18th ISoP Annual Meeting “Pharmacovigilance without borders” Geneva, Switzerland, 11–14 November, 2018

ABSTRACTS

18th ISoP Annual Meeting

“Pharmacovigilance without borders”

Geneva, Switzerland

11–14 November, 2018

1 International Society of Pharmacovigilance

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

ISoP aims to promote the use of all types of information and methodologies in providing optimal drug treatment for patients. The Society is not only for clinical pharmacologists, pharmaceutical industry representatives, epidemiologists and regulators, but also for practising clinicians, other healthcare professionals and anyone else who is interested in learning about better ways for patients to receive and use medicines safely.

Countries where there are ISoP members:

From Argentina to Vietnam, from countries in South-America to North-America, from Europe to Asia and Australia via 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.’’

Sten Olsson, President of the International Society of Pharmacovigilance.

ISoP Membership incentives include:

• Biannual newsletters (ISoP Star)

• Training workshops

• Reduced fees for Annual Meeting and training courses

• Discounted online subscription to the Drug Safety journal

• Other offers/discounts on books

• Involvement in ISoP’s Chapters and Special Interest Groups

For more information you can 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 2018 Local Organising Committee

Chair: Victoria Rollason, University Hospitals of Geneva (Switzerland)

Mario Bertazzoli, Helsinn Healthcare Lugano (Switzerland)

Marie Besson, University Hospitals of Geneva (Switzerland)

Jules Desmeules, University Hospitals of Geneva (Switzerland)

François Girardin, University Hospitals of Geneva (Switzerland)

Roseline Ing Lorenzini, University Hospitals of Geneva (Switzerland)

Christian Lovis, University Hospitals of Geneva (Switzerland)

David Niedrig, University Children’s Hospital Zurich and drugsafety.ch (Switzerland)

Frédérique Rodieux, University Hospitals of Geneva (Switzerland)

Stefan Russmann, Klinik Hirslanden Zürich and drugsafety.ch (Switzerland)

Caroline Samer, University Hospitals of Geneva (Switzerland)

ISoP 2018 Scientific Committee

Chairs: Ian C K Wong, University of Hong Kong and UCL School of Pharmacy (UK)

Mira Harrison-Woolrych (New Zealand)

Victoria Rollason, University Hospitals of Geneva (Switzerland)

Pia Caduff, Uppsala Monitoring Centre (Sweden)

Bruce Donzanti, Genentech, Inc (USA)

Noha Iessa, WHO (Switzerland)

Ambrose Isah, University of Benin City (Nigeria)

Richard Hill, Therapeutic Goods Administration (Australia)

Gurumurthy Parthasarathi, JSS University Mysore (India)

Mónica Tarapués, Central University of Ecuador (Ecuador)

Lynn Zhou, Sanofi (China)

ISoP 2018 Poster Prize Committee

Chair: Pia Caduff, Uppsala Monitoring Centre (Sweden)

Caroline Samer and Marco Tuccori

ISoP Executive Committee and Advisory Board 2016–2019

Sten Olsson, President (Sweden)

Ian C K Wong, Vice-President (UK)

Mira Harrison-Woolrych, Secretary General (New Zealand)

Jean-Christophe Delumeau, Treasurer (Singapore)

Board Members

Hilda Ampadu, Africa/Education and Training Programme (Ghana)

Brian Edwards, Coordinator Chapters (UK)

Deirdre McCarthy, Coordinator Special Interest Groups (USA)

Jan Petracek, America/Education and Training Programme (Czech Republic)

Phil Tregunno, Asia/Education and Training Programme (UK)

Marco Tuccori, Europe/Education and Training Programme (Italy)

Hervé Le Louët, Past-President (France)

Disclaimer

ISoP requests that a high standard of science is followed concerning publications and presentations at all its Annual Meetings 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 official scientific meetings.

It is not within the remit of ISoP, the Advisory Board, the EC or Scientific Committees in particular, 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, e.g., reporting requirements or regulatory actions.

2 O-001 Measuring the Impact of Medication Errors on Public Health: What are the Right Parameters and Criteria?

2.1 R. Soulaymani^*1, G. Benabdallah¹

2.1.1 ¹CAPM WHO CC, Rabat, Morocco

Background/Introduction: A medication Error (ME) is an unintended failure in the treatment process that leads to, or has the potential to lead to, harm to the patient^1,2 and a preventable adverse drug reaction is an injury that is the result of an error at any stage of the treatment process³. These 2 definitions seem to highlight the close relation between ME and adverse drug reactions.

Health injuries due to preventable ADRs are often responsible for hospitalizations, additional length of stay and healthcare costs which are estimated between US$ 6 billion to US$ 29 billion per year^4,5. The burden of ME has been highlighted with the results of the IOM⁶ report which revealed that ME were responsible for 7000 death per year in USA. In LMICs, the probability of patients being harmed is higher than it is in developed countries.

The particularity of ME with serious harm is that they could have legal consequences leading to law impact for healthcare professionals and health institutions.

Objective/Aim: The aim of our presentation is to determine the right parameters and criteria needed to measure the impact of ME on public health through a review of available data at the international level and through the long and efficient experience of the Centre Antipoison et de Pharmacovigilance du Maroc in the field of pharmacovigilance and the integration of medication errors as part of adverse drug reactions (ADRs).

Methods: Literature review of available data related to the assessment of the impact of medication errors on public health.

Results: It is difficult to define the limits between ADRs and MEs because in many cases MEs are preventable ADRs and then lead to overlapping, yet it can be confusing and underappreciated concept. The detection and analysis of medication errors are not well integrated in all PV systems. Furthermore, assessing the impact of medication errors on public health remains a challenge (using of specific tools as pharmaco-epidemiology studies and pharmaco-economy) even for systems leaders in medication errors management.

Conclusion: To be able to assess the impact of ME on public health, Pharmacovigilance Centres need to have an overall view of medication errors data and to develop a close collaboration with patient safety organizations, Poison Control Centres and hospitals that use specific methods to detect any failure in the systems. How are these methods efficient and sufficient to?

References:

• 1. Ferner RE, Aronson JK. Clarification of terminology in medication errors: definitions and classification. Drug Saf 2006;29(11):1011–22

• 2. Goedecke T, Ord K et al., Medication errors: New EU good practice guide on risk minimisation and error prevention. Drug Saf 2016;39(6):491–500

• 3. Reporting and learning systems for medication errors: the role of pharmacovigilance centres: terminology and definitions: consensus during the Delphi survey: http://apps.who.int/medicinedocs/fr/m/abstract/Js21625en/

• 4. Hug BL, Keohane C, Seger DL, Yoon C, Bates DW. The costs of adverse drug events in community hospitals. Jt Comm J Qual Patient Saf 2012; 38(3):120–6

• 5. Bates, David W.; Spell, Nathan; Cullen, David J., et al. The costs of adverse drug events in hospitalized patients. JAMA 1977; 277:307–11

• 6. Kohn LT, Corrigan JM, Donaldson MS. To err is human: building a safer health system. Institute of Medicine (US) Committee on Quality of Health Care in America; Washington (DC): National Academies Press (US); 2000

Disclosure of Interest: None declared.

3 O-002 Opportunities and Pitfalls When Measuring Harm Reduction Through Pharmacovigilance Activities

3.1 A. Kant^*1, L. Peters², H. Gardarsdottir³, F. van Hunsel¹

3.1.1 ¹Pharmacovigilance Centre Lareb, Den Bosch, the Netherlands; ²Master Student, Graduate School of Life Sciences, Utrecht University, the Netherlands; ³Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

Background/Introduction: Pharmacovigilance (PV) activities aim to reduce harm by better use of medicines and promote public health. Assessing the impact of PV actions on public health at population level is an area currently under-investigated [1, 2]. Determining and measuring the right outcomes can be challenging and complicated due to lack of publically available data. Measuring impact should not only include an assessment of the intended but also take into account unintended effects and other simultaneous events such as changes in clinical practice, or secular trends in health outcomes.

Objective/Aim: To investigate the feasibility of measuring impact of pharmacovigilance activities based on publically available data in the Netherlands.

Methods: Five different identified safety risks related to use of medicines were assessed.

• 1. thrombotic risk due to (off-label) use of Diane-35 (cyproterone/ethinyloestradiol)

• 2. pergolide and bromocriptine and the risk of cardiac valvulopathy

• 3. proton pump inhibitors and the risk of hypomagnesaemia

• 4. rosiglitazone withdrawal due to cardiovascular effects

• 5. valproate and the risk of congenital abnormalities and developmental disorders

Assessment was done using the following approach:

• a. Based on the information on the safety signal and following pharmacovigilance actions a definition of impact on health was formulated for each signal;

• b. based on this pre-defined definition of impact of  the specific PV activities, data on change of health were searched in publically available data sources;

• c. If not available, data were searched needed to estimate the impact on health: data on change in use of the medicine or other safety measurements concerning the use of the medicine and the AR or RR of the safety issue.

For b. and c. also other factors that could have influenced the health outcomes were taken into account.

The feasibility of pre-defining a definition of impact, and the public availability of the needed data were evaluated.

Results: Determining the definition of the impact was feasible. However, measuring or estimating the impact was hampered by a lack of publically available data both on outcomes and drug use. For some safety signals (2, 4) it was challenging to determine a time frame. For only one signal (5) data on change of health were publically available, although only in a small cohort. For signal 3 no data on drug use were available, and for signal 4 data on the risk were doubtful, so an estimation of the impact was not possible. For two signals (1, 2) a crude estimation of the impact could be made with a varying degree of assumptions.

Conclusion: Lack of data hampers assessment of the impact of PV activities, but with assumptions a crude estimation of the impact on health can be possible.

References

• 1. Pharmacovigilance Activities (Rev 1) (EMA/165407/2017) [Internet]. 2017 [cited 2018 Apr 10]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Other/2016/01/WC500199756.pdf

• 2. Goedecke T, Morales DR, Pacurariu A, Kurz X. Measuring the impact of medicines regulatory interventions—systematic review and methodological considerations: methods for measuring impact of medicines regulatory interventions. Br J Clin Pharmacol 2018;84(3):419–33

Disclosure of Interest: None declared.

4 O-003 Serious Consequences from Medication Errors Identified in Vigibase

4.1 A. Zekarias^*1, R. Chandler¹, H. Taavola¹, K. Star¹, P. Caduff-Janosa¹

4.1.1 ¹Uppsala Monitoring Centre, Uppsala, Sweden

Background/Introduction: Medication errors (MEs) are “failures in the drug treatment process that lead to, or have the potential to lead to, harm to the patient”[1]. National pharmacovigilance centres have reported MEs to VigiBase for more than two decades (first report:1994) and as per April 2018 VigiBase contains 700 000 reports on MEs. Up until today, very few ME-signals have been identified within the global database of the WHO Programme.

Objective/Aim: To perform a pilot study to investigate the feasibility of using VigiBase to identify medication errors resulting in adverse drug reactions (ADRs) for which there is an opportunity for further risk minimization measures.

Methods: Data was retrieved from VigiBase in December 2017. A drug-event combinations list was generated where ‘events’ were preferred terms from the MedDRA High-Level Group Term “Medication errors and other product use errors and issues”. The combinations were prioritized according to vigiRank [2]. The drug-event combinations represented the following criteria; at least one report received after 2014, ≤ 30 reports per combination and reports from ≥ 2 countries.

During the initial manual assessment of the drug-event combinations, the assessors reviewed a list of pre-defined questions (e.g. regarding patterns of the reported events). The drug-event combinations suggesting a need for further risk minimization measures were assessed in-depth to determine if they should be communicated within the WHO Programme.

Results: Eighty drug-event combinations were initially assessed; six (7.5%) were communicated as signals. Three signals included serious ADRs and one of these reported a fatal outcome. The signals consisted of five types of errors; dosage not adapted to renal clearance as instructed in the product information causing ADRs from overdose; incorrect drug administration rate due to unclear dosing instructions leading to reactions such as mouth ulceration and thrombocytopenia; generic substitution leading to accidental overdose resulting in bleeding; inappropriate dose administration causing dizziness and confusion affecting patients’ quality of life; and co-administration of drugs resulting in death despite warnings of drug–drug interaction in the label. The signals were communicated within the WHO Programme in April 2018.

Conclusion: Medication errors with serious consequences can be identified in a global database of spontaneous reports. While a detailed root-cause analysis can seldom be performed on such a dataset, we identified inadequate labelling, similarities in trade names as well as unclear communication by the health care professionals as actionable causes for the errors reported. Continued use of VigiBase for identifying MEs is encouraged to prevent unnecessary patient harm.

References

• 1. Aronson J.K. Medication errors: what they are, how they happen, and how to avoid them. Q J Med 2009; 102:513–52.

• 2. Caster O., Juhlin K., Watson S., Norén N. Improved statistical signal detection in pharmacovigilance by combining multiple strength-of-evidence aspects in vigiRank. Drug Safety 2014; 37(8):617–28.

Disclosure of Interest: None declared.

5 O-004 The Proforma Project Presentation

5.1 E. Aklillu^*1

5.1.1 ¹Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

Background/Introduction: Supply of Medicines in Africa is increasing but inadequate pharmacovigilance regulatory capacity to process new drug registration and monitoring drug safety profiles locally remains a challenge. The increasing number of clinical trials and the large-scale mass drug administration and immunizations programs being deployed through public health programs in sub Sharan Africa underscores the urgent need to develop/strengthen the pharmacovigilance system for patient safety.

The PROFORMA project (http://proforma.ki.se/) is a joint venture between academia, regulatory authorities, and Reginal and Global pharmacovigilance stakeholders. PROFORMA is funded by European Union’s Framework Program for Research and Innovation Horizon 2020 via the European and Developing Countries Clinical Trials Partnership Association (EDCTP2).

Objective/Aim: Our main objective is to strengthen the national pharmacovigilance infrastructure and post-marketing surveillance system involving mass drug administration and immunizations being deployed under public health programs in Ethiopia, Kenya, Tanzania, and Rwanda.

Methods: The project intends to develop the national pharmacovigilance regulatory training programs by forging partnerships with local academic institutions (training-of-the-trainers for sustainable training programs) and regulatory authorities (practical training to change policy into practice) by using existing structures. Using the Pharmacovigilance Indicators tools, PROFORMA will first assess the current pharmacovigilance system and practice in Ethiopia, Tanzania, Rwanda and Kenya, to identify the missing pharmacovigilance structural elements systems, strength, deficiencies, and gaps. Based on the identified gaps, comprehensive interventional measures aligned with the local needs and priorities will be introduced in each country. PROFORMA will map all ongoing pharmacovigilance activities and tools to foster collaborations and to lower duplication. Harmonized pharmacovigilance tools and indicators will be utilized. The main regulatory functions that need capacity building will be identified and prioritized. We aim to generate a cohort of pharmacovigilance trained human resources from all stockholders including patients, healthcare providers, regulatory staffs that are engaged in pharmacovigilance data collection, analysis, interpretation and data sharing. Emphasis will be given to implement pharmacovigilance in clinical trials regulation and post-marketing surveillance in public health programmes involving mass drug administration and immunization programs. A total of 12 postgraduates will be trained to serves as part of the future PV expert regional task force. The ultimate goal is to establish/strengthen sustainable pharmacovigilance system in East Africa that is aligned with the large-scale African medicine regulatory harmonization and WHO’s Pharmacovigilance program.

Results: A total of 12 postgraduates will be trained to serves as part of the future PV expert regional task force. The ultimate goal is to establish/strengthen sustainable pharmacovigilance system in East Africa that is aligned with the large-scale African medicine regulatory harmonization and WHO’s Pharmacovigilance program.

Conclusion: Overview of the project aims and brief description of the different work packages and the associated tasks will be presented.

Disclosure of Interest: None declared.

6 O-005 Pavia: Strengthening Pharmacovigilance in Africa

6.1 F. Cobelens^*1,2, A. Isah³

6.1.1 ¹Global Health, Academic Medical Center; ²Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands; ³University of Benin, Benin City, Nigeria

Background/Introduction: PAVIA, a project funded by the European-Developing Countries Clinical Trials Platform (EDCTP), aims to improve the readiness of sub-Saharan Africa (SSA) health systems to effectively deliver new medical products for poverty-related diseases and monitor their post-market safety. It will be conducted in Nigeria, Tanzania, Ethiopia, Eswatini (formerly Swaziland) by 13 collaborating partners.

Objective/Aim: PAVIA’s objectives are: (I) To strengthen governance of pharmacovigilance (PV) systems, by strengthening regulatory and organisational structures and defining clear roles and responsibilities for all stakeholders; (II) To improve efficiency and effectiveness of national surveillance systems, by strengthening active (sentinel) surveillance of adverse drug reactions and implementation of tools and technologies for their detection, reporting, analysis and dissemination; (III) To build capacity and skills to sufficiently conduct drug safety monitoring activities throughout the country; and (IV) To improve readiness of health systems within SSA, by improving performance assessment of PV systems allowing identification of enablers and barriers for implementation.

Methods: PAVIA aims to strengthen national PV systems through a highly collaborative effort involving public health programmes (PHPs), National Medical Regulatory Authorities (NMRAs) and medical research institutions (MRIs). PAVIA will initially build up medicines safety surveillance activities in the context of the introduction of new drugs and treatment regimens for multidrug-resistant tuberculosis (MDR-TB) currently being introduced through the national tuberculosis programmes (NTPs). In each of the four project countries the national PV Centre/NMRA will collaborate with the NTP as well as a local MRI in a “triangular” cooperation in which the MRI provides clinical expertise. This “triangle” will provide a channel for reporting and interpreting safety signals in MDR-TB treatment, serve as a training ground for country PV staff and clinicians, and provide a demonstration project for similar linkages with other disease control programs.

The project will start with country-specific baseline assessments and situational analyses, which through a process of country stakeholder engagement will lead to country-specific roadmaps for PV strengthening, including recommendations and policy briefs to strengthen policies, laws and financial sustainability. Activities will include hands-on training of PV Centre/NMRA staff in database entry, data analysis, causality assessment and signal detection. PV systems (e.g. database connectivity) will be improved, and clinicians and other health care providers will be trained in PV by a blended learning approach where PAVIA will develop the materials and train “master trainers”. At the end of the project, best practices, enablers and barriers will be compiled in a blueprint that can guide other SSA countries in strengthening their PV systems. PAVIA’s alignment with relevant global and regional initiatives is ensured through their representation its Advisory Board.

Results: In view.

Conclusion: Through a highly collaborative approach between PV centers, public health programmes and clinicians, the coverage, accessibility and effectiveness of existing evidence-based interventions will be strengthened not only for MDR-TB but also for other poverty-related diseases.

Disclosure of Interest: None declared.

7 O-006 What Future Healthcare Professionals Need to Know About Pharmacovigilance

7.1 R. Van Eekeren^*1

7.1.1 ¹Netherlands Pharmacovigilance Centre Lareb, ‘s-Hertogenbosch, The Netherlands

Background/Introduction: To prevent patients from harm of adverse drug reactions (ADRs), healthcare professionals (HCPs) have to be aware of potential risks and occurrences of ADRs. To build knowledge and raise awareness about ADRs among healthcare professionals more education in the field of ADRs and pharmacovigilance (PV) is needed [1]. Currently, there is no standard for teaching PV at universities for medical, pharmacy, dentistry and nursing students and for this reason a core curriculum needs to be developed [2].

Objective/Aim: The development of a pharmacovigilance core curriculum for university teaching.

Methods: Two stakeholders meetings in 2016 and 2017 addressed and agreed the content, learning outcomes and availability for a PV core curriculum (PVCC) for university education [2]. These meetings were attended by PV professionals and university staff who are actively involved in PV education.

Results: Five key aspects summarize PV competencies that every student should develop. The PV key aspects are: (1) Importance of PV in the context of pharmacotherapy, (2) Preventing ADRs, (3) Recognizing ADRs, (4) Managing ADRs and (5) Reporting ADRs. The content of the PVCC is available on the internet, via www.pv-education.org. At this web portal educational materials and background information are available for all university teachers and PV staff that are involved in therapeutics education [2].

Conclusion: Since most medical, pharmacy and nursing students will enter clinical practice after graduation, the PVCC for university teaching focusses on the clinical aspects of ADRs. Since current educational programmes have limited time, the PVCC is developed as separate modules that can be integrated into existing courses such as pharmacology and therapeutics [3]. However, the content can also be used as a stand-alone course. A Teach-the-Teacher programme is developed which supports university staff to integrate PV key aspects into current courses.

With the five PV key aspects of the PV core curriculum for university education, future healthcare professionals will learn how to use drugs safely in clinical practice and how to share responsibility in ensuring the safety of drugs as well.

References:

• 1. Brinkman DJ, Tichelaar J, Mokkink LB, Christiaens T, Likic R, et al. Key learning outcomes for clinical pharmacology and therapeutics education in Europe: a modified Delphi study. Clin Pharmacol Ther 2017 https://doi.org/10.1002/cpt962 [Epub ahead of print]

• 2. Eekeren van R, Rolfes L, Koster AS, Magro L, Parthasarathi G, et al. What future healthcare professionals need to know about pharmacovigilance: introduction of the WHO PV core curriculum for university teaching with focus on clinical aspects. Drug Saf (accepted); https://doi.org/10.1007/s40264-018-0681-z

• 3. Hartman J, Harmark L, Puijenbroek van EP. A global view of undergraduate education in pharmacovigilance. Eur J Clin Pharmacol 2017;7: 891–9

Disclosure of Interest: None declared.

8 O-007 Anywhere, Anytime: Distance Learning in Pharmacovigilance

8.1 A. Hegerius^*1, P. Caduff¹, R. Savage^1,2, J. Ellenius¹

8.1.1 ¹Uppsala Monitoring Centre, Uppsala, Sweden; ²Department of General Practice, University of Otago, Christchurch, New Zealand

Background/Introduction: There is a growing demand for globally accessible training in pharmacovigilance. The Uppsala Monitoring Centre (UMC) has a long history of supporting the member countries of the WHO Programme for International Drug Monitoring, e.g., through the annual pharmacovigilance course in Uppsala. However, many people are unable to attend this course and the UMC has therefore launched a new distance learning platform with a first course in signal detection and causality assessment [1].

Objective/Aim: To develop and evaluate a distance learning course in pharmacovigilance.

Methods: The course was developed using the microlearning approach. The content, created using Articulate 360 Rise [2], was divided into four modules subdivided into 27 lessons. Each lesson is a short video lecture with a transcript and a clear learning objective. There is a quiz at the end of each module.

Initially, a small pilot study was performed to assess the preferred format of the course. Four months after the launch, an anonymous user survey was performed to assess usability and usefulness. The evaluation model was inspired by a refined version of the unified theory of acceptance and use of technology (UTAUT) [3, 4]. The questionnaire contained 25 questions and was sent to 2067 course participants from 137 countries, out of which 841 had completed the course and 1226 had at least started.

Results: Five hundred and fifty course participants responded to the survey (26.6%). The majority came from the WHO region SEARO (43.3%), followed by EURO (24.2%) and PAHO (19.3%). Twenty-two percent of the course participants were pharmacovigilance centre staff (our primary target audience). However, the course was also very popular among other pharmacovigilance professionals. A selection of questions and answers from the survey are presented in the table.

Almost all course participants (98.5%) responded that they would be able to apply what they had learnt to their practice. When asked to rate the course, 49.9% selected ‘Excellent’, 47.3% ‘Good’ and 2.8% ‘Average’. No one selected ‘Poor’ or ‘Inadequate’. A high proportion, 99.2%, would recommend the course to others and 99.8% intend to take future UMC courses relevant to them. Suggestions for improvements mainly concerned requests for more practical examples and quiz questions, improved display of transcripts and a forum for interaction.

Conclusion: Extending the UMC training portfolio with distance learning was well-received with high overall course satisfaction. Microlearning with video lectures, transcripts and quizzes was an appropriate educational strategy.

References:

• 1. Uppsala Monitoring Centre. Online courses [Internet]. Uppsala: Uppsala Monitoring Centre; 2017. [cited 2018 May 25] Available from: https://www.who-umc.org/education-training/online-courses

• 2. Articulate. Articulate 360 Rise, [authoring app]. New York: Articulate Global, Inc; 2017. [cited 2018 May 25]. Available from: https://articulate.com/360/rise

• 3. Chen, Jian-Liang. The effects of education compatibility and technological expectancy on e-learning acceptance. Comput Educ 2011;57:1501–11

• 4. Venkatesh, V, Morris, MG, Davis, FD. User acceptance of information technology: toward a unified view. MIS Q 2003;27:425–78

Disclosure of Interest: None declared.

9 O-008 Learning by Doing: Implementation of Pharmacovigilance in the Clinical Setting in a National Referral Hospital in Kenya

9.1 F. A. Okalebo^*1, M. N. Oluka¹, A. N. Guantai¹

9.1.1 ¹School of Pharmacy, Nairobi, Kenya

Background/Introduction: Training in detection of adverse drug reactions and reporting can be theoretical and learners may fail to see how pharmacovigilance can be incorporated into routine patient care. In an effort to move away from didactic teaching, the Department of Pharmacology and Pharmacognosy, University of Nairobi made efforts to promote bedside training in adverse event detection and reporting.

Objective/Aim: The objective is to present a case study of implementation of training in pharmacovigilance in Clinical rotations in a National Referral Hospital in Kenya. Opportunities and challenges will be highlighted.

Methods: A qualitative case narrative approach will be used to describe experiences in implementing practical training in pharmacovigilance.

Results: The trainers’ came up with 3 clinical rotation sites where the disease conditions present a large opportunity for detection of adverse drug reactions. These clinical sites were outpatient hematological clinic, in-patient psychiatric ward and out-patient HIV/AIDS clinic. After discussion with the pharmacist in-charge of the HIV/AIDS clinic, the in-patient multi-drug resistant clinic and in-charge of and a female medical ward were added to the rotation sites. The lecturers came up with a list of competencies expected in each of these sites. Based on these, a log book and tools for use by learners were developed. Learners were required to families themselves medication related expected in patients on anti-retroviral, anti-tuberculosis and psychiatric drugs. After 1 month of implementation of the clinical rotations, some of the challenges identified were an overwhelming occurrence of adverse drug events that necessitated a change in the rotations schedule; inappropriate tools; understaffing; and inappropriate tools. These problems were resolved through discussion with learners. Learners expressed satisfaction with the clinical rotations.

Conclusion: Incorporation of pharmacovigilance activities in clinical rotations provide a rich opportunity for training in pharmacovigilance and integration of medication management in routine clinical practice.

Disclosure of Interest: None declared.

10 O-009 Long Term and Clinical Effects of an Pharmacovigilance Educational Intervention in Specialist Oncology Nurses

10.1 M. Reumerman^*1, J. Tichelaar¹, R. van Eekeren², M. Richir¹, M. van Agtmael¹

10.1.1 ¹Section Pharmacotherapy, VUmc, Amsterdam, The Netherlands; ²Netherlands Pharmacovigilance Centre Lareb, ‘s hertogenbosch, The Netherlands

Background/Introduction: The level of underreporting of adverse drug reaction (ADR), especially under nurses, is high (0.9% reporting rate/year) and hinders optimal ADR monitoring. Since (specialist oncology) nurses administer most drugs they could play a major role in monitoring and reporting ADRs. Only several interventions in healthcare professionals have proven effective in increasing knowledge, however failed to produce clinical and durable effects.

Objective/Aim: This study aims to investigate the clinical and long-term effects of a pharmacovigilance educational intervention in specialist oncology nurses (SONs).

Methods: A case–control intervention study in the three postgraduate school who offer the course “prescribing qualification” for SONs was initiated. An innovative educational intervention in pharmacovigilance was added in one postgraduate school. The clinical value was assess by analyzing the number of reported ADR-reports to the Netherlands pharmacovigilance center. SONs competences on ADR-reporting were evaluated using e-questionnaires at T0: direct after graduation and T1: 1 year after graduation.

Results: Thus far, sixty SONs in the intervention group (74% of total) and ten SONs (59% of total) in the control group were included. Seventy ADRs were reported during and after the intervention while the control group did not report any. Six SONs (10%) completed a report within 1 year after the course, which showed an 11 time increase compared to baseline nurse ADR reporting rates. SONs in the intervention group showed an sustainable long-term knowledge-score (T₀: 82%/T₁: 83%) while the control group had a continuous lower level of knowledge (T₀: 65%/T₁: 69%). SONs in the intervention group found themselves more relevant in reporting ADRs than the control group (3.66 ± 0.36 vs 1.75 ± 0.59, 1–5 min/max).

Conclusion: This is the first study that shows a significant and relevant increase in the quantity of reported ADRs after a single educational intervention. The intervention had a sustainable effect on pharmacovigilance knowledge and increases SONs responsibility for their role in ADR-reporting.

Disclosure of Interest: None declared.

11 O-010 Communication: The Key to Implementation of Risk Management and Patient Safety

11.1 P. Bahri^*1,2, K. Ilic ³, U. Hagemann⁴

11.1.1 ¹ISoP CommSIG Coordinator,; ²European Medicines Agency (in personal capacity), London, United Kingdom; ³ISoP Comm SIG Member, Washington, DC, United States; ⁴ISoP CommSIG Member, Berlin, Germany

Background/Introduction: Over the last 10 years, aspirations regarding communication in pharmacovigilance have evolved from linear information flows with educative and instructive intentions to facilitating a dialogue with and within healthcare, involving patients for shared therapeutic decision-making and understanding of how to use medicines safely. We experience however that important information does still not reach those who need it and that the dialogue between patients and healthcare professionals does often not happen at all. Moreover the adoption of safe use behaviours by healthcare professionals as required by risk management programmes is not easily successful, with different challenges in countries around the globe.

Objective/Aim: This session intends to introduce a new way of thinking of risk minimisation measures as interventions within complex systems, and making communication the key to their implementation.

Methods: There will be a range of flash talks and time for discussion of conference participants for sharing their experiences and ideas. This session is sponsored by the ISoP CommSIG on medicinal product risk communication in collaboration with the ISoP special interest groups on women health and medication errors.

Results: A range of flash talks will offer with perspectives from patients, medicines safety specialists from four continents and a guest expert from complex intervention practices, underpinned by real life examples of interventions taking into account human factors to foster safe use behaviours and avoid medication errors.

Conclusion: The session will conclude with a wrap up by the co-chairs on key messages and suggestions for the presenters and participants.

Disclosure of Interest: P. Bahri: None Declared, K. Ilic Shareholder of: Consultant for pharmaceutical industry, U. Hagemann: None declared.

12 O-011 Human Factor Science for Improving the Impact of Risk Communication

12.1 B. Edwards^*1

12.1.1 ¹UK Pharmaceutical Ergonomics & Human Factors Group, Ashtead, Surrey, United Kingdom

Background/Introduction: Ultimately safe and proper use of healthcare products depends on human performance within an effective and supportive system. Unfortunately, this has not been previously thought through by applying organisational science. That is why in November 2015, we established a Pharmaceutical Human Factors & Ergonomics Special Interest Group (PHF&E SIG) within the Chartered Institute Ergonomics & Human Factors with the aim of promoting debate and develop programmes of work that include the capacity and capability of human factors engineering (HFE) and identify what support is needed to enable pharmaceutical organisations of all forms and sizes to embed HFE principles and practices into their culture, systems and processes.

Objective/Aim: This unique group is open to all who work in the pharmaceutical sector at any level and in any discipline who are committed to enhancing human performance towards greater safety and efficiency.

Methods: Since the inception of the PHF&E SIG, a series of sub-groups have been set up with membership from different parts of the system looking at various aspects of improving human performance. The four active groups concern: (1) modelling the system for medicines in the UK, (2) introducing human factors into existing training courses for drug safety, clinical research and pharmacists developing cross-system human factors competencies, (3) evaluating how best to perform human factors studies with healthcare products, (4) how to apply technology in the system and (5) implementation of principles of human-centred organisations (ISO 27500).

Results: From the experiences of these sub-groups we have identified how barriers in adopting safe use behaviours continue to exist despite intensive efforts of risk management programmes. Part of this failure is not ever having analysed the complexity of healthcare systems and designing processes that are evidenced-based, adaptable and flexible for those who work in them. Thus poor communication is inevitable. The lack of training about working and coping in complex systems is notable. We are not aware of sufficient evidence demonstrating the dynamics of how individual human factors (intrinsic) interact with social and organisational issues (extrinsic human factors) impact on the quality and outcomes of risk communication for healthcare products.

Conclusion: Barriers in adopting safe use behaviours continue to exist despite intensive efforts of risk management programmes. Part of this failure is not analysing the complexity of healthcare systems and designing processes that are evidenced-based, adaptable and flexible for those who work in them. The lack of training about working and coping in complex systems is notable. We are not aware of sufficient evidence showing how individual on one hand and social and organisational issues (human factors) impact on the quality and outcomes of risk communication for medicines. By increasing research for such evidence and blending human factors science with good communication practice, outcomes should improve.

References:.y increasing practical real-life research about how to apply such organisational evidence and blending human factors science with good communication practice, outcomes should improve.

Disclosure of Interest: None declared.

13 O-012 Health Care Communication Empowerment: A Successful Programme in Colombia

13.1 A. Caro-Rojas^*1

13.1.1 ¹President, Asociación Colombiana De Farmacovigilancia, Bogotá, Colombia

Background/Introduction: The communication is a process involve in all moment in our life, we are always in constant expressing ideas verbally or not verbally. The communication influence the work environment and in a hospital and affect the system working and the results with the patient.

Nowadays the human factors are a relevant topic in patient safety, It is possible to implement strategies to improve the communication (teamwork, empathy, collaborative leadership,) and in this way reduce the patient safety events included medication errors. The good communication include writing and reading properly, ask and discuss, this tools are necessary in the medicine dispensing and administration. Understand the information of the labelling medication helps to control medication errors.

Objective/Aim: To describe the experience with pharmacy and medicine students, using roleplay and theatre practices.

Methods: The communication skills can be teached to university students, it show a experience in Pharmacy and medicine students who understand the importance of recognize the other professional through roleplay and theatre practices. Parallelly the use of similar strategies was implemented in a institution with good results in decrease of medication events. The strategies was called Health Care Communication empowerment defined as: use of non-conventional tools for the development of communication skills, which the empowerment of the actors in the provision of health services, including the patient, their family and caregivers.

Results: A total of 400 aprox. has been involved in this practice. All the students recognize de importance of the medication safe use and consider that strategy using roleplay are linked with emotions and sensitize.

In other scenarios, nurses and doctors have been sensitized in the safe use of medications, with this strategy the respective decrease in adverse events was obtained.

Conclusion: Innovative strategies can be implemented to sensitize the persons in safe use of medicines and minimize medication errors.

Disclosure of Interest: None declared.

14 O-013 Central to Risk Communication in Healthcare: The National Pharmacovigilance Centre in Tunisia

14.1 M. Bouhlel¹, R. Daghfous ^*1, S. El Aidli¹

14.1.1 ¹Tunisian National Centre of Pharmacovigilance, Tunis, Tunisia

Background/Introduction: The Tunisian pharmacovigilance system essentially includes direct communication with patients during a dedicated consultation. In addition, there is communication with the healthcare professionals with regard to their patients. Thereby, the pharmacovigilance centre establishes communication also between the patient and their healthcare professionals.

Objective/Aim: The work aims to present of the Tunisian pharmacovigilance system and to demonstrate its efficiency in risk communication between patients and healthcare stakeholders.

Methods: A retrospective study was made during the last decade in the National Centre of Pharmacovigilance based on statistical data collected from consultation with patients, patients’ family members, doctors and other stakeholders.

The study was also focusing on the different kinds of issues raised.

Results: The majority of consultation was made with patients, then with the patient’s family members, and later with the doctors and the other stakeholders.

The results showed that detected issues were related to the various side effects due directly to medicinal products, to the misusage of medicines and not to the suspected used drug itself.

The reports of the pharmacovigilance investigation were submitted directly to each doctor treating patients and/or to each patient, after a consultation explaining the content of the report.

Conclusion: The Tunisian pharmacovigilance centre supports a dialogue between all different parties when investigating medication errors and identifying the root cause through consultation made with all stakeholders.

Disclosure of Interest: None declared.

15 O-014 National Campaign in an Israeli Chain of Community-Based Pharmacies to Decrease the Risks of Anticoagulants

15.1 R. I. Fermont^*1,2, A. Amitai^3,4, A. Livneh^1,5, V. Kalamaro^6,7, R. Litman^8,9, P. Pitts¹⁰, N. Sevdalis¹¹, P. Bahri^12,13, B. Edwards^14,15, A. Elad¹⁶

15.1.1 ¹ISOP ISRAEL Chapter, Israel; ²IFC Strategic Safety Consulting, Jerusalem, Israel; ³The Pharmaceutical Society of Israel, Tel Aviv; ⁴Clinical Pharmacology, Meir Medical Centre, Kfar Saba, Israel; ⁵Ministry of Health, Jerusalem, Israel; ⁶Clinical Pharmacists, The Pharmaceutical Society of Israel, Tel Aviv, Israel; ⁷Clinical Pharmacy, Cystic Fibrosis Israeli Foundation, Petah Tikva, Israel; ⁸Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia, Philadelphia, United States; ⁹Medical Direction, Institute for Safe Medication Practices, Horsham, United States; ¹⁰Center for Medicine in the Public Interest, New York, United States; ¹¹Centre for Implementation Science, Kings College London, United Kingdom; ¹²SIGCOMM, ISOP, ¹³Pharmacovigilance, European Medicine Agency, ¹⁴Board of Directors, ISOP, London, United Kingdom; ¹⁵Pharmacovigilance, NDA, Leatherhead, United Kingdom; ¹⁶The Healthcare System Healing Campaign, Zichon Yaakov, Israel

Background/Introduction: The community pharmacists are often the last rampart before drug administration to the patients. Therefore, they should play a significant role in risk prevention, medication errors or interactions detection, and safe use advice to patients.

An Israeli chain of community-based pharmacies is launching a national campaign on the risks of anticoagulants. The project is led by the Pharmaceutical Society of Israel (PSI), in partnership with ISOP ISRAEL.

Objective/Aim: 1. To decrease the risk of anticoagulants via improving risk awareness.

2. To set up a safety methodology applicable to other high-risk medications.

3. To improve the perceived value of the community pharmacist as a Public Health significant actor.

Methods: 1. Training of all the chain pharmacists on risk communication for anticoagulants with key messages and key questions to the patients.

2. Tools identification: ISMP (Institute for Safe Medication Practices) “Self-assessment tools”^1,2,3 are the basis for the key messages. Other tools will be identified by ISOP ISRAEL with the support of ISOP risk communication group and ISMP.

3. On-site advising: For each patient prescribed with anticoagulants, several parameters will be checked: first symptoms awareness for bleeding and thromboembolism leading to immediate medical consultation, dosage, indication, drug and food interactions, compliance and detection of potential adverse reactions. Patients will receive also information leaflets and a safety card.

4. Key performance indicators (KPI) will be integrated the distribution software as tick box to check the number patients advised, medication error or adverse reaction detection.

5. Data collection: In each of the five regions, once a month, a coordinating pharmacist will select and share case(s) where pharmacist’s advice had the most significant impact. 

Results: Timeline.

• Project start: June 2018

• June–October 2018: preparation of training and tools identification

• October 2018: community pharmacists training

• November 2018: starting the national campaign

• June 2019: Interim results presentation in the ISOP ISRAEL symposium

• October 2019: Final results presentation in ISOP Bogota 2019

Conclusion: For this original initiative, we will have to adjust tools and methods during the project to prove its effectiveness and feasibility. We can reasonably expect this campaign to trigger/increase risk awareness on anticoagulants in Healthcare Professionals and patients. The partnership between PSI, ISOP ISRAEL, ISOP and ISMP is innovative and brings all stakeholders together—which, if successful, provides a model to use for further campaigns on other high-risk medications.

References:

• 1. ISMP Medication Safety Self Assessment^® for Community/Ambulatory Pharmacy, January 23, 2017, https://www.ismp.org/sites/default/files/attachments/2018-01/ISMP117C-Pharma%20SA-FINAL%20020317.pdf

• 2. ISMP Medication Safety Self Assessment^® for High-Alert Medications January 25, 2018, https://www.ismp.org/sites/default/files/attachments/2018-01/EntireAssessmentWorkbook.pdf

• 3. Medication Safety Self Assessment^® for Antithrombotic Therapy, March 1, 2017, https://www.ismp.org/sites/default/files/attachments/2017-11/ISMP128-Antithrombotic%20SA-021017.pdf

Disclosure of Interest: None declared.

16 O-015 Medical Devices: Definition, Classifications, and Nomenclatures

16.1 J. Aronson^*1

16.1.1 ¹Centre for Evidence Based Medicine, University of Oxford, Oxford, United Kingdom

Background/Introduction: Medical devices are being increasingly used.

Objective/Aim: Defining a medical device: The WHO’s definition [1] is:

Any instrument, apparatus, implement, machine, appliance, implant, reagent for in vitro use, software, material or other similar or related article, intended by the manufacturer to be used, alone or in combination, for human beings, for one or more of the specific medical purpose(s) of:

• diagnosis, prevention, monitoring, treatment or alleviation of disease,

• diagnosis, monitoring, treatment, alleviation of or compensation for an injury,

• investigation, replacement, modification, or support of the anatomy or of a physiological process,

• supporting or sustaining life,

• control of conception,

• disinfection of medical devices,

• providing information by means of in vitro examination of specimens derived from the human body;

and does not achieve its primary intended action by pharmacological, immunological or metabolic means, in or on the human body, but which may be assisted in its intended function by such means.

Methods: Analysing the definition: A device is “something devised or framed by art or inventive power; an invention, contrivance; especially a mechanical contrivance for some particular purpose” (Oxford English Dictionary). The WHO’s definition attempts comprehensive coverage of all imaginable types of device. However, the items included overlap in meaning, and as new devices appear the definition will become outdated.

Results: A proposed definition: A simpler definition of medical devices would encompass their important features. The following proposed definition builds on that published by the Bundesinstitut für Arzneimittel und Medizinprodukte [2]:

Medical device n: A product intended to benefit human healthcare, whose effects are primarily achieved by physical, chemical, or computerized means, rather than pharmacologically, immunologically, metabolically, or cellularly.

Classifications: The FDA has classified about 1700 types of devices in 16 areas into three different classes, I, II, and III, with different regulatory requirements, depending on how much control is required for a favourable benefit to harm balance [3].

In contrast, the EU classifies devices into four categories, I, IIa, IIb, and III, based on purpose, duration of use, invasiveness, use of a source of energy, and whether something is measured [4].

Nomenclatures: The Universal Medical Device Nomenclature System™ (UMDNS) is a standard international nomenclature and computer coding system for medical devices [5]. The Global Medical Device Nomenclature (GMDN) is a list of generic names used to identify all medical device products [6].

Conclusion: Harmonization and simplification of classifications and nomenclatures is desirable.

References:

• 1. http://www.who.int/medical_devices/full_deffinition/en

• 2. https://www.bfarm.de/EN/MedicalDevices/_node.html;jsessionid=9133BE8F49877DB89997E9920F72C89D.2_cid329

• 3. https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/ClassifyYourDevice

• 4. https://www.gov.uk/topic/medicines-medical-devices-blood/medical-devices-regulation-safety

• 5. https://www.ecri.org/components/UMDNS/Pages/default.aspx

• 6. https://www.gmdnagency.org

Disclosure of Interest: None declared.

17 O-016 A Multidisciplinary Management of Oncologic Patients Treated with Immune Checkpoint Inhibitors (Icpi)

17.1 C. Le Beller¹, P. Mignen¹, E. Fabre², L. Weiss³, J. Pouchot⁴, G. Malamut⁵, M.-A. Dragon-Durey³, E. De Guillebon², A. Lillo-Le Louet^*1, S. Oudard²

17.1.1 ¹Pharmacovigilance Hopital Européen Georges Pompidou, Paris, France; ²Oncology, ³Immunology; ⁴Internal Medicine; ⁵Gastroenterology, Hôpital Européen Georges Pompidou, Paris, France

Background/Introduction: ICPI approvals have changed the management and prognosis of advanced cancer. However, ICPI have a specific toxicity profile which modifies the oncologists’ practices. Immune-related adverse effects (irAEs) can affect all organs, far from usual cytotoxic AEs observed with classical anticancer treatment [1, 2]. Considering their action on the immune system, patients with underlying disease (autoimmune, graft recipients, chronic infections) were not evaluated in clinical trials. Since January 2017 in our hospital, a multidisciplinary team with monthly meetings (MTM) discusses ICPI indications in patients with an underlying disease, manages irAEs or decides ICPI continuation. The MTM gathers oncologists and subspecialists in immunology, internal medicine, gastroenterology, endocrinology, nephrology, radiology and pharmacovigilance.

