in the face. A punch biopsy was taken, and histopathology findings were consistent with fixed drug eruption.

Conclusion: This case shows that the fixed drug eruption can be a result of receiving the ChAdOx1 nCoV‐19 vaccine (Oxford–AstraZeneca).

References/Further Sources of Information

Keywords: fixed drug eruption, COVID-19 vaccine, ChAdOx1 nCoV‐19 vaccine (Oxford–AstraZeneca).

2.125 P153 Adverse Reactions Associated with Comirnaty^® Among Healthcare Professionals: A Cohort Event Monitoring Study in a Portuguese Hospital

2.125.1 I. Tavares^1,2,3, A. Penedones^1,2,3, J. R. Abrantes ^1,2,3, D. Mendes², C. Codeço⁴, G. Rigueiro^3,4, C. Alves^1,2, F.B. Marques^1,2,3

2.125.1.1 ¹Association for Innovation and Biomedical Research on Light and Image, Pharmacovigilance Unit of Coimbra, Coimbra, Portugal; ²School of Pharmacy-University of Coimbra, Laboratory of Social Pharmacy and Public Health, Coimbra, Portugal; ³Drug Safety and Effectiveness Research Network, DruSER.Net, Coimbra, Portugal; ⁴Instituto Português de Oncologia de Coimbra Francisco Gentil-E.P.E, IPO-Coimbra, Coimbra, Portugal

Introduction: The Portuguese government put into practice a vaccination plan soon after the approval of the first COVID-19 vaccine, prioritizing healthcare professionals (HCPs) and other population groups at risk.

Objective: To characterize the case reports of adverse drug reactions (ADRs) associated with the administration of Comirnaty^® to HCPs in a Portuguese oncology hospital (IPO Coimbra).

Methods: This study was a nine-month prospective, observational study following a cohort event monitoring approach focused on signalling ADRs associated with the administration of Comirnaty^® to HCP in IPO Coimbra. The case reports of ADRs were sent to the Pharmacovigilance Unit of Coimbra (UFC) between 14/01/2021 and 13/10/2021. The population of HCP was characterized according to gender and age distribution. The seriousness of ADRs was assessed for each individual case in accordance with WHO criteria [1]. ADRs were coded with MedDRA^® version 24.0 (System Organ Classification [SOC] and Preferred Term [PT]). ADRs were classified as “expected” or “unexpected” according to their description in the Summary of Product Characteristics (SmPC) of Comirnaty^® [2].

Results: A total of 816 HCPs were inoculated with at least one dose of Comirnaty^®. The case reports of ADRs concerned 469 (57.5%) HCPs: 386 (82.3%) females; 642 (78.7%) aged 30-59 years old. Of the 469 case reports, 24 (5%) were assessed as serious, 44 (9.4%) as unexpected, and 11 (2.3%) as both serious and unexpected. The 469 case reports contained a total of 1,955 ADRs. “General disorders and administration site condition” (n = 1,075; 54,9%), such as vaccination site pain, chills and vaccination site swelling; “Musculoskeletal and connective tissue disorders” (n = 373; 19.1%), including myalgia and arthralgia; and “Nervous system disorders” (n = 250; 12.8%), including headache, were the most frequently reported ADRs, which is in line with the SmPC of Comirnaty^®. The 11 case reports classified as both serious and unexpected contained a total of 17 ADRs, including hyperhidrosis and paraesthesia.

Conclusion: The results of this study bring value to the characterization of the safety profile of Comirnaty^® since the use of a cohort of individuals allows to estimate frequencies of ADRs in the real-world. Further, serious, and unexpected ADRs were identified. Importantly, this type of safety data was further included in the SmPC of the vaccine. In conclusion, the results are in favour of the positive benefit-risk ratio of Comirnaty^®, and reinforce the importance of post-marketing pharmacovigilance to increase knowledge on drug safety.

References/Further Sources of Information

• 1. WHO-UMC (2010) World Health Organization criteria for serious adverse event or reaction

• 2. Comirnaty^® Summary of Product Characteristics

2.126 P154 The Impact of the COVID-19 Pandemic on Spontaneous Reporting of Adverse Drug Reactions in the Central Region of Portugal

2.126.1 J. R. Abrantes ^1,2,3, I. Tavares^1,2,3, A. Penedones^1,2,3, D. Figueiredo¹, D. Mendes³, C. Alves^1,3, F. B. Marques^1,2,3

2.126.1.1 ¹Association for Innovation and Biomedical Research on Light and Image, Pharmacovigilance Unit of Coimbra, Coimbra, Portugal; ²Drug Safety and Effectiveness Research Network, DruSER.Net, Coimbra, Portugal; ³School of Pharmacy-University of Coimbra, Laboratory of Social Pharmacy and Public Health, Coimbra, Portugal

Introduction: The COVID-19 pandemic has had an impact on several sectors of the society. Whether it has disrupted drug safety monitoring is yet to be determined.

Objective: To investigate whether the COVID-19 pandemic has had an impact on the proportions of spontaneous reports (SRs) of serious and unexpected adverse drug reactions (ADRs).

Methods: SRs received by the Coimbra Pharmacovigilance Unit (UFC) between January 2017 and December 2021 were included, except for those containing COVID-19 vaccines as suspected medicines. The SRs were categorized into two groups: pre-pandemic (2017–2019); and post-pandemic (2020–2021). The SRs were classified as serious or non-serious, and expected or unexpected, depending on the seriousness and expectedness of the suspected ADRs, according to the WHO criteria and the Summary of Product Characteristics [SmPC] of each suspected medicine, respectively [1,2]. To study the impact of the COVID-19 pandemic on the patterns of spontaneous reporting of suspected ADRs, two null hypotheses were proposed to test whether (i) the seriousness, and (ii) the expectedness were independent of the pandemic (i.e., if the pandemic has had no impact, then the proportions of SRs containing (i) serious and (ii) unexpected ADRs were expected to be the same in both periods). The qui-square test was used to test the hypotheses; p-values < 0.001 were considered statistically significant. Microsoft Excel^® was used for the statistical analyses.

Results: A total of 1,311 and 657 SRs were received in the pre-pandemic and post-pandemic periods, respectively. Of the 1,311 SRs received in the three pre-pandemic years, 1,012 (77%) were serious and 657 (13%) contained unexpected ADRs; of the 657 SR received during the two post-pandemic years, 434 (66%) were serious and 133 (20%) contained unexpected ADRs. The changes from pre- to post-pandemic on both proportions of SRs containing serious (an absolute decrease of 11%; p = 0.01) or unexpected ADRs (an absolute increase of 7%; p = 0.01) were not statistically significant.

Conclusion: The COVID-19 pandemic has had not a significant impact on the proportions of SRs of serious or unexpected ADRs in the Central Region of Portugal. Further research should be carried out in other pharmacovigilance databases to understand if the present conclusions are applicable to other geographic regions.

References/Further Sources of Information

• 1. European Medicines Agency. Guideline on good pharmacovigilance practices (GVP)—Annex I—Definitions (Rev 4).

• 2. WHO-UMC (2010) World Health Organization criteria for serious adverse event or reaction.

2.127 P155 Acute Angle Closure Glaucoma Following COVID-19 Vaccination

2.127.1 Y. Mahjoubi¹, A. Zaiem¹, G. Lakhoua¹, W. E. Dali¹, R. Daghfous ¹, S. E. Aidli¹

2.127.1.1 ¹Chalbi Belkahia National Centre for Pharmacovigilance/Tunis el Manar University Faculty of Medicine of Tunis, Service for the collection and analysis of adverse reactions/Research Unit UR17ES12, Tunis, Tunisia

Introduction: Although vaccines against COVID-19 are strongly recommended as safe and effective at alleviating the morbidity and mortality, different types of ocular complications have been reported after COVID-19 vaccination, including oculomotor nerve palsy, episcleritis, anterior uveitis, multifocal choroiditis, reactivation of Vogt-Koyanagi-Harada disease, acute macular neuroretinopathy and central serous retinopathy(1).Acute angle closure glaucoma (AACG) is an ophthalmic emergency that can be drug induced. If not promptly identified and treated, it can cause irreversible blindness.

Objective: To describe an exceptional case of bilateral AACG that occurred within 4 hours following COVID-19 vaccination.

Methods: This case was notified to the pharmacovigilance department in February 2022.

Results: A 38-year-old woman with a history of high myopia experienced stabbing pain in her left eye 4 hours after she received the second recombinant mRNA vaccine (Pfizer)injection. Few hours later, periorbital headache appeared in left side and the eye pain became much more severe. She took paracetamol by self-medication and stayed in the darkness. The following morning, she complained of sudden loss of vision in both eyes. She consulted an ophtalmologist, where elevated intraocular pressure (IOP) was noted in her left eye (60mm of mercury). Visual acuity examination showed results of 0.5 and 0.3 for right and left eyes, respectively. Goldman visual field test revealed a nasal field defect in her left eye. The angles of both eyes were closed on optical coherence tomography. Anterior segment examination demonstrated areflexic mydriasis. The patient was diagnosed with bilateral AACG. Topical instillation of pilocarpine was provided and the IOP decreased to 45 mm Hg in left eye. Then, the patient was prescribed systemic acetazolamide, and a fixed combination of bimatoprost–timolol. On follow-up after 24 hours, IOP improved to 19, 5 mm Hg in left eye and 11 mm Hg in right eye, however, the decreased vision persisted. Bilateral peripheral iridotomy was performed 10 days later. Two months after onset, the visual acuity was completely restored but the areflexic mydriasis was permanent. There was no recurrence of her glaucoma during a 3-month follow-up period.

Conclusion: To the best of our knowledge, this is the first case to describe AACG following COVID-19 vaccination. The onset of ocular symptoms suggests a possible correlation between this complication and COVID-19 vaccination. However, the presence of other risk factors mainly high myopia puts this cause and effect relationship into question.

References/Further Sources of Information

• 1. Bolletta, E., Iannetta, D., Mastrofilippo, V., De Simone, L., Gozzi, F., Croci, S., ... & Cimino, L. (2021). Uveitis and Other Ocular Complications Following COVID-19 Vaccination. Journal of Clinical Medicine, 10(24), 5960.

2.128 P156 Do Patients with SARS-CoV-2 Vaccine-Induced Chronic Urticaria Can Have Their Second Dose?

2.128.1 Y. Mahjoubi¹, A. Zaiem¹, I. Aouinti¹, M. B. Belgacem¹, M. Daldoul¹, G. Lakhoua¹, S. Kastalli¹, R. Daghfous¹, S. E. Aidli ¹

2.128.1.1 ¹Chalbi Belkahia National Centre for Pharmacovigilance/Tunis el Manar University Faculty of Medicine of Tunis, Service for the collection and analysis of adverse reactions/Research Unit UR17ES12, Tunis, Tunisia

Introduction: Adverse skin reactions, either immediate or delayed, were reported following COVID-19 vaccines [1]. Chronic spontaneous urticaria (CSU), a persisting urticaria beyond six weeks, has been rarely reported. These skin conditions present the challenge of the possibility of taking or not of the second dose and also its nature.

Objective: To report cases of CSU after receiving vaccination against SARS-CoV-2 and the outcome after taking their second dose.

Methods: We performed a research on the database of the pharmacovigilance center from March 2021 to March 2022 using the keywords: urticaria, covid vaccine. The inclusion criteria were

• persisting urticaria beyond six weeks after immunization

• no urticaria prior the immunization during at least one month

• second dose taken

Non inclusion criteria were:

• CSU not related to the vaccine

Results: We retained three cases of CSU following COVID19 vaccine with second dose. There were two women and one man. Their age varied from 24 to 48 years. Two patients had chronic disease: one presented dysthyroidism, and the other presented asthma. The delay of occurrence of CSU varied from few hours to five days. The CSU in the three cases was not associated with other symptoms such as angioedema or dyspnea. In the three cases, the use of antihistamine drugs was only effective in reducing pruritus without complete release of urticaria. Follow up of the patients showed that they had their second dose after a period that varied between one and six months. They took their second dose while they continue to present urticaria. In the three patients, there was no exacerbation or specific complications.

Conclusion: Our study showed that the administration of the second dose in patients that developed CSU after the previous vaccine can be considered safe and is advisable. Most of cases of exacerbation or worsening of CSU reported in the literature appear to be transient and can be managed by antihistamine therapies [2].

References/Further Sources of Information

• 1. Suan D, Lee AYS. Chronic spontaneous urticaria following ChAdOx1-S COVID-19 vaccination. Allergo J Int. 2022 Mar 7:1–2.

• 2. Koç Yıldırım S, Demirel Öğüt N, Erbağcı E. Retrospective evaluation of patients with chronic spontaneous urticaria using omalizumab during the COVID-19 pandemic. J Cosmet Dermatol. 2022 Feb;21(2):431–434.

2.129 P157 Establishing Patient Safety Monitoring in the Benefit-Risk Paradigm for Off-Label and Emergency Use of Medications for COVID-19: A Pharmacovigilance Perspective

2.129.1 M. Malikova ¹, P. Webster², T. Brahmbhatt¹

2.129.1.1 ¹Boston University School of Medicine-Boston University, Surgery, Boston, USA; ²GlaxoSmithKline, Vaccines Safety, Philadelphia, USA

Introduction: With the massive widespread impact of COVID-19 [1, 2], before the accelerated development timelines for vaccines, one of the options to help mitigate disease impact was in repurposing already approved drugs [3-6]. In the race to discover/implement an already approved agent, which may also be effective in treating COVID-19, we have learned lessons to form a pharmacovigilance perspective that is central to the conscientious approach one is required to employ to ensure patient safety and continued assessment. This work was written under the umbrella of NASoP and represents learnings/recommendations for safety monitoring relating to off-label use in future pandemics or other emergency scenarios after an appropriate benefit-risk assessment, it does not represent an official view of our respective companies/institutions.

Objective: Within the lens of optimizing pharmacovigilance through both the planning and the implementation phases of drug repurposing, we outline a strategy and provide suggestions to ensure optimal drug rollout and patient safety.

Methods: An international, multi-institutional expert panel provides a review of lessons learned through a descriptive narrative.

Results: All drug repurposing should be pursued through a systems approach insuring institutional/regional collaboration, innovation, and data-driven decision making. The roll-out of any repurposed drug should occur in two phases: the planning and implementation. Institutional responses in drug repurposing requires identification of key stakeholders, establishment of local expert working groups tasked with continuous assessment and critical review of emerging literature. The off-label use is at the discretion of the healthcare provider, in collaboration with institutional/regional authorities after an appropriate benefit-risk assessment, and we are not recommending or promoting off-label use. A shared decision making strategy is central to ensure patient involvement and understanding of not just the available evidence, but the rationale and acceptance of the repurposed drug. Pharmacovigilance plays a crucial role in the expedient evaluation of new uses for existing therapies and can rely on already established institutional monitoring modalities. A close institutional partnership with regional/national drug regulatory agencies, healthcare professionals, and pharmaceutical companies allows for a wider breadth of information and experience dissemination for the purposes of patient safety and continuation of a drug’s repurposed indication.

Conclusion: As more data emerges during the COVID-19 pandemic, one can presume other medications for off-label use in COVID-19 will have been identified. Therefore, it is important that increased attention and awareness is created regarding drug safety and the potential harm these medications may have on an individual and re-affirm the critical role of pharmacovigilance expertise.

References/Further Sources of Information

• 1. European Centre for Disease Prevention and Control. COVID-19 situation update worldwide as of 9 June 2020. https://www.ecdc.europa.eu/en/geographical-distribution-2019-ncov-cases.

• 2. Matrajt L., Leung T. Evaluating the effectiveness of social distancing interventions to delay or flatten the epidemic curve of coronavirus disease. Emerg Infect Dis. 2020;26(8). https://doi.org/10.3201/eid2608.201093.

• 3. Food and Drug Administration (US). Understanding unapproved use of approved drugs “off label”. US; Food and Drug Administration; Feb, 2018. https://www.fda.gov/patients/learn-about-expanded-access-and-other-treatment-options/understanding-unapproved-use-approved-drugs-label.

• 4. Emergency Use Authorization (EUA) for remdesivir, an unapproved product Center for Drug Evaluation and Research (CDER) Review. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/EUA%20Review%20Remdesivir_050120.pdf.