Objective/Aim: To present an overview of patient’s cases assessed by MTM in 2017.

Methods: We performed a retrospective study of the patients’ cases presented in the MTM during 2017. We used MTM reports and patients’ clinical data from the hospital computerized medical record.

Results: Among the 172 patients who received ICPI, 41 circumstances for 37 patients (18 women and 19 men, aged from 44 to 86 years) were analyzed and discussed in 2017.

16 patients were evaluated prospectively due to an underlying condition:

• an autoimmune disease: rheumatoid arthritis (1), multiple sclerosis (1), Sjögren’s syndrome (1), positivity of ANA (3)

• a chronic viral disease: hepatitis C (2), HBV (1), HIV (1)

• heart transplantation (1)

• other disorders: lymphocytosis (2), allo-immunization HLA (1), idiopathic pulmonary fibrosis (1), hyperthyroidism (1).

In all these 16 patients but one (heart transplantation), the ICPI benefit/risk ratio was considered as favorable.

For the remaining 21 patients, the MTM analyzed 25 AEs: tumor progression or pseudoprogression (5), hepatic injury (5), hyperthyroidism (4), cutaneous reaction (3), cytopenia (2), colitis (2), pulmonary fibrosis, oligoarthritis, weight gain and a suspected drug interaction with phytotherapy (one of each case). For 2 hematological AEs, the relationship with ICPI was ruled out. After discussion, ICPI was continued in 15 patients associated with corticotherapy or curative treatment (11). Additional investigations (biological survey, TDM, liver biopsy, colonoscopy…) were recommended for 8 patients. ICPI were withdrawn in 6 patients.

Conclusion: ICPI is a new class of drugs available for cancer treatment with growing indications and a specific and unusual safety profile. It is a challenge in current oncology practice as several questions are still pending about its benefit in some population and/or in association with other drugs. A new organization with MTM helps clinicians to share experiences with a direct benefit for their patients.

References

• 1. Michot JM, Bigenwald C, Champiat S et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 2016;54:139–48

• 2. Sosa A, Lopez Cadena E, Simon Olive C et al. Clinical assessment of immune-related adverse events. Ther Adv Med Oncol 2018; 10: 1–11

Disclosure of Interest: None declared.

18 O-017 Management of Adverse Experiences from the Use of Herbal Medicines: The Consumers’ Perspectives

18.1 C. Kongkaew^*1, M. Sreerattanachotchai¹, S. Sudnongbua²

18.1.1 ¹Faculty of Pharmaceutical Sciences, Naresuan University, Thailand; ²Department of Community Health, Faculty of Public Health, Naresuan University, Phitsanulok, Thailand

Background/Introduction: Herbal medicines have been used worldwide. There are several the herbal medicine reporting mechanisms, especially spontaneous reporting system, but the number of reports were low and may be underreported. To improve reporting, it is crucial to understand how consumers perceive adverse events from herbal medicines and act upon them.

Objective/Aim: To describe consumer perceptions of how they manage adverse experiences following use of herbal medicines.

Methods: A multiple case study was undertaken in sub-district, in the south-east of Thailand during March/April 2017. In-depth interviews were employed as the method of data collection. Nine participants who had had adverse experiences were selected by criterion sampling.

Results: Key informants perceived the adverse experiences during a course of herbal medicine treatment. They self-diagnosed the adverse experiences, they observed abnormalities of the body using their own experiences. Some of the herbalists did not know that the experience was an adverse reaction to herbal medicine that it may also be called “Sai” symptom. Identification of suspected herbal medicines was deduced by (i) ruling-out other potential causes (ii) a recovery after cessation of treatment and (iii) the return of the symptoms after re-administration of the herbal. The perceived adverse reactions were managed by: (a) taking no action if symptoms were mild and that herbal medicines were believed to be safe (b) self-care including dose moderation or discontinuation, sleeping, drinking a lot to increase excretion, or detoxification by taking laural clock vine (Thunbergia laurifolia), (c) seeking advice/care at sub-district health promoting hospital or drugstore and (d) perform both self-care and care-seeking behaviors.

Conclusion: Consumers of herbal medicine were at risk of adverse events. Therefore, surveillance systems for herbal medicines should be established by promoting consumer and/or healthcare professional reporting in primary care thereby improving the safe use of herbal medicines.

Disclosure of Interest: None declared.

19 O-018 Efforts Made by the University in Costa Rica to Promote Pharmacovigilance

19.1 V. Hall Ramirez^*1

19.1.1 ¹Pharmaceutical Care and Clinical Pharmacy Department, Pharmacy Faculty, University of Costa Rica, San Jose, Costa Rica

Background/Introduction: The Pharmacy Faculty of the University of Costa Rica, compromise, since 1897 with the Costa Rica`s population health, through the training of pharmaceutical professionals, the provision of services and the development of activities that directly affect the public health of the country, had made several efforts to strengthen the role of the pharmacist in ensuring the safety of medicines used by patients, not only through a new curriculum but also with the participation of the professors in several activities regarding Pharmacovigilance.

Objective/Aim: Describe the efforts made the Pharmacy Faculty of the University of Costa Rica and the challenges the academia have in promoting Pharmacovigilance.

Methods: Study Type: Descriptive. Method: Compilation of the activities carried out by the Pharmacy Faculty around Pharmacovigilance integrating the three fundamental pillars of the University of Costa Rica: teaching, research and social action.

Results: In Costa Rica, the National System of Pharmacovigilance, allows the reporting of suspected adverse drug reactions by health professionals and also directly by the pharmaceutical industry, that’s the reason why the training and the continuing education on this topic is essential for the correct functioning of the System.

The Pharmacy Faculty developed a new curriculum in 2016, in which it can be identify several courses related to Pharmacovigilance, defined as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem [1]. The topic is included in different courses with complementary approaches, as for example Pharmaceutical Care, Public Health Elements, Pharmacoepidemiology Topics, Pharmaceutical Legislation and Deontology, Industrial Pharmacy and Introduction to Pharmacy.

Considering that the counterfeit medicines are also part of Pharmacovigilance, the theme is part of the topics included in Pharmaceutical Analysis and Quality Control courses. These activities are complemented by the Pharmaceutical Research Institute and it’s dependencies through their everyday activities and several projects.

On the other hand, the Faculty has developed, joining efforts with different stakeholders, including pharmaceutical associations, industry and health authorities, several continuing education courses and workshops for pharmacist, so they can be more proactive in the filling of the Individual Case Safety Report (ICRS) and send them to the Costa Rican National Pharmacovigilance Center.

Conclusion: The Pharmacy Faculty of the University of Costa Rica has made several efforts to promote the development and strengthening of Pharmacovigilance, working together with different stakeholders, but all the activities done by now, can be improved so it can be guaranteed to the population that the medicines they use are safe and that the professionals are making their biggest effort to ensure that.

References

• 1. World Health Organization. Pharmacovigilance. [Internet] [Accessed on June 4th, 2018]. Available in http://www.who.int/medicines/areas/quality_safety/safety_efficacy/pharmvigi/en/

Disclosure of Interest: None declared.

20 O-019 How the Colombian Pharmacovigilance Association Join the Stakeholders in Pharmacovigilance, and Promote the Best Practices in Latam?

20.1 A. Caro-Rojas^*1

20.1.1 ¹President, Asociación Colombiana De Pharmacovigilancia, Bogotá, Colombia

Background/Introduction: The Colombian Pharmacovigilance Association (ACFV) was founded 2 years ago with a propose “To be a national and international leader, who integrates all the actors who are interested in patient safety and particularly in the safe and efficient use of the medicines.” In this propose the Association has been working with the academy, government, pharmaceutical industry, scientific associations, hospitals, and other stakeholders, earing, learning and understanding about the needs of each one and implementing strategies that answer that problems. The association has worked in regulatory and academic topics, and specially in networking with other Associations and nets in Latam in the project “Bogotá Declaration”.

Objective/Aim: To describe how the ACFV, has been integrated the different stakeholders to share information and develop strategies for medication use in Colombia and Latinamerica.

Methods: The ACFV has been working with the academy, government, pharmaceutical industry, scientific associations, hospitals, and other stakeholders, earing, learning and understanding about the needs of each one and implementing strategies that answer that problems.

The ACFV has doing a net of nets with the participation of people from Mexico, Costa Rica, Ecuador, Peru, Bolivia, Chile, Argentina and of course Colombia. In this net and by social media networks the ACFV share information for use safe of medicines and identify needs of information.

In this way the ACFV has developed virtual conferences to help to share pharmacovigilance information.

Other strategy has been workshops to build solutions like communication between stakeholders (Industry, academy and governement).

Results: In this moment the Virtual net is about 2700 persons in the basic structure, and about 10,000 persons for the other networks interacting for all the stakeholders.

Conclusion: Is important to have strategies that joint stakeholders about pharmacovigilance topics.

Disclosure of Interest: None declared.

21 O-020 Systems Factors Associated with the Use of Intravenous Insulin Infusions: Current Evidence and Future Directions

21.1 B. Edwards^*1

21.1.1 ¹UK Pharmaceutical Ergonomics & Human Factors Group, Ashtead, Surrey, United Kingdom

Background/Introduction: We know that human and other systematic causal factors underlie most medication errors. One of the challenges is how best to persuasively demonstrate this. UK National Health Service Never Events may be a good place to start. Overdose of Insulin due to abbreviations or an incorrect device is an agreed NHS Never Event [1]. The European Medicines Agency has produced specific guidance on prevention of medication errors with high strength insulins [2]. Although much focus has been placed on technical aspects of insulin use, less emphasis has been placed on systemic causal factors and barriers to successful intravenous insulin infusions. Such a case study might then be extrapolated to other high risk medicines and therapeutic areas to illustrate the importance of human factors and systems theory.

Objective/Aim: A workshop was organised at the School of Pharmacy, University of Reading, UK on April 20th 2018 which focussed on human factors at the level of the system, the process and the individual to identify systems-based solutions to optimise use of intravenous insulin. This involved representatives from healthcare, the industry, patients and human factors specialists.

Methods: At a systems level, participants were asked to reflect on hierarchy and leadership, decision-making, team working and collaboration, communication and evidence dissemination, incentives and motivators, principles of quality management leading to controls and feedback, standards and competencies. Discussion of the process concerned the people (role definition), training, working environments (how they differ), error management, metrics and measurement.

Results: In the context of systems and processes there was discussion about quality of evidence on which decisions are made and design and suitability of products available.

Conclusion: A report will be created from this workshop which will make recommendations about how best to disseminate current research findings about i.v. insulin, engage key stakeholders in shaping future directions for research/practical applications and identify barriers and gaps hindering optimal use of intravenous insulin and achievement of the NHS Never Event target. There will be initial proposals for system redesign including the need for a larger conference or meeting to move this topic forward.

References:

• 1. Never Events list 2018 NHS Improvement January 2018 https://improvement.nhs.uk/documents/2266/Never_Events_list_2018_FINAL_v5.pdf

• 2. Guidance on prevention of medication errors with high-strength insulins European Medicines Agency 27 November 2015 EMA/134145/2015 http://www.ema.europa.eu/docs/en_GB/document_library/Recommendation_on_medication_errors/2015/11/WC500197133.pdf

Disclosure of Interest: None declared.

22 O-021 Strengthening HIV Pharmacovigilance in China

22.1 J. Bao^*1

22.1.1 ¹Frontier Biotechnologies, Inc, Nanjing, China

Background/Introduction: AIDS is a harmful infectious disease caused by the HIV virus that attacks the body’s immune system. HIV has caused more than 35 million deaths worldwide and 1 million people worldwide died of HIV-related illnesses in 2016. However, it is estimated that only 70% of people living with HIV are aware of their infection status. Since the first case reported in China in 1885, the incidence of AIDS has grown rapidly. In 2016 (January 1st, 2016 to 22:00, Dec. 31st), the nationwide (excluding Hong Kong, Macau, Taiwan, the same below) reported 6,944,240 communicable diseases and 18,237 deaths. Among them, the number of AIDS cases was 54,360, an increase of 8.0% over the previous year. The incidence of AIDS was 3.9656/100,000 and the number of AIDS deaths was 14,091, an increase of 10.5% from 2015. The mortality rate of AIDS was 1.028 per 100,000.

Objective/Aim: HIV treatment is complex and requires a life-long combination medication. Therefore, a well-designed pharmacovigilance system for HIV drugs presents a unique challenge and opportunity for drug safety as well as public health system.

Methods: This presentation will present the current ADRs associated with the Anti-HIV drug use, as well as the ADRs reporting system and data received for ADRs.

Results: The current reporting system as well as changing regulatory landscape for PV in China after the country joint the ICH will also be discussed. The presentation will also be highlighted with a case study to build the system for the new HIV drug’s AE collecting and reporting.

Conclusion: Little is known about the toxicity profile of ARV drugs in China. The relevant comorbid conditions such as tuberculosis and hepatitis also have complicated the safety profile of ARVs. A strengthened PV system and well-designed risk management plan is necessary for ARVs especially for the newly approved ones.

Disclosure of Interest: None declared.

23 O-022 Clinical Application and Regulation on Oral Diabetic Drugs in China: Current Status and Further Perspective

23.1 X. H. Yang¹, J. K. Huang^*1, L. Zhang¹

23.1.1 ¹Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China

Background/Introduction: Chinese medical and healthcare service is characterized by the coexistence of traditional Chinese medicine (TCM)and Western Medicine (WM). Integrated therapy of Chinese and Western Medicine (ITCWM) can not only improve the symptoms of diabetes, prevent and treat the complications of diabetes effectively, but also enhance the quality of life, moreover it reduces medical expenses. Recent clinical and experimental studies have shown that has obvious advantages in the treatment of diabetes.

Objective/Aim: To summarize the clinical application and risk control modes of oral diabetic drugs (ODDs) in China.

Methods: This authors summarize the status of ODDs registration and management in China, reviewing the participatory ways of physicians, scientific community, enterprises and regulators in the whole life cycle risk management based on the risk characteristics of various Chinese ODDs.

Results: The classification of Chinese authorized ODDs are divided into chemical drugs (CDs), Pure TCM drugs (PTCMDs) and Chinese and Western Compound drugs (CWCDs). CDs have advantage in clearing hypoglycemia, while PTCMDs with fewer side effects in improving complications, symptoms and reducing the side effects of CDs. The safety of CDs and CWCDs have been of great concern lately. The roles concerning risk management have been involved in the risk management by formulating the guidelines on the diabetic therapy and rational application of ODDs, strengthening the publicity and training of safe medication, bringing safe medication course into medical college curriculum, controlling drug marketing approval strictly related to potential drug risks, expanding channels of drug safety information collection and communication between regulators, enterprises, healthcare professionals and the public. Moreover, exploring research modes concerning pharmacovigilance, strengthening marketed sampling and quality supervision and cracking down on counterfeit drugs and inferior drugs are also important [1–5].

Conclusion: ITCWM has complementary advantages in diabetic treatment. It is effective ways promoting rational and safe use of ODDs by establishing convenient patient ADR spontaneous reporting system, carrying out basic research on drug interaction, developing active surveillance large-scale evidence-based clinical studies actively.

References:

• 1. Center for Drug Evaluation, CFDA. Key issues for clinical trials of cardiovascular risk assessment of Type 2 diabetic new drugs. http://www.cde.org.cn/dzkw.do?method=largePage&id=311954 accessed 31 May 2018

• 2. Wang HY, Zhang J, Gao CY, et al. Risk control guidance for clinical studies of cardiovascular end point events in type 2 diabetic patients in China. http://www.cde.org.cn/dzkw.do?method=largePage&id=312453. Accessed 31 May 2018

• 3. Zhang L, Wong L, He Y, et al. Pharmacovigilance in China: current situation, successes and challenges. Drug Saf 2014;37:765–70

• 4. Zhang L, Yang XH. Evaluation and rational use of Chinese patent medicines for diabetes. China J Tradi Chinese Med Pharm 2009;24:1270–3

• 5. Zhang L, Yang XH. Adverse drug reactions and rational use of Xiaoke Wan. Chinese J Pharmacovigilance 2006;3:76–80

Disclosure of Interest: None declared.

24 O-023 Universal Health Coverage is Possible with Effective Pharmacovigilance at Current Expenditure Level in Nigeria

24.1 E. Okoro^*1, B. Oyejola², A. Giwa³

24.1.1 ¹Department of Medicine, ²Department of Statistics, University of Ilorin, Ilorin, Nigeria; ³Department of Jurisprudence & International Law, Delta State University, Abraka, Nigeria

Background/Introduction: Nigeria with > 190 million people will be the third most populous nation by 2050. And citizens each spend on average US$82 annually towards a total health expenditure of US$115 per capita when accessing services. This can rise to US $ 316–4000 for 20–40% of the adult population exhibiting hypertension ± type 2 diabetes. This pattern of personal health expenditure exceeds the financial threshold of 34–86 US$ per capita experts recommends for financing universal health coverage (UHC) including basic treatment of type 2 diabetes/hypertension. Even so, untimely deaths linked to both conditions remain alarming while this is plunging globally from effective interventions.

Objective/Aim: This symposium presentation attempts to highlight possible contributory factors why treatment quality is suboptimal and UHC remains inadequate in Nigeria.

Methods: Mainly academic reports of Nigerian origin after 1999 when National health insurance policy became operational locally were reviewed.

Results: Up to 60–70% of individuals in some cohorts of hypertension/type 2 diabetes each spend US $ 316–4000 annually [1–3] for  treatment whose quality is barely effective in < 20% to optimally diminish  the risk of adverse cardiovascular events. The practice as national treatment standard seem inconsistent with the best possible value-for-money based on dominant disease behavior in Nigeria population [1–5]. In addition, treatment costs can be inflated sometimes beyond internationally quoted prices. Instructively, one Netherlands based organization, operating community health insurance business in Nigeria, recently demonstrated effective antihypertensive therapy, often, the only cardiovascular intervention majority (> 90%) with type 2 diabetes/hypertension require to optimally diminish the risk of sudden death, stroke, etc. with just US$ 28 per person annually. Given what individuals currently pay without reimbursements, these observations reinforce EU recent declaration of Nigeria having enough internal revenue to finance its own development. Moreover, Nigeria’s UHC is 4–5% against > 40% achieved in Ghana with a comparative level of total health expenditure per capita and national health insurance scheme 5 years younger. And today, over 40% of youths in Northern Nigeria may have become addicted to opiates/other substances 13 years after dismantling measures that initially contained their over-prescription while liberalizing access [1, 6]. Incidentally, the epidemic of abuse is fed by a network of criminal gangs/cultists, benefiting indigenous pharmaceutical companies and some health care professionals.

Conclusion: Effective pharmacovigilance can mobilize/optimize Nigeria’s abundant internal revenue for UHC while also minimizing interventions becoming instruments of mass exploitation/destruction.

References:

• 1. Okoro EO. “Towards better prevention/control of hypertension and diabetes” 143rd Inaugural lecture, 27 February 2014, University of Ilorin, Nigeria see www.unilorin.edu.ng

• 2. Okonkwo IL, Ekpemiro JN, Okwor EU, Okpala PU, Adeyemo FO. Economic burden and catastrophic cost among people living with type2diabetes attending a tertiary health institution in South–East zone, Nigeria, BMC Res Notes 2015;8:527

• 3. Okoro C. Assessing the quality of care received by diabetes patients under Nigeria National Health insurance Scheme: does enrollment in health insurance matter? Boston University openBU; http://open.bu.edu

• 4. Chinenye S, Uloko AE, Anthonia O, OgberaE, OAFasanmade OA, et al. Profile of Nigerians with diabetes mellitus—Diabcare Nigeria study group (2008): Results of a multicenter study, India. Journal of Endocrinology 2012, 16, 558–564

• 5. Okoro EO, Oyejola BA. Aspirin and Diabetes Care in Nigeria : Treatment or Expliotation? J Clinic Res Bioeth 2015, 6:2. https://doi.org/10.4172/2155-9627.1000227

• 6. Kazeem Y. Coughing Up: The major ingredient in Nigeria’s codeine abuse crisis is corruption at major drug makers http://qz.com/1266823/block/bbc-investigates-nigeria-codeine-opiod-crisis-from-cough-syrups (visited last on 22 May 2018)

Disclosure of Interest: None declared.

25 O-024 Opportunities of Prospective Observational Entis Studies

25.1 C. Weber-Schoendorfer^*1

25.1.1 ¹Pharmakovigilanzzentrum Embryonaltoxikologie, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

Background/Introduction: The main task of the European Network of Teratology Information Services (ENTIS) is to contribute to the prevention of birth defects and developmental disorders. Callers to the services—either health care professionals and/or pregnant patients—search for risk assessment regarding drug use during pregnancy.

Objective/Aim: This offers the unique possibility to combine counselling with the follow-up of critically exposed and unexposed pregnancies.

Methods: The majority of calls comes in during early pregnancy, thus neither pregnancy outcome nor the results of prenatal diagnostic tests are known. Using a standardized set of questions and variables across services, these prospectively followed up pregnancy courses are the base for observational multicenter cohort studies. By this design, all potential pregnancy outcomes are registered. The range of adverse outcomes can be analyzed, which is important for both, physicians and patients.

Results: TIS studies are cost-saving and are able to provide an equally recruited comparison cohort. Results can be controlled for a variety of confounders. Drug intake is documented in real-time. Through motivated and often thankful callers, the non-responder rate is low. By using a multicenter approach, it is possible to effectively accumulate a meaningful number of exposed pregnancies. Since the founding of ENTIS in 1990, a variety of multicenter studies has been published in peer-reviewed journals. Data quality and data harmonization across sites have been improved over the years as well as the overall study quality by following the STROBE guidelines [1]. However, the sample size of ENTIS studies is usually moderate; the follow-up period is typically limited to weeks after birth and TIS populations might not be representative for the pregnant populations.

Conclusion: Despite these disadvantages, the follow up of exposed pregnancy courses after consultation offers a unique opportunity of drug surveillance in order to contribute to the prevention of birth defects or to enhance data on drug safety.

References:

• 1. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370:1453–7.

Disclosure of Interest: None declared.

26 O-025 A Population-Based Cohort, Pregnant: Day-to-Day Experience with Medication use During Pregnancy and Breastfeeding

26.1 S. Vorstenbosch^*1

26.1.1 ¹Monitoring, Netherlands Pharmacovigilance Centre Lareb, ‘s-Hertogenbosch, The Netherlands

Background/Introduction: In general, safety issues related to medication use during pregnancy and breastfeeding are not addressed in pre-marketing studies. Despite the lack of information, medication use among pregnant women is frequent, with estimates ranging from 40 to 96% [1–5]. This widespread experience does not translate into knowledge that could be used in the pharmacotherapeutic care of pregnant and postpartum women.

In the Netherlands, the Dutch Pregnancy Drug Register pREGnant systemically documents relevant and high-quality information at a central place. Ultimately to obtain insight into medication use among pregnant and breastfeeding women and safety issues concerning maternal and fetal/infant health. In that way, it provides a step towards translation of daily practice with medication use in pregnancy and breastfeeding into actionable knowledge.

Objective/Aim: To discuss the design and strengths and limitations of the Dutch Pregnancy Drug Register pREGnant and its value in signal detection, epidemiologic studies and counseling of health care providers and patients.

Methods: The Dutch Pregnancy Drug Register pREGnant is an initiative of the Teratology Information Service of the Netherlands Pharmacovigilance Centre Lareb. The register has a prospective cohort design. The target population of pREGnant are pregnant women throughout the Netherlands (approximately 170,000 births/year). They are recruited in several ways, e.g., through a digital invitation of their health care professional around the first prenatal care visit, information leaflets or promotion on relevant websites. Data are primarily collected through web-based questionnaires completed by participating women (three times during pregnancy and three times during the infant’s first year of life). Topics in these questionnaires are current pregnancy, obstetric history, maternal lifestyle, health and medication use, delivery, and infant health. If permission is given, the self-reported data can be complemented with information retrieved from Perined, the perinatal registry of the Netherlands, obstetric and medical records, and/or pharmacy records.

Results: The unique aspects of the Dutch Pregnancy Drug Register pREGnant will be presented and discussed in light of its value in increasing knowledge on the safety aspects related to medication use during pregnancy and breastfeeding.

Conclusion: The Dutch Pregnancy Drug Register pREGnant systematically documents high-quality data on exposure, outcome and co-variables. This is a prerequisite to obtain more insight in medication use among pregnant and breastfeeding women and the potential effects on maternal and fetal/infant health.

References:

• 1. Bakker MK, Jentink J, Vroom F, van den Berg PB, de Walle HEK, de Jong-van den Berg. Drug prescription patterns before, during and after pregnancy for chronic, occasional and pregnancy-related drugs in the Netherlands. Bjog 2006;113:559–68

• 2. Cleary BJ, Butt H, Strawbridge JD, Gallagher PJ, Fahey T, Murphy DJ. Medication use in early pregnancy-prevalence and determinants of use in a prospective cohort of women. Pharmacoepidemiol Drug Saf 2010;19:408–17

• 3. Crespin S, Bourrel R, Hurault-Delarue C, Lapeyre-Mestre M, Montastruc JL, mase-Michel C. Drug prescribing before and during pregnancy in South West France: a retrospective study. Drug Saf 2011;34:595–604

• 4. Irvine L, Flynn RWV, Libby G, Crombie IK, Evans JMM. Drugs dispensed in primary care during pregnancy: a record-linkage analysis in tayside, Scotland. Drug Saf 2010;33:593–604

• 5. Mitchell AA, Gilboa SM, Werler MM, Kelley KE, Louik C, Hernandez-Diaz S. Medication use during pregnancy, with particular focus on prescription drugs: 1976–2008. Am J Obstet Gynecol 2011;205:51.e1–51.e8.

Disclosure of Interest: None declared.

27 O-026 Experience with the Who Central Registry for the Epidemiological Surveillance of Drug Safety in Pregnancy

27.1 C. Halleux^*1

27.1.1 ¹Special Programme for Research and Training in Tropical Diseases, World Health Organization, Geneva, Switzerland

Background/Introduction: Healthcare providers, pregnant women and policy-makers need valid information in order to make informed decisions about the use of drugs during pregnancy. Unfortunately evidence of drug safety is usually very limited and hence there is a clear need for more data. This is particularly valid in context when important questions remain on the safety of drugs during pregnancy or specific periods of pregnancy for drugs used by women of childbearing age and/or intentionally used in pregnancy, including for example anti-retroviral or anti-malarials where treatment cannot be postponed or suspended.

Pregnancy exposure registries and birth outcome surveillances systems are the most common approaches used to collect post marketing drug safety data in pregnancy.

While evidence on safety of drug in pregnancy is limited, options offer by data sharing has received considerable attention in recent years with legal, ethical and practical recommendations on how industry, researchers, regulatory bodies, funders and sponsors should facilitate and practice data sharing. Pooled data provides advantages of a larger database, greater statistical power and more robust evidence upon which decision-makers can make policies and recommendations.

Objective/Aim: Based on the existing need for broader evidence on the drug safety in pregnancy, the Special Programme for Research and Training in Tropical Diseases and other departments at the World Health Organization (WHO) have worked to develop a central pregnancy registry. The central registry provides a platform for pooling data from different pregnancy exposure registries and birth outcome surveillance projects that have collected safety data at country level. It built on existing pregnancy exposure registries and the objective is to provide a single harmonised platform into which contributors (sites/countries/projects) can export anonymized individual case data collected.

Methods: The standardised central registry will hold information on pregnancies, drug exposure, births, maternal outcome and congenital anomalies.

Though not limited to Africa or developing countries, the central database is being developed with a special focus on Africa. This responds to the critical need for active toxicity surveillance in countries where HIV and infectious disease burden is high and better understanding the safety of treatment exposure is substantial.

Results: Since it initiation the central pregnancy registry has grown but the challenges of data sharing still constitutes certain limitation.

Conclusion: Safety data following exposure to drugs during pregnancy are scarce. The WHO central registry for the epidemiological surveillance of drug safety in pregnancy represents an opportunity to optimise use of data.

Further efforts are still needed however to strengthen surveillance of drug safety in pregnant women and encourage data sharing.

Disclosure of Interest: None declared.

28 O-027 Back to the Future: The Case Narrative and Artificial Intelligence

28.1 R. Chandler^*1, N. Norén¹

28.1.1 ¹Research, Uppsala Monitoring Centre, Uppsala, Sweden

Background/Introduction: In his commentary “Why Doctors Need Stories” published in the NY Times, psychiatrist Peter Kramer states “…while we wait for conclusive science, stories will preserve diversity in our theories of mind” [1]. Signal detection in pharmacovigilance is a hypothesis-generating exercise, a clinical science using spontaneous reports of adverse events (AE) and other information sources to assess the probability of a causal relationship between a medicinal product and an event. It is logical therefore that clinical story contained with AE reports in the form of the case narrative is integral to the development of hypotheses of drug safety concerns. And yet, preservation of central role of the case narrative in pharmacovigilance is potentially being challenged with the application of automated case processing to handle increasing levels of spontaneous reporting and the increased requirements to ensure the protection of individual patient data.

Objective/Aim: The aims of this symposium are to underscore the importance of the narrative in the practice of medicine, and specifically within the practice of pharmacovigilance and pharmacoepidemiology, and to become familiarised with how AI (novel machine learning/data science methods) can help make best possible use of the case narratives.

Results: The first speaker, Eugene van Puijenbroek, will discuss the role of clinical reasoning and heuristics in the diagnostic process of clinical medical practice and will highlight their importance in causality assessments central to pharmacovigilance. Within the current infrastructure of the practice of pharmacovigilance, a reliance on disproportionality analysis upon structured data in the form of drug—ADR pairs limits the ability of a safety assessor to best understand the clinical reasoning of the reporter. Review of the case narrative is integral to capturing the nuances of diagnostic considerations and to achieving higher quality assessments of individual case safety reports.

The second speaker, Lucie Gattepaille, will introduce machine learning and its use in pharmacovigilance for the purpose of narrative mining. A number of machine learning methods to capture valuable information from large-scale screening of case narratives will be described. Such methods may enable us to automatically extract information important for clinical assessment and may lead to insights that the sole use of structured fields would leave hidden. These innovations can also be harnessed to ensure patient confidentiality.

Conclusion: Current and future advances in data science methodology can bring us back to basics of pharmacovigilance: “listening” to a story of a patient’s experience and making better clinical decisions regarding medicines safety.

References:

• 1. https://opinionator.blogs.nytimes.com/2014/10/18/why-doctors-need-stories/

Disclosure of Interest: None declared.

29 O-028 Information on Clinical Reasoning and Heuristics, a Missing Link in Pharmacovigilance

29.1 E. van Puijenbroek^*1,2

29.1.1 ¹Pharmacovigilance Centre Lareb, ‘s-Hertogenbosch, the Netherlands; ²Groningen Research Institute of Pharmacy, Pharmacotherapy, -Epidemiology & -Economics, University of Groningen, Groningen, the Netherlands

Background/Introduction: The analysis of Individual Case Safety Reports (ICSRs) mainly relies on the detailed clinical and pharmacological information provided by the reporting healthcare professional or patient. This information is usually aimed at the description of the suspected adverse drug reaction. However, the considerations of the reporter for an adverse drug reaction (ADR) to be present, is rarely mentioned on reporting forms. These considerations can be either based on clinical reasoning, be heuristic in nature, or a combination of both. For the assessors of ICSRs, knowledge of these considerations could provide insight in the clinical decision making process and may help to accept or refute alternative diagnoses. Therefore, in the analysis of ICSRs, insight in this process may enable us to distinguish meaningful from less meaningful observations.

Objective/Aim: In this presentation the role of clinical reasoning and heuristics in the diagnostic process will be discussed, with special attention for current developments in pharmacovigilance.

Methods: Review of literature on clinical reasoning and heuristics in clinical practice.

Results: Clinical reasoning is defined as the sum of thinking and the decision making processes associated with clinical practice. Multiple elements of the clinical situation are used to analyse the occurrence of clinical signs. Clinical reasoning has a strict structure but may vary in the way the case is interpreted depending on the experience of the clinician [1]. Heuristics on the other hand are simple, efficient rules usually focusing on one aspect of a complex problem and ignoring others. They can be based on intuitive judgments but can also be used as deliberate mental strategies when working from limited information [2]. Both processes play an important role in the diagnostic process. During the professional development there is a gradual change from structured formal clinical reasoning towards heuristic reasoning [1]. Whereas in the diagnostic process novices strongly rely on clinical reasoning, clinical experts rely more on previous experience and exploratory problem-solving heuristic techniques.

Conclusion: When assessing ICSRs, knowledge of the considerations to report may help us to substantiate causal reasoning. Although elements of clinical reasoning can be found in the discharge letters, elements describing the heuristic processes usually are not explicitly mentioned and may require active follow up. The increasing number of reports that has to be analysed on a national and global level, as well as the introduction of other sources of reporting like patient reporting, have implications for the way this type of information can be used. In disproportionality analysis, applied when analysing large numbers of ICSRs, additional analysis of case narratives and retrieving information about the reason to report may be needed. In clinical complex cases reported by patients, pharmacovigilance centres may have to track down details of the clinical assessment by the healthcare professionals involved. A better understanding of the reasoning behind reporting links the thought process of the reporting healthcare professional with data on the ICSR and may therefore improve the quality of the case assessment.

References:

• 1. Brush JE. How expert clinicians intuitively recognise a medical diagnosis Am J Med 2017;(130):629–34

• 2. Gigerenzer G, et al. Heuristic decision making Annu Rev Psychol. 2011;62:451–82

Disclosure of Interest: None declared.

30 O-029 Enhancing Pharmacovigilance in Sub-Saharan Africa: Sharing Experiences from a GSK Pilot Initiative in Malawi

30.1 V. Jusot^*1, O. Menang², F. Chimimba³, N. Dzabala³, C. Sambakunsi⁴, C. Chulu⁴, J.-U. Stegmann¹, Y. Guerra Mendoza¹

30.1.1 ¹GSK, Wavre, Belgium; ²PATH, Geneva, Switzerland; ³College of Medicine, University of Malawi; Blantyre, ⁴Pharmacy, Medicines and Poisons Board, Lilongwe, Malawi

Background/Introduction: Historically, the safety profile for most medicines in low- and middle-income countries (LMICs) have been established using spontaneous safety data from high income countries with established pharmacovigilance (PV) systems [1]. However, their safety profile may differ markedly due to a variety of factors including environmental and genetic influences. With more medicines being developed exclusively for use in sub-Saharan Africa (SSA), a region with suboptimal PV systems, a strengthened safety surveillance system is critical for reliable adverse events (AE) reporting and requires effective collaboration between the key players in the field of PV. Currently, there are numerous initiatives aimed at strengthening PV capacity in developing countries. Established collaborative partnerships offer the benefit of pooled technical expertise and resources to ensure synergy and sustainability.

Objective/Aim: Facilitate spontaneous reporting of medicine-related AEs in SSA through capacity building.

Methods: Countries with a basic or minimal PV system were selected. Malawi was the first country to implement the project, in collaboration with the Ministry of Health (MOH), regulatory authority, college of Medicine and PATH, through PV trainings and mentoring of health care professionals (HCPs) in their facilities. Pre-selected key performance indicators were evaluated.

Results: Malawi implementation began in October 2016. PV trainings and regular mentoring has been provided to 34 nationwide focal points and over 300 HCPs sensitized at 37 healthcare facilities. Reported AEs significantly increased from 4 before November 2016 to 204 in May 2018, qualifying Malawi to become a full member of the World Health Organization’s Programme for International Drug Monitoring [2]. The quality and timeliness of AE reports require further improvement.

Conclusion: Intensified PV training and mentoring has shown to be effective in the improvement of passive safety surveillance. Partnerships with country MOH and supranational stakeholders are a key pre-requisite for engagement and country-level ownership. Lessons learned from this experience will assist in seeking further partnerships into other PV-related initiatives with additional LMICs.

Funding source: GlaxoSmithKline Biologicals SA.

References

• 1. Amarasinghe A, Black S, Bonhoeffer J et al. Effective vaccine safety systems in all countries: a challenge for more equitable access to immunization. Vaccine 2013; 31: B108–14

• 2. Join the WHO Programme for International Drug Monitoring. Updated in October 2010. Retrieved May 17, 2018, from https://www.who-umc.org/global-pharmacovigilance/who-programme/join-the-who-programme/

Disclosure of Interest: V. Jusot Shareholder of: GSK, Employee of: GSK, O. Menang: None Declared, F. Chimimba: None Declared, N. Dzabala: None Declared, C. Sambakunsi Grant/Research support from: Reports a grant from GSK in the frame of this work, C. Chulu: None Declared, J.-U. Stegmann Shareholder of: GSK, Employee of: GSK, Y. Guerra Mendoza Shareholder of: GSK, Employee of: GSK.

31 O-030 Strengthening Pharmacovigilance Capacity for Vaccine Manufacturers in Low-And-Middle-Income Countries (Lmics)

31.1 O. Menang^*1, V. Sharma², N. Bhat³, M. Socquet¹, F. Berlanda-Scorza⁴, J. Flores⁴

31.1.1 ¹PATH, Geneva, Switzerland; ²PATH, New Delhi, India; ³PATH, Seattle, United States; ⁴PATH, Washington D.C., United States

Background/Introduction: It is estimated that in the next 3–5 years, about 43 vaccines, 30 drugs and 14 diagnostic products targeted for LMICs will be developed [1]. Many of these new vaccines and drugs target diseases unique to LMICs and will be marketed in these regions soon after licensure. As these products advance from the pre- to post-licensure stage, it is imperative that pharmacovigilance (PV) systems are established to ensure adequate safety surveillance. Manufacturers cannot adequately monitor the safety of their products without functional PV systems. Though developed countries mandate that manufacturers must establish PV systems [2], this is not yet the case in majority of LMICs. However, LMIC manufacturers, often with limited PV system functionality, are required to demonstrate capacity for passive and active safety surveillance when seeking WHO prequalification of their products. PATH provides technical and logistical assistance to vaccine manufacturers in LMICs; PV support comprises establishing new or strengthening existing systems based on global and local regulatory requirements.

Objective/Aim: Establish or strengthen pharmacovigilance quality systems for vaccine manufacturers to ensure adequate safety surveillance of authorized products and appropriate benefit/risk evaluation.

Methods: Four-step procedure consisting of: (1) Questionnaire-based assessment and gap analysis of existing PV system using a PV system assessment tool (2) Develop business-friendly PV strengthening plan considering regulatory requirements and industry best practices (3) Implement identified interventions including PV training, standard operating procedures, IT database (4) Continuous monitoring, improvement and communication with NRAs for alignment.

Results: Sustainable functional PV quality systems established for vaccine manufacturers, with structures, processes and outcomes, for continuous risk–benefit evaluation in compliance with local and international requirements.

Conclusion: Going forward, novel vaccines, particularly those specifically designed for use in LMICs, may not be able to rely on safety and risk–benefit assessments conducted in developed countries. Therefore, adequate safety surveillance and evaluation by both manufacturers and NRAs in LMICs is critical at product launch. Such entities may require support in order to achieve the capacity to meet the requirements for effective and cost-efficient pharmacovigilance.

References:

• 1. Lalvani P, Milstein J. Access to new health products in low income countries and the challenge of pharmacovigilance. Retrieved May 28, 2018, from: http://pdpaccess.org/downloads/projects/full-papers/Pharmacovigilance%20Discussion%20Paper.pdf

• 2. European Medicines Agency. Guideline on good pharmacovigilance practices (GVP) Module I—Pharmacovigilance systems and their quality systems: EMA/541760/2011; 2012

Disclosure of Interest: O. Menang Employee of: PATH, V. Sharma Employee of: PATH, N. Bhat Employee of: PATH, M. Socquet Employee of: PATH, F. Berlanda-Scorza Employee of: PATH, J. Flores Employee of: PATH.

32 O-031 Development of Pharmacovigilance System in a Resource-Limited Country, the Experience of the Democratic Republic of Congo

32.1 D. Nzolo Bomene^*1, Y. Lula¹, N. Ntamabyaliro¹, A. Engo¹, G. Tona¹

32.1.1 ¹Unit of Clinical Pharmacology and Pharmacovigilance, University of Kinshasa, Kinshasa, Democratic Republic of the Congo

Background/Introduction: Implementation of a pharmacovigilance system in resource-limited countries has always been a challenge. Despite all the effort, at global and regional level, Africa is still contributing with less than 1% to the World Health Organization’s (WHO) global Individual Case Safety Report (ICSR) database (VigiBase). The Democratic Republic of Congo (DRC) has one of the most active pharmacovigilance centres in sub-Saharan Africa and is currently used as a reference for the development of pharmacovigilance system in the Central of Africa.

Objective/Aim: To describe the experience of DRC to set up a pharmacovigilance system in a resource-limited country in sub-Saharan Africa.

Methods: An analysis of the DRC pharmacovigilance system since launch were performed. Best practices, bottlenecks and main challenges has been identified. Additionaly, VigiLyze (Full dataset, data lock point 03/06/2018) has been consulted to document the contribution of DRC to the WHO global Individual ICSR database.

Results: As best practices, the national pharmacovigilance centre in DRC has been placed at the Unit of Clinical Pharmacology and Pharmacovigilance, at the University of Kinshasa. It employs academic staffs performing research in Pharmacovigilance. It has included pharmacovigilance in the student curriculum. It interacts with the national health system and provides training and supervision at central, intermediate and operational level. It interacts with public health programs like the national immunization program and those using drugs against malaria, tuberculosis, neglected diseases, etc. It uses different strategies to capture ICSRs and consisting in spontaneous reporting, stimulated reported and active pharmacovigilance, including community-based and hospital-based studies. It works in close collaboration with the national regulatory authority about drug safety. The main challenges included the paucity of financial support, the big size of the country with limited accessibility and the sustainability of pharmacovigilance activities in different area at the end of funding projects.

The different strategies used by the DRC national pharmacovigilance centre since 2010 allowed DRC to contribute with 14,540 ICSRS in VigiBase. Half of these ICSRs come from community-based pharmacovigilance during mass vaccination campaigns against yellow fever (30.7%) and poliomyelitis (13.8%).

Conclusion: The experience of the Democratic Republic of Congo shows that it is possible to develop a pharmacovigilance system in a resource-limited country. While lack of funding is one of the challenges, use of universities, collaboration with public health programs and community-based pharmacovigilance constituted different solution to boost pharmacovigilance system.

Disclosure of Interest: None declared.

33 O-032 Drug Utilization and Drug–Drug Interaction Studies in the Field: Examples of South–North Collaboration Projects

33.1 A. Kuemmerle^*1,2, S. Akakpo³, J. Liwono^3,4, S. Duparc³, C. Burri^1,2, A. Stergachis⁵

33.1.1 ¹Swiss Tropical and Public Health Institute, Basel, Switzerland; ²University of Basel, Basel, Switzerland; ³Medicines for Malaria Venture, Geneva, Switzerland; ⁴Clinical Pharmacology and Pharmacovigilance Unit, Kinshasa, The Democratic Republic of the Congo, ⁵School of Pharmacy and School of Public Health, University of Washington, Seattle, United States

Background/Introduction: In low-resource countries, increased urbanization is contributing to a dual burden of infectious diseases and non-communicable diseases. Multiple comorbidities and the corresponding concomitant use of multiple medicines increase the risk of drug–drug interactions (DDI). For example, co-infection with malaria and HIV results in concomitant administration of antimalarial and antiretroviral medicines. Medicines within these two classes of drugs have high DDI risks when used simultaneously^(1,2). Additionally, in spite of their common use, it is not broadly recognized that herbal medicines can alter the efficacy and safety of co-administered prescription drugs⁽³⁾. In sub-Saharan Africa, traditional medicine is widely used in rural and urban areas⁽⁴⁾. As a consequence, the overlap between conventional medicines and herbal medicines is real among countries in health system transition and may lead to drug-herbal interactions (DHI)⁽⁵⁾.