• 5. Food and Drug Administration (US). Highlights of prescribing information Zithromax US; Food and Drug Administration; Apr, 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/050710s049,050711s047,050784s034lbl.pdf.

• 6. Food and Drug Administration (US). Fact sheet for patients and parent/caregivers emergency use authorization (EUA) of remdesivir for coronavirus disease 2019 (COVID-19). US; Food and Drug Administration; 2020. https://www.fda.gov/media/137565/download.

2.130 P158 Active Pharmacovigilance in COVID-19 Patients: The Role of a Clinical Pharmacist in the Reporting of Adverse Drug Events

2.130.1 A. Hida ^1,2, M. Faroudy^1,3, A. Chaibi^1,2, M. A. E. Cadi^1,2

2.130.1.1 ¹Faculty of Medicine and Pharmacy of Rabat, Mohamed V Souissi University, Rabat, Morocco; ²Pharmacy Department, Ibn Sina University Hospital, Rabat, Morocco; ³Intensive Care Unit of Emergency Trauma Department, Ibn Sina University Hospital, Rabat, Morocco

Introduction: Like many countries in the world, the first wave of the COVID-19 (Coronavirus Disease 2019) pandemic in Morocco was marked by an overload of infected patients and unprecedented challenges. This, combined with the unknown nature of the disease, has compelled clinicians to prescribe a wide range of medicines, including experimental drugs as well as symptomatic therapies. These practices were associated with an increase in the incidence of adverse drug events (ADEs), which were reported to be higher in the COVID-19 population [1]. Among front-line health workers, pharmacists were assigned various roles such as active and passive pharmacovigilance in order to ensure the safe use of drugs [2]. This was the case of our hospital, where some pharmacists participate in medical rounds to provide pharmaceutical care near patients.

Objective: To demonstrate the importance of a clinical pharmacist in the reporting of ADEs in hospitalized COVID-19 patients.

Methods: An observational study was conducted between September 2020 and January 2021 at a university hospital in Rabat. Only one of five COVID-19 units had a pharmacist as a full time member of the medical team. The notification of ADEs are made on a sheet designed by the National Pharmacovigilance Center. After assessing the collected ADE’s, the pharmacist compared them to all ADE’s that were reported from other COVID-19 units during the study period. Data were subsequently analyzed using Excel.

Results: A total of 42 ADEs in 35 patients were notified by the pharmacist (population size = 120). Experimental drugs used for the viral treatment (hydroxychloroquine and azithromycin) were the most commonly recorded medications with ADEs (30%), 27% were anticoagulants and 13,5% were corticosteroids. Regarding ADEs, 26% consisted of QT interval prolongation, followed by hyperkalemia (26%), hyperglycemia (19%), bleeding (7%), and hepatic cytolysis (5%). In comparison, only 3 ADEs were notified from other COVID-19 units of the hospital.

Conclusion: Results of our study suggests that the presence of a pharmacist in a multidisciplinary team is crucial to enhance patient care and safety, particularly in these times of crisis. Our study has also shed light on the poor reporting rate of ADEs in the hospitalized patients, which was previously mentioned to be common in the developing world [3]. Strategies to improve the pharmacovigilance system in Morocco are needed to better prepare healthcare structures for future epidemics.

References/Further Sources of Information

• 1. [1] Khan Z, Karataş Y, Rahman H, Qayum M, Alzahrani KJ, Kashif SM. COVID-19 treatments and associated adverse reactions: The need for effective strategies to strengthen pharmacovigilance system in Lower- and middle-income countries. Le Pharmacien Clinicien 2022; 1: 77–80

• 2. [2] Beninger P. Influence of COVID-19 on the Pharmacovigilance Workforce of the Future. Clinical Therapeutics 2021; 2: 369–371

• 3. [3] Aagaard, L, Strandell J, Melskens L, Petersen PSG, Hansen EH. Global Patterns of Adverse Drug Reactions Over a Decade. Drug Saf. 2012; 35: 1171–82.

2.131 P159 Urticaria Reactions after COVID-19 Vaccination: A Case Series

2.131.1 W. Daly¹, O. Charfi^1,2, G. Lakhoua^1,2, I. Aouitni^1,2, R. Daghfous^1,2, S. E. Aidli ^1,2

2.131.1.1 ¹Centre national de pharmacovigilance, Service d’analyse et de recueil des données, Tunis, Tunisia; ²Université Tunis El Manar-Faculté de médecine, Unité de recherche : UR17ES12, Tunis, Tunisia

Introduction: COVID 19 vaccines are considered as an important medical advance in healthcare. It is the most promising approach for curbing the COVID-19 pandemic. However, as the number of people receiving vaccination rises, we are inevitably faced with increasing adverse drug reactions. The most common adverse reactions to vaccines are non-allergic, as flu like-symptoms and injection site reactions. Immediate hypersensitivity reactions are fortunately rare [1,2].

Objective: The aim of our work was to study clinical characteristics of acute urticaria following COVID-19 vaccines reported to the Tunisian National Center of Pharmacovigilance.

Methods: We conducted a retrospective study involving all cases of acute urticaria related to COVID-19 vaccines since the onset of the vaccine campaign in March 2021 to May 2022.

Results: This study included 70 patients. Age ranged from 15 to 77 years old with a median age of 26 years. There were 51 women, and the sex ratio M/F was 0.37.

The onset of urticaria varied from few hours to 17 days following vaccine injection with an average delay of 4 days.

In 56 cases, urticaria occurred following 1st shot, in 10 cases following the 2nd dose and one case was reported following the 3rd dose of vaccine. This data was not mentioned in 3 cases.

Outcome was favorable in 57 cases and unknown in 13 cases.

Involved vaccines were Pfizer/BioNTech (47.14%), SPIKEVAX COVID-19 Vaccine Moderna (20%), AstraZeneca COVID-19 vaccine (15.71%), COVID-19 Vaccine Janssen (11.42%), CORONAVAC SINOVAC COVID-19 VACCINE (2.85%) and Sputnik V (2.85%).

Urticaria was isolated in 58 cases, was associated with angioedema in 7 cases, and with fever in 5 cases.

Conclusion: Our work showed a very low number of cases of acute urticaria following Covid-19 immunization. The Center for Disease Control and Prevention recommend, in patients who had even within 4 hours of getting vaccinated a non-severe allergic reaction to COVID-19 Vaccine to receive another dose of the same vaccine under medical surveillance. This is suggesting a non-specific mechanism.

References/Further Sources of Information

• 1. Kounis NG, Koniari I, de Gregorio C, Velissaris D, Petalas K, Brinia A, et al. Allergic Reactions to Current Available COVID-19 Vaccinations: Pathophysiology, Causality, and Therapeutic Considerations. Vaccines.5 mars 2021;9(3):221.

• 2. Kim MA, Lee YW, Kim SR, Kim JH, Min TK, Park HS, et al. COVID-19 Vaccine-associated Anaphylaxis and Allergic Reactions: Consensus Statements of the KAAACI Urticaria/Angioedema/Anaphylaxis Working Group. Allergy Asthma Immunol Res. juill 2021; 13(4):526–44.

2.132 P160 Dermatomyositis Following Pfizer BioNTeh Covid-19 Vaccination

2.132.1 W. Daly¹, I. Aouinti^1,2, W. Kaabi^1,2, M. Daldoul¹, S. Kastalli^1,2, R. Daghfous^1,2, S. E. Aidli ^1,2

2.132.1.1 ¹Centre national de pharmacovigilance, Service d’analyse et de recueil des données, Tunis, Tunisia; ²Université Tunis El Manar-Faculté de médecine, Unité de recherche : UR17ES12, Tunis, Tunisia

Introduction: Dermatomyositis is an idiopathic autoimmune connective tissue disease. It is typically characterized by proximal muscle weakness and skin rashes. Dermatomyositis is associated with a higher risk of malignancy compared to the general population (1). One case in literature has reported a dermatomysitis post COVID-19 vaccination (2).

Objective: Case report.

Methods: We report a case of dermatomyositis following Covid-19 immunization, notified to the National Centre of Pharmacovigilance of Tunis in May 2021.

Results: A 33 year old woman, with no significant past medical history. She developed in March 2021, two days after 1st dose Pfizer BioNTeh Covid-19 vaccination, a mild facial erythema and ipsilateral auxiliary adenopathy. The evolution was marked by a persistence of the erythema and a regression of the adenopathy

In April 2021, 2 days following the 2nd dose, she presented an accentuation of the symptomatology: skin erythema and edema in the photo-exposed areas: face, neck and upper limbs. As well as a diffuse myalgia in upper and lower limbs. She was afebrile and didn’t present itchiness.

The patient received intravenous methylprednisolone 1 injection per day for 5 days, followed by 1 mg/kg prednisolone and anti histaminic drugs without amelioration.

The diagnosis of dermatomyositis was suspected in view of the persistence of the symptoms 1 month after vaccination and the installation of a proximal muscular deficit.

Laboratory studies revealed a high level of creatine phosphokinase (CPK) at 3800 UI/l (< 140) and Lactate dehydrogenase (LDH) at 628 UI/l (< 248).

The skin biopsy showed an aspect consistent with a moderate inflammatory myopathy.

Autoimmune serology revealed the presence of anti-nuclear antibodies (ANA) (1/100) and a positive anti-Mi-2 antibodies.

The patient underwent thorough malignancy screening. Findings of cervico-thoraco-abdomen pelvic scan didn’t reveal any evidence for solid organ malignancies or interstitial lung disease. However, the mammogram and ultrasound-guided biopsy has identified an invasive carcinoma.

Conclusion: This case showed a dermatomyositis case suspected initially to be associated to mRNA COVID vaccination which was finally related to a breast cancer.

References/Further Sources of Information

• 1. Hu T, Vinik O. Dermatomyositis and malignancy. Can Fam Physician. juin 2019;65(6):409–11.

• 2. Gouda W, Albasri A, Alsaqabi F, Al Sabah HY, Alkandari M, Abdelnaby H. Dermatomyositis Following BNT162b2 mRNA COVID-19 Vaccination. J Korean Med Sci. 7 janv 2022;37(5):e32.

2.133 P161 Investigating a Signal of Acquired Haemophilia Associated with COVID-19 Vaccination: A Systematic Case Review

2.133.1 E. Cappello ¹, M. Franchini², G. Valdiserra¹, M. Bonaso¹, U. Moretti³, D. Focosi⁴, M. Tuccori⁵

2.133.1.1 ¹University of Pisa, Unit of Pharmacology and Pharmacovigilance-Department of Clinical and Experimental Medicine, Pisa, Italy; ²Carlo Poma Hospital, Division of Transfusion Medicine, Mantua, Italy; ³University of Verona, Department of Diagnostics and Public Health, Verona, Italy; ⁴Pisa University Hospital, North-Western Tuscany Blood Bank, Pisa, Italy; ⁵University Hospital of Pisa-University of Pisa, Unit of Adverse Drug Reactions Monitoring-Department of Clinical and Experimental Medicine, Pisa, Italy

Introduction: Acquired haemophilia A (AHA) is a rare, haematological disorder characterized by the development of autoantibodies to Anti-Factor VIII (FVIII), which can cause spontaneous hemorrhage¹. During 2021, some authors reported an unusual and unexpected number of AHA diagnoses that were temporally related to COVID-19 vaccination^2,3

Objective: To explore a possible signal of risk of AHA associated with COVID-19 immunization.

Methods: We performed a disproportionality analysis on the World Health Organization (WHO) database (VigiBase^®) to investigate the presence of a signal of risk for AHA associated with COVID-19 vaccines. We calculated the information component (IC) for all the COVID-19 vaccines and for single COVID-19 vaccine product using the entire database as reference. Reports of AHA have been systematically reviewed all the selected cases to check for clinical plausibility

Results: In Vigibase, we identified 150 cases of suspected AHA associated with COVID-19 vaccines (146 included the PT “acquired haemophilia”). Only three vaccine products have been reported as suspected causative agents for AHA. The disproportionality analysis showed a significant IC for the Preferred term “Acquired haemophilia” associated with all COVID-19 vaccines (IC: 1.3; IC025: 1.1) and with the vaccine product BNT162b2 (IC: 1.9; IC025: 1.6). After the integration with data available on VAERS and on the medical literature, and after the elimination of duplicates, 96 unique cases of AHA following COVID-19 vaccines (mostly mRNA vaccines) have been reviewed. Overall, about 22% of cases occurred in patients ≤ 65 and no case associated with pregnancy was reported. Patients with at least one pre-existing condition that can be considered a risk factor for AHA (history of AHA, cancer, autoimmune disorder) were 20 (21%). A pre-existing condition predisposing to AHA was excluded in 57 (59%) of cases and not reported in 19 (20%) cases. The outcome was death in 10 (11%) patients and complete resolution or recovering in 39 (41%) patients with a single resolution without specific AHA treatment. Median time from last vaccine dose to diagnosis was 18 days and 40% of cases documented the occurrence after the second dose.

Conclusion: Our disproportionality analysis confirmed a reporting risk for AHA associated with COVID-19 vaccines. The case review analysis identified several good-quality reports of AHA for which no alternative causes other than COVID-19 immunization can be considered. Although detection bias should be considered to explain the unexpected frequency of AHA in the population, the signal identified is robust and deserves further investigation.

References/Further Sources of Information

• 1. Franchini M, Vaglio S, Marano G, et al. Acquired hemophilia A: a review of recent data and new therapeutic options. Hematology 2017;22:514–20. https://doi.org/10.1080/10245332.2017.1319115.

• 2. Leone MC, Canovi S, Pilia A, et al. Four cases of acquired hemophilia A following immunization with mRNA BNT162b2 SARS-CoV-2 vaccine. Thromb Res 2022;211:60–2. https://doi.org/10.1016/J.THROMRES.2022.01.017.

• 3. Cittone MG, Battegay R, Condoluci A, et al. The statistical risk of diagnosing coincidental acquired hemophilia A following anti-SARS-CoV-2 vaccination. J Thromb Haemost 2021;19:2360–2. https://doi.org/10.1111/JTH.15421.

2.134 P162 COVID-19 Vaccines and Thromboembolic Events with Thrombocytopenia: Data from Italian Pharmacovigilance Public Database

2.134.1 M. Bonaso ¹, P. Marchione², P. Felicetti², F. Petronzelli², E. Cappello¹, S. Samez³, C. Zappetti⁴, P. Rossi³, C. Merlano⁵, G. Valdiserra¹, S. Ferraro¹, I. Convertino¹, A. R. Marra², M. Parrilli⁶, M. Tuccori⁷

2.134.1.1 ¹University of Pisa, Unit of Pharmacology and Pharmacovigilance-Department of Clinical and Experimental Medicine, Pisa, Italy; ²Agenzia Italiana del Farmaco AIFA, Post Marketing Surveillance Department, Rome, Italy; ³Regione Autonoma Friuli Venezia Giulia, Centro Regionale Farmacovigilanza Friuli Venezia Giulia, Trieste, Italy; ⁴Regione Autonoma Friuli Venezia Giulia, Servizio Prevenzione-sicurezza alimentare e sanità pubblica veterinaria-Direzione centrale salute-politiche sociali e disabilità, Trieste, Italy; ⁵Regione/ARS Liguria, Centro Regionale Farmacovigilanza Liguria, Genoa, Italy; ⁶Azienda USL Toscana Centro, Centro Regionale Farmacovigilanza Toscana, Florence, Italy; ⁷University Hospital of Pisa, Unit of Pharmacology and Pharmacovigilance-Department of Clinical and Experimental Medicine-Unit of Adverse Drug Reactions Monitoring-Centro Regionale Farmacovigilanza Toscana, Pisa, Italy

Introduction: During large-scale vaccination campaign against COVID-19, the Italian Medicines Agency (AIFA) in collaboration with the Regional Centres of Pharmacovigilance have carried out a closely monitoring of Individual Case Safety Reports (ICSRs) about Adverse Event Following Immunisation (AEFIs) related to COVID-19 vaccines and have assured a constant communication through public monthly reports¹. During the first months of the vaccination campaign, a signal of rare events of thrombosis associated with thrombocytopenia², particularly in young women, was detected by health authorities associated with the viral vector vaccines ChAdOx1-S and Ad26.COV2-S.