Objective/Aim: The first objective is to present Swiss Tropical and Public Health Institute’s (SwissTPH) recent and current research in this field conducted with partners from the South and North. Medicine for Malaria Venture’s (MMV) and SwissTPH will also share their point of view from a Product Development Partnership and Research Institution perspective. As a second objective the speakers will present the protocol of their recently planned study. Its aim will be to assess the potential DDIs and DHIs occurring in patients with uncomplicated malaria receiving antimalarial treatment.

Methods: We plan to perform a cross-sectional study in urban Kinshasa, Democratic Republic Congo. The study will be carried out at sentinel health centers and within selected community settings. Each participant and prescriber, after having signed an informed consent form, will be requested to complete a questionnaire designed to collect information on antimalarial treatments, comorbidities, other medications, herbals and socio-economic factors. Drug pairs and drug–herbals pairs will be assessed by at least two different pharmacologists using drug interaction detection software or manually if necessary for drug/herbal interactions. Drug-pairs will be subsequently categorized as deleterious, of potential clinical relevance, of weak clinical significance or not interacting.

Results: Results will be reported on the prevalence of potential DDIs and DHIs among patients as well as factors associated with them. Findings from recent studies, and the expected distribution of new antimalarial drugs in Sub-Saharan Africa, were of MMV and SwissTPH interest since it could generate evidence on real-world drug utilization and the risk of deleterious DDIs.

Conclusion: The long-term goal of our projects is to inform the development of original and locally tailored interventions to create awareness about and mitigate the risk of polymedication in patients receiving antimalarial treatment.

References

• 1. University of Liverpool. HIV Drug Interactions Tables 2018 [cited 2018 01 March]. Available from: https://www.hiv-druginteractions.org/

• 2. Seden K, Gibbons S, Marzolini C, Schapiro JM, Burger DM, Back DJ, et al. Development of an evidence evaluation and synthesis system for drug–drug interactions, and its application to a systematic review of HIV and malaria co-infection. PLoS One. 2017;12:e0173509

• 3. Wheaton AG, Blanck HM, Gizlice Z, Reyes M. Medicinal herb use in a population-based survey of adults: prevalence and frequency of use, reasons for use, and use among their children. Ann Epidemiol. 2005;15:678–85

• 4. Boukandou Mounanga M, Mewono L, Aboughe Angone S. Toxicity studies of medicinal plants used in sub-Saharan Africa. J Ethnopharmacol. 2015;174:618–27

• 5. Thomford NE, Dzobo K, Chopera D, Wonkam A, Skelton M, Blackhurst D, et al. Pharmacogenomics implications of using herbal medicinal plants on African populations in health transition. Pharmaceuticals (Basel) 2015;8:637–63.

Disclosure of Interest: None declared.

34 O-033 Distilling the Value of Narratives with Machine Learning

34.1 L. Gattepaille^*1

34.1.1 ¹Uppsala Monitoring Centre, Uppsala, Sweden

Background/Introduction: With the steady increase in computing resources and the unparalleled amounts of data available, machine learning is a promising technology that has already offered significant improvement in areas such as computer vision and speech recognition. An interesting application of machine learning for pharmacovigilance is narrative mining. Case narratives often contain useful, detailed and nuanced information that might complement what can be found in the structured fields of case reports. Machine learning methods can help us automatically extract and harness this information at scale and may lead to insights that the sole use of structured fields would leave hidden.

Objective/Aim: The Uppsala Monitoring Centre is a firm believer in the unique value of free-text narrative accounts of suspected adverse drug reactions and seeks to develop machine learning methods to distil valuable information from large-scale screening of case narratives.

Methods: For example, we have sought to automatically identify the severity of an adverse event from the narrative, an aspect that is not currently present in the structured description of case reports. Furthermore, we have developed named entity recognition tools that can be used recognize ADRs and their associated drugs, as well as distinguish them from indication mentions. In order to enable signal detection and assessment at the global scale, we should seek to make possible the sharing of case narratives across organisations without compromising patient confidentiality.

Results: To this end, we are developing machine learning techniques to automatically de-identify case narratives allow patient privacy to be protected while keeping the crucial clinical information intact for review. 

Conclusion: Finally, I will briefly present potential areas of interest in narrative mining, illustrating that narratives are a rich resource that provides great potential for a better characterization of case reports, and that efforts in the field should push the science of pharmacovigilance forward.

Disclosure of Interest: None declared.

35 O-034 Similar Sounding Names in Medications Safety: Risky or Not?

35.1 Y. Jani^*1,2, D. Gerrett³

35.1.1 ¹Centre for Medicines Optimisation Research & Education, UCLH NHS Foundation Trust, London, United Kingdom; ²Research Department of Practice & Policy, UCL School of Pharmacy, London, United Kingdom; ³NHS Improvement, London, United Kingdom

Background/Introduction: Medication errors and related harm are an established global patient safety concern. Look-alike sound-alike medicine names and products are implicated as common caustive and contributory factors. However there is little research on the patient safety benefits of International Non-proprietary Name (INN) common stems: a part of the name that expresses the pharmacologically-related group to which the substance belongs.

Objective/Aim: The aim was to determine if there was an association between medication suffixes and pharmacological function. The objectives were to ascertain any differences in association amongst doctors, nurses and pharmacists; and to identify if the association was linked to experience of the professional.

Methods: A combination of actual medicines and fictitious names with suffix extensions based on common drug names where there was a known link between extension and pharmacological function were presented as sentences. Confounder sentences were designed such that there was no known suffix extension and no relationship with a pharmacological function. 88 sentences were developed of which 44 were presented to the participants at random through the survey software.

A convenience sample of doctors, nurses and pharmacists was recruited and invited to complete an online survey to indicate whether the name (actual or fictitious) matched the indication in the sentence presented. 

Results: 10 doctors, 36 nurses (of which 6 = students), 14 pharmacists (of which 5 = pre-registration) and 12 pharmacy staff completed the survey.

Nurses were the least likely and pharmacists and pharmacy staff most likely to correctly match suffixes to the pharmacological function, as shown by an ascending polynomial relationship from the nursing profession through medicine, to pharmacy. There was no difference in correcly matching medicine name to function by experience. ‘cillin’ and ‘mycin’ antimicrobials were the most identifiable drug classes across all professions.

Conclusion: This study supports an association between medicine name suffixes and pharmacological function (presented as suggested indications). The use of International Non-proprietary Names may have a positive safety impact in recognition of critical medicines such as antimicrobials.

Disclosure of Interest: None declared.

36 O-035 Patient Involvement in Adverse Drug Reaction Detection and Reporting

36.1 R. Karwa^*1,2, M. Maina³, B. Jakait^3,4, A. Gardner^4,5, C. Ngetich^3,6

36.1.1 ¹Pharmacy Practice, Purdue University, West Lafayette, United States; ²Pharmacology, Moi University College of Health Sciences, Eldoret, Kenya; ³Pharmacy, Moi Teaching and Referral Hospital, Eldoret, Kenya; ⁴Executive, Academic Model Providing Access to Healthcare, Eldoret, Kenya; ⁵Infectious Diseases, Indiana University, Indianapolis, United States; ⁶Pharmacy, Academic Model Providing Access to Healthcare, Eldoret, Kenya

Background/Introduction: Approximately two-thirds of people living with HIV globally reside in Sub-Saharan Africa. In 2015, 12 million patients in SSA were on antiretroviral therapy (ART) [1]. ART-related drug toxicity is a growing concern in low and middle-income countries, where under-developed pharmacovigilance (PV) infrastructure is common, as it represents a major contributor to treatment interruptions and poor adherence [2, 3]. HIV peer health workers, trained HIV-positive patients have previously been shown to improve outpatient clinic follow up and to increase adherence to ART [4−6]. To address the gap in PV, we set up a peer health worker program.

Objective/Aim: To describe the implementation and impact of an HIV peer health worker program targeting adherence, ADR reporting and medication safety issues in western Kenya.

Methods: In 2012, we conducted a study evaluating ADR reporting approaches, including an arm where HIV peer health workers administered surveys, in an HIV-positive population in western Kenya. The study site, the Academic Model Providing Access to Healthcare (AMPATH), is a partnership with Moi University, Moi Teaching and Referral Hospital (MTRH), the Ministry of Health and a number of North American universities, that provides comprehensive services in the public health sector for a rural, underserved catchment population of over 4 million people. Patient interactions with peers revealed not only ADRs experienced but also complex concerns, adherence issues and an eagerness among patients to converse with someone who held a shared-disease experience. To capitalize on this finding, we held stakeholder meetings with local providers to understand how to transition from a study to a clinical program. Through additional grant funding, we retained 4 peers to set up the program.

Results: The transition from a study to an HIV peer health worker program was successful in creating both inpatient and outpatient programs. Two HIV peer health workers were deployed to the inpatient setting at MTRH, where they provide adherence and disclosure counseling, linkage to outpatient care, medication refills, ADR documentation and post-discharge follow up for approximately 900 patients per year. In an outpatient pharmacy setting, 2 peers provide medication counseling and ADR assessments through group presentations and individual sessions.  Additionally, a novel HIV resistance clinic, which provides care to patients who are failing 2nd line protease inhibitor ART was established with peers playing a pivotal role. Peers interact with the patients first, generating a relationship and an accurate medical history, including ADR assessments prior to provider–patient interactions. Over 200 patients have been enrolled into the resistance clinic with a majority of the patients successfully being retained on second line ART. Peers are currently being employed in the programmatic roll-out of dolutegravir to document ADRs experienced in a western Kenyan population.

Conclusion: The experiences at AMPATH indicate that trained patients can play crucial roles in promoting adherence, enhancing medication safety and improving ADR detection and reporting.

References:

• 1. WHO. HIV/AIDs. 2017  [cited 2018 24/05/]; Available from: http://www.afro.who.int/health-topics/hivaids

• 2. Messou, E., et al., Antiretroviral treatment changes in adults from Cote d’Ivoire: the roles of tuberculosis and pregnancy. Aids 2010; 24: p. 93–9

• 3. Braitstein, P., et al., Sustainability of first-line antiretroviral regimens: findings from a large HIV treatment program in western Kenya. J Acquir Immune Defic Syndr 2010; 53: p. 254–9

• 4. Enriquez, M., et al., A Peer-Led HIV Medication Adherence Intervention Targeting Adults Linked to Medical Care but without a Suppressed Viral Load. J Int Assoc Provid AIDS Care 2015; 14: p. 441–8

• 5. Hatcher, A.M., et al., Predictors of linkage to care following community-based HIV counseling and testing in rural Kenya. AIDS Behav 2012; 16: p. 1295–307

• 6. Richter, L., et al., Pregnant women living with HIV (WLH) supported at clinics by peer WLH: a cluster randomized controlled trial. AIDS Behav 2014; 18: p. 706–15

Disclosure of Interest: None declared.

37 O-036 A Delphi Study on the Development of a risk Proportionality Framework for the Selection of Risk Minimisation Interventions in Asia

37.1 Y. Moride^*1,2, S. Frise^3,4, H. Le Louët⁵, G. Castillon², J.-C. Delumeau⁶

37.1.1 ¹Université de Montreal, Montreal, Canada; ²YOLARX Consultants, Montreal, Canada; ³AstraZeneca, Mississauga, ⁴Dalla Lana School of Public Health, University of Toronto, Toronto, Canada; ⁵Department of Pharmacology, Université Paris-Est, Créteil, France; ⁶Bayer, South East Asia, Singapore

Background/Introduction: Existing risk minimisation interventions (RMIs), frequently used in the European Union and the United States, may not be applicable to Asian countries.

Objective/Aim: This study aims at developing explicit criteria for the evaluation of risk proportionality applicable to RMIs in Asia.

Methods: Project consists of two phases: A Consultation Phase (pre-Delphi) and A Modified Delphi Study. Consultation phase involved a purposeful sample of 8 experts from regions of the world with the highest experience in therapeutic risk management (EU, US, Australia, Canada, Singapore, Taiwan, Japan). In-depth individual interviews were conducted in order to identify key factors (criteria) and circumstances used in the assessment of risk proportionality and their impact on RMIs (low, medium, high stringency interventions). Using those factors as a starting point, a Delphi panel is used to reach consensus on a structured framework (e.g., a set of explicit criteria and associated weights (scoring system) to assess risk proportionality). Pharmacovigilance professionals representing all target groups (regulatory, academia, industry), distributed across countries belonging to the Association of South-East Asian Nations (ASEAN), as well as East-Asian and South-Asian countries, were contacted.

Results: In the Consultation Phase, the following factors were determinants of whether a RMI is needed: Frequency and seriousness of the AE, benefit–risk ratio, severity of the indication, suddenness and unpredictability of the AE, inability of routine medical practice to minimize the risk, teratogenicity, specific AEs (hepatotoxicity, agranulocytosis, SJS, etc.), genetic profile, extent of drug use in the population, risk of off-label use, drug confusion, novelty of the actions that must be taken to treat or manage the risk. The main country-specific factor influencing the selection of the RMI is the local treatment practice (prescription and follow-up by specialists versus general practitioners), drug coverage, as well as access to specialists or procedures for monitoring (e.g., ECG or biomarkers). These factors were used to develop the questionnaire for the Delphi panel. So far, there are 16 participants out of a total of 20–25. Each respondent has to rank the importance of each factor in determining whether a RMI is justified, from 1 (not-important) to 10 (extremely important).

Conclusion: Themes and determinants of risk proportionality were identified in the Pre-Delphi consultation. Panel responses after two Delphi rounds will be synthesized and presented.

Disclosure of Interest: None declared.

38 O-037 Addressing the Challenges Affecting the Implementation of Routine Risk Minimisation and Risk Minimisation Interventions in Diverse Countries

38.1 J.-C. Delumeau^*1

38.1.1 ¹Pharmacovigilance, BAYER, Singapore, Singapore

Background/Introduction: This presentation is part of the Symposium: Risk Minimisation Interventions for diverse health care systems: Following-up on CIOMS IX. As described in CIOMS IX, the decision to implement a risk minimisation intervention and the selection of the method should include a careful analysis of the specificity and capability of the target health care system. A particular attention should be paid to the burden which may result from implementing the intended risk minimisation intervention and from the method used for measuring its effectiveness. It should be ensured that the intended measure is likely capable of providing the expected benefit rather than detrimentally restrict the access to the medicine.

Objective/Aim: The purpose of this presentation on behalf of the ISoP SiG Group on Risk Minimisation Methods for Asian Countries, is to compile and analyse the experience accumulated by the different stakeholders involved in risk minimisation activities in order to determine the lessons learned that can help selecting the methods and optimise their implementation in the contexts of diverse health care systems.

Methods: Challenges affecting the implementation of risk minimisation will be considered and analysed. Both routine risk minimisation methods and risk minimisation interventions will be addressed. The challenges related to the capability of the health care system or other country-specific aspects will be considered, especially to what extent specific risk minimisation interventions can effectively address the sub-optimal impact of routine risk minimisation in some countries to ensure the safe use of targeted products.

Results: From the analysis of the experience accumulated in the past 4 years, the lessons learned will be determined for conventional educational and access restriction methods as well as for methods powered by Web and App communication technologies. The current landscape will be compared to the trends anticipated by CIOMS IX. Further improvements aimed to address the lessons learned will be proposed, and future perspective will be considered.

Conclusion: The presentation will conclude on how the outcome of the ISoP SIG on Risk Minimisation Methods for Asian countries can help the risk minimisation decision making process in consideration of the above lessons learned.

References:

• 1. Practical Approaches to Risk Minimisation for Medicinal Products. Report on CIOMS Working Group IX. Geneva, 2014.

Disclosure of Interest: J.-C. DELUMEAU Employee of: Bayer.

39 O-038 Listening to Kasparov: Putting Human Experts and Artificial Intelligence Together to Create Advanced Pharmacovigilance

39.1 S. Comfort^*1, M. Munoz²

39.1.1 ¹Genentech, San Francisco, United States; ²US Food and Drug Administration, Silver Spring, United States

Background/Introduction: World champion grandmaster chess master Garry Kasparov was defeated by IBM’s “Deep Blue” chess system in 1997, marking the first time in human history that a world champion was defeated by a computer.   Since then, AI has developed rapidly with AlphaGo beating the world No. 1 ranked human player Ke Jie in a 2017 three-game match of Go.  The growing successes of AI in many fields has led some to feel that it will take over everything and replace humans in many fields, including PV.

Objective/Aim: In this talk, the speakers will present perspectives inspired by Mr. Kasparov’s development of “Advanced Chess” to partner machines and humans to play advanced levels of chess.

Methods: Dr. Comfort will present highlights of Machine Learning efforts in PV as a result of internal and external collaborations (e.g., IBM, PDSS, PVIS, PDSI).

Results: His talk illustrates that beyond the headlines of disruption, partnering with AI will actually allow us to develop an “advanced” level of PV that combines the best aspects of human and machine intelligence. The results can be a level of product safety insights, quality, and risk management solutions for patients that are not achievable today.

Dr. Muñoz will highlight opportunities for AI to support PV practices from a regulator’s perspective. She will share findings from ongoing projects demonstrating the potential for advanced PV, such as those aimed at timely signal identification.

Conclusion:

Disclosure of Interest: None declared.

POSTER PRESENTATIONS

40 ISoP18-1021 Developing a New Methodology for Preparing a Guideline: The Case of Good Pharmacovigilance Outsourcing Practices

40.1 G. Furlan¹, B. Van Leeuwen ², M. Bertazzoli³, B. Edwards^*4

40.1.1 ¹Seqirus, Maidenhead, United Kingdom, ²Astellas, Amsterdam, Netherlands, ³ISOP, Lugano, Switzerland, ⁴ACRES, Leatherhead, United Kingdom

Background/Introduction: Structured workflows, organisation and practices can hinder innovation instead of promoting it [1]. In addition, the legal and bureaucratic considerations that govern formal channels for voicing concerns may inhibit from speaking up [2] and proposing solutions. Legal requirements for innovative work practices take a long time to be implemented. Guidelines often are derived from these requirements at an even later stage. In pharmacovigilance, outsourcing could be an example: it has become more and more common practice attracting the authorities’ attention. The Medicines and Healthcare Products Regulatory Agency (MHRA) has recently published the outsourcing areas identified, during inspections, as problematic for Marketing Authorisation Holder and Service Providers [3]. Articles describing the principles of pharmacovigilance outsourcing have been published [4], but a consensus guideline describing all the steps, principles and points to consider for this topic is missing.

Objective/Aim: The authors, members of a volunteer group, are trying to fill this gap by working through a new way of preparing such a guideline.

Methods: A first draft, also referring to guidelines in other areas of industry [5], has been prepared and is undergoing subsequent cycles of review by increasingly wider number of pharmacovigilance experts, both from the industry and from the service providers. Following each cycle of review, the contributions from all stakeholders are evaluated and included in the guideline. The final aim is to have a non-prescriptive and voluntary standard that can be used by both the clients and vendors so to improve mutual understanding and likelihood of success.

Results: The guideline describes how, at first, all clients (the party outsourcing the activity) should have at least an in-house pharmacovigilance system expert who understands regulatory requirements, workflows and risks associated with non-compliance so to mitigate them. This person should also be accustomed to manage and negotiate contracts with vendors in order to select the one that suits the needs of the client best and is empowered to take decision. It goes without saying that the client should have an overview of the outsourced tasks. Service providers, on their end, should be transparent and coherent regarding their experience, marketing positioning and overall strategy; they should always try to understand the exact clients’ needs, expectations and the support they can receive from the client in performing the outsourced tasks.

Conclusion: Setting clear, transparent and reasonable expectations is the basis for both the client and vendor to optimally design and describe their joint pharmacovigilance system.

References:

• 1. Steven S. Hoffman: Make elephants fly. The Process of Radical Innovation. Piatkus, 2017

• 2. Martin GP, et al. Making soft intelligence hard: a multi-site qualitative study of challenges relating to voice about safety concerns. BMJ Qual Saf 2018; https://doi.org/10.1136/bmjqs-2017-007579

• 3. Harper J. MHRA GPvP Inspectorate guide to marketing authorisation holder considerations for agreements with pharmacovigilance system service providers. 22 January 2018 MHRA Inspectorate Blog https://mhrainspectorate.blog.gov.uk/2018/01/22/mhra-gpvp-inspectorate-guide-to-marketing-authorisation-holder-considerations-for-agreements-with-pharmacovigilance-system-service-providers/

• 4. Furlan, G, van Leeuwen, B,Edwards, B. Pharm Med 2017;31:75

• 5. van Leeuwen BP, Prendergast C, Edwards B, Dawson B. Can pharmacovigilance learn from the oil and gas industry, which has been outsourcing for over a century? Ther Innov Regul Sci 2017;51:11–5

Disclosure of Interest: G. Furlan Employee of: pharmaceutical Industry, B. Van Leeuwen Employee of: pharmaceutical industry, M. Bertazzoli: None Declared, B. Edwards Employee of: pharma industry service provider.

41 ISoP18-1022 Fetal Effects of Serotonin-Noradrenaline Reuptake Inhibitor Use During Pregnancy

41.1 F. Martin^*1, J. L. Richardson^1,2, H. Dunstan², A. Greenall², S. Stephens², L. M. Yates^1,2,3, S. H. L. Thomas^1,2

41.1.1 ¹Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, United Kingdom^{; 2}UKTIS, ³Northern Genetics Service, Newcastle-upon-Tyne, United Kingdom

Background/Introduction: The concern for women taking a medication during pregnancy is an important consideration when providing care and data is limited; previous studies have described increased risk of preterm delivery [1] for example. The aim of this study was to determine whether there is an increased risk of adverse pregnancy outcomes for women who use SNRI antidepressants during pregnancy.

Objective/Aim: To perform a prospective cohort study investigating the fetal effects of maternal Serotonin-Noradrenaline Reuptake Inhibitor (SNRI) use during pregnancy.

Methods: This study utilised a prospective comparative cohort design using data obtained by the UK Teratology Information Service (UKTIS) between 1995 and 2017. Inclusion criteria required pregnancies to be singleton, without exposure to known or suspected teratogens (excluding alcohol) and without maternal poisoning/overdose exposures. SNRI exposed pregnancies were matched 1:3 with pregnancies exposed to selective serotonin reuptake inhibitors (SSRI) and 1:5 with non-teratogen exposed (NTE) pregnancies by maternal age and year of enrolment (± 3 years). Malformations were categorised using EUROCAT specifications by two study authors blind to maternal exposure status. Maternal demographics were compared using Chi squared/Fishers exact tests, and odds ratios were computed using exact methods to compare crude pregnancy/fetal outcome rates.

Results: Of 320 pregnancies exposed to SNRIs during pregnancy, all included first trimester exposure, and were matched to 960 SSRI exposed and 1600 NTE comparator groups. We observed no significant difference in the rate of spontaneous abortion, elective termination or intrauterine death between exposed and comparator groups. However, the crude rate of live births was significantly decreased in the SNRI group compared with NTE (OR 0.690, 95% CI 0.545–0.932), but not with the SSRI group (OR 0.895, 95% CI 0.658–1.22). The risk of preterm delivery was significantly increased in SNRI pregnancies compared with the NTE group (OR 1.57, 95% CI 1.06–2.33); no such difference was observed when comparing SSRI exposed. A non-significant increase in major malformation risk was seen in the SNRI group compared with both comparator groups; half of the major malformations in the SNRI exposed were cardiac, showing a non-significant increase in comparison with both controls.

Conclusion: These data do not provide sufficient evidence of an increased risk of adverse pregnancy outcomes following SNRI exposure in human pregnancy, however due to the small sample size there is a limited ability to detect slight increases in adverse outcomes or rare events. Further research is therefore justified.

References:

• 1. Lennestål R, Källén B. Delivery outcome in relation to maternal use of some recently introduced antidepressants. J Clin Psychopharmacol. 2007;27:607–13

Disclosure of Interest: None declared.

42 ISoP18-1025 Sjs/Ten Induced by Carbamazepine and Oxcarbazepine: The Analysis of Drug Injury Relief Applications in Taiwan

42.1 M.-Y. Chien¹, P.-H. Chao^*1, W.-W. Chen¹

42.1.1 ¹Taiwan Drug Relief Foundation, Taipei, Chinese Taipei

Background/Introduction: For the prevention of carbamazepine -induced SJS/TEN (CBZ-SJS/TEN), genetic test of HLA-B*15:02 before carbamazepine (CBZ) prescription has been covered by the national health insurance in Taiwan since 2011. Since then, it is observed that the usage of carbamazepine was significantly declined, whereas the usage of oxcarbazepine (OXC) has risen substantially in the same period of time in Taiwan [1]. A recent study revealed that oxcarbazepine-induced SJS/TEN (OXC-SJS/TEN) is also associated with HLA-B*15:02 in Asian populations (Chinese and Thai), but the incidence and severity of OXC-SJS/TEN are less than that of CBZ-SJS/TEN [2].

Objective/Aim: To examine the trend of carbamazepine and oxcarbazepine associated SJS/TEN in Drug Injury Relief System in Taiwan.

Methods: This research analyzed the applications of Drug Injury Relief System from 1999 to 2017 in Taiwan. Culprit drugs and adverse drug reactions were classified according to their ATC and MedDRA codes, respectively.

Results: From 1999 to 2017, the total case number of drug-induced SJS/TEN is 1044. Among these cases, 218 cases are CBZ-SJS/TEN (17 death cases, 5 disability cases and 196 severe illness cases) and 17 cases are OXC-SJS/TEN (1 death cases, 1 disability cases and 15 severe illness cases). The majority cases of CBZ-SJS/TEN occurred before 2011, whereas the greater part of OXC-SJS/TEN occurred after 2011. It is also noted that cases of OXC-SJS/TEN were not seen until 2008, even though oxcarbazepine has been approved in Taiwan since 2002. The case number of OXC-SJS/TEN was relatively low compared to that of CBZ-SJS/TEN before 2013. However, it has exceeded that of CBZ-SJS/TEN in 2017.

Conclusion: The case number of drug injury application for CBZ-SJS/TEN was decreased significantly after 2012 which may be attributed to the prescribing patterns change due to the HLA-B*15:02 screening policy implemented in 2011. Despite the usage of oxcarbazepine was increased substantially after 2011, only a slight increase of OXC-SJS/TEN was observed from Taiwan Drug Injury Relief Database. However, the potential risk of SJS/TEN induced by oxcarbazepine still cannot be overlooked.

References:

• 1. Wang YH, et al. The medication risk of Stevens–Johnson syndrome and toxic epidermal necrolysis in Asians: the major drug causality and comparison to the USA FDA label. Clin Pharmacol Ther 2018 https://doi.org/10.1002/cpt.1071

• 2. Chen CB, et al. Risk and association of HLA with oxcarbazepine-induced cutaneous adverse reactions in Asians. Neurology 2017; 88: 78–86

Disclosure of Interest: None declared.

43 ISoP18-1032 Analysis of the Risk Management Plans Submitted to the Rational Drug Use and Pharmacovigilance Department at JFDA (2014–2017)

43.1 J. Jaber^*1

43.1.1 ¹Rational Drug Use and Pharmacovigilance Department, Jordan Food and Drug Administration, Amman, Jordan

Background/Introduction: Companies are required to submit a risk-management plan (RMP) to the Jordan Food and Drug Administration (JFDA) when applying for a marketing authorization (MA); as required by the Arab GVP [1] which was effective in July 2015. Accordingly Jordan pharmacovigilance guideline [2] was updated in July 2016, which makes an RMP submission obligatory—article No. 17—in the following situations: (1) Medicine registration; (2) Leaflet update that includes a new indication and/or a new age group and (3) upon JFDA request.

Objective/Aim: The aims of the analysis were to create a national database for the JFDA that includes all of the additional risk minimization measures (ARMM) for the registered medicines in Jordan. This database enhances JFDA decisions regarding proper implementation of these measures and the best approaches to increase their effectiveness.

Methods: Risk management plans submitted to the rational drug use and pharmacovigilance (RDU & Pv) department at JFDA from 2014 to 2017 were analyzed.

Results: The results showed that among all of the submitted and approved RMPs (n = 340), 33 RMPs (10%) had an ARMM; which contains at least one or all of the following; physicians educational materials, pharmacists educational materials, direct healthcare professional communication (DHCP), patients educational materials and controlled access program. The annual rate of RMPs increased gradually over the study period. There was about an 18-fold increase in the number of received RMPs. In year 2014 (12 RMPs) were submitted; 11 RMPs for originator medicines and one RMP for generic medicine, with only one RMP that had an ARMM. At the following year (53 RMPs) were submitted; 31 RMPs for originator medicines and 22 RMPs for generic medicines, six RMPs had an ARMM. At year 2016 (67 RMPs) were submitted; 38 RMPs for originator medicines and 29 RMPs for generic medicines with 10 RMPs having an ARMM. Finally in year 2017(216 RMPs) were submitted; 79 RMPs for originator medicines and 137 for generic medicines with 16 RMPs having an ARMM.

Conclusion: This study highlights the importance of establishing a robust pharmacovigilance system in Jordan, which is strongly needed to safe handle newly registered medicines (biosimilar, biological…) that required a special RMP design with proper risk minimization measures.

References:

• 1. Guideline on good pharmacovigilance practices (GVP) effective from July 2015 (Arab Countries). Available from http://www.jfda.jo/

• 2. Pharmacovigilance guidelines 2016 (Jordan). Available from http://www.jfda.jo/

Disclosure of Interest: J. Jaber Employee of: JFDA there is no conflict of interest.

44 ISoP18-1035 Herpes Simplex Virus Encephalitis After Deep Brain Stimulation for Epilepsy: A Case-Report

44.1 M. Gavard^*1, S. Chabardes², F. Bartolomei³, P.-M. Regis⁴

44.1.1 ¹Clinical Research and Innovation Department,; ²Neurosurgery Department, Grenoble Alpes University Hospital, Grenoble, France; ³Cerebral Epileptology and Rhythmology Department,; ⁴Neurosurgery Department, Timone University Hospital—APHM, MARSEILLE, France

Background/Introduction: Encephalitis is defined by the presence of an inflammatory process of the brain and clinical evidence of neurologic dysfunction [1]. It can be caused by a virus like Herpes simplex virus (HSV), which is the most commonly identified infectious cause of encephalitis in France [2].

Objective/Aim: Herpes simplex virus encephalitis triggered by neurosurgical interventions such as craniotomies has been previously described but it remains a rare occurrence [3, 4]; here we report a case of encephalitis due to herpes simplex virus-1 (HSV-1), following deep brain stimulation (DBS) starting for epilepsy.

Methods: Herpes simplex virus-1 infection was confirmed by cerebrospinal fluid (CSF) polymerase chain reaction (PCR).

Results: The patient was a 33-year-old man who benefited from implantation of leads for deep brain stimulation (target: anterior nucleus). Indeed, he suffered from epilepsy secondary to viral encephalitis at 7-months-old. About 1 month after leads implantation, the day after deep brain stimulation gets started, he developed a transient confusional state. Computerized tomogram did not reveal any bleeding. Confusion recurred 6 days later, with fever and headaches. The CSF PCR was positive for HSV1 and DBS was stopped. Aciclovir treatment was introduced.

Conclusion: DBS probably stimulated the herpes simplex virus that was asleep in this patient. The risk of HSV reactivation after DBS must be taken into account in patients who suffered from HSV brain infections in the past.

References:

• 1. Tunkel AR, Glaser CA, Bloch KC, Sejvar JJ, Marra CM, Roos KL, et al. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2008;47:303–27

• 2. Mailles A, Stahl JP. Infectious Encephalitis in France in 2007: A National Prospective Study Clin Infect Dis 2009:49:1838–47

• 3. Jaques DA, Bagetakou S, L’Huillier AG, Bartoli A, Vargas MI, Fluss J, et al. Herpes simplex encephalitis as a complication of neurosurgical procedures: report of 3 cases and review of the literature. Virol J 2016;13:83

• 4. De Almeida SM, Crippa A, Cruz C, De Paola L, De Souza LP, Noronha L, et al. Reactivation of herpes simplex virus-1 following epilepsy surgery. Epilepsy Behav Case Rep 2015;27:76–8

Disclosure of Interest: None declared.

45 ISoP18-1040 Adverse Drug Reactions Leading to Hospitalization in the Elderly Using Prospective Identification Versus Administrative Coding

45.1 N. Parameswaran Nair^*1, L. Chalmers¹, G. Peterson¹, B. Bereznicki¹, C. Curtain¹, L. Bereznicki¹

45.1.1 ¹Pharmacy, School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Australia

Background/Introduction: Adverse drug reactions (ADRs) are a major public health problem in the elderly, accounting for 6–12% of hospital admissions [1]. Effective detection and prevention are important to tackle the global burden of ADRs [2]. The use of different methods of ADR detection results in studies identifying varying rates and types of ADRs, and different drug classes responsible for ADRs [3]. There is a lack of data comparing different ADR identification methods in the same cohort of patients. 

Objective/Aim: To compare prospective identification of ADR-related hospital admissions in the elderly with administrative coding using the International Classification of Diseases 10th Revision Australian Modification (ICD-10-AM) coding system.

Methods: We linked the records of 768 enrolled patients from an earlier study (the PADR-EC study) [4], where clinical pharmacists identified ADRs using prospective data collection, to their hospital administrative data. We identified patients in the study whose admissions were coded as ADRs using ICD-10-AM codes. We then compared the prevalence and characteristics of ADR-related hospital admissions identified by the two approaches.

Results: According to ICD-10-AM coding, 2.7% of patients were admitted due to ADRs, while 15.0% of patients were deemed to have been admitted due to ADRs based on prospective identification by clinical pharmacists. Most (85.7%) patients coded as having an ADR-related admission were also identified as such prospectively. Haematological (23.1%) and metabolic reactions (23.1%) were frequent causes of ADRs identified by coding, whereas cardiovascular ADRs (27.8%) were more commonly identified prospectively by pharmacists. Antidepressants (16.7%) and cardiac glycosides (16.7%) were the most commonly implicated drug groups in ADRs identified by coding, whereas diuretics (28.8%) and renin-angiotensin system inhibitors (17.0%) were frequently implicated in the prospective identification.

Conclusion: Reliance on administrative coding potentially underestimates the extent of the problem of ADRs as a cause of hospitalization in the elderly, and more detailed prospective analysis of admissions provides additional targets for strategies to prevent ADRs. The types of ADRs identified also differ between the two approaches.

References:

• 1. Parameswaran Nair N, Chalmers L, Peterson GM, Bereznicki BJ, Castelino RL, Bereznicki LR. Hospitalization in older patients due to adverse drug reactions—the need for a prediction tool. Clin Interv Aging 2016;11:497–505

• 2. World Health Organization. International drug monitoring: the role of the hospital. Geneva: World Health Organization; 1969. Technical Report Series no. 425. http://apps.who.int/iris/handle/10665/40747. Accessed 10 April 2018

• 3. Thurmann PA. Methods and systems to detect adverse drug reactions in hospitals. Drug Saf 2001;24:961–8

• 4. Parameswaran Nair N, Chalmers L, Connolly M, Bereznicki BJ, Peterson GM, Curtain C, et al. Prediction of hospitalization due to Adverse Drug Reactions in Elderly Community-Dwelling Patients (The PADR-EC Score). PLoS One 2016;11:e0165757

Disclosure of Interest: N. Parameswaran Nair: None Declared, L. Chalmers: None Declared, G. Peterson: None Declared, B. Bereznicki Other: Bonnie Bereznicki has received funding from Boehringer Ingelheim Pty Ltd. Disclosed funding was for activities outside of this research., C. Curtain: None Declared, L. Bereznicki Other: Luke Bereznicki has received funding from Boehringer Ingelheim Pty Ltd. Disclosed funding was for activities outside of this research.

46 ISoP18-1045 Drug- or Herb- Induced Liver Injury in China

46.1 J.-B. Wang^*1,2, Y.-M. Guo¹, X.-H. Xiao^1,2

46.1.1 ¹Beijing 302 Hospital of China, Beijing, China; ²China National Advisory Council of Traditional Chinese Medicines-Induced Liver Injury, Beijing, China

Background/Introduction: Drug- or herb- induced liver injury (DILI or HILI) constitutes major concerns in drug safety issues [1, 2], which has been illustrated to cause high medical and socioeconomic burdens in developed countries [3]. However, the prevalence and burden of DILI or HIIL in developing countries are almost unknown [4, 5].

Objective/Aim: To investigate the pharmacoepidemiologic profiles and trends of DILI or HILI in the world’s largest developing country—China.

Methods: The national adverse drug reactions (ADR) monitoring data, nationwide health insurance data, million-scale community medical data and the hospital network medical data were involved in this study. 

Results: DILI has faster expansion than that of all ADRs in China. And DILI has been dramatically under-estimated in China, especially in primary health system. The under-recognition rate and the under-reporting rate of DILI (including HILI) in a typical primary healthcare system is over 80 and 90%, respectively. HILI is one of the major parts of DILI in China. Under-recognition rate and under-reporting rate of HILI were even higher than those of synthetic drugs. The proportion of severe reports of HILI increased faster than that of synthetic drugs. There are great regional differences in China regarding monitoring and controlling ability of DILI. The low-income/underdeveloped regions showed worse data than those high-income/developed regions.DILI has faster expansion than that of all ADRs in China. And DILI has been dramatically under-estimated in China, especially in primary health system. The under-recognition rate and the under-reporting rate of DILI (including HILI) in a typical primary healthcare system is over 80 and 90%, respectively. HILI is one of the major parts of DILI in China. Under-recognition rate and under-reporting rate of HILI were even higher than those of synthetic drugs. The proportion of severe reports of HILI increased faster than that of synthetic drugs. There are great regional differences in China regarding monitoring and controlling ability of DILI. The low-income/underdeveloped regions showed worse data than those high-income/developed regions.

Conclusion: There are significant under-estimation and under-recognition of DILI, especially HILI, in China, which suggest dramatically large medical and socioeconomic burdens. The income level positively related to the monitoring and controlling ability of DILI, which suggests substantial concerns in developing countries of low income and limited medical resources.

References:

• 1. Björnsson ES, Bergmann OM, Björnsson HK, et al. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013;144:1419–25

• 2. Navarro VJ, Khan I, Björnsson E, et al. Liver injury from herbal and dietary supplements. Hepatology 2017;65:363–73

• 3. Sultana J, Cutroneo P, Trifirò G. Clinical and economic burden of adverse drug reactions. J Pharmacol Pharmacother 2013;4(Suppl 1): S73–7

• 4. Wang JB, Zhu Y, Bai ZF, et al. Guidelines for the Diagnosis and Management of Herb-Induced Liver Injury. Chin J Integr Med 2018; https://doi.org/10.1007/s11655-018-3000-8

• 5. Zhang L, Wong LY, He Y, et al. Pharmacovigilance in China: current situation, successes and challenges. Drug Saf 2014; 37: 765–70

Disclosure of Interest: None declared.

47 ISoP18-1051 Adverse Effects Due to Inappropriate Use of Topical Steroids for Common Dermatological Disorders: Need for Public Awareness

47.1 R. Jhaj^*1, D. Asati², D. Chaudhary¹, S. Jain², B. Sadasivam¹

47.1.1 ¹Pharmacology, All India Institute of Medical Sciences, Bhopal, India; ²Dermatology, All India Institute of Medical Sciences, Bhopal, India

Background/Introduction: Background: Despite a ban by the Indian regulatory authorities [1], a large number of irrational fixed-dose combinations (FDCs) of topical corticosteroids with antibacterial, antifungal and other drugs are available over the counter in India [2], facilitating their indiscriminate use for symptomatic treatment of dermatological disorders like acne, fungal infections, undiagnosed skin rash and as a fairness cream [3]. This has lead to an upsurge of adverse effects, including topical steroid dependent/damaged face (TSDF) [4] and is also responsible for drug resistant superficial fungal infections [5].

Objective/Aim: To assess the burden of adverse drug events due to topical steroid preparations reported to an Adverse Drug Monitoring Centre in a tertiary care hospital in Central India.

Methods: All adverse drug events due to topical steroid preparations reported to the Adverse Drug Monitoring Centre between January and December 2017 were analysed for suspected steroid preparations, indications of use, type of use (prescribed or self-administered), type of adverse effect and its outcome.

Results: A total of 224 reports of adverse drug events with topical steroids were received, making up 42.8% of total ADEs and 50.1% of cutaneous reactions reported during the study period. Males aged between 18 and 35 years (71%) were predominantly affected. Skin atrophy (50%), hypopigmentation (29.9%), striae (28.1%) and Tinea incognito/extensive Tinea (20.5%) were the major adverse effects reported. TDSF was reported in 18 (8%) cases. Thighs (45.1%) and face (27.2%) were the major sites of these reactions. Clobetasone propionate (69.2%) alone or in combination was the most frequent suspected agent, followed by betamethasone (26.3%). Most of the topical steroids had been purchased over the counter (88.8%) for treatment of dermatophytoes (88.4%). In more than half the patients, the reactions had not abated (47.8%) or abated only partially (13.8%) till last follow-up.

Conclusion: Topical steroid containing FDCs continue to be available over the counter and are responsible for various irreversible cutaneous adverse effects. Increased awareness of the treating physicians as well as the public is required to counter this problem.

References:

• 1. Pande S. Steroid containing fixed drug combinations banned by government of India: A big step towards dermatologic drug safety. Indian J Drugs Dermatol 2016; 2: 1–2

• 2. Kumar S, Goyal A, Gupta Y. Abuse of topical corticosteroids in India: Concerns and the way forward. J Pharmacol Pharmacother 2016; 7: 1–5

• 3. Saraswat A, Lahiri K, Chatterjee M, Barua S, Coondoo A, Mittal A, et al. Topical corticosteroid abuse on the face: A prospective, multicenter study of dermatology outpatients. Indian J Dermatol Venereol Leprol 2011; 77: 160–6

• 4. Lahiri K, Coondoo A. Topical steroid damaged/dependent face (TSDF): An entity of cutaneous pharmacodependence. Indian J Dermatol 2016; 61: 265–72

• 5. Verma S, Madhu R. The great Indian epidemic of superficial dermatophytosis: An appraisal. Indian J Dermatol 2017; 62: 227–36

Disclosure of Interest: None declared.

48 ISoP18-1053 The Moroccan Phytovigilance System: An Experience of Involving Patients from 2012 to 2016

48.1 S. Skalli^*1, R. Soulaymani Bencheikh²

48.1.1 ¹Faculty of Sciences, Mohammed V Universtity, Rabat, Morrocco; ²Centre Anti Poison et de Pharmacovigilance du Maroc, Rabat, Morocco

Background/Introduction: Patients frequently self-select Herbal medicines (HM), without the advice of a qualified health provider and they do not disclose their use of HM to their physicians or pharmacists. This prevents the reporting to national pharmacovigilance centres .

Objective/Aim: to describe how the active involvement of patients may remedy the under-reporting of adverse reactions (ARs) to herbal medicines (HMs) to the existing Moroccan phytovigilance program.

Methods: A survey was conducted once a week from January 2012 to December 2016 and consisted of a personal interview with patients, or their caregivers, in four clinical services: Medical Oncology, Paediatrics, Urology and Maternity in the Ibn Sina University Hospital in Rabat. The Moroccan reporting form used for spontaneous ARs reporting for was used for this surveyfor which participationwas voluntary.

Results: 1129 reports (70.5%) were in agreement with the inclusion criteria. These reports constitute 90% of the total of patient reports received by the pharmacovigilance of Herbal Medicines Unit during the same period, including reports received by the spontaneous reporting system. 52.3% of ARs were recorded in females and 47.7% of ARs in males. Children and adults were involved in 31.4 and 68.6% of reports, respectively. HMs were used either as crude material form in 96% of cases, or modern pharmaceutical form in 4% of cases. 29.3% of the HMs were in the form of a single plant and 70.7% of the HMs were a mixture of two or more plants. Twenty signals were detected of which two alerts were generated.

Conclusion: The additional reports from patient’s makes an important contribution to the monitoring of HM safety by detecting signals and generating.

Disclosure of Interest: None declared.