Objective: To present a comprehensive assessment of thrombotic and thromboembolic events associated with thrombocytopenia following COVID-19 immunisation with viral vector vaccines recorded in the Italian National Pharmacovigilance Network database

Methods: We selected all ICSRs reported from 27 December 2020 to 26 December 2021 containing Preferred Terms (PT) related to platelet count reduction associated with PT related to thrombotic and thromboembolic events (clinical symptoms and/or diagnostic tests). All cases of thrombotic and thromboembolic events reporting thrombocytopenia in the narrative description of the report were also reviewed. The selected ICRSs were submitted to the independent evaluation of three pharmacovigilance experts who blindly classified into 5 levels of diagnostic certainty, according to the definition provided by the Brighton Collaboration Group (BCG)³. Disagreement were resolved by plenary discussion.

Results: 12,166,236 doses of ChAdOx1-S and 1,500,746 of Ad26.COV2-S have been administered in Italy during the considered interval with overall 23,358/117,947 ICSRs related to ChAdOx1-S (19.8 %) and 1,580/117,947 related to Ad26.COV2-S (1.3 %). A total of 134 reports after vaccination with adenoviral vaccines were identified according to the inclusion criteria, of which 107 cases were defined as thrombotic thrombocytopenia (95 following ChAdOx1-S and 12 after Ad26.COV2-S). 27 reports were defined as "not case" (level 5, Brighton) on the basis of clinical examination or investigation, or because of the presence of heparin as a concomitant drug. Furthermore, 3 reports were excluded because of a hereditary thrombophilia or a previous history of other thrombotic episodes. Seventy-seven cases were classifiable as BCG levels 1, 2, and 3 (definite, probable and possible cases, respectively) with an overall reporting rate at about 1 case per approximately 200,000 doses administered. Women aged 30 to 49 years showed the highest reporting rates.

Conclusion: In Italy, the rates of thrombotic thrombocytopenia following COVID-19 immunisation with viral vector vaccines are in line with those reported in other Countries.

References/Further Sources of Information

• 1. https://www.aifa.gov.it/documents/20142/1315190/Rapporto_annuale_su_sicurezza_vaccini%20anti-COVID-19.pdf.

• 2. https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-6-9-april-2021.

• 3. https://brightoncollaboration.us/thrombosis-with-thrombocytopenia-syndrome-interim-case-definition/.

2.135 P163 Leveraging Free-Text Information to Detect Duplicates in COVID-19 Vaccine Adverse Event Reports

2.135.1 E. Turesson¹, J. Barrett ¹

2.135.1.1 ¹Uppsala Monitoring Centre, Research, Uppsala, Sweden

Introduction: Uppsala Monitoring Centre (UMC) manage VigiBase; the largest global database of reports of suspected adverse events (side effects) to medicines, on behalf of the World Health organisation (WHO). Following the emergency rollout of the vaccines against COVID-19, combined with a global focus on monitoring their safety, UMC saw a sharp increase in the volume of reports of suspected side effects of the vaccines.

UMC sometimes receives multiple reports corresponding to the same suspected adverse event. This can have undesirable effects when it comes to both statistical signal detection and manual review of cases. Duplicate detection of vaccines has historically been especially challenging, due to homogeneity of patients. However, the extreme quantity of COVID-19 vaccine reports has highlighted the necessity for automated duplicate detection to be performant for them.

Detecting duplicate reports is a non-trivial problem. Since reports do not always contain the same level of detail, and data errors can lead to different values in corresponding fields for duplicate reports, reports cannot simply be compared field by field. Several methods have been proposed for detecting duplicates based on information provided in structured form (sex, age, date of onset etc) (1,2). In our study we additionally incorporate free text information into a duplicate detection model.

Objective: To leverage the free text information in suspected adverse event reports to identify duplicate reports which are referring to the same adverse event.

Methods: Our method ensembles state-of-the-art machine learning methods. Narratives are placed in a space where a smaller distance between two narratives conveys higher semantic similarity. This is done with vector embeddings using the SapBERT model, fine-tuned on a set of known duplicate reports (3). Two reports are then compared using the cosine similarity between the vector embeddings for the two narratives. This similarity is combined with representations of the structured information used in other methods in a gradient boosted decision tree model, calibrated by a logistic regression model to fine tune the probability output (4).

These methods are evaluated on a set of curated datasets of COVID-19 vaccine reports comprising 1239 pairs of known duplicates. We use random pairs of COVID-19 vaccine reports as examples of non-duplicates.

Results: Our model successfully identifies 78.9% of known duplicate pairs. It achieved a false positive rate (the number of non-duplicates erroneously marked as duplicates) of 0.001%. The full results can be seen in table 1.

Conclusion: Not Applicable.

References/Further Sources of Information

• 1. Norén GN, Orre R, Bate A. A hit-miss model for duplicate detection in the WHO drug safety database. In: Proceeding of the eleventh ACM SIGKDD international conference on Knowledge discovery in data mining-KDD ’05 [Internet]. Chicago, Illinois, USA: ACM Press; 2005 [cited 2020 Apr 28]. p. 459. Available from: http://portal.acm.org/citation.cfm?doid=1081870.1081923.

• 2. Kreimeyer K, Menschik D, Winiecki S, Paul W, Barash F, Woo EJ, et al. Using Probabilistic Record Linkage of Structured and Unstructured Data to Identify Duplicate Cases in Spontaneous Adverse Event Reporting Systems. Drug Saf. 2017 Jul 1;40(7):571–82.

• 3. Liu F, Shareghi E, Meng Z, Basaldella M, Collier N. Self-Alignment Pretraining for Biomedical Entity Representations. ArXiv201011784 Cs [Internet]. 2021 Apr 7 [cited 2022 May 12]; Available from: http://arxiv.org/abs/2010.11784.

• 4. He X, Bowers S, Candela JQ, Pan J, Jin O, Xu T, et al. Practical Lessons from Predicting Clicks on Ads at Facebook. In: Proceedings of 20th ACM SIGKDD Conference on Knowledge Discovery and Data Mining—ADKDD’14 [Internet]. New York, NY, USA: ACM Press; 2014 [cited 2022 May 12]. p. 1–9. Available from: http://dl.acm.org/citation.cfm?doid=2648584.2648589.

2.136 P164 Enhanced Surveillance of Italian Vaccinovigilance Group During COVID-19 Pandemic

2.136.1 F. Petronzelli ¹, M. Marvulli², V. Saccomandi², M. Conte³, M. Guarducci³, G. Pimpinella¹, A. R. Marra³

2.136.1.1 ¹Italian Medicines Agency, Pharmacovigilance Office, Rome, Italy; ²Italian Medicines Agency, Signal Management Office, Rome, Italy; ³; ³Italian Medicines Agency, Post-marketing surveillance Area, Rome, Italy

Introduction: The vaccinovigilance Italian group was established since 2014 (1), with members from AIFA, Italian National Institute of Health (ISS), Ministry of Health (MH), Pharmacovigilance Regional Centers (PVRC) and Regional Prevention (RP). Signal detection of vaccines, annual reports on vaccine surveillance and supporting documents for pharmacovigilance activity are the main core of the group activities (2). During pandemic, enhanced surveillance was conducted to better characterize safety profile of the new anti-COVID-19 vaccines.

Objective: We reported the enhanced surveillance for anti-COVID-19 vaccines, managed by the AIFA in collaboration with ISS, MH, PVRC and RP.

Methods: Actions implemented for the enhanced surveillance: daily control of the RNF and follow-up requests, periodic publication of reports, interactive graphs on web site updated monthly, meetings of signal detection for anti-COVID-19 vaccines on a monthly basis.

Results: From the first month of the vaccination campaign (27/12/2020-26/01/2021) a report on the course of safety surveillance was made publicly available (3). Until 26/09/2022 the report was published on a monthly basis, then, considering the downward trend in report submission and the greater knowledge of the vaccine safety profile, we moved to a quarterly frequency. The 10th report is referred to an observation period of one year from the start of the vaccination campaign with 117.920 reports submitted to RNF and 108.530.987 administered doses. In this annual report, there are specific focuses developed with the contribution of the regions, tailored on reproductive health, pediatric population and adverse events of special interest such as anaphylaxis, Guillain Barré syndrome, myocarditis/pericarditis, Bell paralysis and thrombosis with thrombocytopenia syndrome. The report was presented in live streaming on the AIFA YouTube channel. Regarding the signal detection within the group, it was performed monthly since September 2021; the work was distributed among regions on the basis of vaccines and MedDRA System Organ Class (SOC). As a result of the analysis two signals were validated by AIFA. The signal CLS-Elasomeran was confirmed by the lead member state and determined the update of the Product Information (4).

Conclusion: Despite the high number of reports, coordination with the territory and continuous and enhanced surveillance, supported by an integrated group with different expertise (epidemiologist, pharmacist, medical doctors), have proved to be effective in safety monitoring of COVID vaccines.

References/Further Sources of Information

• 1. https://www.aifa.gov.it/sites/default/files/determina_vaccinovigilanza.pdf.

• 2. Santuccio C, Trotta F, Felicetti P, Ongoing Pharmacovigilance on vaccines. Pharmacol Res. 2015 Feb;92:2–5.

• 3. https://www.aifa.gov.it/en/rapporti-su-sorveglianza-dei-vaccini-covid-19.

• 4. https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-7-10-march-2022-prac-meeting_en.pdf.

2.137 P165 Pharmacovigilance Contribution During National Mass Immunization Days

2.137.1 S. Debbeche¹, G. Lakhoua ¹, O. Charfi¹, Y. Mahjoubi¹, R. Daghfous¹, S. E. Aidli¹

2.137.1.1 ¹Université Tunis El Manar/Faculté de Médecine de Tunis/Unité de recherche UR17ES12, Centre National Chalbi Belkahia de Pharmacovigilance/ Service de recueil et d'analyse des effets indésirables, Tunis, Tunisia

Introduction: Rapid vaccination rollout against COVID-19 is the current main solution to overcome the pandemic morbidity and mortality but also to restart economies [1]. In Tunisia, 8 mass vaccination days have reinforced the national strategy. During these days, pharmacovigilance provided a real time monitoring regarding therapeutic advices and Adverse Events Following Immunizations (AEFIs).

Objective: The objective of this study is to describe pharmacovigilance activities during these days.

Methods: This is a descriptive study. The reporting system was a combination of both passive and active surveillance. Notifications concerned therapeutic advices and adverse events following immunization (AEFI).

Results: We collected 855 reports among 3,423,884 vaccinated people during these 08-mass vaccination days, corresponding to an average of 25 reports per 100,000 administrated doses.

Reports of 720 AEFI’s were collected: 268 (37.2%) were collected from the passive monitoring and 313 (43.4%) from the active surveillance.

The passive surveillance reported 80% of vasovagal reaction, 19,3% vaccine errors and others notifications concerned cutaneous eruption, face swelling…

Vaccine errors (139) which occurred in 63.1% of cases during the 3rd National immunization day, concerned dilution errors, a double dose administration or errors in the vaccination pattern.

AEFIs active monitoring revealed vasovagal reactions in 96.8% of cases, an elevated blood pressure, cutaneous eruption...

The Pharmacovigilance team managed 135 therapeutic advices concerning history of drug reaction, previous vaccine reaction, comorbidities…

Conclusion: The specificity of these immunization days was the increase of vasovagal cases and vaccination errors. Therefore, health authorities should deploy necessary means to prevent avoidable AEFIS during mass vaccination days.

References/Further Sources of Information

Grech V, Souness J, and Agius S. Mass population vaccination for Covid-19 in Malta. Journal of Visual Communication in Medicine; 2021. https://doi.org/10.1080/17453054.2021.1920829.

2.138 P166 The Italian Approach to Improve Standard Quality of ICSRs for COVID 19 Vaccines: From Patient Data to Causality Assessment

2.138.1 P. Marchione¹, P. Felicetti¹, F. Petronzelli ², M. Marvulli¹, V. Saccomandi¹, M. Conte³, M. Guarducci³, G. Pimpinella², A. R. Marra³

2.138.1.1 ¹Italian Medicines Agency, Signal management Office, Rome, Italy; ²Italian Medicines Agency, Pharmacovigilance Office, Rome, Italy; ³Italian Medicines Agency, Post-marketing surveillance Area, Rome, Italy

Introduction: The COVID-19 pandemic determined a necessary reorganization of pharmacovigilance resources and strategies, particularly after vaccines authorization. Enhanced monitoring and quality of ICSRs is crucial for the causality assessment of the adverse events following immunization (AEFI) occurred in the COVID-19 vaccinated population [1].

Objective: To evaluate the effectiveness of enhanced Italian Pharmacovigilance activities during the first year of COVID-19 vaccination campaign on the quality of the ICSRs.

Methods: The Italian PharmacoVigilance System is a network connecting the Italian Medicine Agency (AIFA) to local health authorities [2]. The collected ICRSs were prioritized by seriousness, special interest and disproportionality and harmonized for coding and key information requirements. Further follow up information were requested to reporters from Local/Regional PhV Representatives or AIFA. Targeted templates tailored on Brighton Collaboration Group case definitions were implemented for adverse events of special interest (AESI) [3]. The percentage of completed ICSRs by fields and the rate of evaluable causality assessments by WHO causality assessment tool for AEFI [4] were used as indicators for descriptive analysis of effectiveness. Completeness of ICSRs was evaluated for the following AESI: anaphylaxis, Guillain-Barrè syndrome, peripheral facial palsy, vaccine-induced thrombotic thrombocytopenia, myocarditis and pericarditis.

Results: Between 26 December 2020 and 26 December 2021, 117.920 ICSRs were reported (98.717 not serious and 19.055 serious). Overall, patients’ demographic field were updated in 35% of ICSRs, with a total of 97,6% of cases with valid age and sex data. Suspected medicinal products section was modified in 11% of ICSRs with 91% of cases reporting batch number and administration date. Follow up was obtained in 26% of ICSRs (7% after AIFA request). Available information on seriousness and outcome was reported in 97,6% of cases. Time-to-onset was assessable in 95,2% of cases. Overall, causality assessment was applicable in 15.731/19055 (83%) of serious reports, only 751/15.731 (4,8%) of which was unclassifiable. Follow up information was not obtained in 831/3887 cases related to selected AESI (21%). Complete clinical data were available in the remaining 3056/3887 ICSRs (79%) and were used for BCG classification as cases (38%) or not cases (62%).

Conclusion: A harmonized approach to ICSR enhanced surveillance and management through a structured Pharmacovigilance network was effective in improving the quality of AEFI reports related to COVID-19 vaccines, resulting in a high percentage of cases with complete information.

References/Further Sources of Information

• 1. https://www.ema.europa.eu/en/documents/other/european-medicines-regulatory-network-covid-19-business-continuity-plan_en.pdf.

• 2. Santuccio C, Trotta F, Felicetti P, Ongoing Pharmacovigilance on vaccines. Pharmacol Res. 2015 Feb;92:2–5.

• 3. https://brightoncollaboration.us/category/pubs-tools/case-definitions/.

• 4. https://www.who.int/publications/i/item/9789241516990.

2.139 P167 COVID-19 Vaccination and Herpes Zoster/ Herpes Simplex Reactivation in Tthe Elderly Population: A Pharmacovigilance Analysis

2.139.1 V. Battini ¹, M. Gringeri¹, G. Mosini¹, G. Guarnieri¹, A. Bombelli¹, L. Bakir², S. Galbiati³, M. Zaccalà⁴, R. Folchino², V. Marangon³, S. Vecchio⁴, S. Radice¹, E. Clementi^1,5

2.139.1.1 ¹Università degli Studi di Milano, Department of Biomedical and Clinical Sciences, Milano, Italy; ²Agency for Health Protection ATS Milano, Pharmacy Department, Milano, Italy; ³Agency for Health Protection ATS Monza e Brianza, Pharmacovigilance Unit, Lecco, Italy; ⁴Health Protection Agency ATS Pavia, Unit of control of Territorial pharmaceutical and prosthetic Performances-HTA, Pavia, Italy; ⁵Scientific Institute, IRCCS E. Medea, Bosisio Parini, Italy

Introduction: After the primary infection, the reactivation of both Herpes Simplex viruses (HSV) and Varicella Zoster virus (VZV) is mainly triggered by a secondary immunodeficiency state, either age-related or iatrogenic, or due to concomitant diseases (e.g., HIV, cancer), especially in the elderly population [1–3]. Indeed, Herpes reactivation has not been commonly associated with immunization and only few cases are described in literature [4]. To date, HSV/VZV reactivation is listed in the Summary of Product Characteristics (SPC) of only one COVID-19 mRNA vaccine [5]. However, even if limited, evidence on a potential correlation between vaccines expressing the SARS-CoV-2 spike (S) glycoprotein and Herpes reactivation is increasing [6]. In Italy, elderly patients represent a population of particular interest for this specific adverse event (AE) since they are currently involved in the 4th booster campaign (which may not be the last one).

Objective: To investigate the occurrence of Herpes reactivation following COVID-19 vaccination of elderly patients (≥ 65 years old) who are going to be frequently vaccinated with this type of vaccines.

Methods: We present Individual Case Safety Reports (ICSRs) concerning COVID-19 vaccination and Herpes reactivation that were collected at our Pharmacovigilance Unit (Milan, Italy) from January 2021.

Results: So far, 21 ICSRs have been collected, 16 (76%) from ordinary citizens, mainly men (62%) and non-serious. Median age was 74 years (min-max: 65–89). Further analyses are ongoing.

Conclusion: Cases of interest were of non-serious nature and the estimated incidence of pharmacovigilance reports concerning Herpes reactivation was non-significant compared to the total number of Italian citizens who usually suffer from these conditions and to those who have been vaccinated. The vaccination remains strongly recommended. However, it is crucial that clinicians continue to monitor and report all suspected AEs in order to better characterize the safety profile of vaccines.

References/Further Sources of Information

• 1. Schmader K. Herpes zoster in older adults. Clinical infectious diseases. 2001;1481–6.

• 2. Tseng HF, Bruxvoort K, Ackerson B, Luo Y, Tanenbaum H, Tian Y, et al. The Epidemiology of Herpes Zoster in Immunocompetent, Unvaccinated Adults ≥ 50 Years Old: Incidence, Complications, Hospitalization, Mortality, and Recurrence. J Infect Dis. 2020 Aug;222(5):798–806.

• 3. Kawai K, Yawn BP, Wollan P, Harpaz R. Increasing Incidence of Herpes Zoster Over a 60-year Period From a Population-based Study. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2016 Jul;63(2):221–6.

• 4. Walter R, Hartmann K, Fleisch F, Reinhart WH, Kuhn M. Reactivation of herpesvirus infections after vaccinations? Vol. 353, Lancet (London, England). England; 1999. p. 810.

• 5. Spikevax-FDA Package Insert. Available from: https://www.fda.gov/vaccines-blood-biologics/spikevax.

• 6. Gringeri M, Battini V, Cammarata G, Mosini G, Guarnieri G, Leoni C, et al. Herpes zoster and simplex reactivation following COVID-19 vaccination: new insights from a vaccine adverse event reporting system (VAERS) database analysis. Expert Rev Vaccines. 2022 May;21(5):675–84.

2.140 P168 Menstrual Changes Following COVID-19 Vaccination: A Pharmacovigilance Study Based on Spontaneous Reports of Adverse Events Following Immunization (AEFI)

2.140.1 G. Mosini ¹, V. Battini¹, M. Gringeri¹, G. Guarnieri¹, A. Bombelli¹, L. Bakir², S. Galbiati³, M. Zaccalà⁴, R. Folchino², V. Marangon³, S. Vecchio⁴, C. Carnovale¹, S. Radice¹

2.140.1.1 ¹Università degli Studi di Milano, Unit of Clinical Pharmacology-Department of Biomedical and Clinical Sciences-"Luigi Sacco" University Hospital, Milan, Italy; ²Agency for Health Protection ATS Milan, Pharmacy Department, Milan, Italy; ³Agency for Health Protection ATS Monza e Brianza, Pharmacovigilance Unit, Lecco, Italy; ⁴Health Protection Agency ATS Pavia, Unit of control of Territorial pharmaceutical and prosthetic Performances-HTA, Pavia, Italy

Introduction: Vaccination remains the best option for the prevention and control of SARS-CoV2 infection, and a key topic of interest is its safety. Although many studies reported vaccine-related side effects, ranging from mild symptoms such as injection site pain, fever, headache, and fatigue to rare and serious side effects like anaphylaxis and thrombosis, their safety profile is overall acceptable [1;2]. Recently, given the increase of spontaneous reports of menstrual disorders with mRNA COVID-19 vaccines and sporadic observational studies from the scientific literature, the European Medicine Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) has decided to assess the causal link between these vaccines and menstrual changes [3].

Objective: To describe the occurrence of menstrual changes following the COVID-19 vaccination.

Methods: We collected Adverse Events Following Immunization (AEFI) related to menstrual changes after the COVID-19 vaccination received up until April 30th, 2022, at the Pharmacovigilance Unit of the Fatebenefratelli-Sacco Hospital and have performed a descriptive analysis.

Results: A total of 14 AEFI reporting menstrual changes following COVID-19 vaccines were analyzed. All patients were female, with a mean age of 26.5 years. Most cases were referred to the Comirnaty vaccine (85.7%), whereas 14.3% of cases were attributed to Spikevax. The most commonly reported events were amenorrhea and menstrual cycle abnormal, and 78.6% of cases were defined as nonserious.

Conclusion: The relationship between the occurrence of menstrual changes and COVID-19 vaccines has not been fully characterized yet. Our analysis provides additional evidence to the issue. Continuous monitoring of these events plays a key role in better characterizing the safety profile of COVID-19 vaccines.

References/Further Sources of Information

• 1. Muhaidat N, Alshrouf MA, Azzam MI, Karam AM, Al-Nazer M, Al-Ani A. Menstrual symptoms after COVID-19 vaccine: A cross-sectional investigation in the MENA region. International Journal of Women's Health. 2022 Mar; Volume 14:395–404.

• 2. Selected adverse events reported after COVID-19 vaccination [Internet]. Centers for Disease Control and Prevention. Available from: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/adverse-events.html.

• 3. Ema. Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 7–10 February 2022 European Medicines Agency [Internet]. European Medicines Agency. 2022. Available from: https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-7-10-february-2022.

2.141 P169 Risk Management Strategy to Promote the Uptake of COVID-19 Vaccination at a Tertiary Care Facility in Kenya

2.141.1 D. Aywak ¹, L. Okutoyi², J. Kinuthia³, A. Guleid⁴

2.141.1.1 ¹Kenyatta National Hospital, Pharmaceutical Services, Nairobi, Kenya; ²Kenyatta National Hospital, Healthcare Quality Division, Nairobi, Kenya; ³Kenyatta National Hospital, Research and Programs, Nairobi, Kenya; ⁴Kenyatta National Hospital, Affiliations and Institutional Development, Nairobi, Kenya

Introduction: An essential component of risk management strategy is effective risk communication, which includes range of communication capacities required to manage serious public health events from preparedness, response to recovery phase. Risk communication became even more vital in COVID 19 global health crisis and utilized in European countries in roll out of COVID vaccines, especially since vaccinations are not mandatory therefore public willingness must be high to achieve herd immunity in the population (1). Taking note of the unique authorization of pandemic vaccines, it implies that only limited safety and immunogenicity data is available when post marketing phase commences (2).

Objective: To describe a hospital initiative to promote COVID 19 vaccine uptake through safety monitoring and educational campaigns

Methods: We reviewed all Adverse Events Following Immunization (AEFI) reports from healthcare workers after administration of the COVID 19 vaccine reported to the Kenyatta National Hospital Pharmacovigilance system from 7th March 2021 to 30th September 2022. All reports were classified by age group, by system organ class and Preferred Term according to Medical Dictionary for Regulatory Activities Terminology and degree of seriousness. We identified the educational sessions held where: possible adverse events were described, channels of support and reporting were shared and, monitored the trend in reporting of AEFIs over the period of roll out of the first dose of vaccine.

Results: From the 11,773 vaccinations administered to healthcare workers during the period,328 AEFI reports were received all but 1 were categorized as non-serious AEFI events. The trend in AEFI events reported reduced markedly from 236 reported in first 2 weeks of campaign to 5 reports after 8 weeks of campaign. The weekly education sessions on COVID vaccines and vaccine vigilance reported attendance of 800 healthcare workers on average. The uptake of vaccines was reported to be high among healthcare workers as misinformation and concerns with regards to AEFIs was addressed.

Conclusion: Institutional initiatives for vaccine pharmaco-vigilance coupled with educational sessions, in a season where vaccine hesitancy was high, enable risk management for early COVID vaccine rollout in Kenya.

References/Further Sources of Information

• 1. Warren GW, Lofstedt R. COVID-19 vaccine rollout risk communication strategies in Europe: a rapid response. J Risk Res. 2021 Apr 3;24(3–4):369–79.

• 2. Parretta E, Ianniello B, Ferrazin F, Rossi F, Capuano A. Italian post-marketing surveillance for adverse event reports after MF59-adjuvanted H1N1v vaccination. Vaccine. 2011 May 9;29(20):3708–13.

2.142 P170 Cases of Guillan Barré Syndrome Following COVID-19 Vaccination

2.142.1 K. Berrim¹, G. Lakhoua¹, O. Charfi ¹, M. B. Belgacem¹, S. Kastalli¹, R. Daghfous¹, K. Zghal², S. E. Aidli¹

2.142.1.1 ¹Université Tunis el Manar Faculté de médecine de Tunis/Unité de recherche UR17ES12, Centre national Chalbi Belkahia de pharmacovigilance/ Service de recueil et d'analyse des effets indésirables, Tunis, Tunisia; ²Centre régional de pharmacovigilance de Sfax-3029 Sfax-Tunisie, Service Régional de Pharmacovigilance de Sfax-faculté de Médecine de Sfax. Université de Sfax., sfax, Tunisia

Introduction: Guillain-Barré Syndrome (GBS) is a rare immune system disorder that results in muscle weakness, pain or numbness, and, in severe cases, paralysis. GBS is usually due to infections, and occurs more frequently in males and persons over 50 years old [1]. Some cases were described following vaccination among them COVID-19 vaccines.

Objective: To describe features of COVID-19 vaccine-associated GBS.

Methods: We carried out a retrospective, descriptive study of GBS patients following COVID-19 vaccine, submitted to the World Health Organization (WHO) global adverse drug reaction database (VigiBase^®) from Tunisia during the period between march 2021 and May 2022. We extracted the data using VigiLyze^® software with the English version 25 of MedDRA to identify features of COVID-19 vaccine-associated GBS. In addition, we evaluated vaccine causality using the updated French causality assessment method [2].

Results: Overall, we retrieved 8 patients with GBS post COVID-19 vaccination: Men were representing 62.5% (5/3) of cases. The median age of affected patients was 59 (range: 41; 80) years. The most frequently reported vaccine type was followed in order by Comirnaty^® Pfizer-BioNTech vaccine (n = 3 reports [37.5%]), Vaxzevria^® AstraZeneca vaccine (n = 3 [37.5%]) and Janssen^® vaccine (n = 2 [25%]). The mean time interval from vaccination to symptom onset was 15.3 days (range 7-30 days). Four patients developed GBS after receiving the first dose of a COVID-19 vaccine, three after the second dose and one after the third dose. Clinical manifestations were different with varying severity: classical GBS [1] (progressive ascending limb weakness associated with reduced or absent reflexes) in 5 cases, and GBS with unilateral facial palsy in 3. In all cases, electromyography (EMG) studies were consistent with the demyelinating pathology of GBS. Cerebrospinal fluid (CSF) examination showed albuminocytologic dissociation in 3 cases, was normal in 3 and not done in 2. Five patients were treated with a course of intravenous immune globulin (IVIg) for five days and one patient received a total of 2 sessions of plasma exchange. In 2 patients the nature of the treatment was unknown. Six patients reported clinical improvement within 7–10 days while two showed treatment-related fluctuations (TRF).

Conclusion: Our observations suggest that COVID-19 vaccines may be associated with GBS. Continuous surveillance and further studies are warranted to assess the significance of the association.

References/Further Sources of Information

• 1. Shahrizaila N, Lehmann HC, Kuwabara S. Guillain-Barré syndrome. Lancet. 2021 Mar 27;397(10280):1214–1228.

• 2. Arimone Y, Bidault I, Dutertre J-P, et al. Updating the French method for the causality assessment of adverse drug reactions. Therapie. 2013;68:69–76

2.143 P172 Notoriety Bias in the Reporting of Adverse Events Following Immunization with COVID-19 Vaccines in the United States and Canada

2.143.1 P. Laurence^1,2, G. Castillon ¹, T. Cristarella¹, A. M. Castilloux¹, Y. Moride^1,3

2.143.1.1 ¹YolaRX Consultants, Pharmacoepidemiology & Risk Management, Montreal, Canada; ²Universite de Montreal, Pharmacy, Montreal, Canada; ³Rutgers The State University of New Jersey, Center for Pharmacoepidemiology and Treatment Science PETS, New Brunswick, USA

Introduction: The large-scale immunization with COVID-19 vaccines has brought safety surveillance to unprecedented levels. This context provides a unique opportunity to study the impact of communication on the reporting of adverse events following immunization (AEFIs), also known as notoriety bias.

Objective: To describe trends over time in the reporting of AEFIs with COVID-19 vaccines in the US and Canada following regulatory and major media communications, without implying causality.

Methods: Data sources were US VAERS and Canada Vigilance. Weekly reporting rates were estimated by vaccine type (mRNA vs. non-replicating viral vectors) using the number of doses administered in each country, and time trends were derived. Study period started on the date of availability of vaccines in each country until 24 December 2021 (VAERS) and 31 August 2021 (Canada Vigilance), last available updates. A rapid review was conducted to identify major communications on COVID-19 vaccine safety. The dates and contents of communications were compared to time trends in reporting rates, without making causal inferences.

Results: In the US, the risk of thrombosis associated with viral vector vaccines was covered by 5 major communications [13 April 2021, 2 warnings, 20 April 2021, 30 April 2021, 16 December 2021], which was followed by an increase in reporting rate of thrombotic events of 529.6% within 1 week after the first communication. There were 2 communications on thrombosis in Canada (16 March 2021, 13 May 2021) as well as 1 warning on capillary leak syndrome (29 June 2021). In Canada Vigilance, an increase in reporting rate of 452.5% was found almost 3 weeks prior to the publication of the first communication, which coincides with the date of release of the communication in the US. There was 1 major communication on the risk of pericarditis and myocarditis associated with mRNA vaccines in the US (24 June 2021) where an increase in reporting rate of 33.6% was observed less than 1 week before the warning. There were 2 communications in Canada (both on 30 June 2021) where the reporting rate of pericarditis and myocarditis for mRNA vaccines increased by 47.8% within 1 week following the communications. Changes in reporting rates were not observed for AEFIs not covered in communications. Observed trends were the same for reports submitted by health care providers and consumers.

Conclusion: The dramatic increase in reporting rate immediately after, or sometimes just before, the release of communications was likely due notoriety bias. There was no spillover effect to other AEFIs.

References/Further Sources of Information

Not applicable.

2.144 P173 Thromboembolic Events and COVID-19 Vaccine

2.144.1 R. Kammoun¹, S. Dabbeche¹, O. Charfi ¹, W. Daly¹, R. Daghfous¹, S. E. Aidli¹

2.144.1.1 ¹Université Tunis el Manar Faculté de médecine de Tunis/Unité de recherche UR17ES12, Centre national Chalbi Belkahia de pharmacovigilance/ Service de recueil et d'analyse des effets indésirables, Tunis, Tunisia

Introduction: Thromboembolic events (TE) are a major source of morbidity and mortality. Several risk factors have been associated to this condition such as age over 65 years, obesity, history of venous thromboembolism and hereditary thrombophilias [1]. Otherwise, TE have been associated with SARS-CoV-2 infection. Following the introduction of COVID-19 vaccines, these events were expected to decrease significantly [2]. However, some TE cases appeared after COVID-19 vaccination.

Objective: The aim of this study was to summarize all the cases of TE that occurred after COVID-19 immunization in Tunisia.

Methods: We conducted a retrospective study involving all cases of TE that occurred after COVID-19 vaccination, from the beginning of the campaign of immunization in March 2021 to May 2022. These cases were notified to the National Center of Pharmacovigilance, Tunisia.