49 ISoP18-1056 Chronic Disease Sufferers’ Willingness to Participate in Spontaneous Adverse Drug Reaction Reporting System

49.1 V. Getova^*1,2, E. Naseva³, H. Lebanova⁴, I. Getov³

49.1.1 ¹Medical University of Plovdiv, Plovdiv, Bulgaria; ²Bulgarian Drug Agency, Sofia; Bulgaria; ³Medical University of Sofia, Sofia, Bulgaria; ⁴Medical University of Pleven, Pleven, Bulgaria

Background/Introduction: The tendency for high consumption of medicinal products in Europe is a prerequisite for the greater number of adverse drug reactions (ADRs) in some countries. Patients are valuable source of information on post-marketing drug safety data collection as they can thoroughly explain the direct impact of therapy on daily life activities [1, 3]. This is especially important for people whose chronic disease management requires every day medicines use. Hence their participation in spontaneous reporting systems is of special value and importance for the development of pharmacovigilance knowledge [2,4].

Objective/Aim: The aim of the study was to analyze and assess the level of patient knowledge on ADR reporting, with a special focus on chronic disease sufferers. The survey investigates participants’ past experience with ADRs and their attitude towards sources of reliable drug information.

Methods: A close-ended questionnaire study was conducted among patients and consumers. The minimum sample size was calculated to 267 people for a proportion of 50% with maximal error ± 6%. Quantitative variables were represented as median and range (minimum and maximum), and categorical ones—as absolute and relative frequencies. For analyzing the results were applied Pearson Chi square analysis to assess the relationship between categorical variables (for Table 2 × 2 Fisher’s Exact test was used) and Mann–Whitney and Kruskal–Wallis for comparison of quantitative variables in independent samples.

Results: The majority of the participants in the study who claimed to suffer from a chronic disease also confirmed everyday medicines intake. A third (36%) of all participants in the study reported having experienced ADRs, with a greater number amongst everyday medicine users. However, the level of participants’ awareness of the direct ADR reporting option remains insufficient and the number of reports sent to regulators—very small. Healthcare professionals (HCP) are the most preferred source of drug information followed by internet resources, friends and family.

Conclusion: The conducted study showed a notable lack of knowledge on spontaneous reporting and insufficient chronic disease patients’ involvement in collection of post-marketing drug safety data. The majority of participants would consult HCPs in all matters regarding ADRs which emphasizes the role they play in educating consumers on pharmacovigilance activities.

References:

• 1. Arlett R, Kurz X, New approaches to strenghten pharmacovigilance, Drug Discov Today Technol 2011; 8: e1–e42

• 2. Hazell L, Shakir S. Under-reporting of adverse drug reactions, Drug Saf, 2006;29: 385–96

• 3. Rolfes L, van Husel F, van der Linden L, Taxis K, van Puijenbroek E. The quality of clinical information in adverse drug reaction reports by patients and healthcare professionals: a retrospective comparative analysis, Drug Saf, 2017; 40: 607–14

• 4. PGEU Best Practice paper: Pharmacovigilance and risk minimization, 25/09/2017

Disclosure of Interest: None declared.

50 ISoP18-1057 Passive Enhanced Safety Surveillance in Children Receiving Fluenz^® Tetra Vaccination in England During the Early 2017–2018 Influenza Season

50.1 L. Hazell¹, S. Shakir^*1, J. Dentith², E. Hammond³, D. Brooks³

50.1.1 ¹Drug Safety Research Unit, Southampton, United Kingdom; ²AstraZeneca, Luton, United Kingdom; ³AstraZeneca, Gaithersburg, United States

Background/Introduction: Fluenz^® Tetra is a quadrivalent, live attenuated, intranasal, influenza vaccine recommended for use in children aged 2–17 years vaccinated as part of the seasonal influenza immunisation campaign in the UK [1]. Here, we present results from a third season of passive enhanced safety surveillance (ESS) for the vaccine in 2017–2018.

Objective/Aim: To measure and assess the frequencies of suspected adverse drug reactions (sADRs) in children receiving Fluenz^® Tetra during the early 2017–2018 influenza season in England.

Methods: Vaccinees or parents/guardians received a Safety Report Card (SRC) to return if children experienced sADRs after vaccination with Fluenz^® Tetra. At participating sites, 38 general practices and 36 primary schools in England, immunisation teams recorded numbers of SRCs distributed. The study was approved by an NHS Research Ethics Committee (Hampshire B South Central NRES Committee).

Results: Between 29th September 2017 and 2nd December 2017, 12,193 children were vaccinated at study sites, with 16 different vaccine lots used. In total, 10,793 SRCs were issued for children aged 2–17 including 5189 children (48.1%) aged 2–4 years, 5036 (46.7%) aged 5–10 years and 568 (5.3%) aged 11–17 years.

Of 114 SRCs returned (by 9th January 2018 datalock), 101 reported at least one sADR (0.9% of all SRCs issued). The most frequently reported sADRs were rhinorrhoea (n = 36), pyrexia (31) and cough (14). Three reported sADRs were classified as serious due to hospitalisation (0.03% of all SRCs issued) including nasal symptoms, general cold/flu symptoms and croup. The frequency of sADRs reported in the current ESS season was consistent with that reported in previous seasons.

Conclusion: Overall, the number of sADRs reported for Fluenz^® Tetra in the 2017–2018 ESS remains low. Reported sADRs were typically minor expected events with serious sADRs rarely reported. The pattern and frequency of reported sADRs in the 2017–2018 season were consistent with previous seasons with no safety signals detected. Despite the limited number of reports received, the ESS method continues to be a useful extension to routine pharmacovigilance activities in the monitoring of possible sADRs.

Project sponsored by DSRU and AstraZeneca.

References:

• 1. AstraZeneca. Fluenz^® Tetra. Summary of Product Characteristics. Last updated: 22 March 2018. Available at https://www.medicines.org.uk/emc/product/3296/smpc. Accessed 9 May 2018

Disclosure of Interest: L. Hazell Grant/Research support from: AstraZeneca for current project, S. Shakir Grant/Research support from: AstraZeneca for current project, J. Dentith Employee of: AstraZeneca, E. Hammond Employee of: AstraZeneca, D. Brooks Employee of: AstraZeneca.

51 ISoP18-1061 Utilisation and Safety of Asenapine in Primary Care in England: Results Rom a PASS

51.1 S. Dhanda^1,2, F. Coukan^1,2, L. Wise¹, S. Shakir^*1,2

51.1.1 ¹Drug Safety Research Unit, Southampton, United Kingdom; ²University of Portsmouth, Portsmouth, United Kingdom

Background/Introduction: Asenapine is approved in the EU for the treatment of manic episodes associated with bipolar I disorder in adults. A PASS was carried out to monitor the use and safety of asenapine using real-world primary care data in England; targeted safety outcomes were oral hypoaesthesia, oropharyngeal swelling, somnolence and sedation, acute allergic reactions and weight gain (defined as weight (kg) and/or BMI (kg/m²) increase of ≥ 7% at end of study vs. index).

Objective/Aim: To describe the utilisation and safety of asenapine in primary care in England.

Methods: A cohort study identified patients from dispensed prescriptions of asenapine in England from January 2012–June 2016. Patient characteristics, drug utilisation and outcome data were collected from prescribing general practitioners via questionnaires sent at ≥ 3, and ≥ 12 months after the 1st prescription issued for each patient. Summary descriptive statistics were calculated.

Results: The cohort consisted of 122 patients with 3-month data of whom 56 patients had corresponding 12-month data [median age 44 years (IQR 35–55); 66.4% female]. The most frequent indication was bipolar disorder (n = 81, 66.4%); for 10 patients (12.3%), the indication was specifically reported as bipolar I disorder. There were also a number of off-label indications, e.g., schizophrenia (n = 21, 17.2%). Asenapine was prescribed in accordance with the product label for 61 patients (50.0%) who were started on 5 mg bd; 19 patients (15.6%) were prescribed 10 mg bd.

For the 3-month cohort, incidence of targeted events was; oral hypoaesthesia n = 0 (0.0%), oropharyngeal swelling n = 1 (0.8%), sedation/somnolence n = 5 (4.1%), acute allergic reactions n = 0 (0.0%).

For the 12-month cohort, incidence of targeted events was; oral hypoaesthesia n = 0 (0.0%), oropharyngeal swelling n = 1 (1.8%), sedation/somnolence n = 6 (10.7%), acute allergic reactions n = 0 (0.0%), weight gain n = 10 (17.9%).

In addition to the targeted outcomes other events of interest included four deaths, one of which was a completed suicide, and a case of foetal spina bifida diagnosed in a pregnant patient taking multiple psychiatric medications.

Conclusion: Asenapine was largely prescribed in accordance with prescribing recommendations. Event counts were small and no new safety signals were identified. This study design allowed for the timely collection of drug utilisation and safety data directly from prescribing GPs. However, as a result of the small cohort size, any conclusions from this study should be put into context with results from other post-marketing studies.

Disclosure of Interest: S. Dhanda Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Merck, the manufacturer of Sycrest^®. The DSRU makes the final decision on the publication of external communications, F. Coukan Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Merck, the manufacturer of Sycrest^®. The DSRU makes the final decision on the publication of external communications. L. Wise Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Merck, the manufacturer of Sycrest^®. The DSRU makes the final decision on the publication of external communications., S. Shakir Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Merck, the manufacturer of Sycrest^®. The DSRU makes the final decision on the publication of external communications.

52 ISoP18-1062 Utilisation and Safety of Asenapine in Secondary Care in the UK: Results from the Observational Safety Evaluation of Asenapine (OBSERVA) Study

52.1 S. Dhanda^1,2, J. Slade¹, V. Obsorne¹, L. Wise¹, S. Shakir^*1,2

52.1.1 ¹Drug Safety Research Unit, Southampton, United Kingdom; ²University of Portsmouth, Portsmouth, United Kingdom

Background/Introduction: The OBSERVA specialist cohort event monitoring (SCEM) study, conducted in secondary care in the UK, formed part of an EU risk management plan to monitor the use and short-term safety of asenapine, licensed for the treatment of moderate to severe manic episodes associated with bipolar I disorder in adults. Targeted safety outcomes were oral hypoaesthesia, oropharyngeal swelling, somnolence and sedation, acute allergic reactions and weight gain (defined as weight (kg) and/or BMI (kg/m²) increase of ≥ 7% at end of study vs. index).

Objective/Aim: To describe the utilisation and safety of asenapine prescribed in secondary care in the UK.

Methods: An observational cohort study identified patients via a network of psychiatrists in collaboration with the Mental Health Research Network from November 2012–September 2016. Patient characteristics, drug utilisation and outcome data were collected via questionnaires completed by specialists sent at baseline and after 12 weeks of observation. Summary descriptive statistics were calculated.

Results: The final cohort consisted of 125 patients; the median age was 44 years (IQR 35–52); 63 (50.4%) were male. Asenapine was most frequently prescribed for bipolar disorder (n = 81, 64.8%); 15 of these patients (18.5%) had bipolar I disorder reported. There were also a number of off-label indications, e.g., schizophrenia (n = 18, 14.4%). Asenapine was largely prescribed in accordance with the product label; 56 patients (44.8%) were started on 5 mg bd and at 12 weeks 34 patients (27.2%) were taking 10 mg bd.

The incidence of targeted events was as follows; oral hypoaesthesia n = 9 (7.2%), oropharyngeal swelling n = 0 (0.0%), sedation n = 13 (10.4%), somnolence n = 11 (8.8%), acute allergic reactions n = 0 (0.0%), weight gain n = 1 (0.8%).

No deaths or pregnancies were reported in the OBSERVA study.

Conclusion: Asenapine was largely prescribed in accordance with prescribing recommendations; the majority of patients were taking asenapine for bipolar disorder at the recommended dose. Event counts were small and no new safety signals were identified. This study provides valuable real-word data to support the post marketing risk–benefit profile of asenapine, however as a result of the small cohort size, any conclusions from this study should be put into context with results from other research evidence.

Disclosure of Interest: S. Dhanda Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Merck, the manufacturer of Sycrest^®. The DSRU makes the final decision on the publication of external communications., J. Slade Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Merck, the manufacturer of Sycrest^®. The DSRU makes the final decision on the publication of external communications., V. Obsorne Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Merck, the manufacturer of Sycrest^®. The DSRU makes the final decision on the publication of external communications, L. Wise Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Merck, the manufacturer of Sycrest^®. The DSRU makes the final decision on the publication of external communications., S. Shakir Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Merck, the manufacturer of Sycrest^®. The DSRU makes the final decision on the publication of external communications.

53 ISoP18-1063 Risk of Major and Clinically Relevant Non-major (CRNM) Bleeding in Patients Prescribed Rivaroxaban in Primary Care in England

53.1 S. Dhanda^1,2, M. Davies^1,2, D. Roy^1,2, L. Wise¹, S. Shakir ^*1,2

53.1.1 ¹Drug Safety Research Unit, Southampton, United Kingdom; ²University of Portsmouth, Portsmouth, United Kingdom

Background/Introduction: Clinical trials and observational studies have reported bleeding risk in patients taking rivaroxaban. A PASS was carried out as part of the Risk Management Plan to monitor the safety and use of rivaroxaban using real-world primary care data in England.

Objective/Aim: To estimate the risk of Major and CRNM bleeding in patients prescribed rivaroxaban for Stroke prevention in non-valvular AF (SPAF) and for the prevention and/or treatment of Deep Vein Thrombosis and/or Pulmonary Embolism DVT/PE in primary care.

Methods: Patients identified from dispensed prescriptions in England (2012–2016). Detailed questionnaires sent to general practitioners (GPs) at ≥ 3 and ≥ 12 months of observation collected information on risk factors for bleeding (HAS-BLED) and bleeding outcomes. Summary descriptive statistics and 12-month risk estimates were calculated.

Results: Cohort = 17,546 patients: 10,225 patients with AF (58.3% of cohort, median age 78 years (IQR 70–84), 5253 (51.4%) male); 5959 patients with DVT/PE (34.0% of cohort, median age 66 years (IQR 50–78); 3197 (53.6%) female). In both groups, the median HAS-BLED score was 1 (IQR 1–2, 0–1, respectively) reflecting a low risk of major bleeding.

AF group: Risk Major + CRNM bleeding 8.3% [(95% CI 7.8, 8.9); n = 825]. Risk Major bleed 2.4% [(95% CI 2.1, 2.7); n = 239], CRNM bleeding 6.0% [(95% CI 5.5, 6.4); n = 592]. Major bleeding further stratified by site: gastrointestinal (GI) (1.2%; n = 117), urogenital (UG) (0.1%; n = 13), intracranial (IC) (0.4%; n = 42), all other critical organ (excluding IC) (0.3%; n = 26) and all non-critical organ sites (0.4%; n = 44).

DVT/PE group: Risk Major + CRNM bleeding 4.2% [(95% CI 3.7, 4.7); n = 240]. Risk Major bleed 1.4% [(95% CI 1.1, 1.7); n = 82], CRNM bleeding 2.8% [(95% CI 2.4, 3.3); n = 162]. Major bleeding further stratified by site: GI (0.7%; n = 38), UG (0.3%; n = 18), IC (0.2%; n = 12), all other critical organ (excluding IC) (0.1%; n = 4) and all non-critical organ sites (0.2%; n = 10).

Conclusion: For the primary outcome of major bleeding, the estimates of risk in the AF and DVT/PE rivaroxaban user populations were overall low and consistent with those estimated from clinical trial data. Differences in methodologies and analysed study populations prevent meaningful comparisons with other studies. This study design has unique strengths, including the collection of timely, granular data directly from prescribing GPs, however selective reporting of outcomes and selection bias might be present, and should be considered when interpreting results.

Disclosure of Interest: S. Dhanda Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications., M. Davies Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications. D. Roy Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications. L. Wise Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications. S. Shakir Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications.

54 ISoP18-1064 Pharmacovigilance in Emerging Markets: An Industry Initiative to Strengthen Global Engagement and Support

54.1 E. Herrero Martinez^*1

54.1.1 ¹Regulatory Policy and Intelligence, AbbVie, Maidenhead, United Kingdom

Background/Introduction: In recent years, there has been a marked increase in the development of pharmacovigilance (PV) legislation worldwide. This ranges from setting up basic frameworks, to regional coordination across multiple countries, often inspired by stringent regulatory requirements such as the EU Good Pharmacovigilance Practices, the US FDA, WHO and/or ICH.

Objective/Aim: All impacted stakeholders, including industry, have a responsibility to ensure robust PV frameworks are established to protect patients but monitoring developments, providing timely and aligned industry input to local bodies and ensuring compliance is increasingly challenging due to the speed and complexity of change.

Methods: For this reason, the European Federation of Pharmaceutical Industries and Associations (EFPIA) has set up a permanent team to focus on emerging market pharmacovigilance, which works in partnership with key industry and regulatory bodies to support robust and harmonised PV legislation development and to aid companies in compliance.

Results: This team is called the EFPIA International PV Group (IPVG) and it was set up 2 years ago. The IPVG is now very active, engaging globally via 5 regional workstreams, and progressing strategic objectives at a global level.

Conclusion: This presentation will introduce the team and its activities, focusing on where they may help support ISOP objectives going forward.

Disclosure of Interest: None declared.

55 ISoP18-1065 A Methodological Review of Observational Studies on Central Nervous System Drugs Use in Pregnancy and Outcomes in Children

55.1 Z. Wang¹, P. Ho², M. Choy², I. Wong^*1, K. Man²

55.1.1 ¹University College London, London, United Kingdom; ²University of Hong Kong, Hong Kong, Hong Kong

Background/Introduction: Various epidemiological approaches have been used to study the association between central nervous system (CNS) drugs use in pregnancy and CNS outcomes in children in the literature. 

Objective/Aim: To identify the methodological characteristics of existing studies in order to examine research gaps and recommend further research in this area.

Methods: A systematic literature search was conducted on observational studies written in English in PubMed that studied CNS drugs use in pregnancy and CNS outcomes in children up to 21 Sep 2017. Following independent screening and data extraction, a critical summary including the trend of relevant studies, differences between various data sources, methods to address bias and confounders, and the used statistical analysis methods was presented.

Results: 110 observational studies, 25 case–control studies, and 85 cohort studies were included in this review. Publications targeting antiepileptic drugs (AEDs) dominated in the early years, but a gradual increase in research on antidepressants (ADs) in recent years contributed to the vast majority of relevant studies to date. No study on antipsychotics (APs) was identified in this review.

Conclusion: Evidence suggests that multiple factors, such as different study designs and data source choices, lead to inconsistent findings in the association between the use of ADs and AEDs in pregnancy and CNS outcome. Researchers should optimise study design including reasonable exposure period, data source, confounding adjustment methodology, as well as statistical analysis to minimise underlying bias for better precision, validity and generalisability of results.

References:

Man KKC, Chan EW, Ip P, Coghill D, Simonoff E, Chan PKL, et al. Prenatal antidepressant use and risk of attention-deficit/hyperactivity disorder in offspring: population based cohort study. BMJ 2017;357:j2350

Hernandez-Diaz S, Smith CR, Shen A, Mittendorf R, Hauser WA, Yerby M, et al. Comparative safety of antiepileptic drugs during pregnancy. Neurology 2012;78:1692–9

Lao KS, Chui CS, Man KK, Lau WC, Chan EW, Wong IC. Medication safety research by observational study design. Int J Clin Pharm. 2016;38:676–84

Disclosure of Interest: None declared.

56 ISoP18-1066 What German Physicians Think About the Spontaneous Reporting System and How They Would Change It. Results of an Online Survey

56.1 T. Stammschulte^*1, M. Litwa¹, U. Köberle¹, L. Prause¹, K. Bräutigam¹, M. Pitzer², U. Gundert-Remy¹

56.1.1 ¹Drug Commission of the German Medical Association, Berlin, Germany; ²Klinik Rheinhöhe, Vitos Rheingau, Eltville, Germany

Background/Introduction: German physicians are requested by their code of conduct to report adverse drug reactions (ADRs) to the Drug Commission of the German Medical Association (DCGMA). However, underreporting is a noticed problem and strategies for motivation are required.

Objective/Aim: To elucidate the attitiude of German physicians towards spontaneous reporting and to identify their suggestions for improving reporting in clinical practice.

Methods: We conducted an online survey consisting of 12 questions. A link to the survey was distributed between November 2017 and February 2018 using six different newsletters. In theory, these newsletters reach approximately 120,000 physicians but a considerable overlap of recipients is expected.

Results: A total of 1974 replies were received (response rate 1.6%), most of which came from physicians (86.9%, pharmacists: 9.5%, others: 3.6%). For this analysis only responses from physicians (n = 1716) were included. 69.2% stated they have at least once suspected or diagnosed a serious ADR. 41.6% have never reported an ADR, while 43.9% have reported an ADR one to three times (4–10 times: 12%, > 10 times: 4.8%).

Reasons for not reporting that applied completely or to some extent for the respondents were: the required time (59.9%), lack of knowledge about the reporting system (50.6%) or the involved organisations (53.1%), uncertainty about which ADRs should be reported (56.1%) and privacy policy (47.61%). Only 2.2% considered reporting of ADRs to be useless, 17.5% missed incentives and 28.3% stated uncertainty about judicial consequences.

The majority would spend a maximum of 15 min for reporting an ADR (≤ 5 min: 43.9%, > 5 ≤ 15 min: 46.7%) and the most preferred ways to report were: online via website, via fax or directly via software systems used in private practice or hospital, respectively.

Apart from an acknowledgement of receipt (64.5%), physicians appreciated receiving a response regarding assessment of seriousness and causality (63.3%) as well as further information on the reported ADR (49.5%) and therapy advice (57.6%).

With regard to follow-up information there was willingness to provide additional documents (67.3%) or to answer precise questions (63.1%). Approximately one quarter of respondents considered further inquiries bothersome (23.5%) or didn’t answer them at all (3.3%).

Suggestions to improve the reporting system were given in 321 out of 1716 replies (18.7%). They referred to: simplification, reduction of required time, better information on what and how to report, avoidance of time-consuming follow-ups, the inclusion of reporting tools to clinical software systems, feedback to reports and incentives for reporting.

Conclusion: In principle, physicians seem to acknowledge the necessity of reporting ADRs. However, they require proper guidance and a fast and simple reporting system which should include useful feedback information. To our knowledge this has been the biggest survey relating to this topic ever done in Germany even though our response rate was low. We expect that only physicians who are interested in the topic in general completed the survey. Thus, our results may overestimate a positive attitude towards spontaneous reporting. However, the high proportion of respondents that have never reported an ADR prior to the survey demonstrates a capability to improve spontaneous reporting in Germany.

Disclosure of Interest: None declared.

57 ISoP18-1068 An Ecological Study on Consumer Adverse Event Reporting to the US Food and Drug Administration

57.1 M. Munoz^*1,2, G. Dal Pan¹, H. Xiao², C. Delcher³, J. Wei², C. Kortepeter¹, A. Winterstein^2,4

57.1.1 ¹Office of Surveillance and Epidemiology, US Food and Drug Administration, Silver Spring, Maryland, United States; ²Department of Pharmaceutical Outcomes and Policy,; ³Department of Health Outcomes and Biomedical Informatics,; ⁴Department of Epidemiology, University of Florida, Gainesville, Florida, United States

Background/Introduction: For nearly 50 years, the FDA Adverse Event Reporting System (FAERS) has been a central component of postmarketing drug safety surveillance. FAERS relies on health care professionals, consumers, and others to voluntarily report adverse events. Potential disparities in United States (US) consumer reporting have not been previously examined.

Objective/Aim: To determine if consumer reporting is uniform across the US and to evaluate potential factors associated with geographic reporting patterns.

Methods: We extracted all FAERS reports directly submitted to the FDA by US consumers with an FDA initial received date from January 1, 2011 to December 31, 2015. Reports were geocoded and aggregated by county. Population data from the US Census Bureau’s American Community Survey (ACS) was used to calculate the number of reports per 100,000 residents (i.e., reporting rate). To evaluate the correlation of county-level sociodemographic, socioeconomic, and health factors to reporting, we collapsed counties into reporting rate quartiles. Population characteristics in areas of high reporting (highest quartile) were compared to low reporting (lowest quartile). The characteristics evaluated were derived from measures in ACS and County Health Rankings and Roadmaps (CHR&R) data. Ongoing analyses include utilizing small-area estimation techniques to produce stable county-level estimates.

Results: We identified 52,403 consumer reports in the 5-year study period of which 90.3% were successfully geocoded to the county-level. One-fifth (19.5%) of the 3136 counties in the US had no reports in FAERS, with a median population of 6572 residents. Counties ranked lowest (n = 784) and highest (n = 784) in reporting had ≤ 5.5 reports per 100,000 residents and ≥ 17.6 reports per 100,000 residents, respectively, over the 5 years. Counties in the highest reporting quartile had significantly lower proportions of Hispanic (6.5 vs. 11.8%, p < 0.01), American Indian/Alaskan Native (1.5 vs. 4.0%, p < 0.01), and extent of rural area (57.7 vs. 75.4%, p < 0.01) than counties in the lowest reporting quartile. Counties in the highest reporting quartile also had higher mean household income ($50,506 vs. $45,651, p < 0.01), more primary care providers (64.2 vs. 43.7, p < 0.01), and more mental health providers (150.8 vs. 95.1, p < 0.01) per 100,000 residents. After excluding counties with < 20,000 residents, the significant patterns remained consistent.

Conclusion: Our findings suggest there are significant variations in consumer reporting across the US. Population representativeness in adverse event reporting is important given certain patient groups may be at an increased risk for adverse reactions. Opportunities exist for more rigorous evaluations of reporting disparities.

Disclosure of Interest: None declared.

58 ISoP18-1069 Multi-Level Modelling to Investigate Factors Impacting Prescribing Variability

58.1 D. Roy^1,2, L. Wise¹, S. Shakir^*1,2

58.1.1 ¹Drug Safety Research Unit, Southampton, United Kingdom; ²University of Portsmouth, Portsmouth, United Kingdom

Background/Introduction: Prescribing guidelines influence treatment choice based on patient and healthcare system factors. Multi-level modelling can provide insight into sources of variability in healthcare, especially where nested hierarchical structures exist [1]. A Specialist Cohort Event Monitoring study investigated the safety and use of rivaroxaban in clinical use, with a warfarin cohort for context.

Objective/Aim: Study to investigate prescribing variability using Multi-level modelling.

Methods: Data on NHS acute trusts in England/Wales (e.g. population size, trust type) were linked to study patient demographic and drug utilization data, and prescriber details (e.g. degree, specialty).

Using Multi-level modelling we explored the influence of patient, prescriber and trust characteristics on prescribing variability in 2106 rivaroxaban (59%) vs. 1468 warfarin (41%) adult patients nested in 780 prescribers, nested in 73 trusts. The majority of patients had an indication of DVT/PE (56.4%) or non-valvular AF (AF) (41.2%). The binary outcome was rivaroxaban or warfarin treatment.

Variance components estimate the variability accounted for by each level in the model and are expressed as: Median Odd Ratios (MOR—median relative increase in odds of rivaroxaban treatment if patient changed prescriber (PR) or trust (T)); Proportional Change in Variance (PCV) between models when successively adding fixed effects.

Results: DVT/PE group:

Adjusting for patient factors, MOR_T = 6.9 (PCV = − 0.6%); MOR_PR = 2.8 (PCV = 3.8%).

Adjusting for patient and prescriber factors, MOR_T = 6.8 (PCV = − 2.9%); MOR_PR = 2.6 (PCV = − 15.4%).

Adjusting for patient, prescriber and trust factors, MOR_T = 4.9 (PCV = − 30.2%); MOR_PR = 2.6 (PCV = 3.4%).

Differences between trusts and prescribers (in trusts) are important in treatment choice; trust being more influential. Some patient factors had a relatively large effect on odds of treatment choice although the absolute number of patient impacted was often small. Trust type, was shown to be associated with the odds of treatment choice [Final model: foundation vs acute trusts OR 4.0 (95% CI 1.5, 9.9)].

Data on AF and all indications (combined) will be included in the final presentation.

Conclusion: This study highlights the utility of Multi-level modelling in exploring patient and non-patient factors in nested hierarchical healthcare settings. Prescribing variability appears dominated by differences between trusts and prescribers (in trusts). Some patient factors were important in treatment choice, but PCV between models suggest that accounting for patient differences does not fully explain the variance between prescribers (in trusts) and between trusts.

References:

• 1. Zuidgeest MG, van Dijk L, Spreeuwenberg P, Smit HA, Brunekreef B, Arets HG, et al. What drives prescribing of asthma medication to children? A multilevel population-based study. Ann Fam Med 2009;7:32–40

Disclosure of Interest: D. Roy Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications. L. Wise Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications. S. Shakir Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications.

59 ISoP18-1074 Objectives and Design of the Post-Authorization Studies Evaluating the Effectiveness of the Risk Minimization Measures in the EU PAS Register

59.1 A. Farcas^*1, M. Huruba¹, C. Mogosan¹

59.1.1 ¹Drug Information Research Center, University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania

Background/Introduction: Risk minimization measures (RMMs) are public interventions aimed to prevent the occurrence of adverse events correlated with exposure to a medicinal product. Routine or additional, these RMMs aim to optimize the safe and effective use of a medicine all throughout its lifecycle.

Objective/Aim: The aim of this review is to characterize the objectives, methods and study design used in post-authorization studies that evaluate the effectiveness of RMMs.

Methods: All studies that aimed to evaluate the effectiveness of RMMs, available in the EU Electronic Register of Post-Authorization Studies (EU PAS Register) up to 31st of April 2018, were included in our analysis.

Results: Out of the 359 effectiveness studies registered in the EU PAS Register, 31 evaluated the effectiveness of at least one RMM. 2 studies were excluded from the review due to early termination. Out of the 29 relevant studies, 18 were finalized, 6 were ongoing and 5 were planned at the time of the present analysis. A total of 9 studies evaluated routine RMMs [SPC (n = 9), PIL (n = 3) and  label updates (n = 1)], while 27 analyzed additional RMMs [patient/caregiver brochure (n = 9), prescriber guide (n = 8), Patient Alert Card (n = 8), healthcare provider brochure (n = 8), other educational materials (n = 4), Direct Healthcare Provider Communication (n = 4), prescriber checklist (n = 3), website (n = 1), Q&A (n = 1)].

With respect to study design, 24 studies used primary data sources, while 8 used secondary, analyzing chart review (n = 4), databases such as IMS (n = 2), patient based data (n = 2), EMA (n = 1), EU PAS Register (n = 1), Public Health England (n = 1), pharmaceutical companies database (n = 1), MedLINE (n = 1), NHS Business Services Authority (n = 1); 24 studies were surveys, 20 cross-sectional, 6 observational, 5 non-interventional, 2 cohort studies, 1 was a systematic review and 1 a meta-analysis.

The top 5 countries where effectiveness studies were conducted in were France (n = 20), Finland (n = 20), United Kingdom (n = 18), Spain (n = 16) and Ireland (n = 13).

Conclusion: Risk minimization programs integrate interventions designed to support safe and adequate use of medicines. A qualitative review of these studies adds to the fundament of development of the process design, and communication of the results in a standardized and transparent manner.

Disclosure of Interest: None declared.

60 ISoP18-1076 Profile of Adverse Events Related to Long-Lasting Insecticide-Treated Nets During Mass Campaigns in the Democratic Republic of the Congo

60.1 N. M. T. Mpiempie^*1, G. K. Ilombe ¹, N. N. Koka ², F. B.-M. Makila¹, M. O. Mboma¹, N. C. Nsibu³, L. G. Tona¹, M. P. Mitashi⁴, K. G. Mesia⁵

60.1.1 ¹National Pharmacovigilance Centre, Kinshasa, Congo, The Democratic Republic of the; ²National Malaria Control Program, Kongo Central, Congo, The Democratic Republic of the; ³Paediatric, Kinshasa University Hospital, Kinshasa, Congo, The Democratic Republic of the;, ⁴Tropical Medecine, University of Kinshasa, Congo, The Democratic Republic of the; ⁵National Pharmacovigilance Centre, Kinshasaa, The Democratic Republic of the Congo

Background/Introduction: The Long-Lasting Insecticide-Treated Nets (LLIN) is still used as the main tool of malaria prevention in the Democratic Republic of Congo (DRC). Approximately 23 million LLINs were distributed during mass campaigns between 2016 and 2017, with a coverage rate approaching 80%. However, the utilization rate remains low in some endemic communities. Pyrethroids group are recommended by the World Health Organization for nets impregnation. No relevant studies have investigated the potential adverse reactions of exposure to LLIN in DRC. It is therefore necessary to establish its safety profile in order to improve its use in the community.

Objective/Aim: Determine the profile of adverse events related to the use of the long-acting insecticide-treated net, their timing and duration.

Methods: This is a cross-sectional study nested on a randomized controlled LLIN effectiveness of 2 LLIN Dawa plus 2.0 (impregnated with deltamethrin) and Permanet 3.0 (impregnated with deltamethrin + PBO) in the communities of Kisantu in DRC. Thirty villages were randomly selected. An adverse event (AE) collection form was used during interviews with the heads of households. Data were entered using the Epi-info7 and analyzed with SPSS 20.0. The Pearson’s Chi square test was used to compare proportions of AEs between categories format of LLIN, with a p value < 0.05 being considered significant.

Results: Two LLIN formats were distributed: 60% Dawa plus versus 40% Permanet 3.0. Of the 505 households visited, 200 (42.2%) reported experiencing an AE. A total of 306 AEs have been reported including 1 serious adverse event (0.3%). Half of the AEs (49.7%) were respiratory (cough, cold, dyspnoea, asthma, bronchitis, choking), 36.9% cutaneous (pruritus, tingling, burning sensation) and 13.1% ocular. The occurrence of AEs is statistically related to the use of the Dawa plus format (X² = 12.845, ddl 3, p = 0.005). The onset of AE was 1.5 days while the duration was estimated to 5.15 days.

Conclusion: The use of Dawa plus LLLIN format is significantly associated with the appearance of AEs. Moreover, the occurrence of AEs may hinder the acceptability of LLIN in the community and negatively impact on malaria implementation strategies in the DRC.

References:

Sécurité d’emploi des moustiquaires imprégnées de pyrethrinoides WHO/CDS/CPE/WHOPES/99.5FR

Disclosure of Interest: None declared.

61 ISoP18-1077 Incidence of Major and Clinically-Relevant Non-major Bleeding in Patients Prescribed Rivaroxaban: Results RROM the ROSE Study

61.1 A. Evans^1,2, M. Davies^1,2, L. Wise¹, S. Shakir^*1,2

61.1.1 ¹Drug Safety Research Unit, Southampton, United Kindgom; ²University of Portsmouth, Portsmouth, United Kingdom

Background/Introduction: The ROSE (Rivaroxaban Observational Safety Evaluation) Specialist Cohort Event Monitoring (SCEM) study was conducted to monitor the safety and use of rivaroxaban for Stroke Prevention in patients with non-valvular AF (SPAF) and the prevention and/or treatment of Deep Vein Thrombosis and/or Pulmonary Embolism (DVT/PE) in the secondary care setting in England and Wales. The study complements another study conducted in primary care by focusing on the acute phase of treatment.

Objective/Aim: To estimate the incidence of major and clinically-relevant non-major (CRNM) bleeding (ISTH definition) in patients prescribed rivaroxaban for the first time for SPAF and DVT/PE indications.

Methods: Patients were identified through speciality groups (2013–2016), supported by UK Clinical Research Networks. Risk factors for bleeding (HAS-BLED) and bleeding outcomes were collected via detailed questionnaires completed by hospital specialists at baseline and ≥ 12 weeks. Summary descriptive statistics and 12 week incidence risk and rate (per 100 patient years) were calculated.

Results: The cohort consisted of 2542 patients including 965 patients with AF [38.0% of cohort; median age 76 years (IQR 69, 83); 517 (53.6%) male], median HAS-BLED score 2 (IQR 1–3) (moderate risk of major bleeding) and 1532 patients with DVT/PE [60.3% of cohort; median age 63 years (IQR 48, 73); 836 (54.6%) male], median HAS-BLED score 1 (IQR 0–2) (low risk of major bleeding).

AF group: Rate: Major + CRNM bleeding 28.2 (95% CI 21.0, 37.1; n = 51), Major Bleed 5.5 (95% CI 2.6–10.1; n = 10), CRNM bleeding 22.7 (95% CI 16.3–30.8; n = 41).

Major Bleed risk in pre-specified sites: gastrointestinal (GI) (0.2%; n = 2), urogenital (UG) (0.2%; n = 2), intracranial (IC) (0.2%; n = 2) and all other critical organ (excluding IC) (0.1%; n = 1).

DVT/PE group: Rate: Major + CRNM bleeding 36.2 (95% CI 29.4, 44.1; n = 98), Major Bleed 8.3 (95% CI 5.3, 12.5; n = 23), CRNM bleeding 27.6 (95% CI 21.7, 34.6; n = 75).

Major Bleed risk in pre-specified sites: GI (0.7%; n = 11), UG (0.3%; n = 5), IC (0.1%; n = 1) and all other critical organ (excluding IC) (0.0%; n = 0).

Conclusion: The incidence of major bleeding was low and no new safety concerns were raised. Unique aspects of this study design enabled collection of highly detailed information from cardiologists, faciliating accurate calculation of risk scores and the application of clinical trial outcome definitions, in a real-word setting. Differences in methodology between this and other study designs prevents meaningful comparison.

Disclosure of Interest: A. Evans Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications. M. Davies Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications. L. Wise Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications. S. Shakir Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications.

62 ISoP18-1078 Tamoxifen and the Risk of Parkinsonism: A Case Non-case Study

62.1 F. Montastruc¹, F. Khosrow-Khavar², J. Benevent¹, C. Renoux², J.-L. Montastruc^*1

62.1.1 ¹Medical Pharmacology, Faculté de Médecine—Centre Hospitalier Universitaire, Toulouse, France; ²Clinical Epidemiology, Jewish General Hospital and McGill University, Montreal, Quebec, Canada

Background/Introduction: Three recent epidemiological studies have suggested an association between use of tamoxifen in breast cancer and risk of Parkinsonism, mainly after long term exposure (4–6 years).

Objective/Aim: Since these studies have several limitations, we explored this potential signal, performing a case/non-case study using Vigibase^®, the World Health Organization Global Individual Case Safety Reports (ICSRs) database, between 1979 and 2018.

Methods: Among post-menopausal women aged ≥ 55 years, we measured the risk of reporting “Parkinsonism” compared with all other adverse drug reactions [as a reporting odds ratio with 95% confidence interval (ROR 95%CI)] for tamoxifen compared to all other drugs. To assess the stability of our results, we performed several sensitivity analyses, first, comparing tamoxifen to aromatase inhibitors (another drug class used in breast cancer) and, second, excluding reports with drugs known to induce Parkinsonism.

Results: Among 13,964 women aged ≥ 55 years and exposed to tamoxifen, we identified 356 cases of Parkinsonism (mainly in women aged 65–74 years, n = 146, 41%) and 13,599 non cases. Among cases exposed to tamoxifen, MedDRA Preferred Terms reported were mainly tremor (n = 125, 35.1%) and gait disturbance (n = 118, 33.1%). We failed to find a positive association between tamoxifen exposure and Parkinsonism in comparison with exposure to other drugs [ROR = 0.79 (95% CI 0.71–0.88)] or aromatase inhibitors [ROR = 0.39 (95% CI 0.33–0.46)]. No association was found after exclusion of reports with drugs known to induce Parkinsonism [ROR = 0.76 (95% CI 0.68–0.85)]. In contrast, a significant association was found with flunarizin, a drug well known to induce Parkinsonism, selected as a positive exposure control [ROR = 6.76 (95% CI 5.96–7.68)].

Conclusion: This study, performed in a real world context and in a large pharmacovigilance database, did not allow to confirm a potential signal of tamoxifen and Parkinsonism, whatever the comparator used.

Disclosure of Interest: None declared.

63 ISoP18-1080 Characterization and Disproportionality Analysis of Spontaneously Reported Cases of Medication Errors to the U S-F D A Adverse Event Reporting System

63.1 F. Mazhar^*1, C. Carnovale², M. Gentili¹, E. Clementi ¹, S. Radice^3,4

63.1.1 ¹Department of Biomedical and Clinical Sciences L. Sacco, “ Luigi Sacco”, Università di Milano, Milan, Italy; ²Department of Biomedical and Clinical Sciences L. Sacco, “ Luigi Sacco”, Milan, Italy; ³Scientific Institute, IRCCS E. Medea, Bosisio Parini LC, Italy; ⁴Department Biomedical and Clinical Sciences, CNR Institute of Neuroscience, L. Sacco University Hospital, Università di Milano, Milan, Italy, Milano, Italy

Background/Introduction: Medications errors (ME) are a leading source of unintended patient harm in worldwide. In recent past years, the World Health Organization (WHO) has also highlighted the importance of identifying ME and is now working toward expansion of existing roles of pharmacovigilance centres to include monitoring of ME. Having a strong pharmacovigilance system would also help in running and strengthening a good ME reporting and monitoring program.

Objective/Aim: To characterize adverse reactions associated with medication errors (ME) reported in US Food and Drug Administration Adverse Event Reporting System (US-FAERS), and to identify the signals of disproportionate reporting (SDR) for different drugs over the period 2004–2017.

Methods: Individual Case Study Report (ICSRs) were identified through the narrow Standardised Medical Dictionary for Regulatory Activities (MedDRA) Query for ME. ICSRs were categorized by MedDRA^® terms, patient age groups, affected stages of medication process and Anatomical Therapeutic Chemical classification system. We performed a disproportional analysis of drugs mostly reported according to age groups by using reporting odds Ratio (ROR), proportional reporting ratio (PRR) and information component (IC). A value of ROR-1.96SE > 1, PRR ≥ 2, IC-2SD > 0 were considered as the positive signal.

Results: 46,8677 ICSRs associated with ME were retrieved. An increasing trend in reporting activity were observed during the study period, with a peak in the year 2015. About 57% of ME ICSR occurred in adults, 35% in elderly and 8.2% in children. Majority of reports were submitted by consumers. Immunosuppressants (L04) and Psycholeptics (N05) were most frequently involved. Administration errors were reported most frequently (87%), followed by prescribing (5%) and dispensing errors (5%). In neonates, SDR reporting for wrong drug administration, wrong dose, and accidental overdose were associated with methylergonovine, zidovudine, and acetaminophen. In elderlies, SDR were found for dose omission and underdose error associated with etanercept and evolocumab.

Conclusion: The reporting rate of ME increased between 2004 and 2017 likely due to an increased awareness of ME in consumers and physician. Overall, a wide variety of SDR for drug-ME terms were identified, some of which in agreement with the literature, suggesting that ME recording and assessment within the existing FAERS dataset is feasible. The inclusion of relevant aspects of ME, such as risk factors that cannot be coded with MedDRA, could enhance detection of ME by using spontaneous reports.

References:

• 1. Gandhi TK, Weingart SN, Borus J, Seger AC, Peterson J, Burdick E, et al. Adverse drug events in ambulatory care. N Engl J Med 2003; 348:1556–64

• 2. WHO. Patient safety: extending the scope of pharmacovigilance centres. WHO Pharmaceuticals Newsletter No. 6. Geneva: WHO, 2007

• 3. Bencheikh RS, Benabdallah G. Medication errors: pharmacovigilance centres in detection and prevention. Br J Clin Pharmacol 2009; 67: 687–90

• 4. FDA adverse event reporting system. http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/surveillance/adversedrugeffects/default.htm. Accessed 27 Jan 2018.

Disclosure of Interest: None declared.

64 ISoP18-1082 Medication Prescribing Practices of Eating Disorder Consultants for the Treatment of Young People with Anorexia Nervosa: A Questionnaire Study

64.1 M. Yakhchi Beykloo¹, D. Nicholls², M. Simic³, R. Brauer¹, I. Wong^*1

64.1.1 ¹Research Department of Practice and Policy, University College London, London, United Kingdom; ²Great Ormand Street Hospital, ³South London and Maudsley NHS Foundation Trust, London, United Kingdom

Background/Introduction: Anorexia Nervosa (AN) is a condition that onsets in young people (YP). First line treatment consists of psychological interventions; however psychotropic medications are sometimes prescribed if there is a less than optimal treatment response [1, 2].