Results: There were 25 cases of thrombotic events over about 12 million doses of vaccine. The mean age was 51.2±15,8 years. The sex ratio (M/F) was 1,27. Symptom onset occurred within 1 to 60 days. Both arterial and venous thrombotic events were reported. Venous thromboembolism was observed in 21 cases (84%). Deep vein thrombosis in 9 cases (36%), superficial vein thrombosis in 3 cases (12%), pulmonary embolism in 3 cases (12%) and the site of venous thrombosis was not specified in 6 cases (24%). Arteriel thromboembolism was reported in 4 patients: splenic infarction (1 case), thrombosis of the renal artery (1 case), thrombosis of the brachial artery (1 case) and femoral artery embolism (1 case). The TE were reported after the first shot in 72% of cases, after the second shot in 24% and after the third shot in one case (4%). The involved vaccines are summarized in table 1.

Investigations revealed risk factors for TE in 12 patients. There were: age over 65 years in 25% of cases, thrombophilia in 25%, thromboembolic events histories in 25%, varicose vein thrombosis in 16.7% and immobilization in 8.3% of cases. This data was not provided for the 13 other patients. The outcome was favorable in 19 patients, one patient died and 5 patients were lost to follow up. There were no cases of Thrombotic Thrombocytopenia syndrome.

Conclusion: Despite a temporal relationship, the vaccine responsibility cannot be retained given the patient’s medical histories.

References/Further Sources of Information

• 1. Wong P, Baglin T. Epidemiology, risk factors and sequelae of venous thromboembolism. Phlebol J Venous Dis 2012; 27: 2–11.

• 2. Afshar ZM, Barary M, Babazadeh A, Hosseinzadeh R, Alijanpour A, Miri SR, et al. SARS-CoV-2-related and Covid-19 vaccine-induced thromboembolic events: A comparative review. Rev Med Virol 2022; e2327: 1–12.

2.145 P174 Adverse Effects of Hydroxychloroquine in COVID-19 Patients—A Review of Eudravigilance Database

2.145.1 M. I. Marmé¹, C. Matos ¹

2.145.1.1 ¹Instituto Politécnico De Coimbra-ESTESC-Coimbra Health School, Farmácia, Coimbra, Portugal

Introduction: Hydroxychloroquine is an antimalarial drug that belongs to the 4-aminoquinolone group [1]. Despite of this properties presents several immunomodulatory and anti-inflammatory characteristics [1,2]. In 2020, with the emergence of the COVID-19 pandemic, researchers used existing drugs with potential for the treatment of COVID-19, including hydroxychloroquine, which ended up being used off-label [3,4]. From the clinical trials hydroxychloroquine has many adverse effects that can increase risk for the SARS-COV-2 patients health. Common adverse effects are related to gastrointestinal and cardiovascular systems, neurotoxicity and retinopathy [2,5].

Objective: The objective of this research was to describe the adverse effects profile of hydroxychloroquine in COVID-19 patients and to characterize the risks associated with off-label use of hydroxychloroquine.

Methods: An observational, retrospective and descriptive study was conducted. Information collected from the “Eudravigilance” database was analyzed using descriptive statistics with R Studio^® software. Information about the source of reporting, patient sex, serious adverse reactions, deaths and off-label cases and their outcome, were evaluated and compared in the pre- and post-pandemic period.

Results: The number of reports of adverse reactions to hydroxychloroquine increased significantly during the pandemic period (increase of 310.3%), with health professionals (92.0%) and woman (2020: 64%; 2021: 81%) reporting the most. The analysis of age groups allowed us to conclude that the 18-64 age group has the highest number of reported patients (2020: 49%; 2021: 53%). The off-label use of hydroxychloroquine was also an important aspect to consider in this study: in the period of 2020-2021, a total of 29.8% of suspected ADR have been caused by hydroxychloroquine in off-label use, with an important percentage of those being associated with COVID utilization (20.0%). Finally, deaths associated with the use of hydroxychloroquine were also evaluated, of which 67.0% are described in off-label use.

Conclusion: The number of reports of adverse reactions to hydroxychloroquine increased significantly during the pandemic. The potential for harm increased as off-label administration of hydroxychloroquine was associated with an increased incidence and severity of adverse reactions. However, associated with other drugs, this drug may potentiate certain adverse reactions, such as QT interval prolongation, nausea, dizziness, hypoglycaemia, heart failure, among others. Regarding outcomes, there seems to be an increase in the number of deaths associated with hydroxychloroquine, however causality has not been established for the observed data. Hydroxychloroquine presented varied adverse reactions in the observed data, and its off-label use during the pandemic showed an increase in its incidence.

References/Further Sources of Information

• 1. White NJ, Watson JA, Hoglund RM, Chan XHS, Cheah PY, Tarning J. COVID-19 prevention and treatment: A critical analysis of chloroquine and hydroxychloroquine clinical pharmacology. PLoS Med [Internet]. 2020;17(9):1–24. Available from: https://doi.org/10.1371/journal.pmed.1003252.

• 2. Pastick KA, Okafor EC, Wang F, Lofgren SM, Skipper CP, Nicol MR, et al. Review: Hydroxychloroquine and chloroquine for treatment of SARS-CoV-2 (COVID-19). Open Forum Infect Dis. 2020;7(4):1–9.

• 3. Garcia P, Revet A, Yrondi A, Rousseau V, Degboe Y, Montastruc F. Psychiatric Disorders and Hydroxychloroquine for Coronavirus Disease 2019 (COVID-19): A VigiBase Study. Drug Saf [Internet]. 2020;43(12):1315–22. Available from: https://doi.org/10.1007/s40264-020-01013-3.

• 4. World Health Organization. Off-label use of medicines for COVID-19. World Heal Organ [Internet]. 2020;(March):3–5. Available from: https://www.who.int/news-room/commentaries/detail/off-label-use-of-medicines-for-covid-19.

• 5. Yusuf IH, Sharma S, Luqmani R, Downes SM. Hydroxychloroquine retinopathy. Eye. 2017;31(6):828–45. Available from: https://doi.org/10.1038/eye.2016.298.

2.146 P175 Guillan-Barré Syndrome Following COVID-19 Vaccines: Analysis of the Vaccine Adverse Event Reporting System (VAERS) Database

2.146.1 M. Gaio ¹, A. Zinzi¹, C. Riccardi¹, N. Balzano¹, G.M. Sullo¹, L. Sportiello¹, C. Rafaniello¹, F. Rossi¹, A. Capuano¹

2.146.1.1 ¹Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine-University of Campania "L. Vanvitelli", Napoli, Italy

Introduction: As part of post-authorization safety surveillance, the European Medicines Agency (EMA) has identified a potential safety concern for Guillain-Barré syndrome (GBS) following COronaVIrusDisease 2019 (COVID-19) vaccines [1,2].

Objective: To assess reports of GBS reported in the Vaccine Adverse Event Reporting System (VAERS) following COVID-19 vaccination and to evaluate if a COVID-19 vaccine has a lower/higher probability of reporting Individual Case Safety Reports (ICSRs) with GBS in a direct comparison with all other COVID-19 vaccines.

Methods: After selecting all ICRSs of GBS following vaccination reported in VAERS from 1 January 2021 to 31 December 2021, we assessed them through the case definition and classification of the Brighton Collaboration (BC). We performed a descriptive analysis. Finally, we used the Reporting Odds Ratio with a 95% of Confidence Interval to investigate disproportional reporting of GBS among the vaccines included in the analysis.

Results: 774 ICSRs of GBS have been reported in VAERS, and 279 of them met the BC Case Definition: 30 (10.7%) have been evaluated as Definitive, 56 (20.0%) as Probable, and 193 (69.3%) as Possible. COVID-19 Vaccine Pfizer-BioNTech was the most commonly vaccine reported (N = 118; 42.3%) followed by COVID-19 Vaccine Moderna (N = 82; 29.4%) and COVID-19 Vaccine Janssen (N = 79; 28.3%). GBS was more commonly reported for male subjects (N = 143; 51.3%) aged between 12 and 20 years (N = 59; 21.1%). GBS mainly occurred between the 1st and 12th day following the first dose administration of mRNA vaccines and between the 4th and the 15th day following COVID-19 Vaccine Janssen. COVID-19 Vaccine Janssen was significantly associated with increased risks for Guillan-Barrè syndrome (ROR 3.47, CI 95% = 2.58–4.65) compared to COVID-19 Vaccine Pfizer-BioNTech and COVID-19 Vaccine Moderna.

Conclusion: GBS is an adverse event of special interest for all COVID-19 vaccines requiring specific safety monitoring. GBS is very rare, and the benefit-risk balance of the vaccine remains unchanged.

References/Further Sources of Information

• 1. European Medicine Agency. Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 3-6 May 2021. Available from: https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-3-6-may-2021.

• 2. European Medicine Agency. COVID-19 Vaccine Janssen: Guillain-Barré syndrome listed as a very rare side effect; 2021. Available from: https://www.ema.europa.eu/en/news/covid-19-vaccine-janssen-guillain-barre-syndrome-listed-very-rare-side-effect.

2.147 P176 Capillary Leak Syndrome and COVID-19 Vaccines: An Analysis of the European Spontaneous Reporting System EudraVigilance

2.147.1 R. D. Napoli ¹, R. Ruggiero¹, N. Balzano¹, A. Mascolo¹, C. Rafaniello¹, S. Liberata¹, F. Rossi¹, C. Annalisa¹

2.147.1.1 ¹University of Campania “Luigi Vanvitelli, Department of Experimental Medicine-Section of Pharmacology, Naples, Italy

Introduction: Recently, capillary leak syndrome (CLS) emerged as new suspected adverse event after immunization (AEFI) associated to COVID-19 vaccination. This condition is rare, but serious and potentially fatal [1].

Objective: Our pharmacovigilance study aims to evaluate the onset of CLS as AEFI with COVID-19 mRNA vaccines (Spikevax and Comirnaty) compared to viral vector vaccines (Janssen and Vaxzevria).

Methods: We carried out descriptive and disproportionality analyses of all Individual Case Safety Reports (ICSRs) reporting a vaccine COVID-19 as suspected drug and the CLS as AEFI, which were collected in the pharmacovigilance database EudraVigilance from January 1st, 2021, to January 14th, 2022. For the disproportionality analysis we applied the Reporting Odds Ratio (ROR) 95% CI.

Results: During study period, CLS was described as AEFI in 84 out of 1,357,962 ICRs reporting a vaccine COVID-19 as suspected drug and collected in the EV database.

Overall, the ICSR reported by CLS were mainly related to the viral vector COVID-19, Vaxzevria^®, (N = 36) and Janssen^®, (N = 9), while the ICSR reported to vaccines COVID-19 mRNA were 39 (Comirnaty^®, N = 33; Spikevax^®, N = 6). Majority of ICSRs were reported by healthcare professionals (N = 60; 71.4%). The non-healthcare professional represented the primary source in the 41.7% of Vaxzevria^® related ICSRs.

Majority of the patients were adult (N = 49; 58.3%). The female gender accounted in more than 65% of ICSRs referred both to mRNA and viral vector vaccines.

The CLS outcome was more frequently favorable in mRNA ICSRs (N = 13; 33,3%). On the other hand, among the ICSRs reporting CLS with unfavorable outcome (N = 25; 29.8%) we found 9 ICSRs describing fatal CLS (Comirnaty^® N = 1; Vaxzevria^® N = 4; Janssen^® N = 4).

From disproportionality analysis emerged a lower CLS reporting probability after COVID-19 vaccination with mRNA vaccines compared to viral vector-based ones.

Conclusion: According to our results, few ICSRs describing CLS have been collected in EV in front of billion administered doses. This could underline the rarity of this AEFI or the limit of underreporting of spontaneous reporting and therefore also our study. Since the significant clinical relevance of CLS, this AEFI requires a careful monitoring.

Healthcare professionals as well as patients should be aware of the signs and symptoms of CLS. Patients with a history of CLS require particular attention because of a possible risk of flare-up of disease. Since a precise mechanism is still not identified, further studies are necessary to confirm the causal relationship between CLS and COVID-19 vaccination.

References/Further Sources of Information

• 1. Siddall E, Khatri M, Radhakrishnan J. Capillary leak syndrome: etiologies, pathophysiology, and management. Kidney Int. 2017 Jul;92(1):37–46.

2.148 P177 European Safety Analysis of mRNA and Viral Vector COVID-19 Vaccines on Glucose Metabolism Events

2.148.1 G. D. Mauro ¹, A. Mascolo², M. Longo³, M. I. Maiorino³, L. Scappaticcio³, G. Bellastella³, K. Esposito³, A. Capuano¹

2.148.1.1 ¹Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine-University of Campania “Luigi Vanvitelli”, Naples, Italy; ²Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine-University of Campania “Luigi Vanvitelli”, Naples, Italy; ³Division of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences-University of Campania “Luigi Vanvitelli”, Naples, Italy

Introduction: COVID-19 is a complex disease with several clinical phases of progression, affecting many organs apart from the respiratory tract that has shown a worst prognosis in both patients with type 1 and type 2 diabetes mellitus [1]. Based on these considerations, the vaccination for COVID-19 is a priority for this subpopulation [2]. However, few data have been published on the effects of impaired glucose metabolism induced by COVID-19 vaccines.

Objective: We decided to perform a study to describe Individual Case Safety Reports (ICSRs) of impaired glucose metabolism events reported in the European database (Eudravigilance, EV).

Methods: ICSRs were retrieved for the period from January 1st, 2021 to December 11th, 2021. An ICSR related to events of impaired glucose metabolism was identified by using selected preferred terms (PTs) from Standardized MedDRA Queries “Hyperglycaemia/new onset diabetes mellitus” and “Hypoglycaemia”. Impaired glucose metabolism events were described and analyzed based on the Dia-betologists’ classification into nine groups: “diabetes in pregnancy”, “acute complications of diabetes”, “pre-diabetes”, “type 1 diabetes mellitus”, “type 2 diabetes mellitus”, “high glucose levels”, “diabetes mellitus inadequate control”, “diabetes melli-tus not specified”, and “hypoglycaemia”. The reporting odds ratios were computed to assess the reporting frequency for COVID-19 mRNA vaccines compared to COVID-19 viral vector-based vaccines.

Results: During the study period, 3,917 ICSRs with a COVID-19 vaccine as suspected and at least an event of impaired glucose metabolism were retrieved from the EV, of which 2,027 (51.75%) referred to Pfizer-BioNTech vaccine, 586 (14.96%) to Moderna vaccine, 1,163 (29.70%) to Oxford-AstraZeneca vaccine, and 141 (3.59%) to Janssen vaccine. From 3,917 ICSRs, we observed 4,275 impaired glucose metabolism events (1.09 adverse events per ICSR). Most adverse events were classified as serious (2,694; 63.02%), and the most reported events were related to “high glucose levels” (2,012; 47.06%). The mRNA vaccines were associated with an increased reporting frequency of “type 1 diabetes mellitus” (ROR 1.86; 95% CI 1.33–2.60), “type 2 diabetes mellitus” (ROR 1.58; 95% CI 1.03–2.42), “high glucose levels” (ROR 1.16; 95% CI 1.06–1.27), “diabetes mellitus inadequate control” (ROR 1.63; 95% CI 1.25–2.11), and “hypoglycemia” (ROR 1.62; 95% CI 1.41–1.86) compared to viral vector-based vaccines. The highest reporting rate per 100,000 was observed for Oxford-AstraZeneca vaccine (1.87; 95% CI 1.77–1.97).

Conclusion: In conclusion, mRNA COVID-19 vaccines were associated with an increased reporting frequency of alterations of glucose homeostasis compared to viral-vector COVID-19 vaccines. Clinicians should be aware of these events to better manage glycaemic perturbations. Larger nationwide studies are warranted to verify these findings.

References/Further Sources of Information

• 1. Liu, Z.; Bai, X.; Han, X.; Jiang, W.; Qiu, L.; Chen, S.; Yu, X. The association of diabetes and the prognosis of COVID-19 patients: A retrospective study. Diabetes Res. Clin. Pract. 2020, 169, https://doi.org/10.1016/J.DIABRES.2020.108386.

• 2. Powers, A.C.; Aronoff, D.M.; Eckel, R.H. COVID-19 vaccine prioritisation for type 1 and type 2 diabetes. Lancet Diabetes Endocrinol. 2021, 9, 140–141, https://doi.org/10.1016/S2213-8587(21)00017-6.