Objective/Aim: This study aimed to describe contemporary prescribing practices of consultant child and young people eating disorder (CAED) psychiatrists, including the most common medications they prescribe and their process of continuing pharmacotherapy among AN patients.

Methods: We developed a self-administered exploratory questionnaire which was distributed among all child and adolescent eating disorder services (CYP EDS) in England during the Health Education England national training days.

Results: From 71 CYP EDS, 40 teams represented by an ED consultant responded (response rate 56%). Most (40%) consultants estimated < 10% of patients with AN to be on psychotropic medications. 38% of consultants reported olanzapine as their most commonly prescribed medication for AN, followed by fluoxetine (29%) and sertraline (10%). The minimum olanzapine initiation dose was at 2.5 mg for 2–4 weeks, reaching a maximum dose of 5 mg. 38% ED consultants met their patients once every 2 weeks on average, whereas 30 and 22% met once weekly and once monthly, respectively. Over 40% of consultants reported to continue olanzapine prescribing with the ED service teams, in contrast to the 30% who transferred prescribing to general practitioners.

Conclusion: The study showed that despite a lack of evidence, psychotropic medications are still prescribed, most commonly olanzapine. Further evidence is needed on which patients may potentially benefit from pharmacotherapy as an adjunct to psychological interventions.

References:

• 1. Gowers S., et al. Drug prescribing in child and adolescent eating disorder services. Child Adolesc Ment Health 2010; 15: 18–22

• 2. McKnight RF, Park RJ. Atypical antipsychotics and anorexia nervosa: a review. Eur Eat Disord Rev 2010; 18:10–21

Disclosure of Interest: None declared.

65 ISoP18-1084 The Efficacy and Safety of Psychotropic Drug Treatment in Adolescents with Anorexia Nervosa: A Systematic Review

65.1 M. Yakhchi Beykloo¹, A. Naser¹, D. Nicholls², M. Simic³, R. Brauer¹, I. Wong^*1

65.1.1 ¹Research Department of Practice and Policy, University College London, London, United Kingdom; ²Great Ormand Street Hospital, London, United Kingdom; ³South London and Maudsley NHS Foundation Trust, London, United Kingdom

Background/Introduction: Anorexia Nervosa (AN) is a mental disorder that onsets in adolescents. Treatment of anorexia nervosa is mainly carried out through a multidisciplinary approach, with psychological interventions given as first line treatment. However, psychotropic medications are sometimes prescribed if initial psychotherapy does not provide an optimal treatment response [1, 2].

Objective/Aim: This systematic review aims to review the existing literature on the safety and efficacy of psychotropic medications treatment in adolescents with anorexia nervosa.

Methods: The PubMed, EMBASE, PsychINFO and Cochrane Review databases were searched for relevant studies published up to October 2017 investigating psychotropic medications and their safety and efficacy in adolescents with AN. Randomised controlled trials (RCTs) and observational studies were included with no restrictions on study design or psychotropic medication therapeutic class. The primary outcome was defined as weight change as a measurement of drug efficacy, while secondary outcomes included safety of psychotropic medications with regards to adverse events, side effects, safety measurements and death.

Results: A total of 824 citations were identified of which 10 studies were included in our narrative review. These comprised of three RCTs and seven observational studies, covering a total of 1032 individuals ranging from 10 to 21 years of age. All studies did not find a significant association between the use of psychotropic medications for adolescents with AN and weight change. 70% of the studies (7 out of 10) confirmed safety issues among users of psychotropic medications, however the safety outcomes varied even between medications from the same therapeutic class, thus prevented us from aggregating the results.

Conclusion: The findings of this review fails to provide strong evidence for the efficacy of the use of psychotropic medications treatment in adolescents with anorexia nervosa. These preliminary results demonstrate a need to characterise the behaviours that lead clinicians to prescribe, and to explore the effects of medication on those specific behaviours, in order to establish the therapeutic efficacy and safety of psychotropics in the treatment of adolescents with anorexia nervosa.

References:

• 1. Gowers S, Claxton M, Rowlands L, Inbasagaran A, Wood D, Yi I, et al. Drug prescribing in child and adolescent eating disorder services. Child Adolesc Ment Health 2010;15:18–22

• 2. McKnight RF, Park RJ. Atypical antipsychotics and anorexia nervosa: a review. Euro Eat Disord Rev 2010;18:10–21

Disclosure of Interest: None declared.

66 ISoP18-1085 Risk Minimization Measures of a Paediatric Orphan Drug for Treatment of Neonatal Diabetes

66.1 M. Exposito^*1, J. Magnaud¹

66.1.1 ¹Pharmacovigilance, AMRING, Paris, France

Background/Introduction: In the context of Risk Management Plan for the Marketing authorization, specific Risk Minimization Measures (RMM) have been developed due to particular presentations of a glibenclamide suspension (2 dosages/2 syringes in 4 different presentations).

Objective/Aim: To reduce risks in a vulnerable population.

Methods:

• 1. Risks identification

• a Safety issues identified in a very small population during clinical trial [1],

• b adverse events described in glibenclamide product monograph for adult population,

• c missing information on neonatal population.

  • 2. Risks assessment

For each important risk, evaluation was performed to determine if additional minimization measures were necessary.

Results: Hypoglycaemia due to mix ups of the different strengths and different syringes was identified as major potential risk, especially in neonates and infants, for which routine minimization measures were considered as insufficient.

Consequently, three minimization measures were implemented:

• 1. Packaging: The dosage is clearly identified on the packaging by two different colours with reverse type. One syringe is thin and small while one syringe is thick and long. An appropriate drawing of the syringe included in the pack is present on the outer carton,

• 2. specific questionnaire for hypoglycaemia in order to further characterize the risk,

• 3. prescriber guide: provided to prescribers to describe each steps and parameters to be considered for prescription of the right dose and the right syringe.

Conclusion: Although the safety profile of glibenclamide is well known due to its well-established use, the context of an orphan drug intended for very young population associated to particular presentations has led to the development of specific MMRs. The effectiveness will be monitored during pharmacovigilance activities.

References:

• 1. Bouazza N, Djerada Z, Gozalo C, Busiah K, Beltrand J, Berdugo M, et al. Evaluation of the pharmacokinetics of glibenclamide tablet given, off label, orally to children suffering from neonatal syndromic hyperglycemia. Euro J Clin Pharmacol 2016;72:1373–9

Disclosure of Interest: None declared.

67 ISoP18-1086 Process Indicators vs. Correlated Endpoints in Studies Evaluating the Effectiveness of Risk Minimization Measures in the EU PAS Register

67.1 A. Farcas^*1, M. Huruba¹, C. Mogosan¹

67.1.1 ¹Drug Information Research Center, University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania

Background/Introduction: An important pillar of risk management is the evaluation of the risk minimization measures (RMMs) implemented in order to meet a targeted safety concern. The implementation and effectiveness of the RMMs can be evaluated through process indicators correlated with pre-established endpoints.

Objective/Aim: The aim of this review is to characterize process indicators and correlated endpoints from post-authorization studies that evaluate the effectiveness of RMMs.

Methods: All finalized studies that aimed to evaluate the effectiveness of RMMs, available in the EU Electronic Register of Post-Authorization Studies (EU PAS Register) up to 31st of April 2018, were included in the study.

Results: Out of the 359 effectiveness studies registered in the EU PAS Register, 31 evaluated the effectiveness of at least one RMM. 2 studies were excluded from the review due to early termination. Out of the 29 relevant studies 18 were finalized at the time of the present analysis. Among the finalized 18, 12 studies had both full protocol and final study results uploaded in the database, 2 had only the protocol available and 1 had only the final results uploaded.

Among the finalized studies, RMMs were evaluated through process indicators such as: knowledge (n = 18), behavior (n = 16), understanding (n = 15), utilization (n = 15), awareness (n = 10), receipt of materials (n = 9), and distribution (n = 3); 11 studies discussed the evaluation of the process indicators versus correlated endpoints, consisting of whether or not the pre-established threshold for assessed process indicator(s) was met. 7 mentioned that the study was effective, thus successfully proved the effectiveness of the analyzed RMMs by meeting their target endpoints: awareness (n = 6), knowledge (n = 5), receipt of materials (n = 4), behavior (n = 3), understanding (n = 2), utilization (n = 1), while only 1 study mentioned that the results led to discontinuation of RM tools, due to proved inefficacy.

Conclusion: Evaluation of effectiveness through process indicators versus clearly established endpoints facilitates the standardization of these studies, thus adding to development of further guidance to improve study designs and reporting.

Disclosure of Interest: None declared.

68 ISoP18-1087 A Description of Medicines Associated Safety Issues Evaluated Through a Referral Procedure at the EU Level

68.1 A. Farcas^*1, T. Balcescu¹, C. Mogosan¹

68.1.1 ¹Drug Information Research Center, University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania

Background/Introduction: Important safety issues are evaluated through a referral procedure at the EU level, when the Pharmacovigilance Risk Assessment Committee (PRAC) within the European Medicines Agency (EMA) is requested to conduct a scientific assessment of a particular medicine/class of medicines and to make a recommendation for a harmonized position across the EU.

Objective/Aim: To describe all referrals assessed by the PRAC and having a final recommendation.

Methods: Publicly available data on safety issues assessment through a referral procedure for the period June 2012–March 2018 were collected, analyzed and classified according to predefined criteria.

Results: 46 safety-related referrals were assessed by PRAC for 42 medicines/classes of medicines/combinations in our study’s timeframe. The ATC drug classes for which most referrals were initiated were the nervous system class (n = 8), blood and blood forming organs class (n = 6), respiratory system class (n = 6), genito-urinary system and sex hormones class (n = 5) and musculo-skeletal system class (n = 5). 8 drugs were authorized in the last 5 years, the rest being well-established drugs.  Referrals were triggered for cardiac disorders (n = 14), blood and lymphatic system disorders (n = 6), hepatobiliary disorders (n = 6) and nervous system disorders (n = 6). Most referrals were triggered through article 31 (n = 27), followed by article 20 (n = 12) and fewer by article 107i, considered an urgent procedure (n = 7). Referrals were initiated mostly by the European Commission (13), France (7), United Kingdom (6), and Germany (5). In three cases (for flupirtine, hydroxyethyl-starch solutions and valproate) re-assessments of the same risks were carried out by PRAC due to the fact that previous recommended restrictions have not been sufficiently effective. Final recommendations consisted in summary of product characteristics (SmPC) and package leaflet (PIL) updates in 38 cases, in sending a Direct Healthcare Professional Communication in 28 cases, and in other additional risk minimization measures. Recommendations for withdrawal were made for 7 active substances and 6 pharmaceutical forms. The SmPC sections that was most often modified towards a safer drug use were special warnings and precautions for use (n = 35), undesirable effects (n = 26), contraindications (n = 21) and posology and method of administration (n = 20) sections.

Conclusion: In most referral procedures PRAC recommended routine or additional risk minimization measures such as amendments to the product information and communication to healthcare professionals, towards an optimized use of medicinal products.

Disclosure of Interest: None declared.

69 ISoP18-1092 Doxycycline Associated Fixed Drug Eruptions Safety Review

69.1 A. Alakeel^*1, M. Fouda¹, A. Alshahrani¹, M. Almofada¹

69.1.1 ¹Vigilance and Benefit–Risk Assessment Executive Directorate, Saudi Food and Drug Authority, Riyadh, Saudi Arabia

Background/Introduction:

Like for all medications, antibiotics are not free of adverse drug reactions (ADRs). Fixed drug eruption (FDE) is a serious special type of cutaneous reactions [1]. As a disease condition, FDE is considered a type of reactive erythema (erythema-multiform-like) [2]. Characteristically, the reaction recurs in the same site on skin/mucosa each time the offending drug is administered (hence called “fixed”). Doxycycline is a broad-spectrum bacteriostatic antibiotic belongs to tetracycline class. It is active against a wide range of microorganisms.

The Saudi Food and Drug Authority (SFDA) has initiated a safety review based on a published case report of potential association between doxycycline and the risk of FDE [1]. A 37-year-old female presented to the hospital with a history of fluid filled lesions all over her body following single dose of doxycycline. Her previous medical record shows rashes over the trunk due to former doxycycline intake as well.

Objective/Aim:

The purpose of this review is to evaluate the risk of FDE associated with doxycycline use and if required, to suggest regulatory recommendations.

Methods:

SFDA performed a search in the national ADRs database, World Health Organization (WHO) global ADRs database along with literature screening to retrieve all related information for the sake of investigating causality of drug-event combination.

Results:

The Saudi National Pharmacovigilance Center database showed two reports of doxycycline associated with FDE. One of the two cases has been excluded due to suspected duplication.

The WHO database revealed 364 international ADR reports. Of them, 356 cases were not sufficiently documented for proper medical assessment. The rest of the cases (i.e. eight cases), were reported a positive de-challenge and one case reported unknown re-challenge outcome.

During literature search, a published study evaluating the cross-reactivity of FDE with tetracycline antibiotics. The study included 16 patients who have FDE following tetracycline use. The patients challenged to doxycycline or minocycline at least 6 weeks after the last episode of FDE. Among these 16 patients, ten developed FDEs to doxycycline within 6 h after doxycycline intake [3].

Another published case-report of a 30-year-old male who has 4-day-history of erythematous patches. The patient reported that lesions developed 3 h following a single dose of doxycycline. The case reported a positive de-challenge and re-challenge [4].

Conclusion:

The SFDA investigations concluded that the current available evidence supports probable relationship between doxycycline and FDE. Therefore, the reference safety information is updated and a safety communication released.

References:

• 1. Nitya S, Deepa K, Mangaiarkkarasi A, Karthikeyan K. Doxycycline induced generalized bullous fixed drug eruption—A case report. J Young Pharm 2013; 5:195–6

• 2. Cohen BA. (2013). Reactive Erythema. In Pediatric Dermatology: Fourth Edition. Elsevier Inc.

• 3. Tham SN, Kwok YK, Chan HL. Cross-reactivity in fixed drug eruptions to tetracyclines. Arch Dermatol 1996; 132: 1134–5

• 4. Podder I, Chandra S, Das A,Gharami RC. Doxycycline induced generalized bullous fixed drug eruption. Indian J Dermatol 2016; 61:128

Disclosure of Interest: None declared.

70 ISoP18-1094 Expectedness of Antimicrobials Adverse Drug Reactions in Iraqi, 2010–2017

70.1 M. M. Younus^*1, A. AL-Charakh²

70.1.1 ¹Iraqi Pharmacovigilance Center, MOH, Baghdad, Iraq; ²Faculty of pharmacy, University of Kufa, Najaf, Iraq

Background/Introduction: Antimicrobials are among the most widely used medicines worldwide to treat or prevent different types of infections and it is not always true that their use is free from problems; in fact many studies showed different non-expected or expected adverse drug reactions (ADRs) events accompanying their use. The expectedness or Predictability of these ADRs vary widely depending on the type of antimicrobial agent, patients factors, concomitant medicines, underlying co-morbidities and many other reasons.

Objective/Aim: Analyze Iraqi pharmacovigilance center (IPC) database regarding antimicrobial ADRs expectedness. This is the first published data regarding the antimicrobials ADRs from the IPC database.

Methods: This is a retrospective study, where all antimicrobial ADRs, spontaneously reported to the IPC database using the national individual case safety report (ICSR) form, during the period 2010–1 Nov 2017 were analyzed. Data regarding patient demography, antimicrobial group (ATC code J01), and type of ADRs classified according to MedDRA by system-organ classes (SOC) and preferred terms (PT) were collected.

The expectedness was evaluated through the review of the summary of product characteristics of all the reported antimicrobials depending on the EMA definition of expectedness. The relationship between expectedness and patients characteristics (age, sex) was studied. Also, the seriousness of the reports was evaluated according to EMA criteria. The relationship between expectedness and seriousness was studied.

Statistical Package for the Social sciences (SPSS) version 17 was used to analyze the results. The data was expressed in (%). Chi square test was applied and p value < 0.05 was considered to be significant.

Results: The total number of reports included in this study were 896 reports, 45 (5.0%) of them were unexpected. Age group (2–11 years) showed 6.2% unexpected ADRs, followed by (12–17 years) with 5.9 and 5.1% in both (18–44 years) and (65+ years). Males represented 45.2% of the total number of patients and 56.9% of the unexpected ADRs were reported in males.

The most predominant SOC for antimicrobials involved in this study were; immune system disorders (347 adverse effects), gastrointestinal disorders (220 adverse effects) and skin and subcutaneous disorders (177 adverse effects). On the other hand skin and subcutaneous disorders with (25 adverse effects) was the most predominant of the unexpected adverse effects of the antimicrobials while gastrointestinal disorders showed (15 adverse effects) and the immune system disorders (11 adverse effects) was in the third place.

Antimicrobial groups most frequently involved with unexpectedness were; sulfonamides 16.7%, β-lactam 7.8%, quinolone (6.4%). Other β-lactam antibacterials (5.7%). Unexpected, serious reports represent 57.7% (26 reports) of the total unexpected reports and the results were significant at p < 0.05.

Conclusion: In this study, there were (5%) 45/896 unexpected ADRs among antimicrobials reported to the IPC. Different antimicrobial groups were involved, mostly sulfonamides, β-lactam and quinolone. Varying MedDRA terminology were reported; skin and subcutaneous, gastrointestinal and immune system disorders were the most predominant terminologies. Seriousness compared with expectedness showed significant results.

Disclosure of Interest: None declared.

71 ISoP18-1096 Snapshot of the Overprescription of Proton Pump Inhibitors in a Primary Care Hospital

71.1 C. Lenoir^*1, M. El Biali¹, C. Luthy², O. Grosgurin³, J. Desmeules¹, V. Rollason¹

71.1.1 ¹Division of Clinical Pharmacology and Toxicology,; ²Division of General Medical Rehabilitation, Geneva University Hospitals & University of Geneva, Switzerland; ³Division of Internal Medicine, Geneva University Hospitals, Geneva, Switzerland

Background/Introduction: Proton pump inhibitors (PPIs) are among the most widely prescribed drugs in the world, but more than half of the indications for prescription are unjustified [1, 2]. The misuse of this therapeutic class has heavy consequences such as additional health costs, adverse drug reactions following long-term use and gastric acid rebound when the PPI is discontinued [3–5]. The overprescription of PPIs is therefore becoming a public health problem, which led us to evaluate its use within the Geneva University Hospitals (HUG).

Objective/Aim: To characterize the PPI prescription within the HUG and in particular to determine if the PPI prescription is made according to the market authorization and known guidelines.

Methods: This prospective observational study collected data by consulting the electronic records of patients hospitalized in two divisions of the department of internal medicine of the HUG (division of general internal medicine and division of general medical rehabilitation) on a single day (instant photography) using the computerized patient record system of HUG (DPI^®).

Results: 180 (95 men and 85 women) patients were included. 54% (N = 97) of patients were on PPIs, 29% (N = 28) of whom had their treatment initiated at HUG. For patients for whom home treatment was known 46% (N = 78) of patients were already treated at home. Regardless of dosage, 72% (N = 70) of the indications for treatment were not justified, 24% (N = 23) of the indications were justified and 4% (N = 4) were eventually justified. Regarding dose, 56% of the justified indications and 75% of the possibly justified indications did not have an adequate dosage. Therefore, in all patients with a PPI at HUG, only 11% had a justified and possibly justified indication with an adequate dose. Esomeprazole was the most prescribed PPI with a rate of 97% (N = 94) at HUG and 70% (N = 54) at home. Among them, respectively 50% (N = 47) and 60% (N = 32) were prescribed 40 mg/d. Finally, 87% (N = 68) of known home prescriptions were renewed on admission and among them, 71% (N = 40) did not have a justified or possibly justified indication according to the guidelines.

Conclusion: Our study highlights the multifactorial problem surrounding the prescription of PPIs. Indication for treatment inside the hospital was not justified in 72% of patients. Moreover when taking also dose into account, only 11% of our patient had a justified indication with a correct dose. Precise guidelines with evidence-based indications and adequate daily doses would help the prescribers, in the hospital and in the community, to adequately prescribe PPIs. Moreover, patients should benefit from a thorough evaluation of their treatment at admission and on discharge.

References:

• 1. Sukhovershin RA, Cooke JP. How may proton pump inhibitors impair cardiovascular health? Am J Cardiovasc Drugs 2016;16:153-61

• 2. Rotman SR, Bishop TF. Proton pump inhibitor use in the U.S. ambulatory setting, 2002–2009. PLoS One 2013;8:e56060

• 3. Martin RM, Dunn NR, Freemantle S, Shakir S. The rates of common adverse events reported during treatment with proton pump inhibitors used in general practice in England: cohort studies. Br J Clin Pharmacol 2000;50:366-72

• 4. Nardino RJ, Vender RJ, Herbert PN. Overuse of acid-suppressive therapy in hospitalized patients. Am J Gastroenterol 2000;95:3118-22

• 5. West DS, Johnson JT, Hong SH. A 30-month evaluation of the effects on the cost and utilization of proton pump inhibitors from adding omeprazole OTC to drug benefit coverage in a state employee health plan. J Manag Care Pharm 2006;12:25-32

Disclosure of Interest: None declared.

72 ISoP18-1097 High Dose Methotrexate Delayed Elimination: A Case Series

72.1 B. Azzouz¹, C. Feliu², Q. Jarrion¹, L. Aubert¹, A. Morel¹, Z. Djerada², T. Trenque^*1

72.1.1 ¹Regional Centre of Pharmacovigilance and Pharmacoepidemiology,; ²Department of Pharmacology, Reims University Hospital, Reims, France

Background/Introduction: High dose methotrexate (HDMTX, defined as > 1 g/m²) is used to treat a variety of adult and pediatric cancers, including acute lymphoblastic leukemia, osteosarcoma and lymphoma. More than 90% of MTX is eliminated by the kidneys. Hyperhydratation, urine alkalinization, leucovorin, close monitoring of plasma MTX concentrations and kidney function, drug–drug interaction analysis are mandatory to prevent delayed MTX elimination.

Objective/Aim: To raise healthcare professionals awareness about HDMTX delayed elimination and its toxicity.

Methods: We reviewed spontaneous reports of delayed HDMTX excretion notified to the Pharmacovigilance Center of Reims within the last 6 months (December 2017 to May 2018).

Results: Despite adequate preventive measures, 5 spontaneous reports of delayed HDMTX, within the last 6 months, were notified. Mean age was 57.2 ± 9.5 years (range 44–67 years), patients were exclusively males. Indications of HDMTX were: B cell lymphoma, Burkitt’s lymphoma, blastic plasmacytoid dendritic cell neoplasia and cerebral lymphoma. MTX dose was 3 g/m² for all cases, infusion durations were: 3 h (n = 3), 24 h (n = 1) and 30 min (n = 1). Delayed MTX elimination occured at the second cycle in 4 cases. Mean CKD-EPI before the MTX regimen was: 71.6 ± 13.5 mL/min (range 59–90 mL/min). Mean serum MTX concentration at H24 (C_24H) was: 50.6 ± 37.8 µmol/L (range 20.4–114.2 µmol/L). Mean CKD-EPI at H24 was: 28.4 ± 3.5 mL/min (range 25–34 mL/min). Toxicities observed were: nephrotoxicity (renal tubular necrosis, acute kidney injury), hepatotoxicity (acute liver injury), myelosuppression (febrile aplasia, febrile neutropenia), neurotoxicity (encephalopathy), respiratory distress, epidermolysis and mucositis. Leucovorin rescue, hyperhydratation and urine alkalinization were performed for all patients. Glucarpidase was introduced in 4 cases. Despite the glucarpidase therapy, a septic shock with fatal outcome was observed in 2 cases (C_24H were: 53.2 and 114.2 µmol/L, fatal outcome occurred 9 days after MTX infusion).

Conclusion: HDMTX delayed elimination can lead to serious and life-threatening toxicities. The same MTX dose, 3 g/m², was given for patients with different kidney function levels. MTX dose should be adjusted to the kidney function. Protocol with MTX 3 g/m² during 30 min (R-MBVP) should be updated, a slower MTX infusion would be prudent. Serum MTX concentration levels should be measured at earlier stages. Serum MTX concentration assessed before 24 h would enable an early detection of HDMTX delayed elimination. Health professionals awareness is needed even if the first MTX cycle went with a good tolerance.

Disclosure of Interest: None declared.

73 ISoP18-1098 Awareness Survey on Drug–Drug Interactions Among Argentinean Health Care Professionals

73.1 G. Darderes^*1, C. Brown², J. C. Gallo³, L. D´Alessio⁴, E. Roldan⁵

73.1.1 ¹Head of Pharmacovigilance, ² GADOR S.A;, ³; ⁴ENyS-CONICET, Buenos Aires, Argentina; ⁵Scientific Direction, GADOR S.A., Buenos Aires, Argentina

Background/Introduction: Since 1994, Argentinean National Regulatory Health Authority (ANMAT) is an official member of the WHO Program for International Drug Monitoring. However, the number of adverse reactions related to drug–drug interactions reported is still very low. As surveys developed with healthcare professionals (HCP) in other countries showed that the knowledge and awareness about drug–drug interactions, and the number of reports increase, we develop a similar experience in our country.

Objective/Aim: The aim of this survey was to assess the level of knowledge about drug–drug interactions and the activity of reporting adverse events related to drug–drug interactions among local HCP. Likely, the survey will be used as an awareness tool. We hereby report on the outcomes.

Methods: A cross-sectional on-line survey was designed, using a validated self-administered questionnaire form with a set of 10 questions and their correspondent multiple choice options for answering. The questionnaires were distributed to 20,653 HCP from an own database, including medical doctors, dentists and pharmacists. The questionnaire was related to adverse events linked to drug–drug interactions and the subsequent reporting behavior of HCP in ordinary practice. Questions were chosen based on daily practice situations. Data was collected and clustered by the type of HCP, analyzed by descriptive statistic, and Chi square test and z-scores corrected with Bonferroni Test for multiple comparisons were determined using a PC software.

Results: A total of 583 HCP, answered the survey; 354 (69%) were medical doctors, 182 (63%) dentists, and 47 (43.5%) pharmacists. Most part of medical doctors 61.1% prescribe and or discharge at least one drug in more than a half of their patients, 40.4% among pharmacies but only 20.9% among dentists (p < 0.05). Inquired about a clinical intercurrence situation, the most common response was to maintain the basal treatment and only change the temporal treatment, agreeing 52.0% of medical doctors, 41.2% of dentists, and 36.2% of pharmacists (p > 0.05), and the rest react differently. Regarding the source of getting update information about adverse reactions, 30.8% of medical doctors, 28.6% of dentists and 21.3% of pharmacies, similarly answered they prefer to use electronic media (p > 0.05), and the remaining choosing other options. During a situation of a drug interaction, medical doctors choose more frequently the option about revising the medical bibliography, 59.6%, comparing dentists, 30.8% and pharmacies, 31.9% (p < 0.05).

Conclusion: In this preliminary analysis it is shown that awareness is diverse and reactions to situations from practice are variable. Hence, apart from promoting awareness between HCP on their reporting role of adverse reactions related to drug–drug interactions, there is a need of guiding health professionals on good practice reporting AE related to drug–drug interactions.

References:

• 1. Metta H, Floor-Schreudering A, Wouters H, De Smet PAGM, Bouvy ML. Preferences of patients and pharmacists with regard to the management of drug–drug interactions: a choice-based conjoint analysis. Drug Saf 2018; 41: 179–89

• 2. Floor-Schreudering A, Geerts AF, Aronson JK, Bouvy ML, Ferner RE, De Smet PA. Checklist for standardized reporting of drug–drug interaction management guidelines. Eur J Clin Pharmacol. 2014;70:313–8

• 3. Pollard S, Bansback N, Bryan S. Physician attitudes toward shared decision making: a systematic review. Patient Educ Couns 2015;98:1046–57

• 4. -Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE, Liberati A, et al. Going from evidence to recommendations. BMJ. 2008;336:1049–51

Disclosure of Interest: G. Darderes Grant/Research support from: Gador support the survey, C. Brown Grant/Research support from: Gador support the survey, J. C. Gallo: None Declared, L. D´Alessio: None Declared, E. Roldan Grant/Research support from: Gador support the survey.

74 ISoP18-1101 The Degree of Impact of Adverse Drug Reactions as Experienced by Patients

74.1 M. Haaksman^*1, L. Rolfes¹

74.1.1 ¹Netherlands Pharmacovigilance Centre Lareb, ‘s-Hertogenbosch, The Netherlands

Background/Introduction: Little is known about the degree by which patients experience the impact of adverse drug reactions (ADRs).

Objective/Aim: To explore the degree by which patients experience the impact of ADRs that they reported to the Netherlands Pharmacovigilance Centre Lareb. The secondary objective was to explore factors correlated to the impact-score.

Methods: A retrospective observational study about the degree of impact of ADRs. The patient ADR reporting form of the Netherlands Pharmacovigilance Centre Lareb contains a question about the degree of impact of the ADR. The answer option is a 5-point scale, ranging from ‘not at all’ (score 1) to ‘very much’ (score 5). All drug-ADR associations, reported by patients between 10 July 2017 and 5 February 2018 were included.

Impact-scores were analyzed for all included ADRs on Preferred Term (PT) level, with serious and non-serious ADRs being analyzed separately. In-depth analysis on correlated factors was done for gender (men/women), age (< 65/65 or older), outcome of the ADR (recovered/not recovered), and action taken on the drug (withdrawn/dose not changed). Data were analyzed using Pearson Chi²-test. Statistical significance was based on p < 0.05.

Results: In total 1.015 ADR reports, including 2.718 drug-ADR associations were included, of which 44 concerning serious ADRs and 971 non-serious ADRs. The average impact-score for serious ADRs was 4.8 and for non-serious ADRs 3.7 (Table 1). This difference in impact-score was statistically significant (p value < 0.001). Due to this difference and the low number of serious ADRs in our output, the in-depth analysis included only non-serious ADRs.

ADRs concerning anxiety, suicidal ideation and pain had the highest average impact-score (4.8, 4.8 and 4.6, respectively) and injection site reactions, dry eyes and drug ineffective the lowest (2.9, 3.0 and 3.0, respectively).

There was no significant difference for the impact-score between men and women (p value 0.169). Patients over 65 years experienced a higher impact compared to those under age 65 (p value < 0.001). Patients experienced a higher impact for ADRs that recovered compared to ADRs that were not recovered (p value < 0.001). The impact-score was furthermore higher for patients by whom the drug was withdrawn compared to those by whom the dose of the drug was not changed (p value < 0.001).

Conclusion: This study demonstrated the degree by which patients experience the impact of ADRs. In addition, it indicated factors that correlated the impact-score. This knowledge is useful for healthcare professionals and patients to better understand the meaning of experiencing ADRs.

Disclosure of Interest: None declared.

75 ISoP18-1102 Automatic Detection and Removal of Personal Identifiers on Case Narratives Using Deep Learning

75.1 E.-L. Meldau¹, S. Hedfors Vidlin¹, L. Gattepaille¹, H. Taavola¹, L. Sandberg^*1, Y. Aoki¹, G. N. Norén¹

75.1.1 ¹Uppsala Monitoring Centre, Uppsala, Sweden

Background/Introduction: Removing personal information (de-identification) from free-text narratives in individual case safety reports is important to preserve patient privacy. It is, however, a demanding task for human annotators [1] as well as for any automatic system that would have to face the complex challenge of deciphering natural language. The case reports provide information about the suspected adverse drug reactions experienced by patients through both structured fields and free-text narrative descriptions. Both have been found to have an impact on the causality and clinical assessment [2]. The narrative can for example provide information about the severity of the reaction or the impact on the patient’s quality of life which may not be easily conveyed in structured fields. Automatic de-identification of narratives would allow sharing these narratives between organizations to ultimately improve patient safety while preserving patient privacy.

Objective/Aim: To develop an automatic de-identification method for narratives. In this abstract, we present interim results from ongoing research.

Methods: Our de-identification method combines the prediction of several models through an ensemble method using logistic regression. Each token in the narrative is labelled “personal” or “non-personal” where names, dates and locations are considered personal identifiers for the purpose of this study. The models used are different deep neural networks, a logistic regression, a part-of-speech tagger, and rule-based methods. The neural networks and logistic regression are particularly flexible in the sense that they can be retrained on new data with different properties such as other languages, writing styles or formats. This training requires large amounts of annotated data, but at this point of our research, there is a shortage in annotated narratives. We therefore used the training data from the 2014 i2b2 de-identification challenge [3], containing 521 medical records. A validation set of 269 i2b2 records was divided; 75% were used for training the ensemble method and 25% for evaluating the method. The method was also evaluated on 300 narratives from reports in VigiBase, the World Health Organization’s global database of individual case safety reports.

Results: 95% of the personal identifiers were detected (recall), while 90% of the detected parts were actually personal identifiers (precision). For the categories names and dates the recall was higher than 95% (98 and 96%, respectively) and for locations lower (86%). From the VigiBase narratives, 90% of the personal identifiers were recalled with a precision of 45%. Parts of the annotated personal identifiers that were missed by the algorithm, for example of in “4th of May”, would not compromise the confidentiality but do decrease the recall, suggesting that the method preserves privacy better than the recall indicates.

Conclusion: Our recall on i2b2 data exceeds human recall for all three categories, while humans are more precise in their detection [1]. The high recall and intermediate precision on narratives is promising, considering that our method was only trained on medical records but not yet on the target data. With access to original narratives that can be annotated for further training and fine-tuning, we expect the performance to improve even further.

References:

• 1. South BR, Mowery D, Suo Y, Leng J, Ferrández Ó, Meystre SM, et al. Evaluating the effects of machine pre-annotation and an interactive annotation interface on manual de-identification of clinical text. J Biomed Inform 2014; 50: 162–72

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

• 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

Disclosure of Interest: None declared.

76 ISoP18-1103 Suicidal and Self-Injurious Behaviour Under Desogestrel: The Patient’s View

76.1 S. Watson^*1, L. Härmark², P. Caduff- Janosa¹

76.1.1 ¹Uppsala Monitoring Centre, Uppsala, Sweden, ²Lareb, ‘s’Hertogenbosch, The Netherlands

Background/Introduction: Altered and depressed mood are listed adverse drug reactions (ADRs) for the contraceptive drug desogestrel. More severe reactions like suicidal ideation and self-injurious behaviour are not^1,2. These ADRs were highlighted as potential signals for desogestrel in a joint signal detection workshop between Uppsala Monitoring Centre and the Netherlands Pharmacovigilance Centre Lareb, focusing on patient reports using the WHO global database of individual case safety reports, VigiBase.

Objective/Aim: To explore the evidence in VigiBase for the causal association between desogestrel and suicidal and self-injurious behaviour.

Methods: Case-by-case assessment of relevant reports in VigiBase up until October 2016.

Results: At the time of the workshop, October 2016, there were 34 reports for the MedDRA High level term Suicidal and self-injurious behaviour. Desogestrel was the only suspected drug in 27 reports. In seven reports there were more than one suspect drug; other contraceptives in two cases, topiramate in one, (es)citalopram in two and in two cases multiple drugs in two of the suicide attempts. In 19 reports desogestrel was the only reported drug and no concomitant drugs were reported. The time to onset (where this information was recorded) ranged from 1 day to 5 months. In 20 cases the patients recovered after stopping the drug and one patient mentions a rechallenge, although it is not clear if the same contraceptive drug was used.

Two patients had a medical history of depression or depressive episodes but both recovered after discontinuing desogestrel.

Conclusion: Although mood changes and depressed mood are listed as ‘common’ in the product label and patient information leaflets of desogestrel, the more severe reactions suicidal ideation and self-injurious behaviour are not mentioned at all. A literature review revealed no published case reports of desogestrel in relation to these events. Severe depressions can lead to self-harm or even suicide, which is what the reports in VigiBase describe. Although in some cases there might be confounding factors present, in 20 cases there was a positive dechallenge which strengthens the relationship between the drug and the events. These reports send a signal to both women using contraceptives and prescribers to be vigilant of the severity of the depressions that may occur while on this contraceptive. Further investigations to identify the women at risk for psychiatric disorders as ADRs for hormonal contraceptives in general are needed.

Note! In May 2018 the number of reports has increased to 45.

References:

• 1. Electronic Medicines Compendium: Summary of Product Characteristics for desogestrel (Cerazette^®) Available from https://www.medicines.org.uk/emc/medicine/10098 Accessed: May 2018

• 2. Electronic Medicines Compendium: Patient Information Leaflet for desogestrel (Cerazette^®). Available from: https://www.medicines.org.uk/emc/product/1698/pil Accessed: May 2018

Disclosure of Interest: None declared.

77 ISoP18-1104 Gender Differences in Adverse Drug Reaction Reports; How can they be Explained?

77.1 S. de Vries¹, E. van Puijenbroek^*2,3, P. Mol¹, C. Ekhart², P. Denig¹

77.1.1 ¹Dept. of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; ²Pharmacovigilance Centre Lareb, ‘s-Hertogenbosch, the Netherlands; ³Groningen Research Institute of Pharmacy, Pharmacotherapy, Epidemiology & -Economics, University of Groningen, Groningen, the Netherlands

Background/Introduction: In general, women have a higher risk for adverse drug reactions (ADRs) being reported than men [1]. Women also generally use more drugs as compared to men in various therapeutic areas [2]. It is unclear which differences in reporting pattern for both genders exist after correcting for drug use. Knowledge of these differences, and possible mechanisms that may explain them, may help in optimizing gender-specific pharmacotherapy.

Objective/Aim: To assess and characterize gender differences in reported drug-ADR combinations to the national pharmacovigilance centre in the Netherlands, corrected for differences in drug use.

Methods: We included drug–ADR combinations reported by healthcare professionals and patients to the Netherlands Pharmacovigilance Centre Lareb. Only combinations (ATC-MedDRA preferred term) that were reported at least 10 times between 2003 and 2016 for drugs that were used by ≥ 10,000 persons in that period were taken into account. Gender-specific ADRs, like gynaecological problems, were excluded. Data from the National Health Care Institute were used to correct for the number of users per drug. Gender differences in specific drug–ADR combinations were tested using bivariate logistic regression analyses, adjusted for the number of drug users per gender.

Results: A total number of 2482 drug–ADR combinations were analysed. Statistically significant differences (p < 0.05) were shown in 363 combinations (15%). Most of these drug–ADR combinations were reported more often for women (321 combinations, 88%). Drugs with the highest number of ADRs that were more often reported for women included thyroid hormones, and antidepressants. Some ADRs were predominantly reported for women across a range of drugs like headache and dizziness whereas other ADRs like tendon ruptures and aggression were reported more often for men.

Conclusion: Identified gender differences in reporting ADRs often referred to women. These differences may have various causes. Men and women differ in respect to their physiology, immunological processes and type and function of various hormones. This may result in differences in pharmacokinetics and pharmacodynamics. Examples are the predominance of dose depending ADRs being reported in women which may depend on pharmacokinetic properties and the predominance of ADRs associated with psychotropic drugs which may be caused by differences in pharmacodynamics. Gender differences may also result of variations in perception by reporter and patient since they are experienced as bothersome depending on a gender-specific self-image. An example is the occurrence of hair thinning and hair loss, which is more common in aging men but is likely to be considered as disturbing particularly when it occurs in women. In addition, differences in background incidence in disorders and diseases between both genders exist and may be reflected in reporting ADRs. Finally, gender differences in reporting may result from variations in reporting behaviour of the reporter, either healthcare professional or patient. Further studies are needed to assess underlying reasons, including pharmacological and behavioural factors. The results may ultimately lead to gender-specific prescribing or monitoring recommendations.

References:

• 1. Rademaker M. Do women have more adverse drug reactions? Am J Clin Dermatol 2001;2:349–5

• 2. Loikas et al., Differences in drug utilisation between men and women: a cross-sectional analysis of all dispensed drugs in Sweden. BMJ Open 2013;3:e002378

Disclosure of Interest: None declared.

78 ISoP18-1110 Who’s At Risk? Identifying Risk Groups for Adverse Drug Reactions Using Vigibase

78.1 Y. Aoki¹, L. Sandberg^*1, H. Taavola¹, R. Chandler¹, G. N. Norén¹

78.1.1 ¹Uppsala Monitoring Centre, Uppsala, Sweden

Background/Introduction: Early identification of previously unknown causal associations between medicines and adverse events has been the primary focus of pharmacovigilance. In recent years, Uppsala Monitoring Centre has initiated a shift toward signal characterisation and risk group identification in support of our vision for wise therapeutic decisions. As a first attempt at broader open-ended risk group detection, we conducted a signal screening focused on identifying risk groups for adverse drug reactions (ADR).

Objective/Aim: To explore the possibility of identifying risk groups for ADRs using VigiBase, the World Health Organization’s global database of individual case safety reports.

Methods: We considered 15.4 million reports received up until August 2017 in VigiBase. The following covariates were explored as potential risk factors for ADRs: age, sex, body mass index, pregnancy status, underlying disease, and reporting country/continent.

Disproportionality analysis was performed for all drug-adverse event (AE) pairs (1) in the entire database, and (2) across a range of data subsets defined by the selected covariates. Drug-AE pairs disproportionally reported in at least one of the subsets but not in the database as a whole were considered for initial manual assessment. To reduce the chance of highlighting spurious associations, higher confidence levels were used in the subset analyses. Further, a drug–AE-subset association was required to have at least one report received in 2012 or later and the observed-to-expected ratio in the subset needed to be at least twice that of the corresponding value in the database as a whole.

The highlighted associations were prioritised for initial manual assessment using vigiRank [1], while ensuring that a balanced number of drug–AE pairs for all covariates were assessed. The assessments were performed by physicians, pharmacists and data scientists working in teams. During this initial manual assessment, the association was determined to be a potential signal if the risk factor was not communicated in the label, there was no obvious confounder, and the reports for that association were informative enough to conduct the in-depth review. The selected potential signals were subject to in-depth clinical reviews by the domain experts and the biological evidence for the risk factor for the ADR was further investigated.

Results: The initial manual assessment covered 386 associations, of which 18 were deemed to be potential signals. A breakdown of the potential signals by covariate is tabulated below. The top 3 risk groups by the number of potential signals were females (5), underweight patients (3) and the elderly (3).

As of May 2018, in-depth clinical reviews have been completed for 14 out of 18 potential signals, resulting in seven signals describing potential risk groups for ADRs (sex: 2, age: 2, body mass index: 2, continent: 1).

Conclusion: Signals of ADRs in risk groups can be identified from a global database using subset disproportionality analysis. Continued development of statistical screening methodologies to highlight potential signals within subgroups could usher in a new era of “precision pharmacovigilance”.

References:

• 1. Caster O, Juhlin K, Watson S, Norén GN. Improved statistical signal detection in pharmacovigilance by combining multiple strength-of-evidence aspects in vigiRank. Drug Saf 2014;37:617–28

Disclosure of Interest: None declared.

79 ISoP18-1117 Pvknow: A Pharmacovigilance Knowledge Management System

79.1 J. Boer^*1, L. Härmark¹

79.1.1 ¹Netherlands Pharmacovigilance Centre Lareb, ‘s-Hertogenbosch, The Netherlands

Background/Introduction: During the daily pharmacovigilance processes at the Netherlands Pharmacovigilance Centre Lareb, multiple information sources, located in different places, are consulted by the individual assessors. The fragmentation of information leads to process inefficiencies, and as all assessors might not know the existence and location of certain information, it might lead to sub-optimal quality of the output of the processes. Clustering all the relevant information in one place would improve the quality and efficacy of internal processes.

Objective/Aim: To develop a knowledge management system in which all relevant knowledge can be stored centrally, to support the internal processes.

Methods: An internal working group was formed, to identify all the functional requirements for the system. This group consisted of Lareb staff that are involved in the knowledge intensive processes within the organisation and a Business Analyst. The system was developed using Agile methodology. This means that the building process starts before the plans are finalised, which increases flexibility. In subsequent sessions within this process additional adjustments could be made based on newly gained insights [1].

Results: The knowledge management system, called PVknow, was designed as a modular application where the core consists of knowledge pages. These pages contain the relevant and updated information about a particular drug–adverse drug reaction (ADR) association. The knowledge pages can also be shared with the public through a connection to the website. Key in designing this functionality was a search function with which you can search for a specific drug, ADR or drug–ADR combination. Other modules in PVknow are a helpdesk function, a signal management tool and a library.

Conclusion: PVknow is the result of the idea to create a knowledge management system to store pharmacovigilance related information centrally. By involving Lareb staff with in depth knowledge about the scientific processes it was ensured that the developed system would fit for purpose. By developing in an Agile way, it was possible to have maximal flexibility in adapting the system to the current needs. The experiences so far are positive; the information is well organized and easily available for assessors and thereby supporting the daily activities at Lareb. Although it was developed with the primary aim to support internal processes, it will also enable Lareb to share the content of PVknow with external partners through our own website or partner websites.

References:

• 1. Hoogendoorn S. Dit is agile. Van introductie tot implementatie. Amsterdam. Pearson Benelux. 2012.

Disclosure of Interest: None declared.

80 ISoP18-1118 Risk of Diabetes Associated with Statins Fibrates and their Association

80.1 F. Montastruc¹, J. Benevent¹, V. Rousseau¹, G. Durrieu¹, A. Sommet¹, J.-L. Montastruc^*1

80.1.1 ¹Medical and Clinical Pharmacology, Faculté de Médecine, Toulouse, France

Background/Introduction: Relations between use of hypolipidemic drugs and occurrence of diabetes are controversial.

Objective/Aim: The aim of our study was to assess the association between diabetes and use of statins, fibrates and their association using the World Health Organization (WHO) global individual case safety reports database, VigiBase^®, which records reports from over 130 countries worldwide.

Methods: We performed a disproportionality analysis including all reports until the 31st December 2017 to measure the risk of reporting “new onset of diabetes” compared with all other reports [as a reporting odds ratio (ROR 95% CI)] for statins, fibrates and their association. The likelihood that diabetes resulted from statin–fibrate pharmacodynamic interaction was also estimated. According to the interaction additive model, a ROR value for coexposure exceeding the sum of the RORs estimated for each individual class of drug supports a potential drug–drug interaction (DDI). To assess the stability of our results, we performed several sensitivity analyses, according to outcome definition and excluding reports with drugs known to induce hyperglycaemia or diabetes (putative competitors).

Results: Among the 177,323 reports with statins (without fibrates), 7633 were diabetes (mainly with atorvastatin). Among the 19,149 reports with fibrates (without statins), 189 were diabetes (mainly with fenofibrate). Sixty other diabetes reports involved the combination statin+fibrates. Statin use alone was associated with an increase in the ROR of diabetes [ROR = 1.75 (1.72–1.78)], but not with fibrate use alone [ROR = 0.76 (0.71–0.82)]. The combination statin + fibrate was also associated with an increase in the ROR of diabetes [ROR = 1.46 (1.28–1.67)]. Similar results were found in sensitivity analyses, using different outcome definitions and after exclusion of putative competitors.

Conclusion: Using the WHO pharmacovigilance database, our study strengthens the signal of diabetes with statins but failed to find any potential signal with the use of fibrates alone. Furthermore, our data did not suggest a pharmacodynamic DDI with the use of statin + fibrate.

Disclosure of Interest: None declared.

81 ISoP18-1119 Fluoroquinolones and Aortic Aneurysms: What are the Fluoroquinolones at Risk?

81.1 A. Sommet¹, V. Rousseau¹, L. Chebane¹, G. Durrieu¹, F. Montastruc¹, J.-L. Montastruc^*1

81.1.1 ¹Medical and Clinical Pharmacology, Faculte de Medecine, Toulouse, France

Background/Introduction: Association between fluoroquinolone use and risk of aortic aneurysm and dissection has been previously suggested from observational data (2 cohort studies and 1 case–control analysis).

Objective/Aim: The present study was performed to investigate this putative association in Vigibase^®, the World Health Organization Global Individual Case Safety Reports (ICSRs) database. We also studied the fluoroquinolones most at risk.

Methods: We performed a case non-case study where cases were ICSRs of “aortic aneurysms and dissections” (HLGT) with fluoroquinolones (J01MA) registered until the 31th December 2017 as “suspected” or “concomitant” in patients ≥ 50 years. In order to reduce possible confounding, comparison was made with amoxicillin. Similar analyses were made for “tendonitis”, “tendon injury, pain and rupture” (PT terms), a well-known adverse drug reaction of fluoroquinolones, comparing each fluoroquinolone versus all others. Only fluoroquinolones with more than 3 reports were included. Results are shown as Reporting Odds Ratios (ROR) of the exposure odds among reported cases of aortic aneurysms to the exposure odds among reported non-cases.

Results: Among the 172,588 ICSRs with fluoroquinolones, 113 were aortic aneurysms. Most of the patients were females (54.9%) with a mean age of 67.6 ± 11.1 years. Aortic aneurysms were reported with levofloxacin (n = 78), ciprofloxacin (26), moxifloxacin (15). The first ICSR was reported in 2000. There were 8 aortic aneurysms among the 40,954 ICSRs with amoxicillin. The ROR value for fluoroquinolones versus amoxicillin was 3.13 (1.53–6.43) after adjustment on age and sex. Compared with use of other fluoroquinolones, use of levofloxacin was associated with a significant increase in the ROR of aortic aneurysms [RORa = 4.44 (2.94–6.72)] and also of tendinopathy [RORa = 3.02 (2.89–3.15)].

Conclusion: The present study strengthens the signal of aortic aneurysms with fluoroquinolones and shows for the first time that, among the different fluoroquinolones, the most at risk is levofloxacin. Moreover, the similarity of results concerning the most at risk fluoroquinolones could suggest the involvement of some common pharmacological mechanisms for aneurysms and tendinopathy with these drugs, like, for example, chelating properties and upregulation of metalloproteinases resulting in extracellular matrix alterations.

Disclosure of Interest: None declared.

82 ISoP18-1120 Pharmacovigilance: Analysis of Medication Errors Reports Received by Argentine Regulatory Authority (Anmat) During the Period 2013–2017

82.1 M. G. Papazian^*1, S. Schiaffino², R. Papale³, R. Heredia³

82.1.1 ¹Italian Hospital University of Buenos Aires, Buenos Aires, Argentina; ²School of Medicine, Buenos Aires University, Buenos Aires, Argentina; ³Pharmacovigilance, ANMAT, Buenos Aires, Argentina

Background/Introduction: Drug safety has undergone significant changes and proper drugs use are currently priorities for developed countries. For improving patient safety, it’s not only necessary to develop safer medicines, but also create error-proof use systems to minimize medication error (ME) and guarantee that if it occurs, it doesn´t reach and determine negative consequences on patients. Therefore, it´s essential to identify and have a close understanding of this topic. The detection of ME contributes to effective practices for a rational medicine´s use, thus increasing patient safety [1]. In Argentina this problem hasn´t been studied and it´s necessary to know the characteristics of ME, mainly studying the frequency and impact, in order to establish local strategies to prevent the occurrence. Argentine Health Authority—ANMAT [2]—has a National Pharmacovigilance System in which ME reports are considered as part of Medications Related Problems. Hence, a validated ME Notification Form [3] is available since 2013. The rate of ME reports since the implementation, has increased significantly. According to ANMAT´s Annual Reports [2], in 2012-prior to the GPV implementation there were just 210 reports received, increasing to 1299 in 2017.

Objective/Aim: Analyze the ME reporting in Argentina from 01 Jan 2013 to 31 Dec 2017 received by ANMAT.

Methods: The study is a transversal, retrospective and observational. It´s descriptive, since it´ll determine the frequency of the results in terms of ME reported to ANMAT. Subsequently, the frequency that could have occurred since the implementation of the Form[3] will be analyzed, from 2013 to 2017.

Results: 3090 ME reports were included. Each variable was analyzed according to the data available. Regarding ATC code, the number for each category has increased for all the classifications. The “L” has the highest ME reports with 34.9%, followed by “C” with 15.8%. 88.1% of the patients received the drug. 94.6% of the reports belong to the Pharma Industry and only 3.8% to others reporters (hospitals and universities). Female patient reports lead with 60.8%. Regarding age, 27.6% patients were adults, followed by the elderly. 75.8% of the reporters were HCP. According to the error category 76.3% were errors that reached the patient, but fortunately did not cause harm. 70.3% of ME occurred at home.51% of ME occurred during the administration phase, and 25.8% in prescription. Incorrect interval frequency was the main ME identified, 27.3%. From 2013 to 2017, there was a fourfold increase in the ME reports.

Conclusion: The analysis of ME provides the basic knowledge about them. Beside the real importance lies in investigating the behavior of them, in order to avoid future errors or to take measures that properly interposed in the system of use of drugs as security filters. Strengthen education on the safe use of medicines, both the patient and the treating health professional is an indispensable tool to achieve a more appropriate and safe use of them, the solution to the problem lies in prevention. It is essential to continue with policies to reduce and prevent morbidity related to medication errors in both outpatient and inpatient patients and to further disseminate the current ANMAT Medication Errors notification program. Encouraging this program by intensifying the analysis will contribute to the greater knowledge of this problem.

References:

• 1. Santos LD, Winkler N, Santos MAD, Martinbiancho JK. Descripción de los errores de medicación detectados en un centro de información sobre medicamentos en el sur de Brasil. Pharmacy Pract (Granada) [Internet]. 2015 [cited 2017 Jun 29];13(1):0–0. Available from: http://scielo.isciii.es/scielo.php?script=sci_arttext&pid=S1885-642X2015000100007&lang=pt

• 2. ANMAT. A.N.M.A.T [Internet]. [cited 2017 Jun 29]. Available from http://www.anmat.gov.ar/principal.asp

• 3. ANMAT. Ficha de Notificación de Errores de Medicación [Internet]. Available from: http://www.anmat.gov.ar/farmacovigilancia/notificaciones/FichaERRORES.pdf

Disclosure of Interest: M. G. Papazian Employee of: Boehringer Ingelheim, S. Schiaffino Employee of: Boehringer Ingelheim, R. Papale: None Declared, R. Heredia: None Declared.

83 ISoP18-1123 Drospirenone and Its Association with Gall Bladder Diseases: A Retrospective Study of Canadian Adverse Drug Reaction Monitoring Program, 1965–2017

83.1 M. Shah^*1, C. Kothari¹

83.1.1 ¹Institute of Pharmacy, Nirma University, Ahmedabad, India

Background/Introduction: Drospirenone, a fourth generation progestin combined with ethinyl estradiol is one of the most prescribed oral contraceptives in North America. In past, various concerns have been raised in media as well as published reports for the association of Drospirenone and Gallbladder diseases [1–4].

Objective/Aim: The objective of the study was to identify possible signal induced by drospirenone and its significance with gall bladder diseases by searching database from Canadian Adverse Reaction Monitoring Program (CADRMP).

Methods: A total of 9938 reports of patients from January 1965 to December 2017 were downloaded from CADRMP website. These reports contained information of adverse events associated with all other drugs inclusive of Drospirenone. Signal detection were determined by proportional reporting ratio (PRR), reporting odds ratio (ROR), PRR calculated by Chi square statistics, 95% confidence interval of PRR, observed to expected (O/E) ratio and De Mouchel method calculated PRR. Information component (IC) was given by Bayesian confidence propagation neural network. (As per regulatory criteria, PRR ≥ 2, ROR ≥ 1, Chi square statistics calculated PRR ≥ 4 and lower bound of 95% CI of PRR ≥ 1 to consider particular adverse drug reaction as a signal. Further by BCPNN method, if IC-2SD ≤ 0 then that drug-ADR pair considered has no signal; if 0 < IC-2SD ≤ 1.5, then that drug-ADR pair considered as weak signal; if 1.5 < IC-2SD ≤ 3.0, then that drug-ADR pair considered as middle signal; if IC-2SD > 3.0, then that drug-ADR pair considered as strong signal).

Results: A total of 120 reports of Drospirenone induced gallbladder diseases were reported in CADRMP database. The PRR was found to be 37.73 and by the Du Mouchel method it was 2.18. Further, the PRR calculated by Chi square statistics was 140.61 (p value < 0.0001). The lower and upper limits of 95% CI of PRR was found to be 2.17 and 4.16, respectively The O/E ratio was found to be 2.19 and ROR was found to be 40. The value of PRR > 2, ROR > 1, Chi square statistics calculated PRR > 4 (p value < 0.0001) and lower limit of 95% CI of PRR ≥ 1, also IC-2 SD is 1.12 indicating a significant weak signal associated with drospirenone and gall bladder diseases.

Conclusion: Study shows a low risk associated with drospirenone and gallbladder diseases. These data will enhance the information available to healthcare professional and may be found useful in management of women’s health.

References:

• 1. Wang F, Shen X, Guo X, Peng Y. Oral contraceptives and risk of gallbladder disease. CMAJ 2011;183:1517; author reply 1517.

• 2. Etminan M, Delaney JAC, Bressler B, Brophy JM. Oral contraceptives and the risk of gallbladder disease: a comparative safety study. CMAJ 2011;183:899–904

• 3. Jick S, Pennap D. Drospirenone- and levonorgestrel-containing oral contraceptives and the risk of gallbladder disease. Contraception2012;86:220–3Bayer to Pay $24 M to Settle Yaz Gallbladder Lawsuits [Internet]. 2013 [cited 2018 Jun 2]. Available from: https://topclassactions.com/lawsuit-settlements/prescription/3808-bayer-to-pay-24m-to-settle-yaz-gallbladder-lawsuits/

Disclosure of Interest: M. Shah Other: No conflicts of interest, C. Kothari Other: No conflicts of interest.

84 ISoP18-1124 Statistics Trend: Vaccine Reports Regarding Pediatric People in Korea

84.1 M. Kim^*1, S. Chung¹, Y. Woo¹, J. Park¹, S. Kim¹

84.1.1 ¹Korea Institute of Drug Safety and Risk Management, Anyang, Korea, Republic Of

Background/Introduction: Since the nature of immunization is mainly for healthy children, monitoring of adverse events after vaccination is important. We analyze the status of vaccine spontaneous reports in pediatric population for which factors might need to be considered when monitoring vaccine safety.

Objective/Aim: Understanding the current trend of spontaneous adverse event (AE) reports about vaccine in Korea.

Methods: We used dataset from Korea Adverse Event Reporting System, which is for collecting and managing ICRSs. We used ATC code for drugs and WHO-ART code for AEs, to analyze the comparison between number of reports regarding vaccines and non-vaccines, from 2013 to 2017. Only initial reports and the drug type of suspect or drug–drug interaction were analyzed. Ages are divided into 2 groups; infants/children/teens (pediatric group) birth through age 18, and adults age 19 and older. J07 were selected for the vaccine, and ATC codes except J07 were for non-vaccines.

Results: Total of 873,314 ICSRs were reported to the KAERS for the last 5 years. Non-vaccines (98.1%) were reported more than vaccines (1.9%). The No. of vaccine reports were 7873 (14.8%) among reports for pediatric group and 8755 (1.1%) among reports for adults. The reporting proportion of vaccine in pediatric group was much higher than that in adults group.

In the pediatric group, the most frequently reported vaccine type was followed in order by influenza (inactivated) (27.80%), rota virus (13.54%), tuberculosis (9.62%), hemophilus influenzae B/combinations with meningococcus C/conjugated (9.54%), and hemophilus influenzae B/combinations with toxoids (9.02%).

The most commonly reported AEs among pediatric group included fever (18.19%), vomiting (12.35%), lymphadenopathy (7.19%), pharyngitis (7.02%), headache (6.48%), injection site pain (5.27%), and injection site inflammation (4.85%). The most frequent reported SAEs included fever (2.10%), headache (1.00%), asthenia (0.80%), convulsions (0.75%), myalgia (0.72%), dizziness (0.58%), dyspnoea (0.52%), pneumonia (0.47%), and paralysis (0.32%).

Conclusion: As Korea has implemented national immunization program (NIP), the most frequent reported vaccine types were also influenced by NIP [1]. Injection site reaction or well-known AEs were most frequently reported for total vaccine reports among pediatric group. AEs which need careful reviewing and monitoring were identified among the SAE reports.

References:

• 1. Lee JK, Choi WS. Immunization policy in Korea. Infect Chemother 2008;40:14–23

Disclosure of Interest: None declared.

85 ISoP18-1125 The Impact of a Restrictive Regulatory Action on the Utilization Of Pregabalin Containing Products in Saudi Arabia

85.1 A. Alshatri Almotiry^*1, W. AlGhannam¹, N. AlJasser¹, A. AlShahrani¹

85.1.1 ¹Vigilance and Benefit–Risk Assessment Executive Directorate, Saudi Food and Drug Authority (SFDA), Riyadh, Saudi Arabia

Background/Introduction: Pregabalin, a drug indicated in epilepsy, neuropathic pain, and Generalized Anxiety Disorder known to be associated with drug abuse and misuse [1, 2]. In Saudi Arabia, the Saudi Food and Drug Authority (SFDA) received numerous cases of misuse and product access through community pharmacies without prescription. This provoked the SFDA to issue a circular in May 2015 banning pregabalin products from community pharmacies and restricting its dispensing to hospital and primary care centers’ pharmacies only [3].

Objective/Aim: To display the impact of pregabalin dispensing restrictions on the utilization of pregabalin products in Saudi Arabia.

Methods: The Intercontinental Marketing Statistics (IMS Health) database was accessed to determine the sales data of four pregabalin products in Saudi Arabia in the period within 2 years before and 2 years after executing the pregabalin restriction rules in May 2015 [4]. Data collected were in terms of number of packs sold to all dispensing channels. The four pregabalin products were the only registered pregabalin products at the time of the application of pregabalin restriction.

Results: In the period before the restriction of pregabalin, from 2013 to the first half of 2015, we found that the total utilization of the four pregabalin products have peaked in the 2^nd half of 2014, reaching 1,119,228 packs (Table 1). After restricting the product in mid-2015, the sales dropped from 984,731 in the first half of the year to 601,786 packs in the remaining months. This drop was followed by a slight increase in 2016, and a rebound in the first half of 2017.

The average utilization of the selected products prior to the implementation of the restriction was 173,892 packs per month. Whilst post the restriction, the average utilization decreased to 114,002 per month (34.4% decrease).

Conclusion: After restricting pregabalin products to hospital and primary care centers’ pharmacies in Saudi Arabia, the utilization notably decreased. This roughly suggests the effectiveness of this regulatory action in restricting the access of pregabalin to abusers and misusers. More structured Drug Utilization Studies are required to assure that it does not influence the access of pregabalin in legitimate patients.

References:

• 1. LYRICA^® (Pregabalin) Summary of Product Characteristics. 4th ed. Saudi Arabia: Pfizer; 2016.

• 2. Schjerning O, Rosenzweig M,Pottegård A,Damkier P,Nielsen J. Abuse potential of pregabalin. CNS Drugs 2016; 30:9–25

• 3. SFDA Strengthens Prescribing Rules on Products Containing Pregabalin. (2015). Saudi Arabia: Saudi Food and Drug Authority. Available at: https://www.sfda.gov.sa/en/drug/about/sector_departments/national_pharmacovigilance_center/Documents/Pregabalin_Safety_Communication.pdf [Accessed 22 May 2018].

• 4. IMS Health, IMS National Sales Perspectives™. January 2013–September 2017.  Extracted May 2018.

Disclosure of Interest: None declared.

86 ISoP18-1126 Outcomes of Drug Exposition During Pregnancy: Analysis from a Teratology Information Service

86.1 C. Lenoir^*1, S. Boumaïza¹, M. Boulvain², K. R. Ing Lorenzini¹, J. Desmeules¹, V. Rollason¹

86.1.1 ¹Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals & Geneva University, Switzerland; ²Department of Obstetrics & Gynaecology, Geneva University Hospitals, Geneva, Switzerland

Background/Introduction: Many pregnant women are exposed to drugs and this often in early pregnancy because 50% of pregnancies are unplanned and/or detected after the 6th to 8th week of amenorrhea [1]. Studies show that the percentage of pregnant women exposed to drugs is substantial with a number of drugs being also high [2–3]. Drugs can be teratogenic, with occurrence of insufficient/abnormal fetal development, spontaneous miscarriages, in-uterine deaths, and malformations [4]. The risk of malformation in the general population is estimated at 3–5% and drugs explain approximately 4–5% of this percentage [5–6]. When a drug arrives on the market, in vitro, in vivo and animal studies show part of the potential teratogenic/foetotoxic effects, but epidemiological studies and case studies are needed to further highlight the risks.

Objective/Aim: To characterize drug exposures during pregnancy where the outcome a birth was known that came from our counselling service between 1994 and 2016.

Methods: This observational study analysed all data collected through the drug exposures during pregnancy counselling. Age, numbers and type of drug taken, timing of drug exposition and outcome of the pregnancy were retrieved. Data was analysed descriptively.

Results: A total of 1378 pregnant women were analysed. Women were between 30 and 34 years old in 31.6% (N = 435) of the cases with a global mean age of 32 years. These women were exposed to one drug in 49.1% (N = 676) of cases and more than ten drugs in 1.4% (N = 19) of cases, with a mean drug intake of 2. Analysis of the drugs altogether (N = 3137) showed that FDA Pregnancy Category C drugs represented 42.8% (N = 1344) of drugs and ATC code N (nervous system) represented 36.5% (N = 1144). The onset of drug exposure was during the first trimester of pregnancy in 95.2% (N = 2987) of patients. Regarding outcomes, the rate of induced abortion was 10.8% (N = 151), of pregnancy complications was 19.1% (N = 268) and of malformations was 3.7% (N = 52).

Conclusion: Pregnant women counselled by our information service take a mean of 2 drugs, ranging from one to 17. Drugs are from FDA Pregnancy Category C and ATC N drugs in most cases, 42.8 and 36.5%, respectively. Almost all exposures begin in the first trimester probably because women are not yet aware of their pregnancy. The rate of malformation of our cohort was of 3.7%, close to the estimated spontaneous rate of malformation. This data gives a reassuring aspect of drug exposure in pregnancy but takes into account the outcome at birth only.

References:

• 1. Rousso P. [Drug exposure during pregnancy: a differentiated approach]. Praxis 2004;93:943–7

• 2. Lacroix I, Damase-Michel C, Lapeyre-Mestre M, Montastruc JL. Prescription of drugs during pregnancy in France. Lancet. 2000;356:1735–6

• 3. Malm H, Martikainen J, Klaukka T, Neuvonen PJ; Finnish register-based study. Prescription drugs during pregnancy and lactation—a Finnish register-based study. Eur J Clin Pharmacol 2003;59:127–33

• 4. Audus KL. Controlling drug delivery across the placenta. Eur J Pharm Sci 1999;8:161–5

• 5. European Network Teratology Information Service (ENTIS) [Internet]. [23 Mai 2018]. Available on https://www.entis-org.eu/

• 6. Stevenson R, Hall J. Human malformations and related anomalies. 2nd ed. Oxford University Press. Oxford. New York. 2006

Disclosure of Interest: None declared.

87 ISoP18-1128 Monitor the Benefit and Risk of Medicines in Primary Care; Building a Bridge Between Daily Practice and Research

87.1 L. Rolfes¹, K. Hek², R. Verheij², L. van Dijk², E. van Puijenbroek^*1,3

87.1.1 ¹Netherlands Pharmacovigilance Centre Lareb, Den Bosch, the Netherlands; ²NIVEL, Netherlands Institute for Health Services Research, Utrecht, the Netherlands; ³University of Groningen, Groningen Research Institute of Pharmacy, Unit of PharmacoTherapy, Epidemiology & -Economics, Groningen, the Netherlands

Background/Introduction: Monitoring the benefits and risks of medicines in the post-marketing phase is important for a safe and effective treatment of patients. The aim of this project is to create an infrastructure in which data from the patient’s electronic health records from general practitioners (GPs) can be linked to patient reported outcomes (PROs) about their perspective of the effect and adverse drug reactions (ADRs) of medicines. In this way information about (cost) effectiveness and ADRs of medicines can be acquired. The system is designed to be applied to any new medication on the market and has several advantages above more traditional monitoring instruments like larger cohorts, longer follow-up, and a real life setting.

Objective/Aim: To evaluate the feasibility of acquiring real world data to monitor the (cost) effectiveness and ADRs of medicines.

Methods: For this pilot study, two GP practices in the Netherlands were included. Patients with an overactive bladder (OAB) were used as a use case. OAB patients were selected from electronic health records from the two GPs as obtained in the Nivel Primary Care Database. The GP indicated whether the patient was suitable to be included in the monitor.

PROs were obtained by an electronic questionnaire, using the Lareb Intensive Monitoring system. Questions were posed about patient characteristics, bladder complaints, treatment (physiotherapeutic interventions and medicines), ADRs, therapy compliance, and quality of life.

Results: 109 OAB patients were selected from the electronic health records. After revision by the GPs, an invitation to contribute to the monitor was send to 82 (75%) patients. Reasons for excluding patients were: patient cannot work with a computer or questionnaire (10×), cognitive/mental not able to fill in questionnaire (10×), patient in hospital (3×), patient died/moved (2×). GPs were enthusiastic about the method.

Nineteen patients (23%) filled in the questionnaire. Average age was 63 years (38–79 years) and it concerned 14 women. Patients reported an average score of 4.0 for urogenital complaints, on a scale from 1 (none) to 10 (very much). Eleven patients received physiotherapeutic interventions and 5 received medicines to treat the OAB. Of these, 3 patients mentioned that they experience ADRs; dry mouth (3×), dry eyes (1×) and dry vagina (1×). The OAB had an average influence of 3.0 on the quality of life, on a scale from 1 (none) to 10 (very much). These data indicate that patients are willing and able to give proper information about the effect and ADRs of their OAB treatment. After analysis, the wording of some questions was revised to make the question clearer.

Conclusion: GPs are enthusiastic and a sufficient number of patients per GP practice have been included, providing clear information about their perspective of the effect and ADRs of their treatment. A next step is to expand the registry to a greater number of patients and to develop an automatic feedback module. This concerns individualized feedback for patients which will give them insight in their own situation. In addition, there will be feedback for patients and GPs to get a general insight in the patient’s perspectives of effects and risk of medicines. This could result in better treatment, tailored to patients’ needs and experiences.

Disclosure of Interest: None declared.

88 ISoP18-1129 Spontaneous Reporting of Suspected Adverse Drug ReactionsiIn Patients with Arthritis: A Scoping Literature and Data Review

88.1 G. Greer^*1, A. Sabokbar¹, C. Anderson², J. Aronson³

88.1.1 ¹Nuffield Department of Orthopaedics, Rheumatology & Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom; ²School of Pharmacy, University of Nottingham, Nottingham, United Kingdom; ³Centre for Evidence Based Medicine, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom

Background/Introduction: Biological products (biologics) are medicines whose active principles derive from biological sources or are produced by biotechnology [1]. The types of biologics most commonly used to treat rheumatoid arthritis (RA) [2] and ankylosing spondylitis (AS) [2] are TNF inhibitors, anti-IL-1/6/17, and JAK inhibitors. The most commonly used TNF inhibitors are adalimumab, certolizumab, etanercept, golimumab, and infliximab. Their main adverse effects include skin reactions and infections, including reactivation of tuberculosis. Suspected adverse drug reactions (ADRs) are reported in various ways (e.g. as case reports and spontaneous reports to schemes such as the UK’s Yellow Card Scheme and in randomized trials, observational studies, and Biologics Registers). However, under-reporting is common and continues to be a global problem [3, 4], with a risk of worldwide mortality and morbidity [5]. The extent of under-reporting to worldwide schemes of suspected ADRs in patients taking TNF inhibitors for RA & AS is unknown.

Objective/Aim: To review the scientific literature and available data on suspected ADRs in response to biologics for treating patients with RAor AS, seeking information on reporting rates.

Methods: We searched for papers using 54 search engines from the University of Oxford’s online libraries (e.g. PubMed, Medline). We imposed no restrictions, apart from the period surveyed (2012–2017). We also searched other online information sources (e.g. the website of the National Institute of Health and Care Excellence). We generated a series of tables describing examples of the classes and types of biologics used and examples of the associated ADRs. We also generated figures to describe suspected ADRs reported to the UK Yellow Card Scheme for five biologics used in the treatment of RA and AS (adalimumab, certolizumab, etanercept, golimumab, and infliximab).

Results: We retrieved 120 papers, of which 30 passed screening of titles; of those, 14 were published during 2012–2017, of which we were able to retrieve 11. None of those dealt with any aspects of international spontaneous reporting schemes, including the extent of reporting/under-reporting. The MHRA received 22,773 Yellow Card reports (1999–2017) for the five selected biologics, including 3226 reports of musculoskeletaland connective tissue disorders (six fatal) and 1637 reports of joint disorders.

Conclusion: Compared with other biologics, the rate of Yellow Card reporting of suspected ADRs associated with biologics used to treat RA and AS is relatively high, although the extent of under-reporting for these drugs is not known and has not been studied.

References:

• 1. Giezen TJ, Mantel-Teeuwisse AK, Straus SM, Schellekens H, Leufkens HG, Egberts AC. Safety-related regulatory actions for biologicals approved in the United States and the European Union. JAMA 2008; 300: 1887–96

• 2. Scherer K, Spoerl D, Bircher AJ. Adverse drug reactions to biologics. J Dtsch Dermatol Ges 2010; 8: 411–26

• 3. Hazell L,Shakir SAW. Under-reporting of adverse drug reactions: a systematic review. Drug Saf 2006; 29: 385–96

• 4. Lopez Gonzalez E, Herdeiro M, Figueiras A. Determinants of under-reporting of adverse drug reactions: a systematic review. Drug Saf 2009; 32: 19–31

• 5. World Health Organization (WHO). Safety of Medicines—A Guide to Detecting and Reporting Adverse Drug Reactions—Why Healthcare Professionals Need to Take Action. Geneva; WHO: 2002; http://apps.who.int/medicinedocs/en/d/Jh2992e/

Disclosure of Interest: None declared.

89 ISoP18-1130 Assessment Of Cyclosporine Blood Concentrations In Adults With Aplastic Anemia

89.1 S. Ben Tekaya¹, M. Ben sassi^1,2, R. Charfi^1,2, E. Gaies^1,2, I. Salouage¹, N. Jebabli², H. El Jebari², R. Daghfous^*1,2, S. Trabelsi^1,2

89.1.1 ¹National Pharmacovigilance center; ²Clinical and Experimental Pharmacology Research Laboratory LR16SP02, Tunis, Tunisia

Background/Introduction: Aplastic anemia is defined as peripheral blood pancytopenia caused by bone marrow failure [1]. Patients are treated successfully with a combinaison of antilymphocyte globulin and cyclosporine (CsA), especially in case of lack of a histocompatible donor. CsA is an immunosuppressive agent with a narrow therapeutic index and a high variability between individuals [2]. That’s why therapeutic drug monitoring (TDM) of CsA is important to optimize therapy and to avoid toxicity.

Objective/Aim: To assess CsA blood concentrations in adults with aplastic anemia.

Methods: It consisted in a retrospective study made between February 2016 and December 2017 in the Department of Clinical Pharmacology. We included 130 samples collected from 17 patients who were treated by CsA for aplastic anemia. We measured CsA trough blood concentration (C0) by an immunological method. C0 should be maintained between 200 and 400 ng/mL.

Results: Median age of our population was 26 years. The sex ratio (M/W) was 0,74 and average weight was 67 kg. Mean C0 was 223 ± 140  ng/mL. Among samples, 59 were from oral administration and 71 were from intravenous administration. Median dose of our population was 2 mg/kg/day. More than half of measured C0 (53%) was infratherapeutic. The results showed that 39% of measured C0 was in therapeutic range and 8% was supratherapeutic. Median dose and concentration among three each group are showed in Table 1.

Table 1 Median dose and C0 of CsA

	Infratherapeutic (< 200 ng/mL)	In therapeutic range	Spratherapeutic (> 400 ng/mL)
Dose (mg/kg/day)*	2.06	2.05	1.71
C0 (ng/mL)**	132.72	279.54	553.12

1. *p = 0.5; **p = 003

Conclusion: In our study, despite similar dose, there is a significant difference between CsA concentrations. Because of inter and intra-variability of CsA pharmacokinetic, TDM is required to adjust the individual doses of the drug.

References:

• 1. Ni S, Zhao W, Wang J, Zeng S, Chen S, Jacqz-Aigrain E, et al. Population pharmacokinetics of ciclosporin in Chinese children with aplastic anemia: effects of weight, renal function and stanozolol administration. Acta Pharmacol Sin. 2013;34(7):969–75.

• 2. Xue L, Zhang W, Ding X, Zhang J, Miao L, Bao J. Population Pharmacokinetics and Individualized Dosage Prediction of Cyclosporine in Allogeneic Hematopoietic Stem Cell Transplant Patients. Am J Med Sci. 2014;348(6):448–54.

Disclosure of Interest: None declared.

90 ISoP18-1131 Facilitating Safety Signal Triage and Prioritization Through Literature Based Matrix Factorization Ranking of Drug and Designated Medical Event Pairs

90.1 K. Bannout¹, K. Shen², W. Wallis¹, S. Spangler^*3

90.1.1 ¹Celgene, Summit, New Jersey, NY, United States; ²IBM Watson Health, New York, NY, United States; ³IBM Research-Almaden, San Jose, CA United States

Background/Introduction: Adverse drug reactions, especially those which are Designated Medical Events (DMEs), are a serious concern for patients, physicians, regulatory authorities, pharmaceutical companies, drug safety professionals and pharmacoepidemiologists. A number of methods have been employed to try and predict drug-adverse event (AE) associations [1], but those methods do not tap into hidden underlying patterns in literature text for their predictions.

Objective/Aim: We sought to predict potential drug-AE associations to support prioritization of AE reports in safety signal evaluation.

Methods: We employed matrix factorization (MF) within a network of drug and AE relationships for the drug-AE prediction. The network relationships were derived through natural language processing on Medline abstracts and PubMed Central Open Access (PMCOA) articles. Matrix factorization is a computational technique for collaborative filtering that creates a dense matrix from a sparse one by creating two product matrices which when multiplied approximate the original network [2]. It is commonly used in recommender systems (e.g. suggesting movies to watch) [3], but has not been employed in drug safety.

We selected 9 AE types from the 2016 EMA DME list [4] that were also included in the 2016 FDA DME list [5] and for which a single term was considered likely to capture the majority of events. Medications that included the selected DME in both the Warnings & Precautions section and ADR section of the drug label, but not in the Indications section, were selected as positive controls for MF scoring using Dr. Evidence^® prescribing information analytics on both US and UK medications. Negative controls for MF scoring were medications where the selected DME did not appear in any part of the label. The positive drug–AE pairs were zeroed out (removed) from the input matrix and then the matrix factored to yield a drug–AE score. From these observed scores, Z-scores were calculated using a simulated expected score and standard deviation for each pair.

Results: Our model achieved an average AUC (the area under the receiver operating characteristic curve) of 0.78 over the the 9 DMEs. On average for a given DME, the mean true positive Z-score was 2.97 and the mean true negative Z-score was − 1.35.

Conclusion: Matrix factorization of DME-drug pairs shows promise as a useful tool in supporting safety signal triage and warrants further evaluation with other drug-AE pairings and in prospective studies.

References:

• 1. Huang LC, Wu X, Chen JY. Predicting adverse side effects of drugs. BMC Genomics 2011; 12(Suppl 5): S11

• 2. Lee DD, Seung HS. Learning the parts of objects by non-negative matrix factorization. Nature 1999; 401: 788–791

• 3. Koren Y. The BellKor Solution to the Netflix Grand Prize [Internet]. 2009. Available from: http://www.netflixprize.com/assets/GrandPrize2009_BPC_BellKor.pdf

• 4. Designated Medical Event (DME) list [Internet]. European Medicines Agency; 2016. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Other/2016/08/WC500212079.xls

• 5. 2016 FDA OSE DMEs and Associated MedDRA Preferred Terms [Internet]. US Food and Drug Administration; 2016. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/206843Orig1s001,s003OtherR.pdf

Disclosure of Interest: None declared.

91 ISoP18-1132 Product Confusion Errors: A Pharmacovigilance Analysis of Vigibase™ and Canada Vigilance Case Narratives

91.1 G. Castillon^*1, Z. Gesztesi², Y. Moride^1,3

91.1.1 ¹YOLARX Consultants, Montreal, Canada; ²AstraZeneca, Mississauga, Canada; ³Faculty of Pharmacy, Université de Montréal, Montreal, Canada

Background/Introduction: Product confusion errors (associated with drug name, dosage, label, packaging) are a common cause of medication errors that are preventable and may lead to inappropriate medication use or patient harm. The types of product confusion errors that occur most frequently, as well as their consequences, have not been extensively examined to date.

Objective/Aim: (1) To describe the product confusion errors that have been reported worldwide; (2) To assess the consequences of confusion errors [serious or non-serious adverse events (AE), lack of effectiveness]; (3) To characterize the populations affected by these errors.

Methods: We conducted an analysis of VigiBase™ (an international spontaneous reporting database that covers over 110 countries) over the period 2007–2016. In order to identify the relevant cases, we identified four MedDRA Preferred Terms (PTs) related to product confusion errors. As VigiBase™ does not collect information on the party responsible for the confusion error, we performed a qualitative review of individual case safety reports (ICSRs) recorded in Canada Vigilance spontaneous reporting system.

Results: A total of 1769 individual cases of product confusion errors were found in VigiBase™, corresponding to 2409 PTs related to confusion errors (average of 1.4 per ICSR). Product label confusion (e.g., confusing or vague instructions) was the most common error reported (54.1%), followed by product name confusion (e.g., similar names of drugs with different indications) (26.3%). Patients or consumers accounted for the most frequent reporting source (39.4%), and the number of reports has been increasing dramatically over time. Among the 30% reports providing patient age, median age was 57 years [34.8–70 (Q1–Q3)]. There appeared to be a small female predominance (58.0%). Of the reported confusion errors, 76.5% resulted in non-serious AEs, 22.0% in serious AEs, 4.6% in lack of effectiveness, and 3.2% had no adverse effect. Antithrombotic agents were often involved in the serious AEs related to packaging confusion. Insulins were the most frequently involved in name or label confusions, followed by drugs to treat peptic ulcer and gastro-oesophageal reflux disease. The qualitative review of the 52 case narratives of product confusion errors identified in Canada Vigilance revealed that 53.8% of errors were made by patients or their families, 11.5%, respectively, by pharmacists and unspecified healthcare professionals, and 9.6%, respectively by physicians and nurses.

Conclusion: Although regulatory agencies have issued guidelines to avoid look-alike/sound-alike drug names, confusion errors still occur, with some leading to serious AEs. Study showed that errors are made principally by patients or their families, and are also mainly reported by consumers. These findings highlight the opportunity to minimize the occurrence of product confusion errors through patient-centered interventions.

Disclosure of Interest: G. Castillon Grant/Research support from: AstraZeneca Canada, Z. Gesztesi Employee of: AstraZeneca Canada, Y. Moride Grant/Research support from: AstraZeneca Canada.

92 ISoP18-1133 Framework for Analyzing Consumer Health Questions

92.1 J. Cao^*1

92.1.1 ¹Global Post Market Safety Surveillance, Herbalife Nutrition, Torrance, California, United States

Background/Introduction: Consumer health questions glean valuable insight into consumer attitudes and behaviors, and provide opportunities for educational initiatives. However, consumer health questions are typically lengthy, complex, and often utilize open-domain language rather than medical terminology [1, 2].

Objective/Aim: To develop a framework for analyzing consumer health questions in the knowledge management database.

Methods: We extracted consumer health questions created in the internal knowledge management system from January 1, 2017 to December 31, 2017 and limited to only English language submissions. The data was analyzed using R and the tm package [3, 4]. Singularly occurring words were excluded from any analyses, common English stopwords and additional stopwords assembled from company specific terms (e.g., department names, brand names) were removed, and related words in the top 250 underwent word stemming as part of the data preprocessing. With the final dataset, a word cloud was constructed from the top 250 frequently occurring terms. Additionally, word associations for key terms were calculated using a correlation limit of 0.2.

Results: 1636 consumer health questions were created in the knowledge management database in 2017. There were 2278 unique terms in the consumer health questions dataset after preprocessing of the data. The most frequently occurring terms were: product, shake, weight, use, and loss. Other key terms that were identified were: protein, safe, and allergy. We analyzed the key terms for word associations to identify other key terms that appear to be correlated. The results are presented in Table 1.

Conclusion: Text mining techniques can be used as a framework for analyzing consumer health questions. Frequently occurring words elucidate the topics of greatest interest to consumers, and word associations provide general context to the questions being asked. This framework can be used to guide the development of educational materials related to health and safe product use for consumers.

References:

• 1. Kilicoglu H, Abacha AB, Mrabet Y, Shooshan SE, Rodriguez L, Masterton K, et al. Semantic annotation of consumer health questions. BMC Bioinformatics 2018;19:1–28

• 2. Roberts K, Demner-Fushman D. Interactive use of online health resources: a comparison of consumer and professional questions. J Am Med Inform Assoc 2016;23:801–11

• 3. R Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2017

• 4. Feinerer I, Hornik K. tm: Text Mining Package. 2017

Disclosure of Interest: J. Cao Employee of: Herbalife Nutrition.

93 ISoP18-1134 Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir Related Liver Injury in Real-World Setting: Data from Taiwan National ADR Reporting System

93.1 P.-H. Chao^*1,2, W.-I. Huang^1,2, W.-W. Chen^1,2

93.1.1 ¹Taiwan Drug Relief Foundation, Taipei City, Taiwan; ²Taiwan National ADR Reporting Center, Taipei City, Chinese Taipei

Background/Introduction: In 2015, U.S. FDA has announced that paritaprevir/ritonavir/ombitasvir and dasabuvir (PrOD) regimen, which is used for hepatitis C virus (HCV) infection, can cause serious liver injury mostly in patients with underlying advanced liver disease [1, 2]. PrOD has been approved for the treatment of genotype 1 and 4 HCV infection in Taiwan and was reimbursed by Taiwan National Health Insurance since January 2017 for patients with advanced hepatic fibrosis or compensated cirrhosis who had experienced treatment failure with interferon and ribavirin therapy [3].

Objective/Aim: To evaluate the liver injury risks associated with PrOD in real clinical practice in Taiwan.

Methods: We reviewed all PrOD-associated reports collected in Taiwan National Adverse Drug Reaction (ADR) Reporting System from 2015 to 2017. Reported adverse events were categorized by MedDRA System Organ Class (SOC). Liver injury cases were identified by the search of MedDRA Preferred Term (PT) under drug related hepatic disorders of Standardised MedDRA Query (SMQ) version 21.0. Baseline characteristics and the patterns of liver injuries of these cases were analyzed.

Results: 59 PrOD-associated reports were derived from the database, and among them 41 cases were related to liver injury. The mean age of those cases was 67.6 ± 17.8 years old and females accounted for 61%. 40 cases (97.5%) were classified as serious and 15 cases (6 duplicate reports) were led to death. 28 cases using WHO-UMC causality assessment were classified as possible or above. In these cases, 14 and 6 patients were with underlying liver cirrhosis and previous/concurrent hepatocellular carcinoma, respectively. Two cases were reported with HBV reactivation and 1 case was resulting in death. All of the above cases were reported with elevated serum bilirubin. Substantial serum total bilirubin (t-bil) and direct bilirubin (d-bil) elevation without concomitant significant increase of liver enzymes within 7 days after initiating PrOD regimen were found in 12 cases, of which t-bil level ranged from 2.2 to 14.2 mg/dl and 80% were greater than 4 mg/dl. The majority of the cases developed initial t-bil elevation within 6 weeks of regimen introduction, except cases with HBV reactivation was found to be around 90 days.

Conclusion: Our findings suggest that possible risk of liver injury with the use of PrOD regimen in Taiwan and patients with moderate to severe cirrhosis prior to the therapy may be at risk. Close monitoring for clinical signs and symptoms of hepatic decompensation as well as intensively performing hepatic laboratory testing including bilirubin levels during the first 4 weeks of treatment are strongly recommended to prevent such risks.