2.149 P178 Safety of mRNA-Platform based Covid-19 Vaccines in Pediatric Population: An Analysis of the European Pharmacovigilance Database Eudravigilance

2.149.1 R. Ruggiero ¹, C. Pentella¹, A. Mascolo¹, M. Gaio¹, G. d. Mauro¹, C. Scavone¹, L. Sportiello¹, F. Rossi¹, A. Capuano¹

2.149.1.1 ¹University of Campania Luigi Vanvitelli, Department of Experimental Medicine L. Donatelli, Naples, Italy

Introduction: Recently mRNA-based COVID-19 vaccines have been approved also for use in pediatric population. Vaccines safety require particular attention in this population. Analysis of pharmacovigilance database allows to extrapolate important information to identify possible safety signals.

Objective: Our pharmacovigilance study aims to describe and evaluate the onset of adverse events following immunization (AEFIs) with COVID-19 mRNA vaccines in the pediatric population.

Methods: We retrieved all pediatric Individual Case Safety Reports (ICSRs) collected in the European pharmacovigilance database, Eudravigilance from the 01/01/2021 to 4/03/2022 related to Spikevax and Comirnaty. We carried out a disproportionality analysis (Reporting Odds Ratio-95% CI) to compare the reporting probability of some AEFIs of interest (seizure, pericarditis, myocarditis, multisystem inflammatory syndrome (MIS), menstrual disorders, failure and anaphylactic shock) between Comirnaty and Spikevax.

Results: We retrieved in Eudravigilance 25.019 ICSR related to Comirnaty describing a total of 75.040 AEFIs and 1.862 ICSRs referred to Spikevax reporting overall 5.361 AEFIs occurred in pediatric population. Majority of ICSRs reported well-known general disorders (headache, pyrexia, fatigue and nausea) for both mRNA vaccines. ICSRs were more frequently referred the adolescent patients (Comirnaty, 86.2%; Spikevax, 86.4%). We found a slight prevalence of female gender for both mRNA vaccine (Spikevax, 52.6 %; Comirnaty 53.9%). Reproductive system disorders were more frequently referred to females. In particular, these events included menstrual disorders (N = 609, Comirnaty; N = 23, Spikevax), amenorrhoea (N = 408, Comirnaty; N = 16, Spikevax) or intermenstrual bleeding (N = 169, Comirnaty; N = 10, Spikevax), polymenorrhoea (N = 172, Comirnaty; N = 10, Spikevax). Few cases described reproductive system disorders in males, mainly related to Comirnaty. These AEFIs included testicular pain (N = 14, Comirnaty; N = 1, Spikevax), erectile dysfunction (N = 5, Comirnaty), testicular torsion (N = 4, Comirnaty) or swelling (N = 4, Comirnaty), scrotal pain (N = 3, Comirnaty) or oedema (N = 1, Comirnaty). Outcome of AEFIs was unknown in 14.8% and 21.1% cases for Spikevax and Comirnaty, respectively. AEFIs had a favorable outcome in more than 50% of cases for both mRNA vaccines, including a complete resolution (30%) or an ongoing resolution (20%). From disproportionality analysis emerged a statistically significant ROR for menstrual disorders (ROR 1.72, 95% CI 1.43–2.10; p < 0.05), failure (ROR 8.11, 95% CI 5.05–13.97; p < 0.05) and seizure (ROR 1.54, 95% CI 1.03–2.41; p = 0.037) when compared Comirnaty versus Spikevax.

Conclusion: Majority of pediatric AEFIs are mild and with a positive outcome, supporting the role of ongoing COVID-19 vaccination campaign in this population as a critical public health tool for disease prevention and control of pandemic. Further investigations are needed in this population.

References/Further Sources of Information

Kamidani S, Rostad CA, Anderson EJ. COVID-19 vaccine development: a pediatric perspective. Curr Opin Pediatr. 2021 Feb 1;33(1):144–151. https://doi.org/10.1097/MOP.0000000000000978. PMID: 33278108.

2.150 P179 Pharmacovigilance Among Patients from the Perspective of Pharmacists: A Survey Study in Morocco

2.150.1 O. Oullada ¹, M. Benali², T. Amina³, S. Rachida⁴, A. Ahmed², R. Said²

2.150.1.1 ¹National Higher School of Electricity and Mechanics-ENSEM-Hassan II University of Casablanca-B.P: 8118 Oasis-Casablanca-Morocco. Laboratory of Mechanics-Production and Industrial Engineering-LMPGI-Higher School of Technology of Casablanca-ES, Laboratory of Mechanics-Production and Industrial Engineering-LMPGI, Casablanca, Morocco; ²Laboratory of Mechanics-Production and Industrial Engineering-LMPGI-Higher School of Technology of Casablanca-ESTC-Hassan II University of Casablanca-B.P 8112 Oasis-Casablanca-Morocco., Laboratory of Mechanics-Production and Industrial Engineering-LMPGI-Higher School of Technology of Casablanca-ESTC-Hassan II University of Casablanca-B.P 8112 Oasis-Casablanca-Morocco., Casablanca, Morocco; ³Center Anti Poison et de Pharmacovigilance du Maroc-Rue Lamfedel Cherkaoui-Rabat Institutes-Madinate Al Irfane-B.P. 6671-Rabat 10100-Morocco, Pharmacovigilance, Rabat, Morocco; ⁴Managing Director at Centre Anti Poison et de Pharmacovigilance du Maroc, Managing Director at Centre Anti Poison et de Pharmacovigilance du Maroc, Rabat, Morocco

Introduction: Patient reporting of adverse drug reactions (ADRs) could supplement the existing reporting system of the Moroccan Pharmacovigilance Poison Control Center (CAPM) and contribute to the early detection of ADRs, which are important causes of morbidity and mortality worldwide.

Objective: This study is considered the first study in the region it was conducted to assess the knowledge, attitude, notification, and practice of pharmacovigilance among patients during the COVID-19 period, through pharmacists of the DRAA-TAFILALET region in Morocco. In order to model the impact of Good Pharmacovigilance Practices over the COVID-19 period on pharmacist’s reactivity to pharmacovigilance.

Methods: It was a questionnaire-based cross-sectional study devoted to 120 pharmacists in the DRAA-TAFILALET region. Using latent variable structural modeling by the partial least squares (PLS) method via the XLSTAT software (version 2017).

Results: A total of 120 pharmacists completed and returned the questionnaire. The reliability of the measurement was > 0.7, which allows us to test the internal and external validity of our conceptual model. Nine hypotheses were validated, against two invalid derivative hypotheses. The results obtained allow us to propose areas for improvement and action plans to be taken into account by the Moroccan strategy of pharmacovigilance.

Conclusion: Spontaneous ADRs reporting is the cornerstone of any pharmacovigilance system to maintain patient safety. Indeed, it is necessary first to initiate all healthcare professionals to report through training and secondly to inform the general public of the availability of a national pharmacovigilance center where they can report an ADR, in order to keep the culture of ADR reporting perennial.

References/Further Sources of Information

• 1. https://www.capm-sante.ma/uploads/documents/BPPV.pdf Good Practice of Pharmacovigilance-Poison Control and Pharmacovigilance Moroccan Center (Accessed Jan.23,2022)

• 2. D. Thomas and S. Zachariah, Knowledge, Attitude, and Practice of Pharmacovigilance in Developing Countries. Elsevier Inc., 2018.

• 3. P. Inácio, A. Cavaco, and M. Airaksinen, “The value of patient reporting to the pharmacovigilance system: a systematic review,” Br. J. Clin. Pharmacol., vol. 83, no. 2, pp. 227–246, 2017, https://doi.org/10.1111/bcp.13098.

• 4. L. Hazell, V. Cornelius, P. Hannaford, S. Shakir, and A. J. Avery, “How do patients contribute to signal detection?: A retrospective analysis of spontaneous reporting of adverse drug reactions in the UK’s yellow card scheme,” Drug Saf., vol. 36, no. 3, pp. 199–206, 2013, https://doi.org/10.1007/s40264-013-0021-2.

• 5. W. W. Chin, “The partial least squares approach for structural equation modeling.,” Mod. methods Bus. Res., no. April, pp. 295–336, 1998

• 6. M. Ben Ali, S. Rifai, O. Bouksour, and S. Barrijal, “Understanding the impact of quality practices on firm performance: insights from a structural equation modeling study of young manufacturing enterprises in Tetouan, Morocco,” Int. J. Qual. Innov., vol. 4, no. 3/4, p. 189, 2019, https://doi.org/10.1504/ijqi.2019.105759.

2.151 P180 Vogt-Koyanagi-Harada Uveitis Following Covid-19 Vaccine

2.151.1 M. Daldoul¹, G. Lakhoua¹, A. Zaiem¹, W. Kaabi¹, R. Daghfous¹, S. E. Aidli ¹

2.151.1.1 ¹Université Tunis el Manar Faculté de médecine de Tunis/Unité de recherche UR17ES12, Centre national Chalbi Belkahia de pharmacovigilance/ Service de recueil et d'analyse des effets indésirables, Tunis, Tunisia

Introduction: Vogt-Koyanagi-Harada (VKH) syndrome is a multisystem condition with chronic, bilateral, non-necrotizing, granulomatous panuveitis and exudative retinal detachment (1). It is a very rare adverse event of vaccination, and cases of VKH disease following Covid-19 vaccine have rarely been reported so far [1-3].

Objective: Herein, we report a case of VKH disease following mRNA-1273 (SpikeVax^®) COVID-19 vaccination.

Methods: This case was notified in November 2021 to the National Centre of Pharmacovigilance and evaluated according to the updated French method of causality assessment.

Results: A 33-year-old female patient with a medical history of renal failure and without any history of ophthalmic disease, received her second dose of SpikeVax^® on August 20, 2021. Four days later, she experienced headache and fatigue and subsequently developed bilateral blurred vision seven days following the vaccination. The evolution was marked by the persistence of symptoms and a decreased bilateral visual acuity a week later. Ophthalmologic examination showed an aqueous flare, keratic precipitates, iris nodules and cells in the anterior vitreous in both eyes work up ruled out systemic infection or autoimmune disease. ANCA were negative. ACE levels were normal. Serology test for HBV, HIV, syphilis and mycobacterium tuberculosis were also negative. A VKH syndrome was diagnosed. One month after treatment with oral prednisolone and mycophenolate mofetil, the evolution was favorable without any sequels.

Conclusion: Although there is a chronological relation between the onset of VKH and the SpikeVax^®, the role of vaccination couldn’t be certainly assessed.

References/Further Sources of Information

• 1. Saraceno, J.J.F., Souza, G.M., dos Santos Finamor, L.P. et al. Vogt-Koyanagi-Harada Syndrome following COVID-19 and ChAdOx1 nCoV-19 (AZD1222) vaccine. Int J Retin Vitr 7, 49 (2021).

• 2. De Domingo B, López M, Lopez-Valladares M, Ortegon-Aguilar E, Sopeña-Perez-Argüelles B, Gonzalez F. Exacerbation de la maladie de Vogt-Koyanagi-Harada associée au vaccin COVID-19. Cellules. 2022;11(6):1012. Publié le 16 mars 2022.

• 3. Joo CW, Kim YK, Park SP. Vogt-Koyanagi-Harada Disease following mRNA-1273 (Moderna)COVID-19 Vaccination. Ocul Immunol Inflamm. 2022 Apr 11:1–5.

2.152 P182 Pattern of Adverse Effets of COVID-19 Vaccine Among the People of Bangladesh

2.152.1 E. Sharmin ¹, S. Ahmed², M. Haque³, A. Khan⁴, A. Azim⁵, S. Ahmed⁶

2.152.1.1 ¹Bangabandhu Sheikh Mujib Medical University, Pharmacology-Associate Professor, Dhaka, Bangladesh; ²Bangabandhu Sheikh Mujib Medical University, Community Opthalmology, Dhaka, Bangladesh; ³Bangabandhu Sheikh Mujib Medical University, Paediatric, Dhaka, Bangladesh; ⁴Bangabandhu Sheikh Mujib Medical University, Medicine, Dhaka, Bangladesh; ⁵Community medical college, Anatomy, Dhaka, Bangladesh; ⁶Bangabandhu Sheikh Mujib Medical University, Cardiology, Dhaka, Bangladesh

Introduction: Since the WHO classified COVID-19 a pandemic, vaccines have been developed to minimize the SARS-CoV-2 virus's incidence around the world. [1] For better understanding of the safety and effectiveness of the vaccines the identification of the localized and systemic side-effects after vaccination is important because the side effects between in a real-world community setting than reported in phase 3 trials, mostly minor in severity, and self-limiting. [2-5]

Objective: To identify pattern of adverse effects of covid-19 vaccine among the people of Bangladesh.

Methods: This follow up study was conducted among 2345 vaccinated people at Bangabandhu Sheikh Mujib Medical University from June 2021 to December 2021. Data was collected by face to face and telephone interviewing through a structured questionnaire for 7 days daily for local effect and upto 28 days for systemic side effects after vaccination and SPSS software version 25.0 was used for statistical analysis

Results: Among the total participants 2345, Most of the people were male 1565 (66.7%). 17.1% of people had local side effects. About 33.1% participants were experienced systemic side effects. Among the local side effects pain was more common and chill and shiver in systemic effects respectively 14.3% and 2%. About 89.1% participants were with co morbidity. Male were predominant and middle aged were more than older people.

Conclusion: This study portrayed a precise scenario about the adverse effects of vaccine. The adverse effects of vaccine should be evidence based. Further education and research needed to encourage on evidenced based vaccination among the people. This was generated information for the clinical care providers to take necessary steps as a precaution in treating the adverse effects of any patients and the policy makers to take necessary steps in related to vaccine to handle this pandemic.

References/Further Sources of Information

• 1. Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, and Fouchier RA. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med. 2012; 367: 1814–20.

• 2. Wang, MD, Jolly, AM. Changing virulence of the SARS virus: The epidemiological evidence. Bull World Health Organ. 2004; 82:547–8.

• 3. Centers for Disease Control and Prevention: Disease burden of influenza. Available at: https://www.cdc.gov/flu/about/burden/index.html. Accessed March 4, 2020.

• 4. C. van den Dool, M.J. Bonten, E. Hak, J. Wallinga, Modeling the effects of influenza vaccination of health care workers in hospital departments, Vaccine. 27 (44) (2009) 6261–6267, https://doi.org/10.1016/j.vaccine.2009.07.104.

• 5. CDC, Food and Drug Administration. Vaccine Adverse Event Reporting System. VAERS Form. Available from: http://www.vaers.org. (Last accessed on 2012 Feb 04).

2.153 P187 Ecchymotic Plaques Induced by Spikevax: About 2 Cases

2.153.1 I. Bouaziz¹, R. Atheymen¹, M. Ksentini¹, R. Sahnoun¹, H. Affes¹, K. Ksouda¹, S. Hammami¹, K. Zghal ¹, l. B. Mahmoud¹

2.153.1.1 ¹Regional pharmacovigilance service of Sfax-pharmacology laboratory., Faculty of Medicine-University of Sfax., Sfax, Tunisia

Introduction: Several post-vaccination adverse events (AEFI) have been reported after anti-COVID 19 vaccine SPIKEVAX^® administration. By the way, we can mention cutaneous manifestations (1).

Objective: We report 2 cases of women who presented ecchymotic skin plaques after vaccination with SPIKEVAX^® notified in the Regional Pharmacovigilance Service of Sfax.

Methods: The assessment of the causal link was made according to the method of the World Health Organization.

Results: Two women, with no previous medical history, presented ecchymotic skin patches after SPIKEVAX^®(Moderna) vaccination. Platelet and D-dimer levels were normal in both cases. But an immunological assessment was not requested. The first woman was 33 years old. She presented 2 days after the first dose of the vaccine generalized ecchymotic plaques which measured 7 cm of diameter and was located on the right flank. These plaques persisted for one month before disappearing. The second woman was 26 years old, she presented 20 days after the second dose of the vaccine, 3 ecchymotic plaques on one thigh followed. Two days later, another plaque was appeared on the other thigh. These lesions were associated with myalgias in the lower limbs and headaches and disappears after 2 months. A probable causal link was established in these patients.

Conclusion: The ecchymotic plaques in our patients may suggest vascular involvement particularly a vasculitis. Few cases have been reported with anti-COVID 19 vaccination (1).

References/Further Sources of Information

• 1. AZD1222 vaccine‐related coagulopathy and thrombocytopenia without thrombosis in a young female. Eileen Ryan et al ;2021 Aug;194(3):553–556. https://doi.org/10.1111/bjh.17530. Epub 2021 May 25.

2.154 P188 Pharmacovigilance Before and After COVID-19 Pandemic: A 3-Years Analysis of Adverse Drug Reactions Reporting at the University Hospital of Catania

2.154.1 S. Brancati¹, R. Ruscica¹, L. Gozzo², L. Longo¹, D.C. Vitale¹, F. Drago ²

2.154.1.1 ¹Clinical Pharmacology Program/Regional Pharmacovigilance Centre, Clinical Pharmacology Program/Regional Pharmacovigilance Centre, Catania, Italy; ²University of Catania, Biomedical and Biotechnological Sciences, Catania, Italy

Introduction: COVID-19 pandemic has dramatically affected healthcare systems, as well as everyday life worldwide [1,2]. Pharmacovigilance has definitely had a central role in this context of emergency, for both new and old molecules being investigated as potential treatments for COVID-19, but above all for the monitoring of COVID-19 vaccines [3].

Objective: The aim of this study was to investigate how COVID-19 pandemic has changed the adverse drug reactions (ADRs) reporting at the University Hospital of Catania.

Methods: We performed a descriptive analysis of individual case safety reports (ICSRs) collected in the Italian National Pharmacovigilance Network by the University Hospital of Catania from January 2019 to December 2021. Data were compared in terms of number of reports per year, patient characteristics, treatments, severity of reactions, and type of reporter.

Results: Overall, the number of ICSRs collected was 1,664, 463 in 2019, 590 in 2020 and 611 in 2021 (Figure 1). In the majority of cases, ADRs have involved female subjects in the 18–65 years age group (mean age 49 years). Most cases were classified as not serious (81%); nevertheless, reports of serious ADRs progressively raised from 13.2% in 2019 to 16.6% in 2020 and 25% in 2021. In 2019 and 2020 almost all ICSRs were spontaneously sent by physicians, while in 2021 a greater reporting by citizens (13.9%), pharmacists (11.1%) and other health care professionals (3.8%) has been observed. Adalimumab represented the most frequently reported suspected drug in 2019 and 2020, with the highest number of ICSRs concerning lack of therapeutic response (77% and 92.5%, respectively). In 2021 the number of ADRs caused by vaccines has dramatically risen, from zero in 2019–2020 to 251 in 2021, as a consequence of COVID-19 vaccination campaign (tozinameran 32.6%). Most of ICSRs concerned general and administration site conditions (68.8%), with fever being the most frequently reported ADR (29.1%). Tozinameran was also associated with the highest number of serious ADRs (n = 34) in 2021.

Conclusion: This study showed that COVID-19 outbreak did not have a significant impact on ADRs reporting until the introduction of COVID-19 vaccines. It is noteworthy that treatments for COVID-19 were not listed among the suspected drugs, although the high number of patients treated in our institution during 2020 and 2021. It will be useful to investigate the possible underlying reasons (lack of ADR? difficulty in distinguishing ADR from the disease? lack of time in an emergency situation?) with healthcare professionals directly involved in the treatment of COVID-19.

References/Further Sources of Information

• 1. Wang C et al. Transduct Target Ther 2021

• 2. Moynihan R et al. BMJ Open 2021

• 3. AIFA. Accessed on May 2022. http://www.aifa.gov.it/en/farmacovigilanza-vaccini-covid-19.

2.155 P189 Adverse Drug Reactions Associated with Anti-Infective Agents Reported to the National Pharmacovigilance Centre in Saudi Arabia: A Descriptive Study

2.155.1 G. Alshehri ¹, R. Alshammari¹, R. Alkahtani¹, R. Alsaggabi¹, W. Almuteri¹, S. Bahakeem², A. Alghamdi¹, M. Fouda²

2.155.1.1 ¹Princess Noura Bint Abdularahman University, Pharmacy Practice Departemnt, Riyadh, Saudi Arabia; ²Saudi Food and Drug Authority, Benefit-Risk Evaluation Department, Riyadh, Saudi Arabia

Introduction: Adverse Drug Reactions (ADRs) are among the leading causes of mortality and morbidity worldwide [1]. International organisations such as the World Health Organisation (WHO) [2] has recognised the need for detecting, assessing and understanding ADRs in order to ensure safe drug use. In Saudi Arabia (SA), the National Pharmacovigilance Center (NPC) within the Saudi Food and Drug Authority (SFDA) has been responsible for collecting, analysing and learning from ADRs reported in SA, allowing it to contribute to the global effort to minimise ADRs [3]. A recent study has analysed around17,730 ADRs reported to NPC in the period between 2015 and 2017 which found that anti-infective agents were most commonly involved with ADRs (22.27%) [4]. Whilst informative, these reports were not analysed extensively in terms of their composition, seriousness, and patient group commonly involved in these ADRs. The present study, however, presents an updated and a more extensive review of anti-infective agents involved with ADRs over the period between 2018 and 2020.

Objective: The aim of this study is to analyse and characterise ADRs associated with anti-infective agents reported to the NPC within the SFDA between the years 2018 and 2020.

Methods: A retrospective review was carried out of all ADRs involved with anti-infective agents submitted to the NPC between 2018 and 2020. A descriptive analysis was undertaken to determine the number of ADRs, and then to characterise them according to their Medical Dictionary for Regulatory Activities (MedDRA) classification, age and gender of patients involved, as well as seriousness and type of anti-infective class(es) involved. The SFDA's Ethics Committee has exempted this study from formal ethical approval.

Results: A total of 12,567 ADRs were included, of which 53.78% occurred in males. Among all age groups, adults between the age of 45 and 64 were the ones most reported (10.89%). The most reported ADRs were classified according to the MedDRA in terms of investigations (26.76%), gastrointestinal disorders (22.76%), as well as skin and subcutaneous tissue disorders (14.88%). The level of seriousness was not specified in 91.47% of the reports. Almost two percent of ADRs were reported to require intervention to prevent permanent damage followed by ADRs that resulted in prolonged hospitalisation (1%). Antibacterials were commonly reported (83.5%), followed by antiviral (10.9%), and antifungal medications (3.8%).

Conclusion: This is the first study to characterise ADRs associated with anti-infective agents. Our study showed that these anti-infective agents pose a threat to patient safety in our health care system.

References/Further Sources of Information

• 1. Beijer H, De Blaey C. Hospitalisations caused by adverse drug reactions (ADR): a meta-analysis of observational studies. Pharmacy World and Science. 2002;24(2):46–54.

• 2. https://apps.who.int/iris/bitstream/handle/10665/42493/a75646.pdf [Last accessed May 2021]. 2002.

• 3. Alharf A, Alqahtani N, Saeed G, Alshahrani A, Alshahrani M, Aljasser N, et al. Saudi vigilance program: challenges and lessons learned. Saudi pharmaceutical journal. 2018;26(3):388–95.

• 4. Yousef NB, Yenugadhati N, Alqahtani N, Alshahrani A, Alshahrani M, Al Jeraisy M, et al. Patterns of adverse drug reactions (ADRs) in Saudi Arabia. Saudi Pharmaceutical Journal. 2022;30(1):8–13.

2.156 P190 Post-marketing Safety of Onasemnogene Abeparvovec and Nusinersen in Pediatric Population: Analysis of FAERS Database

2.156.1 A. Zinzi ¹, M. Gaio¹, G. d. Mauro¹, C. Pentella¹, V. Liguori¹, N. Balzano¹, C. Rafaniello¹, F. Rossi¹, A. Capuano¹

2.156.1.1 ¹Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine-University of Campania “Luigi Vanvitelli”, Napoli, Italy

Introduction: Spinal muscular atrophy (SMA) is a degenerative neuromuscular disorder recognized as the most common genetic cause of infantile mortality described so far [1]. Food and Drug Administration (FDA) approved two new treatments in SMA: nusinersen, the first new oligonucleotide-based drug targeting the central nervous system, and onasemnogene abeparvovec, the first gene therapy approved to treat children less than two years of age [2,3].

Objective: A post-marketing evaluation of the safety of onasemnogene abeparvovec and nusinersen through the analysis of the FDA Adverse Event Reporting System (FAERS) database with a focus on the pediatric population (0–17 years).

Methods: Data on Individual Case Safety Reports (ICSRs) reported in children (0–17 years) were retrieved from the FAERS database for the period January 2017–December 2021. A descriptive analysis was performed, and characteristics of all ICSRs, including the reported drugs and events, were described and stratified by drugs and age groups. Moreover, cases with fatal outcomes were investigated as a sub-analysis. All data manipulation and statistical analysis were performed using R Statistical Software.

Results: We included 2,263 pediatric ICSRs (48.0% females and 68.1% from United States). The median age was 3.0 years. 59.8% was submitted through expedited (15-days) (65%) or periodic reporting (39.4%) and 0.8% by non-manufacturers. A total of 63.2% of all ICSRs were serious and 10.2% had a fatal outcome. The most frequent reported System Organ Classes (SOCs) were “Infections and Infestations” (N = 572), “General disorders” (N = 542), and “Investigations” (N = 511). The most commonly Preferred Terms (PT) were pyrexia (N = 214), vomiting (N = 169), and headache (N = 132). In sub-analysis, a fatal outcome was reported in 121 male (52.9%) and infants (59.9%) with a median age of 1.0 years. The adverse events more frequently reported as cause of death was cardio-respiratory arrest (3.7%), respiratory failure (3.6%), cardiac arrest (3.3%) and pneumonia (3.0%).

Conclusion: Onasemnogene abeparvovec and nusinersen demonstrated a favorable long-term benefit-risk profile in real-world context. Since only a few years of marketing is available, further followed-up studies need to be performed to investigate the longer-term safety of onasemnogene abeparvovec and nusinersen.

References/Further Sources of Information

• 1. Lee S, Lee YJ, Kong J, et al. Short-term clinical outcomes of onasemnogene abeparvovec treatment for spinal muscular atrophy. Brain Dev. 2022;44(4):287–293.

• 2. U.S. Food and Drug Administration (FDA). Spinraza (nusinersen); 2016. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-spinal-muscular-atrophy.

• 3. U.S. Food and Drug Administration (FDA). Zolgensma (onasemnogene abeparvovec); 2019. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease.

2.157 P191 Risk Communication: Ethionamide Mediated Gynecomastia

2.157.1 D. Mwesigwa ¹

2.157.1.1 ¹National Drug authority of Uganda, Directorate of Product safety and in the Pharmacovigilance Unit, Kampala, Uganda

Introduction: Gynaecomastia is defined as enlargement of male breast due to benign enlargement of the duct tissue and periductal stroma in the male breast. It can be bilateral and symmetrical or unilateral or asymmetrical. For reasons unknown, unilateral gynecomastia seems to be more common on the left side (1). But for the cases in Uganda, the breast tissue swelling was bilateral. Unlike headache, dizziness, asthenia, and paraesthesia that are labelled common side effects, gynaecomastia is mentioned in the product summary characteristics of Ethionamide as a `Not Known` undesirable effect. This is because it is an ADE that was identified post approval use of the drug.

Objective: To characterize a rare reaction to a commonly used drug for MDR-TB.

Methods: This is a case series presentation of retrospective data from the Ugandan pharmacovigilance database.

Results: There are 8 cases of gynaecomastia, experienced by male clients of mean age 43.625 years taking Ethionamide for treatment of multidrug resistant TB that have been reported to the National Drug Authority.

Conclusion: Usually there is no requirement for treatment of gynaecomastia. However, with the known information, early detection of gynaecomastia and withdrawal of the medication is critical among patients using Ethionamide as the condition usually causes discomfort and embarrassment to some clients thus affecting their quality of life (7). We also recommend that endocrinological and biochemical investigations including LFTs and TFTs should be carried out in order to rule out systemic causes.

References/Further Sources of Information

• 1. Dixit R, George J, Sharma AK, chhabra N, Jangir SK, Mishra V. Ethionamide-induced gynecomastia. J Pharmacol Pharmacother [Internet]. 2012 Apr [cited 2021 Nov 3];3(2):196. Available from: /pmc/articles/PMC3356967/

• 2. Banerjee SN, Ta RK, Mallick MS, Munda MK. Ethionamide-induced gynecomastia: A rare case report. Egypt J Bronchol 2017 111 [Internet]. 2017 Jan 24 [cited 2021 Nov 3];11(1):70–3. Available from: https://link.springer.com/articles/10.4103/1687-8426.198998.

• 3. Braunstein G. Gynecomastia. N Engl J Med [Internet]. 1993 Feb 18 [cited 2021 Nov 3];328(7):490–5. Available from: http://www.nejm.org/doi/abs/10.1056/NEJM199302183280708.

• 4. Carlson H. Gynecomastia. N Engl J Med [Internet]. 1980 Oct 2 [cited 2021 Nov 3];303(14):795–9. Available from: http://www.nejm.org/doi/abs/10.1056/NEJM198010023031405.

• 5. Bansal PKS and R. Gynecomastia caused by ethionamide [Internet]. [cited 2021 Nov 3]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3480805/.

• 6. Dixit R, George J, Sharma AK, Chhabra N, Jangir SK, Mishra V. Ethionamide-induced gynecomastia. J Pharmacol Pharmacother [Internet]. 2012 [cited 2021 Nov 4];3(2):196–9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356967/.

• 7. Fruhstorfer BH, Malata CM. A systematic approach to the surgical treatment of gynaecomastia. Br J Plast Surg [Internet]. 2003 [cited 2021 Nov 4];56(3):237–46. Available from: https://pubmed.ncbi.nlm.nih.gov/12859919/.

2.158 P192 Signal of Congestive Cardiomyopathy in Association with Olanzapine—Evidence Review from Pharmacovigilance Data

2.158.1 A. Alakeel ¹, M. Fouda¹, A. Almutairi¹, R. Alamri¹

2.158.1.1 ¹Saudi Food and Drug Authority, Pharmacovigilance Center, Riyadh, Saudi Arabia

Introduction: Olanzapine is atypical antipsychotic. The drug’s mechanism of action is not fully understood. It mainly mediates its antipsychotic action via dopamine and serotonin type 2 (5HT2) antagonism [1]. Congestive Cardiomyopathy (a.k.a. Dilated Cardiomyopathy) is a type of cardiomyopathy characterized by structural modifications of myocardium. Due to these modifications, abnormal stretching and dilation of heart chambers results in reduced pumping activity of heart muscle. Patients with Congestive Cardiomyopathy may remain symptom-free for unspecified period of time and then experience sharp deterioration in cardiac functions suddenly [2].

Objective: The aim of this review is to evaluate the risk of Congestive Cardiomyopathy associated with the use of Olanzapine and to suggest regulatory recommendations if required.

Methods: Signal Detection team at SFDA performed a signal review using National Pharmacovigilance Center (NPC) database, and World Health Organization (WHO) database, VigiBase, with literature screening to retrieve all related information to assess the causality between congestive cardiomyopathy and olanzapine use. The search conducted on August 26^th, 2021.

Results: Case Review: Signal detection team at SFDA have searched Saudi national database and WHO database to find individual case safety reports (ICSRs) of congestive cardiomyopathy associated with olanzapine. While the search resulted in zero reported local cases, the search in the WHO database resulted in 20 global case-reports. The authors used signal detection tool (Vigilyze) to retrieve all reported cases [3]. Authors also applied WHO-UMC causality assessment criteria on ICSRs with completeness score (0.5) and above (n = 9). Among them, 6 cases of congestive cardiomyopathy were possibly linked to olanzapine.

Literature: A scientific literature search was performed for olanzapine and risk of congestive cardiomyopathy. We found a case of 28-year-old male patient with bipolar disorder suffered congestive cardiomyopathy after taking olanzapine for 10 years was published in 2016 [4].

Datamining: The disproportionality of the observed and the expected reporting rate for drug/adverse drug reaction pair is estimated using information component (IC), a tool developed by WHO-UMC to measure the reporting ratio. Positive IC reflects higher statistical association while negative values indicates less statistical association, considering the null value equal to zero. The results of (IC = 1.4) revealed a positive statistical association for the drug/ADR combination.