References:

• 1. DA Drug Safety Communication. FDA warns of serious liver injury risk with hepatitis C treatments Viekira Pak and Technivie (2015 Oct.). https://www.fda.gov/Drugs/DrugSafety/ucm468634.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery

• 2. Armen MP, Corneliu PP, Corneliu B, et al. Real-world efficacy and safety of ombitasvir, paritaprevir/r + dasabuvir + ribavirin in genotype 1b patients with hepatitis C virus cirrhosis. Liver Int 2018;38:602–10

• 3. Liu CH, Liu CJ, Su TH, et al. Real-world effectiveness and safety of paritaprevir/ritonavir, ombitasvir, and dasabuvir with or without ribavirin for patients with chronic hepatitis C virus genotype 1b infection in Taiwan. J Gastroenterol Hepatol 2018;33:710–7

Disclosure of Interest: None declared.

94 ISoP18-1135 Hepatotoxicity with a Natural Dietary Supplement, Artemisia Annua L. Extract in Grapeseed Oil. New Zealand Pharmacovigilance Centre Reports

94.1 R. L. Savage^*1, M. Tatley¹, J. Barnes²

94.1.1 ¹New Zealand Pharmacovigilance Centre, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand; ²School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

Background/Introduction: Artemisia annua L. (Qing Hao, sweet wormwood; family: Asteraceae) has been used in traditional Chinese medicine for two millenia [1]. Recently, an extract of A. annua in grapeseed oil (Arthrem^®) has been marketed in New Zealand (NZ) as a natural dietary supplement for maintaining and supporting joint health. Between February 2016–December 2017, the NZ Pharmacovigilance Centre (NZPhvC) received 14 reports of hepatic adverse drug reactions (ADRs) associated with Arthrem^®.

Objective/Aim: To analyse reports of Arthrem^®-associated hepatotoxicity for causality, seriousness and patterns of hepatotoxicity.

Methods: Qualitative anaysis of NZPhvC reports for patient characteristics, patterns of hepatotoxicity, temporality, seriousness and outcome.

Results: The 14 reports originated from several reporter groups and geographic areas in NZ. Cases (ten females, four males) were aged 48-77 years. Six reports were classified’serious’ as the patients involved were hospitalised. Where stated, the indication for use was osteoarthritis or joint pain. Arthrem^® was the sole medicine in nine reports and the sole suspect in four. There were no preceding clinical conditions or concomitant medicines considered a more likely cause of the hepatic reactions. Increased hepatic enzyme concentrations were reported for 10 cases and hepatitis for four. A prominent feature was jaundice (ten patients), in some cases symptomatic and/or the presenting manifestation. Reports with sufficient information indicated that two patients had hepatocellular reactions, both with jaundice, one confirmed by biopsy; three had mixed hepatic reactions. One other biopsy confirmed toxicity. Hepatobiliary scans, serology and alcohol intake were reported for a minority and did not provide alternative explanations. The time to ADR onset from Arthrem^® initiation (12 patients) was typically within 2 months. Twelve patients were recovered/recovering following Arthrem^® dechallenge, most within 2 months (8).

Conclusion: A case series of suspected ADRs associated with an extract of A. annua in grapeseed oil provides evidence of hepatotoxicity sometimes leading to hospitalisation. The reaction appears reversible on dechallenge. The finding is unexpected since there is little reference to hepatoxicity with A. annua in the literature or VigiBase, the WHO Global Database of Individual Case Safety Reports although hepatotoxicity associated with the constituent artemisinin has been described [2]. This raises several questions, including whether these reports reflect increased exposure following the product’s wide promotion, and/or whether product formulation (e.g. type of extract) or quality (e.g. source of raw material) issues are involved.

References:

• 1. Hsu E. The history of qing hao in the Chinese materia medica. Trans R Soc Trop Med Hyg 2006;100:505–50

• 2. National Institutes of Health. LiverTox. Clinical and Research Information on Drug-Induced Liver Injury. Artemisinin derivatives. Available at https://livertox.nih.gov/ArtemisininDerivatives.htm [last accessed June 3, 2018]

Disclosure of Interest: None declared.

95 ISoP18-1137 Using WHO Recommendations Antibiotic Consumption Evaluation in Kazakhstan for the Period 2012–2017

95.1 G. Zhussupova¹, S. Zhaldybayeva¹, D. Utepova^*1, L. Yesbatyrova¹

95.1.1 ¹RSE Republican Center for Healthcare Development of the Ministry of Health of the Republic of Kazakhstan, Astana, Kazakhstan

Background/Introduction: Antimicrobial resistance is a global problem, one of the reasons of which is the inadequate antibiotic prescribing and use practice. Regular monitoring of antibiotic consumption will reveal the reasons of antibiotic resistance and improper use.

Objective/Aim: Antibacterial drugs consumption estimation for identifying the problems of using antibiotics at a stationary level in Kazakhstan.

Methods: (1) ATC/DDD-methodology;

(2) Analytical.

ATC/DDD-methodology—consuption indicators determination using DDD—defined daily dose, recommended by WHO and medicines’ATC code. The measure—DID [1].

A comparative analysis of antibacterial preparations (ABP) consumption was conducted by pharmacological groups and routes of administration.

Results: The total ABP for systemic use consumption in 2012-2016 was systematically decreasing, but in 2017 there is significantly increased by 30%, and amounted 3.0 DID compared with 2016 (2.3).

Consumer leader is cephalosporin subgroup: consumption has increased to 1.1 in 2017, compared with 0.9 in 2012.

The most frequently consumed antibiotics in 2017 were I- and III-generation cephalosporins—48 and 42%, respectively. 82% of the total consumption of III-generation cephalosporins in 2017 was ceftriaxone.

A comparative analysis of amoxicillin and amoxicillin with clavulanic acid consumption showed an consumption increase of the second to 76% in 2017, while the share of amoxicillin fell steadily to 24% in 2017, compared to 57% in 2012.

Analysis of the ABP consumption by the routes of administration also revealed a gradual decrease of oral and parenteral forms consumption in 2012–2016, but a significant increase of both forms consumption in 2017—by 27 and 35%, respectively. 

Conclusion: Cephalosporins (I- and III-generation representatives) excessive consumption without results of sensitivity analysis may lead to the development of resistance of microorganisms to antibiotics, including hospital strains.

Cephalosporins are the most “unreliable” antibiotics, the use of which is accompanied by a pronounced “parallel damage”—selection of multiresistant microorganisms not only among strains of pathogens, but also among not etiologically significant microorganisms [2].

Amoxicillin with clavulanic acid more actively suppresses microorganisms that produce β-lactamases. However, hepatotoxic effects of clavulanic acid, especially among children should be taken into account, and the daily dose (no more than 6 mg/kg) should be monitored.

References:

• 1. WHO Collaborating Centre for Drug Statistics, Norwegian Institute of Public Health; Irene Little Scare, Seminar on ATC/DDD, Copenhagen, 26.02.2015

• 2. Kozlov RS. Selection of resistant organisms when using antimicrobial drugs: the concept of parallel damage. Antimicrobials, 2010, Edition 12, №4, P. 284

Disclosure of Interest: None declared.

96 ISoP18-1138 Pharmacovigilance Awareness in Healthcare Professionals

96.1 E. D. Aral Karakulak^*1, H. Barışkaner²

96.1.1 ¹Konya Beyhekim State Hospital, Konya, Turkey; ²Medical Faculty Pharmacology Department, Selcuk University, Konya, Turkey

Background/Introduction: Pharmacovigilance is the pharmacological science relating to the collection, detection, assessment, monitoring, and prevention of adverse effects with pharmaceutical product [1]. In this study a questionnaire was conducted to 200 healthcare professionals in Beyhekim State Hospital to evaluate knowledge and attitude about pharmacovigilance and adverse effects. 200 healthcare professionals consist of 60 doctors (57 specialists, 3 general practitioners), 5 pharmacists, 100 nurses, 10 midwifes, 8 health officers, 5 first aid care technicians, 12 anesthesia technicians. For statistical analysis respondents evaluated in 3 groups: doctors group n = 60, nurses group n = 110 and the other healthcare professionals group n = 30.

Objective/Aim: The aim is to increase pharmacovigilance awareness in healthcare professionals in Turkey by measuring the knowledge, attitude and practices towards pharmacovigilance and adverse drug reactions by conducting a questionnarie in healthcare professionals. 

Methods: A-15 question survey was directed to 200 healthcare professionals. The statistical evaluation of the study was made by using SPSS 21 statistical package program. For the analysis of the obtained data, Chi square test, Pearson Chi Square test, Fisher’s Exact Test was used (statistically significant when p < 0.05).

Results: 71 of 200 respondents (35.5%) had received pharmacovigilance education. 21.7% of 60 doctors, 43.6% of 100 nurses, 33.3% of 30 other healthcare professionals had received pharmacovigilance education. In comparison with the Chi square test, it was determined that there is a significant relationship between health professionals occupations and their education status.

63% of healthcare professionals experienced an adverse drug reaction (ADR) at least. 37% of them had never experienced any ADRs. 15% of the respondents had previously reported an ADR. 85% had never reported any ADRs. Respondents’ main reason (26.5%) for not reporting is not knowing where to report.

73.5% of respondents selected the correct answer when asked who should report ADRs. 68.2% of nurses provided the correct answer of definition of ADRs. 91.7% of doctors provided the correct answer of definition of ADRs. Doctors rate for this question is higher than the other groups. There is a significant relationship between health professionals occupations and their knowledge about definition of ADRs (p < 0.05).

41% of respondents selected correct answer when asked where to report ADRs in Turkey and 6.5% has no idea.

Conclusion: The survey showed that the awareness of pharmacovigilance of health professionals is not sufficient. The awareness of pharmacovigilance among healthcare professionals in other hospitals in our country can give similar results. Therefore, the inclusion of pharmacovigilance in the curricula of pharmacology education in faculties can increase the awareness of pharmacovigilance in healthcare professionals through training, seminars and in hospitals. The formation of accurate information about pharmacovigilance in health workers can be provided by central and/or regional training, seminars, congresses, workshops and so on.

References:

• 1. World Health Organization Definitions [document on the Internet]. 09.10.2017. Available from: http://www.who.int/medicines/areas/quality_safety/safety_efficacy/trainingcourses/definitions.pdf

Disclosure of Interest: None declared.

97 ISoP18-1140 Factors Influencing Low Adverse Drug Reaction Reporting Among Healthcare Professionals in Ghana

97.1 W.-R. Nagumo^*1, R. Cooper¹, R. Akparibo¹

97.1.1 ¹ScHARR, University of Sheffield, Sheffield, United Kingdom

Background/Introduction: Adverse Drug Reaction (ADR) is one of the leading causes of morbidity, mortality and increased healthcare cost. For instance, recent studies in the UK show that ADR costs the NHS £98.5 million and 712 deaths yearly [1]. Elsewhere in the USA, it is estimated that ADRs have led to over 2 million hospitalizations and over 100,000 fatalities making it the fourth leading cause of death [2]. Given this burden, the reporting of ADRs is essential and requires attention from Health Care Professionals (HCPs) to save costs and improve patient safety.

In Ghana, studies are scant and ADR reporting rates are very low. For instance, only 30 reports were received in 2016, which is below the WHO recommendation of 200–250 reports per million inhabitants [3].

Objective/Aim: The study objective is to assess the perceived factors affecting low spontaneous adverse drug reaction reporting among HCPs in Ghana.

Methods: This was a cross-sectional survey, designed based on previous studies with modifications to suit the purpose of the study. 450 self-administered questionnaires were distributed randomly to healthcare professionals. 10 departments in four hospitals (3 secondary care facilities and 1 teaching hospital) were purposively selected for the study. The questionnaire items collected data on their backgrounds, knowledge, attitudes, perceptions, and practice of the reporting system. We analyse the data using SPSS version 22.

Results: The overall response rate was 85.7%. There were 386 respondents (277 nurses, 18 midwives, 40 doctors, 8 Physician Assistant, 19 pharmacists, 5 pharmacist technicians and 9 missing data) who return their questionnaires.

The results show that there was generally a positive attitude to ADR reporting among HCPs. Knowledge about ADR reporting was however very low with merely 18% responding correctly to the five questions assessing knowledge. For instance, only 31.9% of HCPs were aware of the national pharmacovigilance center while 0.5% knew the recommended number of days to send any type ADR report. 20% knew the required number of days to submit a serious suspected and unexpected ADR and 5.2% knew the FDA SMS short code to submit a report to. 32.9% knew the basic information required on the ADR form. 75.6% had not reported any ADRs in the year and 45.9% strongly agreed that they were ignorant about the reporting system. A majority of HCPs (68.4%) either disagreed or strongly disagreed that the following factors affected reporting; guilt of wrong doing, fear of litigation, uncertainty about causality, ambition to keep ADRs for cases series and carrier progression, lack of time and complacency that, all drugs are safe.

Conclusion: These results are preliminary with data showing that there is lack of knowledge but a positive attitude towards reporting. There is a need for further inferential statistics on the significance and association between the variables. The qualitative part of this study will also further explain and understand the findings.

References:

• 1. Elliott R, Camacho E, Campbell F, Jankovic D, Martyn St James M, et al. (2018). Prevalence and Economic Burden of Medication Errors in The NHS in England. Rapid evidence synthesis and economic analysis of the prevalence and burden of medication error in the UK. Policy Research Unit in Economic Evaluation of Health and Care Interventions. Universities of Sheffield and York

• 2. Davies EC, Green CF, Taylor S, Williamson PR, Mottram DR, Pirmohamed M. Adverse drug reactions in hospital in-patients: a prospective analysis of 3695 patient-episodes. PLoS One 2009;4:e4439

• 3. Sabblah GT, Akweongo P, Darko D, Dodoo ANO, Sulley AM. Adverse drug reaction reporting by doctors in a developing country: a case study from Ghana. Ghana Med J 2014;48:189–93

Disclosure of Interest: None declared.

98 ISoP18-1141 Characteristics of Patients Started on a Reduced Dose of Rivaroxaban for Atrial Fibrillation—Results from the ROSE Study

98.1 M. Davies^1,2, A. Evans^1,2, F. Coukan^1,2, L. Wise^1,2, S. Shakir^*1,2

98.1.1 ¹Drug Safety Research Unit, Southampton, United Kingdom; ²University of Portsmouth, Portsmouth, United Kingdom

Background/Introduction: Rivaroxaban is used to treat a range of conditions, including prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). This indication requires a fixed once-daily (od) dose (20 mg) with dosage reduction to 15 mg once daily only recommended in patients (pts) with renal impairment (creatinine clearance 15–49 ml/min). However other clinical factors might be considered by the prescriber when choosing an initial dose.

Objective/Aim: To describe the clinical characteristics of pts prescribed an initial dose of (≥ 20 and < 20 mg daily) for treatment of AF in secondary care.

Methods: The Rivaroxaban Observational Safety Evaluation (ROSE) study was a specialist cohort event monitoring study of pts prescribed rivaroxaban. Specialists provided information from medical records via questionnaires at baseline and ≥ 12 weeks. Information on the prescribed initial dose and baseline characteristics including risk factors for bleeding (HAS-BLED criteria) was collected. For pts prescribed a reduced initial dose (< 20 mg daily), we assessed clinical characteristics vs. pts prescribed ≥ 20 mg daily.

Results: The cohort consisted of 965 pts with AF; of whom (18.3%, n = 177), were prescribed an initial dose of < 20 mg daily [15 mg od (n = 173); 10 mg od (n = 3); 4 mg od (n = 1)].

The majority were female (57.6%, median age 84 years) vs. pts prescribed ≥ 20 mg daily [20 mg od (n = 750); 30 mg od (n = 16)], where the majority were male (56.4%, median age 75 years). 36/177 (20.3%) pts had a history of CKD 3–4 or 5. For 22 patients the start dose was unknown.

Frequency of HAS-BLED criteria in pts prescribed < 20 mg daily vs. ≥ 20 mg daily was: Hypertension (37.3 vs. 38.5%), Abnormal renal function (Chronic dialysis, renal transplant, serum creatinine ≥ 2.3 mg/dL or 200 µmol/L) (3.4 vs. 1.2%), Abnormal liver function (0.6 vs. 1.0%), History of Stroke (31.1 vs. 30.4%), History of Bleeding/predisposition (18.6 vs. 16.3%), Labile INR (N/A), age ≥ 65 years (96.1 vs. 81.2%), Drug therapy (52.0 vs. 51.4%), Alcohol (0 vs. 4.8%).

Conclusion: In pts prescribed a reduced total daily dose of rivaroxaban < 20 mg od, there were a higher proportion of females and those aged ≥ 65 years. Patients prescribed this lower dose were also more likely to have abnormal renal function, defined as per HAS-BLED, than those patients prescribed ≥ 20 mg daily. Although the label recommends dose reduction in AF pts with renal impairment, other factors seem to impact the choice of the initial dose in the clinical setting.

Disclosure of Interest: M. Davies Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications. A. Evans Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications. F. Coukan Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications. L. Wise Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications. S. Shakir Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications.

99 ISoP18-1142 Assessment of Start Dose in Patients Prescribed Rivaroxaban for Atrial Fibrillation with Chronic Kidney Disease-Results from the ROSE Study

99.1 M. Davies^1,2, A. Evans^1,2, F. Coukan^1,2, L. Wise^1,2, S. Shakir^*1,2

99.1.1 ¹Drug Safety Research Unit, Southampton, United Kingdom; ²University of Portsmouth, Portsmouth, United Kingdom

Background/Introduction: Rivaroxaban is used to treat patients with non-valvular atrial fibrillation (AF) for the prevention of stroke and systemic embolism. This requires a fixed daily dose (20 mg) with dosage reduction only recommended in patients with a reduced creatinine clearance (15–49 ml/min), a range encompassed within chronic kidney disease (CKD) stage 3–4 (eGFR 15–59) although CKD 3a (eGFR 45–59) is largely outside this range. Rivaroxaban is not recommended in patients with severe renal impairment (creatinine clearance < 15 ml/min).

Objective/Aim: To assess starting dose amongst patients with chronic kidney disease stage 3–4 or 5.

Methods: The Rivaroxaban Observational Safety Evaluation (ROSE) study was a specialist cohort event monitoring study of patients prescribed rivaroxaban. Specialists provided information via detailed questionnaires at baseline (and ≥ 12 weeks). Baseline characteristics included starting dose and presence of either CKD stage 3–4 (eGFR 15–59) or CKD stage 5 (eGFR < 15). Starting dose was examined amongst patients with CKD stage 3–4 and 5 to assess how many patients had a reduced starting dose of less than 20 mg od.

Results: The cohort consisted of 965 patients with AF: 75 patients with history of either stage 3–4 CKD (n = 73, 7.6%) or stage 5 CKD (n = 2, 0.2%). Of the patients with CKD stage 3–4, 36 (49.3%) were started on < 20 mg daily [15 mg od (n = 35); 10 mg od (n = 1)]. 35 patients (48.0%) were started on ≥ 20 mg [20 mg od (n = 34); 30 mg od (n = 1)]. Starting dose was missing for two patients (2.7%). Neither patient with CKD stage 5 had a dose reduction.

Conclusion: Our results suggest that amongst patients with CKD stage 3–4, approximately half were started on the recommended reduced dose of < 20 mg od. Not all patients with CKD stage 3–4 would be recommended a dose reduction as per the product label. A UK audit suggests that approximately 20% of patients in the UK with CKD 3 are 3b rather than 3a although the frequency may be higher in a hospital cohort.

Disclosure of Interest: M. Davies Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications. A. Evans Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications. F. Coukan Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications. L. Wise Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications. S. Shakir Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications.

100 ISoP18-1143 Distribution of Cha2ds2-Vasc Scores in Patients with Atrial Fibrillation Treated with Rivaroxaban in Primary vs. Secondary Care Settings

100.1 M. Davies^1,2, L. Wise^1,2, S. Shakir^*1,2

100.1.1 ¹Drug Safety Research Unit, Southampton, United Kingdom; ²University of Portsmouth, Portsmouth, United Kingdom

Background/Introduction: Since its incorporation in the European Society of Cardiology guidelines in 2010, the CHA2DS2-VASc score is widely used to characterise the risk of stroke in patients (pts) with atrial fibrillation (AF). It is frequently calculated in pharmacoepidemiological studies through retrospective application of the component criteria included in the risk score. CHA2DS2-VASc Scores of 0, 1, or ≥ 2 indicate low, moderate, or high stroke risk, respectively. 

Objective/Aim: To describe the distribution of CHA₂DS₂-VASc scores and individual stroke risk components in two cohorts of pts prescribed rivaroxaban for AF in primary (1°) vs. secondary (2°) care.

Methods: Two PASS were conducted to investigate the safety of rivaroxaban in pts with AF in 1° care (Modified-Prescription Event Monitoring) and 2° care (Specialist Cohort Event Monitoring) (2012–2016). Baseline characteristics were provided by general practitioners (1° care) and specialist prescribers (2° care) using customised questionnaires. An algorithm was used to compute a CHA₂DS₂-VASc score (0–9) for each pt from fixed response options or open questions, according to published guidelines.

Results: The response rate for baseline questionnaires was lower in 1° care vs. 2° care (22.3 vs. 99.7%). The 1° care cohort consisted of 10,225 pts with a primary indication of AF [median age 78 years (IQR 70–84); 5253 (51.4%) male]. The median CHA₂DS₂-VASc score was 4 (IQR 3–5) reflecting a high risk of stroke. The 2° care cohort consisted of 965 pts with a primary indication of AF [median age 76 years (IQR 69–83); 517 (53.6%) male], with a median CHA₂DS₂-VASc score of 4 (IQR 3–6). There were a higher proportion of pts with a score of 6–9 in 2° care vs. 1° care. The proportions of pts in 1° care vs. 2° care with each criterion were:

• Age 65–74 years (25.7 vs. 25.8%)

• ≥ 75 years (61.8 vs. 58.0%)

• Female (48.6 vs. 46.5%)

• Congestive heart failure/left ventricular dysfunction (14.3 vs. 14.6%)

• History hypertension (82.6 vs. 73.2%)

• History stroke, transient ischaemic attack (TIA) or thromboembolism (TE) (19.8 vs. 46.9%)

• Vascular disease (11.3 vs. 26.9%)

• Diabetes mellitus (17.2 vs. 18.8%)

Conclusion: These results suggest that pts initiated rivaroxaban for AF in 2° care are more likely to have a history of stroke, TIA, TE or vascular disease than pts treated in 1° care. This may mean that pts considered to be at ‘higher risk’ with greater co-morbidities are more likely to be managed in 2° care, or that co-morbidities may be less well recorded in 1° care.

Disclosure of Interest: M. Davies Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications. L. Wise Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications. S. Shakir Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications.

101 ISoP18-1144 An Example of Qualitative Signal Detection Within the French Signal Management Process

101.1 M. Abou Taam¹, R. Youdarene¹, M.-L. Veyries¹, M. Benkebil¹, C. Ferard^*1, P. Maison¹

101.1.1 ¹ANSM, Saint-Denis, France

Background/Introduction: According to Guideline on good pharmacovigilance practices, a signal is an information that is judged to be of sufficient likelihood to justify verificatory action. ANSM management signal process includes among others a qualitative signal detection based on ICSR registered in the french pharmacovigilance database (FPD). Those signals are subject to confirmation during the monthly pharmacovigilance Committee between ANSM and the Regional pharmacovigilance network. The relevance of those ICSR is decided according to a decision algorithm (e.g., unexpected, expected with other criteria, cluster of cases, high-risk population) and a risk analysis. In several cases, the signal should be consolidated. In all cases, the signal should be assessed considering all drug related data. If the signal is validated, ANSM or EMA decide then to make actions or measure to consolidate the signal and/or to reduce the risk.

Objective/Aim: To analyze the type of actions or measures which were proposed following a potential signal.

Methods: All actions/measures proposed after validated signal in 2017 were analyzed.

Results: Among the overall 73,991 ICSRs registered in FPD in 2017, 818 (1%) were considered as potential signals. From those signals, the risk analysis allow to detect 531 validated potential signals (65%). In relation to recommendations stemming from those collegial assessments, the majority of actions/measures were mainly to review the data of next PSUR or to discuss the signal through PRAC procedures. In some cases, it was to decide label changes for national authorization procedures and/or additional monitoring including expertise solicitation and all-drug related data retrieval. Less frequently, the decision was to communicate with healthcare professionals and with patients about the risk, to trigger an European signal procedure and to decide a reassessment of the benefit–risk balance at national level.

Conclusion: The signal management of validated signals has led to a number of additional actions or measures. Some potential signals were not validated. However, spontaneous reporting of adverse events continues to play a major role in regulatory decision making. Several other sources of signals are also used including the statistical signal detection. The patient and all stakeholders play an important role in the signal detection.

Disclosure of Interest: None declared.

102 ISoP18-1145 Drug–Drug Interactions Between ß Lactam (Amoxicillin/Clavulanic Acid and Imipenem) and Valproic Acid in the Same Patient

102.1 E. Gaies¹, I. Fazaa¹, R. CharfiI¹, M. Ben SassiI¹, N. Jebabli¹, H. El Jebari¹, I. Salouage¹, S. TrabelsiI¹, R. Daghfous^*1

102.1.1 ¹Clinical Pharmacology, National Centre of Pharmacovigilance, Tunis, Tunisia

Background/Introduction: Valproic acid (VPA) is a commonly used agent for the treatment of both partial and generalized seizure. It can be administrated alone or associated to other antiepileptic drugs (AEDs) and it is known to interact with the most used AEDs and non-AEDs. Concomitant administration of imipenem and VPA leads to a decline in plasma concentrations of VPA, which can sometimes induce seizures [1]. This interaction was previously reported but the mechanism remains unclear. However, interaction with amoxicillin/clavulanic acid (AMC) is reported only in one study evaluating the interaction in healthy volunteers [2].

Objective/Aim: In this context we report a case of drug–drug interactions between AMC and VPA and between imipenem and VPA in the same patient.

Methods: This report describes a 2-year-old male child treated since January 2017 by VPA (Dépakine^®), 400 mg daily (33 mg/kg) for encephalopathy. Therapeutic drug monitoring of VPA was made regularly from January to August 2017 by measuring through plasma concentration (C₀).

Results: VPA concentrations (C₀) varied between 40.61 and 58.16 µg/mL (mean C₀ was 46.61 µg/mL and C₀/Dose ratio = 1.27).

On August 2017, the patient was diagnosed with pneumonia and he was treated initially by AMC (Augmentin^®). Few days later, AMC was changed to imipenem.

One day after AMC administration, the plasma level of VPA was rapidly decreased to 32.88 µg/mL. VPA dose was adjusted to 660 mg daily but the concentration remained low. With the administration of imipenem, VPA dose was adjusted to 800 mg daily (66 mg/kg). Plasma level of VPA were monitored more closely during the imipenem treatment period, and showed C₀ mean of VPA near the therapeutic range (51.65 µg/mL) but a low Co/Dose ratios (Mean ratio 0.87).

Conclusion:

There is a complex interaction between VPA and carbapenem antibiotics due to a combination of different mechanisms, including absorption, distribution, and metabolism [1]. The interaction between AMC and VPA seems rare but its mechanism is clear and involves interruption of the enteroheptic circulation by AMC. So, if concomitant ß lactam therapy with VPA is needed and cannot be avoided, VPA concentration should be monitored more frequently.

References:

• 1. Mancl EE, Gidal BE. The effect of carbapenem antibiotics on plasma concentrations of valproic acid. Ann Pharmacother 2009;43:2082–7

• 2. Lee S-Y, Huh W, Jung JA, Yoo HM, Ko J-W, Kim J-R. Effects of amoxicillin/clavulanic acid on the pharmacokinetics of valproic acid. Drug Des Devel Ther 2015;9:4559–63

Disclosure of Interest: None declared.

103 ISoP18-1146 Alopecia Occurred With Infliximab: What Link? Clinical Case

103.1 I. Bennani¹, R. Soulaymani², A. Tebaa^*2

103.1.1 ¹Faculty of Medicine and Pharmacy of Rabat, University Mohamed V Rabat, Morocco; ²Pharmacovigilance Departement, Poison and Pharmacovigilance center of Morocco, Rabat, Morocco

Background/Introduction: The increased use of biologic drugs has been revealing new adverse effects. The cutaneous reactions described include eczema, erythema, urticaria, lupus-like syndrome and, paradoxically, psoriasis. One cases of alopecia associated with anti-TNF therapy were reported, which resulted in cutaneous psoriasiform lesions. One case of alopecia associated with anti-TNF therapy has been reported at the National Center for Pharmacovigilance in Morocco, which is covered in this communication.

Objective/Aim: The aim of this work is to determine the causality assessment between alopecia and the administration of the Influximab.

Methods: It is a women of 60-year-old, hospitalized for ankylosing spondylitis on 2016, treated by Sulfasalazine and AINS in front of the therapeutical echec with sulfasalazine, she was switched to Infliximab. After the 5th cure/cycle, the patient developed alopecia mainly involving the scalp. The drug was stopped and all etiological causes were eliminated with a positif rechallenge. The relationship between alopecia and Infliximab was suspected and evaluated using the French method of imputability.

Results: Biotherapy represents therapeutic advances in the treatment of immunological and inflammatory diseases.

The accountability score was I5B4 with an informativity level of 2 using the French method In our patient, we were tempted to retain Infliximab as responsible for alopecia. Alopecia is a notorious effect already described in the literature.

However, the Cases notified at the level of the national pharmacovigilance center concerning infliximab which are 48 cases; Our case is the first case of alopecia caused by infiliximab.

According to the literature, the development of alopecia related to anti-TNF is a possible although seldom reported collateral effect. Alopecia is a rare cutaneous reaction to tumor necrosis factor alpha antagonists. This reaction often reverses with discontinuation of the offending drug and initiation of topical treatments; however, irreversible hair loss may occur if a scarring alopecia develops.

Conclusion: the decision to discontinue anti-TNF therapy following adverse skin reactions should be based on a case-by-case assessment of the benefit/risk and benefit/cost ratio of the prolonged treatment.

Disclosure of Interest: None declared.

104 ISoP18-1149 Impact Analyses of European Pharmacovigilance Interventions on Public Health Burden

104.1 S. Lane¹, E. Lynn^1,2, J. Slattery³, S. Shakir^*1,2

104.1.1 ¹Drug Safety Research Unit, Southampton, United Kindgom; ²University of Portsmouth, Portsmouth, United Kingdom; ³European Medicines Agency, London, United Kingdom

Background/Introduction: Adverse drug reactions (ADRs) account for 5% hospital admissions and 197,000 deaths each year in the EU, amounting to a societal cost of €79billion [1, 2]. These ADRs have large impacts on public health in terms of morbidity and mortality. Since the implementation of the 2012 pharmacovigilance (PV) legislation, monitoring success of pharmacovigilance (PV) has become commonplace; however impact of PV regulatory interventions on public health remains mostly unquantified [3]. There is a current need for research identifying the best technique for measuring impact of these actions, and guidelines on reporting impact analyses [3].

Objective/Aim: Interim analysis to assess the feasibility of predictive modelling techniques for estimation of public health impact of PV regulatory interventions.

Methods: Prescription products used in primary care whose marketing authorisations were withdrawn, revoked or suspended in France, Germany or the UK between 2012 and 2016 were previously identified [4]. Databases from France, Germany and the British Health Improvement Network (THIN) were used to estimate usage of the identified products for the year prior to PV action. Systematic searches of the PubMed/MEDLINE database, and European Medicines Agency and national competent authority websites and documents were conducted to identify quantitative studies for the product and ADR of interest. Study data were meta-analysed to produce an overall weighted odds ratio for each ADR relating to each product. Background risk was estimated using THIN data. Modelling of usage figures, odds ratios and background risk allowed the public health impact of the intervention to be estimated in terms of morbidity attributable to the withdrawn, revoked or suspended product.

Results: 18 products were considered for impact analysis; 9 were excluded as no quantitative studies were identified for the respective ADRs. This interim analysis on a subset of these products provides a prediction of the number of ADRs avoided as a result of the included products’ marketing authorisation withdrawal, revocation or suspension, and an estimation of the public health impact of these PV actions using changes in morbidity as an indicator.

Conclusion: This study identifies a method for predicting public health impact of PV interventions, based on drug utilisation data and expected changes in morbidity. This interim analysis tested the method on a subset of products. Further validation of the predictive modelling method will be undertaken before completion of the study.

References:

• 1. Mammi M, Citraro R, Torcasio G, Cusato G, Palleria C, di Paola ED. Pharmacovigilance in pharmaceutical companies: an overview. J Pharmacol Pharmacother 2013;4(Suppl 1):S33–7

• 2. Mazzitello C, Esposito S, De Francesco AE, Capuano A, Russo E, De Sarro G. Pharmacovigilance in Italy: An overview. J Pharmacol Pharmacother 2013;4(Suppl 1):S20–8

• 3. Goedecke T, Morales D, Pacurariu A, Kurz X. Measuring the impact of medicines regulatory interventions—systematic review and methodological considerations. Br J Clin Pharmacol 2018;84:419–33

• 4. Lane S, Lynn E, Shakir S. Investigation assessing the publicly available evidence supporting postmarketing withdrawals, revocations and suspensions of marketing authorisations in the EU since 2012. BMJ Open. 2018;8:e019759

Disclosure of Interest: None declared.

105 ISoP18-1150 Changes in Evidence Supporting Post-marketing Withdrawal of Marketing Authorisation in the EU

105.1 S. Lane¹, E. Lynn^1,2, S. Shakir^*1,2

105.1.1 ¹Drug Safety Research Unit, Southampton, United Kingdom; ²University of Portsmouth, Portsmouth, United Kingdom

Background/Introduction: Market withdrawal of a product affects patients, healthcare professionals, regulators and manufacturers, therefore these decisions should be based on the most robust evidence available [1]. EU pharmacovigilance (PV) legislation was updated in 2012 and led to modernisation of PV systems in Europe. It is necessary to explore whether evolution of PV leads to changes in evidence supporting PV actions (e.g. withdrawals), and how the use of supporting evidence has adapted over time.

Objective/Aim: To evaluate changes in evidence supporting post-marketing product withdrawals from 1999 to 2016.

Methods: Using 3 previously published studies, it was possible to compare evidence used to support post-marketing PV actions in the EU, spanning the period 1999–2016 [1–3]. The number of withdrawals per year was calculated. Study designs supporting post-marketing withdrawals in 1999–2016 were evaluated. Changes to evidence supporting product withdrawals were assessed.

Results: A total of 31 market withdrawals occurred in the EU between 1999 and 2016 and were included in these publications, with an average of 1.72 per year. The number of withdrawals increased between 1999 to its peak in 2010 (5 withdrawals in 2010), and decreased from 2011 to 2016. In general the number of different study designs used to justify withdrawals increased between 1999 and 2016. Spontaneous and published case reports were the most common evidence source, involved in 29 withdrawals (93.5%). This evidence alone led to 4 (12.9%) withdrawals. The least common sources of supporting evidence were epidemiological studies (case–control n = 6; cohort n = 7). Other sources included randomised clinical trials (n = 20), animal studies (n = 13) and meta-analyses (n = 7). The average number of distinct evidence types used was 3.1 per withdrawal. Six (19.4%) withdrawals were justified by just one source of evidence, with the remaining 25 (80.6%) withdrawals supported by at least 2 different types of evidence.

Conclusion: The number of products withdrawn from the EU market appears to have increased until 2010, and has since decreased. Although there is an apparent increase in different types of evidence being used to justify post-marketing withdrawals, spontaneous and published case reports remain a vital source of evidence for regulators.

References:

• 1. Clarke A, Deeks JJ, Shakir SA. An assessment of the publicly disseminated evidence of safety used in decisions to withdraw medicinal products from the UK and US markets. Drug Saf 2006;29:175–81

• 2. Lane S, Lynn E, Shakir SAW. Measuring the impact of product withdrawals and other major pharmacovigilance actions on public health burden in the EU: methodological considerations. Drug Saf 2017; 40: 953–4

• 3. McNaughton R, Huet G, Shakir S. An investigation into drug products withdrawn from the EU market between 2002 and 2011 for safety reasons and the evidence used to support the decision-making. BMJ Open. 2014;4:e004221.

Disclosure of Interest: None declared.

106 ISoP18-1151 Psychiatric Adverse Drug Reactions with Anti-Hypertensive Treatment: Review and Analysis of SmPCs

106.1 P. Biswas^*1, H. Biswas¹

106.1.1 ¹Symogen Limited, Bourne End, United Kingdom

Background/Introduction: Prescription drugs result in myriad of ADRs, including psychiatric ADRs. Psychiatric effects of drugs impact sensorium, attention, concentration, memory and higher cognitive functions resulting in distressing physical illness and psychiatric consultation. In regards to psychiatric effects associated with drug therapy, complications such as depression and suicidality are those most frequently reported. 

Objective/Aim: To review the SmPCs of Antihypertensive drugs used commonly in medical practice and understand the common, uncommon, rare, very rare psychiatric ADRs and risks associated with these drugs.

Methods: List of most common antihypertensives prescribed in medical practice was prepared and review of Section 4.8 Undesireable effects of the SmPCs undertaken. Three drugs each from treatment categories were included for analysis: Angiotensin Receptor Blockers (ARBs):Losartan, Valsartan, Candesartan; ACE Inhibitors: Enalapril, Lisinopril, Ramipril; Beta Blockers; Atenolol, Metoprolol, Carvedilol; Calcium Channel Blockers (CCB): Amlodipine, Diltiazem, Verapamil; Diuretics: Furosemide, Bumetanide, Spironolactone; Alpha Blockers : Prazosin, Terzosin, and others: Clonidine and Minoxidil.

Results:

Analysis involved review of common, uncommon, rare and very rare psychiatric ADRs based on the Pyschiatric System Organ Class (SOC) ranked under headings of frequency as described in Table 1. Almost all the drugs had psychiatric ADRs ranging from common to very rare listed in SmPCs except Valsartan, Candesartan in ACE Inhibitors; Verapamil in CCBs; Bumetanide in Diuretics and Minoxidil. Depression, depressed mood, anxiety, nervousness were common for Alpha and Beta blockers which are the most prescribed antihypertensives. Insomia, sleep disturbances, confusion, psychosis were uncommon, while hallucinations, mental confusion, disturbance in attention, depression and personality disorders were rare and very rare ADRs. None of the drug categories listed suicidality or suicide attempt as an ADR.

Conclusion: Identification of psychiatric ADRs related to drug therapy in real world post-marketing setting is difficult. Reporting rates determined on the basis of spontaneously reported post-marketing ADRs are generally presumed to underestimate the risks associated with treatment. As a medical student, this exercise will help me to assess patients starting therapy with antihypertensives, identify and report ADRs to the MHRA, monitor ongoing ADRs, and lastly read the SmPC as guidance to good medical practice.

Disclosure of Interest: None declared.

107 ISoP18-1152 Is the Risk of Linezolid to Cause Serotonin Syndrome Real in Routine Clinical Practice?

107.1 H. Thirot¹, X. Holemans², F. Jacobs³, C. Briquet⁴, F. Frippiat⁵, A. Spinewine⁶, F. Van Bambeke¹, P. M. Tulkens^*1

107.1.1 ¹Louvain Drug Research Institute, Université catholique de Louvain, Bruxelles, Belgium; ²Médecine Interne générale et infectiologie, Grand Hôpital de Charleroi, Charleroi, Belgium; ³Infectiologie, CUB-Hôpital Erasme, Bruxelles Belgium; ⁴Pharmacie, Cliniques universitaires St-Luc, Bruxelles, Belgium; ⁵Infectiologie, Centre Hospitalo-Universitaire de Liège, Liège, Belgium; ⁶Clinical Pharmacy, Cliniques Universitaires St-Luc, Bruxelles, Belgium

Background/Introduction: Because of structural similarities, linezolid is an inhibitor of monoamine oxidases [1], which may lead to a serotonin syndrome [2, 3] and toxicities in case of co-administration of drugs inhibiting the recapture of serotonin (such as several antidepressants or antihypertensives), drugs undergoing catabolism through monoamine oxidase activity, or direct inhibitors of monoamine oxidase, all of which are then considered as contra-indicated [4, 5]. However, the occurrence of real cases of serotonin syndrome and/or of drug–drug interaction toxicities during routine linezolid treatment of patients receiving contra-indicated drugs remains unsettled [5], especially if considering that linezolid is often prescribed for longer periods and for other indications than recommended in the SmPC.

Objective/Aim: To better document the risk of developing a serotonin syndrome in patients receiving routine linezolid treatments (including off-label uses [6]) and prescribed drugs considered as contra-indicated because of potential toxicities due to linezolid-induced inhibition of monoamine oxidase(s).

Methods: We retrospectively analysed the medical files of hospitalized adult (> 18 years) patients receiving linezolid for treatment of documented infection(s) and assessed their exposure to other drugs based on analysis of pharmacy records. The study covered 4 large Belgian hospitals for a period of 1 year (2016).

Results: We enrolled 236 patients (248 treatments) who received linezolid at the recommended dose (600 mg BID) during a mean period of 14.8 days (median: 10 days; extremes: 1–90 days). Among those, 100 patients were prescribed one or several drugs susceptible to cause serotonin syndrome [tramadol (n = 53), escitalopram (n = 19), trazodone (n = 15), mirtazapine (n = 11), duloxetine (n = 8), amitriptyline (n = 4), venlafaxine (n = 3), sertraline (n = 2), paroxetine (n = 2), melitracene (n = 1)] but no drug acting through monoamine oxidase inhibition. Of all these patients, only one [receiving trazodone (100 mg/day) and duloxetine (60 mg/day)] developed a clinically confirmed serotonin syndrome (with agitation and delirium) after 7 days of treatment with linezolid, leading to the antibiotic withdrawal and recovery within a week.

Conclusion: The documentation of a serotonin syndrome was very low in this cohort of patients receiving linezolid with co-prescription of one or several drugs commonly considered as contra-indicated. The co-administration of linezolid with these drugs may therefore be safer than anticipated in routine clinical practice. However the retrospective design of the study and the common under-diagnosis of serotonin syndrome should trigger the launching of a prospective study where actual drug exposures, clinical status, and risk factors could be controlled and assessed.

References:

• 1. Taylor JJ, Wilson JW and Estes LL. Linezolid and serotonergic drug interactions: a retrospective survey. Clin Infect Dis 2006;43:180–7

• 2. Frykberg RG, Gordon S, Tierney E and Banks J. Linezolid-associated serotonin syndrome. A report of two cases. J Am Podiatr Med Assoc 2015;105:244–8

• 3. Sutton J, Stroup J, Som M. Linezolid-induced serotonin toxicity in a patient not taking monoamine oxidase inhibitors or serotonin receptor antagonists. Proc (Bayl Univ Med Cent) 2016;29:214–5

• 4. Preston CLe (2016) Stockley’s Drug Interactions. Pharmaceutical Press, London, UK

• 5. Linezolid SmPC. Linézolide: Résumé des caractéristiques du produit. Agence fédérale des médicaments et produits de santé. Available from: http://bijsluiters.fagg-afmps.be/DownloadLeafletServlet?id=115863 Last updated: 2014; last accessed: 25-05-2018

• 6. Thirot H, Briquet C, Frippiat F, Jacobs F, Holemans X, Tulkens PM, et al. Review of linezolid (LZD) use and onset of toxicity in 4 belgian hospital centers: a retrospective study. Abstract submitted to the 2018 IDweek, San Diego, CA (3–7 Oct 2018)

Disclosure of Interest: H. Thirot: None Declared, X. Holemans: None Declared, F. Jacobs: None Declared, C. Briquet: None Declared, F. Frippiat: None Declared, A. Spinewine: None Declared, F. Van Bambeke: None declared, P. Tulkens Speaker bureau of: Merck.