Conclusion: The weighted cumulative evidence identified from local and global cases is sufficient to suggest causal association between olanzapine and congestive cardiomyopathy. Despite the need for a more thorough review of safety data to confirm the risk, health care professionals should be aware of the potential risk in drug recipients.

References/Further Sources of Information

• 1. Beasley CM, Tollefson G, Tran P, Satterlee W, Sanger T, Hamilton S. Olanzapine versus Placebo and Haloperidol—Neuropsychopharmacology. Nature 1996. https://www.nature.com/articles/1380403.

• 2. Dilated cardiomyopathy. Dilated Cardiomyopathy—ScienceDirect 2017. https://doi.org/10.1016/S0140-6736(16)31713-5.

• 3. Vigilyze.who-umc.org. 2021. [online] Available at: <https://vigilyze.who-umc.org/> [Accessed 4/January/2022].

• 4. Theodore P. Olanzapine Induced Dilated Cardiomyopathy -. PubMed Central (PMC) 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976704/.

2.159 P193 Isotretinoin Associated Risk of Blood Growth Hormone Decrease-Signal Review

2.159.1 A. S. Almutairi ¹, M. I. Fouda¹, A. Alaqeel¹, R. M. Alamri¹

2.159.1.1 ¹SFDA, National Pharmacovigilance Center, Riyadh, Saudi Arabia

Introduction: Isotretinoin is a form of vitamin A used to treat acne. It is the only therapy that has an impact on all of the major etiological factors implicated in acne [1]. Adults with growth hormone deficiency (which may result from problems with the pituitary gland or hypothalamus) may have symptoms including: poor bone density and osteoporosis, reduced muscle mass, fatigue, depression, and poor memory [2].

Objective: To assess the risk of blood growth hormone decrease associated with isotretinoin and, if necessary, make regulatory recommendations

Methods: The Signal Detection team at SFDA performed a signal review using the National Pharmacovigilance Center (NPC) database and the WHO database, VigiBase, with literature screening to retrieve all related information to assess the causality between blood growth hormone decrease and isotretinoin use. The search was conducted on November 11th, 2021. The disproportionality of the observed and the expected reporting rates for drug/adverse drug reaction pair was estimated using an information component (IC), a tool developed by WHO-UMC to measure the reporting ratio. Positive IC reflects higher statistical association, while negative values indicate less statistical association.

Results: Case Review: A search in the NPC database and WHO database (Vigibase) was conducted to retrieve all reported cases. There were five global ICSRs found, but no local ICSRs. The Signal Detection team applied the WHO-UMC causality assessment tool to all cases. 1 case was found supportive of the association, and 4 cases lacked the necessary information to assess causality.

Datamining: The results of (IC = 2.7) revealed a positive statistical association for the drug/ADR combination.

Literature: In 2015, a pre-and post-exposure study was published. The effects of various isotretinoin dosing regimens on pituitary hormones in drug recipients were studied. Blood samples were taken before the start of treatment and three months later. Growth hormone levels were found to be significantly lower (p = 0.002) [3].

Conclusion: The weighted cumulative evidence identified from global cases, literature and datamining is sufficient to suggest a causal association between isotretinoin and a decrease in blood growth hormone. Despite the need for a more thorough review of safety data to confirm the risk, health care professionals should be aware of the potential risk in drug recipients and monitor signs of blood growth hormone decrease.

References/Further Sources of Information

• 1. Layton A, Dreno M. A review of the European Directive for prescribing systemic isotretinoin for acne vulgaris—PubMed. PubMed 2006. https://pubmed.ncbi.nlm.nih.gov/16898895.

• 2. Bergan-Roller H, Sheridan M. The Growth Hormone Signaling System: Insights into Coordinating the Anabolic and Catabolic Actions of Growth Hormone—ScienceDirect 2017. https://www.sciencedirect.com/science/article/pii/S0016648017302824?via%3Dihub.

• 3. Karadag AS, Takci Z, Ertugrul DT, Bilgili SG, Balahoroglu R, Takir M. The Effect of Different Doses of Isotretinoin on Pituitary Hormones—Abstract—Dermatology 2015, Vol. 230, No. 4—Karger Publishers. The Effect of Different Doses of Isotretinoin on Pituitary Hormones—Abstract—Dermatology 2015, Vol 230, No 4—Karger Publishers 2015. https://www.karger.com/Article/Abstract/375370.

2.160 P194 Pfizer-BioNTech COVID-19 Vaccine Associated Risk of Olfactory Hallucinations-Signal Review

2.160.1 A. S. Almutairi¹, M. I. Fouda ¹, A. Alaqeel¹, R. M. Alamri¹

2.160.1.1 ¹SFDA, National Pharmacovigilance Center, Riyadh, Saudi Arabia

Introduction: Pfizer-BioNTech Covid-19 vaccine is highly purified single-stranded messenger RNA (mRNA) produced using a cell-free in vitro transcription from the corresponding DNA templates indicated for preventing coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]. Olfactory hallucination is a condition in which a person perceives odors that aren't present. Some might notice the odor in just one nostril, while others have it in both [2].

Objective: The purpose of this review is to assess the risk of olfactory hallucinations from the Pfizer-BioNTech Covid-19 vaccine and, if necessary, make regulatory recommendations.

Methods: The Signal Detection (SD) team at SFDA performed a signal review using the National Pharmacovigilance Center (NPC) database and World WHO database, VigiBase, with literature screening to retrieve all related information to assess the causality between olfactory hallucinations and Pfizer-BioNTech Covid-19 vaccine use. The search was conducted on January 4th, 2022.

The disproportionality of the observed and the expected reporting rates for drug/adverse drug reaction pair was estimated using an information component (IC), a tool developed by WHO-UMC to measure the reporting ratio. Positive IC reflects higher statistical association, while negative values indicate less statistical association.

Results: Local Cases: The SD team at SFDA has searched the NPC database for individual case safety reports (ICSR) reporting olfactory hallucinations in association with the Pfizer-BioNTech COVID-19 vaccine. The search resulted in one ISCR and, on the basis of WHO-UMC causality assessment criteria, olfactory hallucinations were considered probably associated with the vaccine.

Global Cases: A search was conducted in the WHO database (Vigibase) to retrieve all reported cases using a signal detection tool (Vigilyze) [3]. The search yielded 59 ICSRs. The signal detection team applied the WHO-UMC causality assessment tool on cases with a completeness score of (0.8) and above (n = 13). 11 cases were found supportive of the association, with 10 being probable and one being possible.

Literature: Late November 2021, a case report of a 57-year-old woman seeking medical care after complaining of "smelling smoke" after receiving her second dose of the vaccine was published [4].

Datamining: The results of (IC = 1.9) revealed a positive statistical association for the vaccine/ADR combination.

Conclusion: The weighted cumulative evidence identified from local and global cases is sufficient to suggest a causal association between the Pfizer-BioNTech COVID-19 vaccine and olfactory hallucinations. While a more thorough review of safety data is needed to confirm the risk, health care professionals should be aware of the risk that could happen after vaccination.

References/Further Sources of Information

• 1. BioNTech Manufacturing GmbH (2021), Canada Monograph of (PFIZER-BIONTECH COVID-19 VACCINE); (retrieved from: https://covid-vaccine.canada.ca/info/pdf/pfizer-biontech-covid-19-vaccine-pm1-en.pdf).

• 2. GmbH, Redaktion Deutsches &Auml;rzteblatt D &Auml;rzteverlag. Classic Phantosmia (09.10.2020). Deutsches rzteblatt, https://doi.org/10.3238/arztebl.2020.0689a.

• 3. Vigilyze.who-umc.org. 2021. [online] Available at: <https://vigilyze.who-umc.org/> [Accessed 4/January/2022].

• 4. Unique Imaging Findings of Neurologic Phantosmia Following Pfizer-BioNtech COVID-19 Vaccination: A Case Report. Topics in Magnetic Resonance Imaging. LWW, https://journals.lww.com/topicsinmri/Fulltext/2021/06000/Unique_Imaging_Findings_of_Neurologic_Phantosmia.2.asp.

2.161 P195 Effect of Direct Healthcare Professional Communication on Citalopram and Escitalopram

2.161.1 U. Köberle ¹, R. Grohmann², M. Belz³, W. Greil⁴, U. G. Remy¹, D. Degner³

2.161.1.1 ¹Drug Commission of the German Medical Association, Pharmacovigilance, Berlin, Germany; ²Ludwig-Maximilians University, Department of Psychiatry, Munich, Germany; ³University Medical Center, Department of Psychiatry, Göttingen, Germany; ⁴Sanatorium Kilchberg, Psychiatric Private Hospital, Kilchberg-Zürich, Switzerland

Introduction: In 2011, the US Food and Drug administration informed on the dose dependent QTc-prolonging effect of citalopram¹. In Germany, direct healthcare professional communication letters (DHPC) were sent out to inform on the cardiac risk associated with citalopram and escitalopram administration. As regulatory measures the maximum daily dose of citalopram and escitalopram was restricted, in the summary of product characteristics QTc-prolonging co-medication was stated as contraindicated^2,3.

Objective: To analyze the effect of the DHPC in inpatients with the diagnosis of an anxiety disorder by using data from the project “Arzneimittelsicherheit in der Psychiatrie e.V.” (AMSP).

Methods: AMSP is a multicenter pharmacovigilance project in which adverse drug reactions of psychotropic drugs are documented. Data on drug utilization is recorded in participating psychiatric hospitals on two days per year (reference dates)⁴. Data from 2004-2010 (pre-DHPC) and 2013-2017 (post-DHPC) were used to examine whether both (1) the proportion of patients treated with a higher than the newly recommended maximum daily dose of citalopram or escitalopram and (2) the proportion of patients with QTc-prolonging co-medication (according to the German SPC) declined post-DHPC. Adult inpatients with anxiety disorders treated with citalopram or escitalopram were included in this analysis. Dose levels and co-medication were screened. Citalopram and escitalopram were evaluated together.

Results: From 1993 to 2017, data of 67.000 patients in total were recorded on reference dates. In this analysis, 364 patients with anxiety disorders treated with citalopram or escitalopram were identified pre-DHPC, 262 post-DHPC. Demographic data pre- and post-DHPC did not differ. The proportion of patients exceeding the recommended daily dose decreased from 10.7 to 5.4 % (p = 0.019). The proportion of patients with QTc-prolonging co-medication remained unchanged (54.7 vs. 51.5 %, p = 0.437).

Conclusion: As in previous studies on different patient populations, the proportion of patients with anxiety disorders exceeding the newly recommended maximum daily dose declined significantly while the proportion of patients with QTc-prolonging co-medication remained unchanged. Precise instructions such as recommendations regarding the reduced maximum daily dose are obviously easier to implement than the introduction of a contraindication with regard to the simultaneous administration of any, but not specified, QTc-prolonging drug.

In conclusion, information on drug risks should be precise and formulated clearly. As far as possible, advice for specific clinical situations should be given. This could facilitate the appropriate implementation of regulatory guidance on drug use in clinical practice.

References/Further Sources of Information

The data presented here are based on the master's thesis of UK. A manuscript with the full publication is submitted to Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz

• 1. U.S. Food and Drug Administration (FDA). FDA Drug Safety Communication: Abnormal heart rhythms associated with high doses of Celexa (citalopram hydrobromide): https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-abnormal-heart-rhythms-associated-high-doses-celexa-citalopram (letzter Zugriff: 29.08.2020). Silver Spring, 24. August 2011.

• 2. Lundbeck GmbH. Wichtige Arzneimittelinformation für medizinisches Fachpersonal: Zusammenhang von Cipramil^® (Citalopramhydrobromid/Citalopram-hydrochlorid) mit dosisabhängiger QT-Intervall-Verlängerung. Rote-Hand-Brief vom 31.10.2011.

• 3. Lundbeck GmbH. Wichtige Arzneimittelinformation für medizinisches Fachpersonal: Zusammenhang von Escitalopram (Cipralex^®) mit dosisabhängiger QT-Intervall-Verlängerung. Rote-Hand-Brief vom 05.12.2011.

• 4. Grohmann R, Engel RR, Ruther E, Hippius H. The AMSP drug safety program: methods and global results. Pharmacopsychiatry. 2004;37 Suppl 1:S4-11.

2.162 P196 Regulatory Action Following Dextromethorphan Misuse in Adolescents in the Czech Republic

2.162.1 V. Deščíková ¹, J. Kopecká¹, L. Kovářová¹

2.162.1.1 ¹State Institute for Drug Control, Pharmacovigilance department, Prague 10, Czech Republic

Introduction: In 2017, Czech regulatory authority (SUKL) was contacted by non-healthcare professionals (non-HCP) who reported concerns about adolescents abusing dextromethorphan (DXM) tablets to achieve psychogenic effects. Therefore, SUKL sought for HCP confirmation. Co-operation with psychiatrists and toxicology centre (TIS) revealed the extent of the problem and misuse of DXM tablets was confirmed as serious concern.

The recommended therapeutic DXM dosage is 15-30 mg every 4 hours. The four dose-dependent levels of abuse are described: feelings of stimulation (100–200 mg), hallucinations, euphoria (200–400 mg), impaired motoric functions (400–600 mg) and strong dissociative effects (over 600 mg). (1,2)

Objective: To describe the national regulatory action in 2017 based on reported cases of DXM misuse and its update.

Methods: Due to active pharmacovigilance and intensive co-operation in field, a total of 113 serious reports of misuse were captured within few months (May–July 2017). Reports identified two risk groups-adolescents and young adults (mainly 12-24 years) and psychiatric patients.

To decrease the risk of DXM abuse, urgent action was required. After thorough assessment, switch of solid forms of monocomponent DXM products from OTC to Rx mode (prescription only) was considered the most appropriate regulatory action. DXM monocomponent syrups and polycomponent tablets and syrups for cough treatment remained OTC available with request for periodic safety reports from MAHs (6-monthly, annually, with 3-years period). Following Rx switch in August 2017, intensive communication was initiated including: DHPC (3), web announcement (4), ADR bulletin (5), scientific publication (6), participation at local psychiatrists’ conferences.

Results: Update in 2022: Rx switch led to withdrawal of both solid monocomponent DXM products authorised in CZ. Moreover, 2 polycomponent syrups were withdrawn, out of 12 DXM products authorised in 2017. The analysis of reports in Q2 2017–Q1 2022 (n = 47) showed listed ADRs in therapeutic doses of DXM (n = 11), unintended exposure to children (n = 4), historical literature cases (n = 6) and cases of misuse reported retrospectively from TIS (n = 26). Few comments from DXM abusers of syrup followed by gastrointestinal ADRs with no or little psychogenic effect were identified in non-scientific discussions (2). The public exposure to DXM has been successfully limited and no new reports of misuse were identified in SUKL database.

Conclusion: This topic shows the importance of spontaneous reporting to the authority which enables strict regulatory action and thus provided useful feedback to HCP to enhance the reporting of ADRs. Rx switch led to desired effect on significant decrease in DXM misuse.

References/Further Sources of Information

• 1. American Addiction Centers [Internet]. Dextromethorphan (DXM) Abuse: Addiction Signs, Symptoms & Treatment, Last Updated: February 22, 2022 [cited 2022 May 05]; Available from: https://americanaddictioncenters.org/dextromethorphan-dxm/abuse.

• 2. Infodrogy—Dextrometorfan [Internet]. [cited 2022 April 12]; Available from: https://infodrogy.estranky.cz/clanky/dextrometorfan--dxm-.8.html [in Czech]

• 3. State Institute for Drug Control [Internet]. DHPC (Direct Healthcare Professional Communication). Prague, The Institute, 2017. [cited 2022 May 05]; Available from: https://www.sukl.cz/leciva/informacni-dopis-dextromethorfan-stopex-na-suchy-kasel-30-mg [in Czech]

• 4. State Institute for Drug Control [Internet]. Web announcement on Rx switch. Prague, The Institute, 2017. [cited 2022 May 05]; Available from: https://www.sukl.cz/stopex-na-suchy-kasel-30-mg-tablety-a-meddex-vicks-pastilky [in Czech]

• 5. State Institute for Drug Control [Internet]. Information Bulletin on ADRs. Prague, The Institute, 2017. [cited 2022 May 05]; Available from: https://www.sukl.cz/sukl/informacni-zpravodaj-nezadouci-ucinky-leciv-3-2017 [in Czech]

• <