108 ISoP18-1153 A Prospective Evaluation of MCEM Method for Drug Safety Signal Detection in Spontaneous Reporting Systems

108.1 Y. Li^*1, C. Xiao², K. Shen³, K. Bannout⁴, W. Wallis⁴, F. Wang^1,5

108.1.1 ¹Center for Computational Health, IBM Research, Yorktown Heights, NY, United States; ²AI for Healthcare, IBM Research, Cambridge, MA, United States; ³IBM Watson Health, Life Science Division, New York, NY, United States; ⁴Global Safety and Risk Management, Celgene, Summit, NJ, United States; ⁵Department of Healthcare Policy and Research, Cornell University, New York, United States

Background/Introduction: Modern signal detection and statistical data-mining methods are used to identify new drug safety signals based on spontaneous reporting systems (SRS). Bayesian methods, such as Multi-Item Gamma Poisson Shrinker (MPGS) [1], are frequently used on such databases to correct for the sampling variance. Although a significant advance, the Bayesian methods do not address other limitations intrinsic to SRS such as confounding effect. We have developed the Monte-Carlo Expectation Maximization (MCEM) method [2] that reduces sampling variance by leveraging the MGPS technique [1], and filters out concomitant confounders in each case report by leveraging a Monte Carlo sampling procedure that could assign each ADR with its major associated drug determined by drugs’ contribution to that ADR [2]. We have previously demonstrated the effectiveness of MCEM according to a reference standard developed by the Observational Medical Outcomes Partnership (OMOP) [2–4]. This evaluation is considered retrospective as most drug-ADR positive pairings in the reference standard were well established at the time of evaluation. In this study, we sought to test the method’s performance in the prospective detection of emerging and unknown ADRs.

Objective/Aim: To test whether MCEM applied prospectively is able to detect the unknown ADRs earlier than the traditional MGPS method.

Methods: We tested the MCEM and the MGPS method using the de-duplicated and standardized (e.g., drug names mapped to RxNorm concepts and ADR outcomes mapped to MedDRA concepts) FDA adverse event reporting system (FAERS) [5]. We divided the data into six cumulative yearly subsets based on the reporting time of each case report from 2007 through 2012. Each successive set consists of reports from that year plus those from preceding years. For example, the 2007 data set consists of reports from only 2007, and 2012 data set consists of all reports from 2007 through 2012. We used a time-indexed reference standard involving 44 drugs and 38 ADRs, which resulted in 62 positive test cases time-stamped with the date on which the relevant ADR was added to the label by the FDA throughout the calendar year 2013, and 75 negative controls [6]. Positive signals were those whose signal scores greater than or equal to the particular threshold that was determined by the pre-specified false discovery rate. Two performance metrics were evaluated: (1) area under the Receiver Operating Characteristics (ROC) curve (AUC) for the six cumulative yearly data sets, and (2) the mean lead time-to-signals (MLT2D) for both MCEM and MGPS.

Results: The MCEM achieved better AUCs from 2008 to 2011, and worse AUCs in 2007 and 2012 than the MGPS. The MCEM was able to identify 19, 24 and 24 true positive signals before 2013 at false discovery rates of 5, 10 and 15%, respectively, and the MLT2D were 2.20, 2.66 and 2.73 years. This compared with that the MGPS that identified 18, 19 and 20 true positive signals at the same levels of false discovery rates, and the MLT2D were 1.95, 2.07 and 2.18 years.

Conclusion: Within the framework of this evaluation, our findings suggest that MCEM leads to earlier signal detection than MGPS. Acknowledging the limitations associated with the data and reference standard used in this work, the MCEM is a promising alternative to MGPS that merits further investigation and validation.

References:

• 1. DuMouchel W. Bayesian data mining in large frequency tables, with an application to the FDA spontaneous reporting system. Am Stat 1999;53:177–90

• 2. Xiao C, Li Y, Baytas IM, Zhou J, Wang F. An MCEM framework for drug safety signal detection and combination from heterogeneous real world evidence. Sci Rep 2018;8:1806

• 3. Ryan PB, Schuemie MJ, Welebob E, Duke J, Valentine S, Hartzema AG. Defining a reference set to support methodological research in drug safety. Drug Saf 2013;36:33–47

• 4. Xiao C, Li Y, Argentinis E, Zhou J, Wang. An MCEM-MTL framework for drug safety signal filtering and detection in spontaneous reporting systems. Drug Saf 2017; 40: 944–5

• 5. Banda JM, Evans L, Vanguri RS, Tatonetti NP, Ryan PB, Shah NH. A curated and standardized adverse drug event resource to accelerate drug safety research. Sci Data 2016;3:160026

• 6. Harpaz R, Odgers D, Gaskin G, et al. A time-indexed reference standard of adverse drug reactions. Sci Data 2014;1:140043

Disclosure of Interest: Y. Li Employee of: IBM Research, C. Xiao Employee of: Celgene, K. Shen Employee of: IBM Watson Health, K. Bannout Employee of: Celgene, W. Wallis Employee of: Celgene, F. Wang Employee of: IBM Research, Other: Assistant Professor at Cornell University.

109 ISoP18-1154 Amusing Ourselves to Death: How Science and Reason are Losing Their Grip in Public Discourse

109.1 B.P.J. Hugman^*1

109.1.1 ¹Global Communications, Uppsala Monitoring Centre, Sweden, Oxford, United Kingdom

Background/Introduction: This new work builds on last year’s study of alternative facts and the threats to the authority of evidence, particularly in medicine. The politicisation of scientific and medical issues and those associated with women’s health and welfare, for example, have led to partisan battles and polarisation which preclude engagement, negotiation and consensus. These problems reflect the wider social and political landscape in which measured debate across tribal boundaries is becoming increasingly rare, if not impossible, and in which policy is driven by idiosyncratic preferences and emotion, not evidence. The title of this proposal is an acknowledgement of Neil Postman’s prescient 1985 book, Amusing Ourselves to Death: Public Discourse in the Age of Show Business. He argued that television was bringing about a realisation of Huxley’s nightmare society in which populations were oppressed and infantilised by their addiction to amusement; in the twenty-first century, popular technology has dramatically intensified those processes, while opening up unprecedented access to human attention.

Objective/Aim: (1) To analyse some of the major current political and cultural trends across the world, including tribalism, polarisation, partisanship, binary thinking, and public cynicism about experts, and (2) To suggest novel ways in which actors in science, medicine and public health, and activists, might respond in order to be heard and for their messages to influence opinion and behaviour.

Methods: The work is part of a larger project examining how medicines information and risk communication can be deployed to stem the tide of irrationality and recover from their failure to deliver full benefits in an increasingly perverse political, social and philosophical context. It has involved extensive reading and research and a degree of original thinking and synthesis.

Results: The analysis reveals the depth of the problems we face and the extent to which they are inter-related with profound social and political currents in recent years. Scientists themselves have contributed through failures and shortcomings in scientific practice and public relations. The solutions are radical and demanding and require commitment and creativity in broad alliances.

Conclusion: It is clear that ‘the institutional structure of science advocacy has created a conservative bystander culture that has failed science abysmally’ [2]; that our methods are often sluggish and bureaucratic; that only an era of radical new communication skills and engagement will begin to diminish the power of superstition, division and unreason. Some ideas for starting this reform, and some speculative methods for pushing it forward, in collaboration with others, will be offered.

References:

• 1. Postman N. Amusing ourselves to death: public discourse in the age of show business. Penguin Books; Anniversary edition, 2005

• 2. Tran L. Why March for science? Because when it is attacked, only the elite benefit. The Guardian, UK, 22 Apr 2017

Disclosure of Interest: None declared.

110 ISoP18-1155 Pharmacovigilance: Inspection and Audit—Are they the Same or Different?

110.1 M. Yaman^*1, E. Canak², S. Dagistanli^3,4

110.1.1 ¹Pharmacovigilance, ²Business Development, ³DeltaPV Ilac Danismanlik Saglik Urun ve Hizmet A.S., Istanbul, Turkey; ⁴Turkish Pharmacovigilance Foundation, Istanbul, Turkey

Background/Introduction: Pharmacovigilance (PV) personnel should always be ready for health authorithy inspections, as well as audits by internal auditors, headquarter PV functions, licensor companies, independent audit companies and others at any time. Pharmacovigilance World currently has many guidelines and written procedures released by different countries to be followed by pharmaceutical companies. They are released in order to manage PV operational system and improve input on benefit/harm perceptions from obtained safety data. PV audits and inspections are conducted to review and analyze the compliance of the systems with these guidelines and procedures which in turn support patient safety.

Objective/Aim: To identify similarities and differences between PV inspections and audits, by sharing experiences from a Contracted Pharmacovigilance Service Company’s view.

Methods: Within the time frame starting from 01 April 2014 to 01 June 2018, a total of 7 inspections conducted by Turkish Health Authorithy and 58 audits were included in our analysis; 16 of these were local affiliate (Contracted Company’s Local PV function) audits, 42 were global (Contracted Company’s Headquarter PV function) and licensor company audits. In terms of methodological approach, a total of 41 face to face audits, 11 questionnaire based audits via e-mail and 6 remote connection audits via videoconference were evaluated in our study. In terms of categories of findings, a total of 1 critical, 26 major and 115 minor finding were identified during this period and they were all closed within 1 year at the latest from inspection or audit date.

Results: All inspections conducted by the Turkish Health Authority Inspection Division were face to face and the longest inspection conducted lasted 5 days by five inspectors in 2016. Majority of other audits and inspections lasted between one and 2 days. In this study, the major observation is that some confusion may occur about the purpose of inspections and audits or the terms may be used interchangeably without realizing that they have many different aspects. Audits are considered to guide a “self check” to ensure compliance in PV system. However, the inspections are considered to be a check list of “have to do’s” of the specified compliance obligations have been met. In Turkey, in cases of noncompliance, various enforcement actions can be forced in the result of Turkish Health Authority Inspections on the pharmaceutical companies and contracted pharmacovigilance service companies by the Turkish Health Authority. Commonly, inspectors and auditors review similar tasks of PV operations; such as quality management systems, agreements, internal and external trainings, procedures and all other PV related documents which are available for data collection.

Conclusion: In this reporting period the impact of the revised pharmacovigilance legislation on pharmaceutical companies and contracted pharmacovigilance service companies in Turkey became more apparent. After the legislation and guidance has been strengthened, an increased number of inspection and audits have been recorded. The PV personnel should always be ready for an inspection and/or audit, since patient safety is considered as priority along with Good Pharmacovigilance Practices.

References:

• 1. Khurana A, Rastogi R, Gamperl HJ. Ready for Pharmacovigilance Inspection—USFDA. Int. J Pharm Sci Rev Res 2015;35:210–7

• 2. EMA. Guideline on good pharmacovigilance practices (GVP), Module III—Pharmacovigilance Inspections, EMA/119871/2012 Rev 1*; 08 September 2014. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/09/WC500172400.pdf

• 3. EMA. Guideline on good pharmacovigilance practices (GVP), Module IV—Pharmacovigilance audits, EMA/228028/2012 Rev 1*; 03 August 2015. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/08/WC500191778.pdf

• 4. MHRA. Pharmacovigilance Inspection Metrics Report. April 2013–March 2014

• 5. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/418323/Pharmacovigilance_Inspection_Metrics_Report_2013-2014.pdf

Disclosure of Interest: M. Yaman Employee of: DeltaPV Ilac Danismanlik Saglik Urun ve Hizmet A.S., E. Canak Employee of: DeltaPV Ilac Danismanlik Saglik Urun ve Hizmet A.S., S. Dagistanli Shareholder of: DeltaPV Ilac Danismanlik Saglik Urun ve Hizmet A.S.

111 ISoP18-1156 From Database to Diagnosis: ‘Intelligent Query’, a Tool to Help With Safety Signal Evaluation

111.1 V. Samal^*1, O. Mahaux¹

111.1.1 ¹GSK, Wavre, Belgium

Background/Introduction: Safety signal evaluation is a core activity in pharmacovigilance. The methods and tools rely on adverse events coded using the Medical Dictionary for Regulatory Activities (MedDRA). Standardized MedDRA Queries (SMQs) represent the current practice to identify groups of adverse event terms (e.g. signs and symptoms) for a particular medical condition. However, missing patient history in spontaneous report databases is an issue. We have developed an algorithm, the ‘Intelligent Query Bayesian Network’ (IQ BayNet), to ascertain the diagnosis of adverse event reports with more specificity and sensitivity by using computed probabilities of natural history of a disease to predict and complement missing case information.

Objective/Aim: To validate the IQ BayNet as a reliable diagnostic tool for spontaneous adverse event reports of Diabetes Mellitus Type II (DMII).

Methods: A relevant list of variables was identified from GSK’s spontaneous safety database, including laboratory results, clinical features, risk factors and medical history. A Bayesian network software (Hugin) was used to develop a graphical model representing the probabilistic relationships between those variables and DMII. Variable-specific probabilities were attributed based on their frequency of occurrence using published peer-reviewed articles, standard algorithms and GSK physicians’ experience that determines their degree of influence on DMII. The IQ BayNet uses specific variables from the safety database as input and provides a probability for diagnosis as output. A sample of 50 DMII cases was output using IQ BayNet and qualitatively reviewed. The output DMII probabilities of those 50 cases were compared with the results of MedDRA SMQ Hyperglycaemia/new onset diabetes mellitus.

Results: The IQ BayNet sensitivity and specificity are observed to be increased when compared to SMQ by 48 and 22.6%, respectively. Eighteen DMII positive cases were detected by the IQ BayNet, all being true positive cases, whereas 13 true positive cases were identified among the 25 positive cases detected by SMQ. Further 32 negative cases were detected by the IQ BayNet, 29 being true negative cases, while 17 true negative cases were identified in the 25 negative cases detected by SMQ.

Conclusion: The IQ BayNet has shown higher sensitivity and specificity in automatic detection of true cases of DMII cases as compared to the SMQ. Future work will focus on developing similar algorithms tailored to other medical conditions.

Funding source: GlaxoSmithKline Biologicals SA.

Disclosure of Interest: V. Samal Shareholder of: GSK group of companies, Employee of: GSK group of companies, O. Mahaux Employee of: GSK group of companies.

112 ISoP18-1158 Adverse Event Recognition in Tweets: Results from a WEB-RADAR Project

112.1 L. Gattepaille^*1, S. Hedfors Vidlin¹, T. Bergvall¹, J. Ellenius¹

112.1.1 ¹Uppsala Monitoring Centre, Uppsala, Sweden

Background/Introduction: Thanks to the large patient coverage and instant availability of open data, pharmacovigilance in Twitter could complement more traditional tools such as spontaneous case reports and electronic health records [1]. In 2014, The WEB-RADR consortium [2] was established to, among other aims, provide an answer to the open question: can social media data be harnessed and reliably utilized for pharmacovigilance purposes?

Objective/Aim: One year after completion of the WEB-RADR consortium, we report the results of a processing pipeline aiming at recognizing Adverse Events in Tweets, developed in the course of the project.

Methods: First, a relevance filter was applied to remove tweets with low probability of containing an adverse event (AE), using a previously published method [3]. Medicinal product detection used a dictionary lookup method based on WHODrug, a global dictionary of medicinal products. Medical event detection used a mix of dictionary lookups, natural language processing and logistic regression classifiers to map the identified text to the Medical Dictionary for Regulatory Activities preferred terms. Finally, a logistic regression classifier was trained to identify AE relationships.

This pipeline was trained on a proprietary dataset of 196,533 tweets manually annotated by MedDRA coders at Epidemico, a WEB-RADR consortium member, and evaluated on an independent benchmark Reference dataset of 57,481 manually annotated tweets produced by WEB-RADR. We present comparative performance results of the pipeline on the WEB-RADR Reference dataset with a previously published method [3] that has reported good performance on similar data.

Results: The Reference dataset contains 1058 posts with at least one medicinal product—AE pair (MP/AE pair) and a total of 1398 MP/AE pairs. Our pipeline could recognize and correctly map 23% of the 1398 gold standard pairs (recall) while 37% of putative MP/AE pairs identified by the pipeline were indeed gold standard pairs (precision), leading to an F-score of 0.28. 36% of the gold standard pairs were lost in the relevance filter module, 54% of the remaining pairs were lost in the medicinal product and medical event recognition modules combined and 35% of the remaining pairs were lost in the AE relation classification module, explaining the low overall recall. Comparatively, the previously published method achieved a recall of 0.32 and a precision of 0.18 (F-score 0.23) on the same dataset, despite a good published performance on another dataset (0.86 recall, 0.72 precision and 0.78 F-score).

Conclusion: This study highlights two major challenges with developing methods of automatic recognition of adverse events in Twitter posts: (1) detecting and normalizing medicinal products and medical events is difficult in Twitter posts, most likely owing to the noisiness of the data [e.g. abbreviations, misspellings, slang and laymen expressions (TB1)], (2) the transferability of models outside the universe of the training data to external datasets is poor, despite the use of a training/validation/test setup. The latter difficulty is poorly understood and should be the object of more research, to investigate the true ability of AE recognition algorithms to harness social media data.

References:

• 1. Sarker A, Ginn R, Nikfarjam A, O’Connor K, Smith K, Jayaraman S, et al. Utilizing social media data for pharmacovigilance: A review. J Biomed Inform 2015;54:202–2

• 2. https://web-radr.eu/about-us/

• 3. Freifeld CC, Brownstein JS, Menone CM, Bao W, Filice R, Kass-Hout T, et al. Digital drug safety surveillance: monitoring pharmaceutical products in twitter. Drug Saf 2014;37:343–50

Disclosure of Interest: None declared.

113 ISoP18-1160 A Cross-Sectional Study of Product and Batch Traceability for Biologics in Clinical Practice and Adverse Drug Reaction Reporting in the United Kingdom

113.1 K. Klein¹, L. Hazell², P. Stolk¹, S. Shakir^*2

113.1.1 ¹Lygature, Utrecht, The Netherlands; ²Drug Safety Research Unit, Southampton, United Kingdom

Background/Introduction: Biological medical products (‘biologics’) are derived from living cells or organisms. Due to their complex molecular structures and sensitivity to changes in the manufacturing process, variations may exist between biologics with the same active substance from different manufactures (e.g. ‘biosimilars’) or between different batches of the same product. It is of vital importance that biologics are traceable by brand name and batch number when reporting an adverse drug reaction (ADR) but such product details are not always provided [1]. In a recent study in the Netherlands, the brand name was identifiable in 76% of ADR reports submitted for biologics, whereas only 5% contained a batch number [2]. Shortcomings in the recording and tracing of product and batch information in clinical practice are believed to be associated with the limited traceability of biologics found in ADR reports.

Objective/Aim: The UK BIO-TRAC study was initiated to assess the current status of traceability of brand names and batch numbers for (recombinant) biologics in UK clinical practice within the hospital setting and in the UK ADR reporting database (Yellow Card Scheme).

Methods: An on-line survey has been set up for hospital pharmacists in England to capture information on recording practices that contribute to the traceability of brand names and batch numbers for biologics in UK clinical practice and to gather the views and experiences of hospital pharmacists on current bottlenecks and how to improve the current systems. In addition, a comprehensive analysis of 9036 ADR reports for biologics submitted to the UK Yellow Card Scheme between 1st January 2009 and 30th September 2017 will be performed to assess the extent to which brand name or batch number details are included in these reports. This includes a stratified analysis by reporter type, therapeutic product classes, calendar year and other variables.

Results: The results of the UK BIO-TRAC study will be presented in the context of both objectives, the assessment of the recording practices for product specific details in routine clinical practice and the ADR data analysis of the MHRA Yellow Card database.

Conclusion: On completion, this study will provide important insights as to the traceability of biologics in the UK.

Disclaimer:

The study is conducted by DSRU Education and Research Ltd in collaboration with Lygature and is funded by a grant from ABPI. This study is based in part on data obtained under licence from the UK Medicines and Healthcare Products Regulatory Agency. However, the interpretation and conclusions contained in this study are those of the author’s alone.

References:

• 1. Directive 2010/84/EU of the European parliament and of the council of 15 December 2010, amending as regards pharmacovigilance, Directive 2001/83/EC on the Community code relating to medicinal products for human use. Available from: http://ec.europa.eu/health/files/eudralex/vol-1/dir_2010_84/dir_2010_84_en.pdf

• 2. Klein K, Scholl JHG, Vermeer NS, Broekmans AW, Van Puijenbroek EP, De Bruin ML, et al. Traceability of biologics in the Netherlands: an analysis of information-recording systems in clinical practice and spontaneous ADR reports. Drug Saf 2016;39:185–92

Disclosure of Interest: None declared.

114 ISoP18-1161 Online Availability of Regulatory Documents, Safety Information and Adverse Drug Reaction Reporting n African Countries

114.1 H. Dominicus^*1,2, J. Doua^2,3, T. Verstraeten^2,4

114.1.1 ¹Dominicus Medicus Consultancy, Voorburg, the Netherlands; ²Consortium for African Regulatory expertise Development, Voorburg, The Netherlands; ³Johnson & Johnson, Breda, The Netherlands; ⁴P-95, Heverlee, Belgium

Background/Introduction: All African countries, except one, have established a Drug Regulatory Authority (DRA); together with the African Medicines Regulatory Harmonisation Programme (AMRH), WHO and ISOP [1]. This is an important step. The Internet being the greatest source of information nowadays, it is important that stakeholders have online access to regulatory information, and that safety information can be reported and accessed online.

Objective/Aim: To assess the free accessibility of regulatory documents on DRAs websites; to assess the availability of online safety information; further to assess the possibility for adverse drug reaction (ADR) reporting online; and to delineate gaps and provide recommendations for regulatory measures.

Methods: All African countries are included. A checklist to collect data from each DRA for analysis was developed based on information from the Regulatory Resources for Africa, WHO and the New Partnership for Africa’s Development (NEPAD). Countries were assessed on the online availability (without logging-in) of documents on global drug regulatory legislation and regulations, pharmacovigilance (PV) guidelines, ADR reporting tools, safety communications, and SmPCs. Three investigators scrutinized the internet and completed the list for their part of countries and one of the others re-checked the other’s country data. In case of discrepancy, investigators reached consensus.

Results: For this review, DRA websites of 55 countries were found and assessed. Libya could not be assessed because none of the investigators could read Arabic. Documents on regulatory legislation in general are online accessible in 51% of the countries, pharmacovigilance guidelines in 31%. Of the websites, 27% provides ADR reporting online, and 24% publish online safety warnings (DHPCs and/or other communications). Some countries have limited or no online information. A list of registered products is accessible in 27%; only 1 country (2%) provides summaries of product characteristics.

Conclusion: Most countries do not have pharmacovigilance guidelines or ADR reporting options or safety information online. For the safe use of medicines, our advice is to at least facilitate the online reporting of adverse drug reactions, and to provide online safety information. A list of registered products could be a way to diminish wrong medicine use. Based on our results, African countries, NEPAD, ISOP, and WHO can decide on quick regulatory wins by ameliorating authorities’ websites.

References:

• 1. Ndomondo-Sigonda M, Miot J, Naidoo S, Dodoo A, Kaale E. Medicines regulation in Africa: current state and opportunities Pharm Med 2017;31:383–397

Disclosure of Interest: None declared.

115 ISoP18-1162 Ecstasy-Induced Hepatitis in a Young Adult

115.1 W. Kaabi¹, I. Hamza¹, F. Zgolli¹, S. ben Hammamia¹, N. Alaya¹, R. Daghfous^*1, S. El Aidli¹, S. Kastalli¹

115.1.1 ¹Service de recueil et d’analyses des effets indésirables des médicaments, Centre National de Pharmacovigilance, Tunis, Tunisia

Background/Introduction: Ecstasy (methylenedioxymethamphetamine, MDMA) is widespread drug among youngs. It is used as a recreational drug in festive settings for its stimulating and hallucinogenic properties. Hepatotoxicity is a rare side effect that can range from asymptomatic liver injury to acute hepatic failure.

Objective/Aim: We present a case of hepatotoxicity following exposure to MDMA with favorable clinical outcome.

Methods: This case was notified on March 13th, 2018 to Tunisian National Centre of Pharmacovigilance and validated by Daman et al. method of imputability.

Results: A 35-year old male patient with no medical history was referred to us for jaundice. He was a regular user of “Ecstasy” over 4 months. One week after the last use of “Ecstasy” he reported abdominal pain, nausea, vomiting, weakness and dark urine. Blood tests were as follows: aspartate aminotransferase (AST), 1771 U/L (reference range 10–37 U/L); alanine aminotransferase (ALT), 1301 U/L (10–40 U/L); alkaline phosphatase, 299 U/L (0–270 U/L); total bilirubin, 7.83 mg/dL (0.2–1 mg/dL); direct bilirubin, 7.54 mg/dL (0–0.3 mg/dL); prothrombin rate 45%. Liver enzymes and bilirubin levels were found to be extremely high (AST = 48 × normal, ALT = 33 × normal, and bilirubin = 8× normal). Viral, autoimmune, and metabolic causes were excluded. Serologic tests for hepatitis A, B, and C viruses were all negative. A diagnosis of ecstasy-induced toxic hepatitis was retained. The patient has recovered after a month and laboratory findings has returned to normal values.

Conclusion: Practitioners might need to be alert to the possible adverse events of ecstasy especially liver injury in young adults. Fulminant hepatic failure associated with MDMA has also been described and should warrant attention in case of hepatic failure in young people.

Disclosure of Interest: None declared.

116 ISoP18-1163 Ototoxic Adverse Drug Reactions: A Pharmacovigilance Study Using the Italian Spontaneous Reporting Database

116.1 M. A. Barbieri^*1, G. Cicala¹, P. M. Cutroneo², E. Mocciaro¹, L. Sottosanti³, F. Freni⁴, F. Galletti⁴, V. Arcoraci¹, E. Spina¹

116.1.1 ¹Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; ²Regional Pharmacovigilance Centre, University Hospital of Messina, Messina, Italy; ³Pharmacovigilance Office, Italian Medicines Agency, Rome, Italy; ⁴Department of Adult and Developmental Human Pathology “Gaetano Barresi”, University of Messina, Messina, Italy

Background/Introduction: Drug ototoxicity can be defined as a temporary or permanent hearing impairment that occurs after a pharmacological treatment [1]. The earliest documentation of ototoxicity regards antimalarials, non–steroidal antiinflammatory drugs, aminoglycosides and other antimicrobials, loop diuretics and antineoplastics [2]. Clinical trials are relevant to evaluate new drugs capable of being ototoxic [3–5]. Nevertheless, the frequency of ear adverse drug reactions (ADRs) and the safety profile of some therapeutic classes remain largely unclear.

Objective/Aim: To perform a descriptive analysis of ototoxic reports using the Italian Spontaneous Reporting System (SRS) Database and to detect any unexpected drug—related ear side effects.

Methods: This study included all reports having at least one ADR related to the System Organ Class (SOC) “ear and labyrinth disorders” recorded in SRS database up to December 31, 2017. All reports with ADRs including the following words “ear”, “hearing” or “auricular” not belonging to the selected SOC were considered. Reports with Preferred Terms (PT) ‘vertigo’ not associated with other auricular diseases were excluded from the analysis because vestibular vertigo could not be discerned from the central ones. Descriptive analyses were carried out to evaluate patient’s characteristics and drug—related variables of selected reports versus the rest of the SRS database. Subsequently, case/non—case method analysis was performed calculating the reporting odds ratio (ROR) as a measure of signals disproportionate reporting (SDRs).

Results: The analysis included 919 reports out of the 381.548 collected into the SRS database. The median age was higher for patients with ototoxic ADRs than for patients with other ADRs (59 vs. 57 years). Reports were almost equally distributed by sex. Overall, 27.2% of ototoxic reports regarded serious ADRs (n = 250). The median number of drugs had no effect in both settings. ADRs (PTs) mostly reported were tinnitus (38.9%) and hypoacusis (23.3%). Antineoplastic and immunomodulating agents and antiinfectives for systemic use were the most involved drugs (n = 260; 28.3% and n = 188; 20.5%, respectively). Among the most reported drugs (n > 20), statistically significantly higher ROR values were observed for antithrombotics, other antineoplastics, quinolones, plant alkaloids, antidepressants, macrolides, antiepileptics, immunostimulants and aminoglycosides.

Conclusion: This study has identified drugs that contributed to developing ototoxic ADRs. In some cases, pharmaceutical classes with significant ROR fully confirm what is reported in the product information while in other cases, they show ADRs whose frequency or causality is not exactly known. Therefore, additional analyses are necessary to better outline the safety profile of ear side effects.

References:

• 1. Yorgason JG, Fayad JN, Kalinec F. Understanding drug ototoxicity: molecular insights for prevention and clinical management. Expert Opin Drug Saf 2006;5:383–99

• 2. Schacht J1, Hawkins JE. Sketches of otohistory: part 11: ototoxicity: drug-induced hearing loss. Audiol Neurootol 2006;11:1–6

• 3. King KA, Brewer CC. Clinical trials, ototoxicity grading scales and the audiologist’s role in the therapeutic decision making. Int J Audiol 2017;23:1–10

• 4. Lanvers-Kaminsky C, Zehnhoff-Dinnesen AA, Parfitt R, Ciarimboli G. Drug-induced ototoxicity: mechanisms, pharmacogenetics, and protective strategies. Clin Pharmacol Ther 2017;101:491–500

• 5. Ganesan P, Schmiedge J, Manchaiah V, Swapna S, Dhandayutham S, Kothandaraman PP. Ototoxicity: a challenge in diagnosis and treatment. J Audiol Otol 2018;22(2):59–68

Disclosure of Interest: None declared.

117 ISoP18-1165 Social Media: the Battleground for Public Opinion on Medicines Safety

117.1 A. Hoegberg^*1

117.1.1 ¹Global Communications, Uppsala Monitoring Centre, Uppsala, Sweden

Background/Introduction: With 2.2 billion users on Facebook, the world’s largest social media platform, and considering the potential for rapid “viral” spread of information, social media has a huge potential to influence public opinion on various topics—particularly issues where opinions are easily polarised, such as recurring debates on the safety of vaccines and medicines. Social media is therefore increasingly important to health communication and to pharmacovigilance advocates.

Objective/Aim: The objective of this work is to outline the challenges faced by pharmacovigilance advocates and healthcare actors when using social media to address various aspects of medicines safety, such as improving the public’s understanding for the benefits and risks of medicines, fostering patient adherence and trust in health authorities, and enhancing adverse drug reaction reporting rates. This also includes the particular challenges posed by strong voices spreading messages that are counterproductive to the work of pharmacovigilance actors.

Methods: This work builds on a review of academic papers; on lectures previously given by the author on the topic of social media management for pharmacovigilance actors; and on observations of user behaviour on social media and of the efficacy of various types of social media messages.

Results: Social media is widely used to search for health information, and the information such searches generate may have a profound impact on the users’ perception of the health issue in question and inform their course of action [1]. Due to the self-publishing nature of social media, every user, whether private or organisational, have the opportunity to share and widely disseminate their messages. In effect, social media platforms can and are used as mouthpieces for the full spectra of voices present online, from healthcare authorities to laymen, from public health actors to anti-vaccine advocates, and every imaginable creed in between.

The traditional top–down model of information dissemination, which is employed by many health authorities, is ineffective on social media where audiences need to be actively engaged and listened to [2, 3].

Conclusion: Many health authorities are poorly equipped both in terms of crafting effective health messages on social media, and in terms of addressing rumors and inaccurate information circulating online. However, with the right insights into audience behavior and with strategies in place to foster trust in one’s own information, social media can be used to proactively build a knowledge-base of medicine safety, and as a vehicle for trustworthy and timely safety information in times of crises [4]. This has the potential to improve public health and to facilitate discussions about the benefits and risks of medicines—whether between individual healthcare providers and patients, or between authorities and the public—and to counteract the flow of inaccurate information that may be harmful to the bottom-line of medicines safety advocates.

References:

• 1. Orr D, et al. Social media as a platform for health-related public debates and discussions: the Polio vaccine on Facebook, Isr Health Policy Res 2016;5:34

• 2. Heldman AB, et al. Social media engagement and public health communication: implications for public health organizations being truly “social”. Public Health Rev 2013;35:13

• 3. Moorhead SA, et al. A New Dimension of Health Care: Systematic Review of the Uses, Benefits, and Limitations of social media for health communication. J Med Internet Res 2013;15:e85

• 4. Novillo-Ortiz D, Hernández-Pérez T, Social media in public health: an analysis of national health authorities and leading causes of death in Spanish-speaking Latin American and Caribbean countries BMC Med Inform Decis Mak 2017;17:16

Disclosure of Interest: None declared.

118 ISoP18-1166 Safety and Tolerability of Antipsychotic Drugs in Pediatric Patients: Data from an Ongoing Active Pharmacovigilance Study in Sicily

118.1 G. Cicala^*1, M.A. Barbieri¹, V. Santoro¹, A. Gagliano², E. Germanò², C. Tata³, V. Colucci⁴, F. Vanadia⁵, F. Drago⁵, C. Russo⁶, P. M. Cutroneo⁷, E. Spina^1,7

118.1.1 ¹Department of Clinical and Experimental Medicine, ²Department of Adult and Developmental Human Pathology “Gaetano Barresi”, University of Messina, Messina, Italy; ³Childhood and Adolescence Neuropsychiatry, Provincial Health Unit 8, Syracuse,Italy; ⁴Complex Operive Unit of Neurology for Mental Disabilities, I.R.C.C.S. Oasi Maria SS., Enna, ⁵Developmental Age Neuropsychiaetry, A.R.N.A.S Civico di Cristina Benfratelli, Palermo, Italy; ⁶Developmental Age Neuropsychiaetry, S. Marta and S. Venera Hospital, Catania, Italy; ⁷Regional Pharmacovigilance Centre, University Hospital of Messina, Messina, Italy

Background/Introduction: Antipsychotic drugs are increasingly used to treat a variety of psychiatric disorders in children and adolescents. However, these medications are frequently used outside of their therapeutic indications. For this reason, a higher level of attention regarding the safety and tolerability profile of these drugs is necessary.

Objective/Aim: To perform an integrated assessment of the risk and tolerability profile associated with the use of antipsychotic drugs (both typical and atypical) in pediatric patients, with a focus on the identification of suspected adverse drug reactions (ADRs).

Methods: Starting from April 2017 pediatric patients followed by 5 units of developmental age neuropsychiatry who initiated a treatment with at least an antipsychotic drug (ATC class N05A) where included into the study, regardless of diagnosis and concomitant administration of other drugs. Data relative to patient’s characteristics, therapy, use indications, clinical and laboratory examinations have been collected at the time of treatment initiation and regularly thereafter into a dedicated database.

Results: To date, 129 patients (84 males and 45 females, mean age ± SD of 13.6 ± 3.4 years) were enrolled into the study, 99 (76.7%) of them were assisted asoutpatients, 25 (19.4%) as inpatients and 5 (3.8%) in day care regimen. Fifty-six patients were initially treated with risperidone, 46 with aripiprazole, 10 with olanzapine, 5 with clozapine, 3 with levomepromazine, 3 with quetiapine, 3 with haloperidol, 1 with asenapine, 1 with clotiapine and 1 with periciazine. The most represented diagnoses, classified according to the ICD10, were: attention-deficit hyperactivity disorder (n = 31), autistic disorder (n = 30), mild intellectual disabilities (n = 16), Tourette’s disorder (n = 14), oppositional defiant disorder (n = 13) and obsessive–compulsive disorder (n = 12). In total, we observed 207 ADRs with the most frequent being weight increase (n = 31), hyperfagia (n = 21), hyperprolactinemia (n = 17) and hypercholesterolaemia (n = 14). Among the 48 cases of ADR reported into the Italian pharmacovigilance network only 7 (14.6%) were serious and were represented by elevated creatinine phosphokinase (n = 2), QTc interval prolongation (n = 2), dystonia (n = 1), leucopenia (n = 1) and hyperprolactinemia (n = 1).

Conclusion: These preliminary datatrace a safety profile for antipsychotics in pediatric patients similar to the one already laid down for adults. However, more data are necessary in order to evaluate risk and tolerability of these drugs when used in pediatric patients.

Disclosure of Interest: None declared.

119 ISoP18-1167 Hepatic Adverse Drug Reactions Associated with Methylprednisolone: Analysis of the French Pharmacovigilance Database

119.1 J. Cottin¹, S. Pierre^*1, V. Pizzoglio¹, C. Simon², G. Durieu³, A. Gouraud¹, B. Kassaï-koupaï¹, J. Dumortier⁴

119.1.1 ¹Centre Régional de Pharmacovigilance, Service Hospitalo-universitaire de Pharmacotoxicologie, Hospices Civils de Lyon, CHU-Lyon, Lyon, France; ²Service de Pharmacosurveillance, Centre Régional de Pharmacovigilance, CHRU Tours, Tours, France; ³Service de Pharmacologie Médicale et Clinique, Centre Midi-Pyrénées de Pharmacovigilance, Pharmacoépidémiologie et Informations sur le Médicament, Pharmacopôle Centre Hospitalier Universitaire et Faculté de Médecine de Toulouse, Toulouse, France; ⁴Service d’Hépato-Gastro-Entérologie, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France

Background/Introduction: Hepatotoxicity associated with methylprednisolone (MP) is rarely described with only few case-reports in the literature [1].

Objective/Aim: Our aim was to review the characteristics of acute hepatic disorders associated with intravenous (IV) or oral MP administration and registered in the French pharmacovigilance database (FPD) since 1985.

Methods: All cases with MP coded as suspected, concomitant or interacting drug associated with hepatic disorders and reported up to May 2016 were extracted from the FPD. “Drug related hepatic disorders” cases were defined using the Standard Medical Query (SMQ).

Results: After exclusion of 317 poorly informative cases and cases more probably related to another drug or non-drug cause, 97 cases of hepatic disorders associated with MP were analyzed. 58.8% (57/97) of patients were women with a median age of 46 years (1–91 years). MP was used for an autoimmune disease in 47.6% (46/97) of cases which including 27% cases of multiple sclerosis. MP was given intravenously in 79.4%. 72.2% of patients had a hepatocellular type of injury with a severity mainly evaluated as mild (45%) or moderate (31%). For 40 patients (52%) liver injury occurred after MP discontinuation. In these cases the median time to onset of the liver injury after the last MP administration was 12.5 days (range 1–191 days). The median cumulative MP dose was 2 g (range 0.06–42.7 g). Most patients (92%) spontaneously and fully recovered within an average of 38.4 days. A rechallenge using the IV route was performed in 13 patients and 10 (76.9%) of them experienced single or multiple positive recurrence of liver injury, which is in favor of MP responsibility. In all of these cases, the initial type of injury was hepatocellular. Regarding IV route of administration (n = 77), MP was coded as the only suspected drug in 22% of cases.

Conclusion: Our results suggest that intravenous MP responsibility should be considered in case of acute liver injury. By contrast, data on oral MP (n = 20) are generally insufficient to conclude and the evidence of a link is not compelling. The EU summary of product characteristics will be updated soon and specialists should consider this potential adverse reaction even if it occurs several weeks after MP discontinuation.

References:

• 1. Davidov Y, Har-Noy O, Pappo O, Achiron A, Dolev M, Ben-Ari Z. Methylprednisolone-induced liver injury: case report and literature review. J Dig Dis 2016;17:55-62

Disclosure of Interest: None declared.

120 ISoP18-1169 The Impact of Sex on the Associations Between Ace Inhibitors and Cough and Angioedema: A Systematic Review and Meta-Analysis

120.1 O. Klungel¹, F. Alharbi^*1, A. de Boer¹, A. Kholod¹

120.1.1 ¹Pharmacoepidemiology & Clinical Pharmacology, Universiteit Utrecht, Utrecht, the Netherlands

Background/Introduction: Cough and angioedema are well-known adverse effects of angiotensin-converting enzyme (ACE) inhibitors. Some observational studies in patients using ACE inhibitors have observed that women have a higher incidence of cough and angioedema than men.

Objective/Aim: To evaluate based on randomized controlled trials (RCTs), whether the risks of developing cough and angioedema with ACE inhibitors are modified by sex.

Methods: We searched PubMed and Cochrane databases for all years to August 2016. We included RCTs that contain information about the incidence of cough and angioedema in users of ACE inhibitors and controls (active/placebo) in men and women. We performed meta-analyses using the random effects model. Pooled risk ratios (RRs) for cough and angioedema associated with ACE inhibitors in women and men were estimated and tested for interaction.

Results: We included four RCTs in our analysis (three studies for cough and two studies for angioedema). We found that there was no difference in the RR to develop cough or angioedema for ACE inhibitors versus controls between women and men. For cough in women, the RR was 3.70; 95%CI (2.55–5.35) and for men, 2.61; 95%CI (1.30–5.27) (P value for interaction 0.39). For angioedema, these RRs were 5.56; 95%CI (2.45–12.62) and 6.35; 95%CI (1.81–22.36), respectively (P value for interaction 0.86).

Conclusion: Our meta-analyses show that the risks of developing cough and angioedema associated with ACE inhibitors are not modified by sex. However, these findings should be interpreted cautiously due to limited number of studies involved.

Disclosure of Interest: O. Klungel Grant/Research support from: GSK HTA methodology grant, Other: Educational lecture on unobserved confounding for Roche, F. Alharbi: None declared, A. de Boer: None declared, A. Kholod: None declared.

121 ISoP18-1170 Abciximab-Induced Delayed Thrombocytopenia: Case Analysis in the French Pharmacovigilance Database

121.1 A. Maurier^*1, S. Delepine², A. Lillo-Le Louët³, A. Grandvuillemin⁴, G. Drablier¹, L. Lagarce¹, M. Briet¹, D. Bourneau-Martin¹

121.1.1 ¹Regional Center of Pharmacovigilance of Angers, France; ²Cardiology Department, CHU Angers, Angers, France; ³Regional Center of Pharmacovigilance of Paris, Hopital Européen Georges Pompidou, Paris, France; ⁴Regional Center of Pharmacovigilance of Dijon, CHU Dijon, Dijon, France

Background/Introduction: Abciximab (ABX) is a chimeric monoclonal antibody Fab fragment, blocking the platelet receptor glycoprotein IIb/IIIa, used as antithrombotic therapy during percutaneous coronary intervention. The most common adverse effects are bleeding and thrombocytopenia. If most cases of thrombocytopenia occur within a few hours after ABX, delayed thrombocytopenia (3–6 days after ABX discontinuation) is described in the literature but not in its monography; this may wrongly incriminate others etiologies.

Objective/Aim: Case description of delayed thrombocytopenia with ABX from the French PharmacoVigilance Database (FPVD).

Methods: A query of FPVD was performed with the following criterias: ABX single suspected drug, thrombocytopenia with onset delay over 3 days. Each case was analyzed separately according to the good pharmacovigilance practices.

Results: In the FPVD, among 292 cases of thrombocytopenia with ABX, we extracted 43 cases of delayed thrombocytopenia. Patients studied (32 men and 11 women) were aged 35–87 years (median 58 years). The mean time of onset for thrombocytopenia was 8.2 ± 2.1 days (median 8 days, range 3–15 days) and the mean time of improvement was 5.1 ± 2.7 days (median 5 days, range 1–14 days). Eight cases were not serious and 35 were considered serious (30 hospitalizations, 4 life threatening, 1 medically significant situation). Two patients had hemorrhagic signs (epistaxis and purpura). When the data were known (n = 27), 16 of these thrombocytopenia were grade IV (< 25 G/L), 5 grade III (25–49 G/L), 5 grade II (50–74 G/L) and 1 grade I (75–99 G/L). The median platelet nadir was 19 G/L (range 1–78 G/L) and a platelet transfusion was realized only for 5 patients, (median platelet nadir 5 G/L, range 1–11 G/L), regarding the thrombotic risk context. Among the 43 cases, thrombocytopenia recovered totally or partially in 38 patients. For 8 patients, the diagnosis of delayed thrombocytopenia with ABX was made after detection of anti-complex (ABX-platelet) antibodies.

Conclusion: Several cases of ABX-induced delayed thrombocytopenia are reported in the literature [1–6]. The median onset delay is 7 days (range 3–17 days) and the median time of improvement is 4 days (range 2–7 days) which is concordant with our results. In some cases, treatment was initiated with platelet transfusion, infusion of corticosteroids and/or intravenous immunoglobulin, which does not seem to be the majority of our study’s cases. More than half of the cases manifested hemorrhagic signs, including 1 fatal outcome with cerebral hemorrhage, while in our study 5% of the cases presented bleeding complications (no death). As in the literature, thrombocytopenias reported in the FPVD were mainly severe (grade III/IV). Anti-complex (ABX-platelet) antibodies were identified in FPVD and in literature. The pharmacological mechanism underlying the occurrence of thrombocytopenia with ABX is not well established, but may be immune-mediated. These anti ABX-platelets antibodies may be specific for murine peptide sequences in ABX [5]. In conclusion, physicians administering ABX should be aware of this severe but reversible complication, which may occur at home, and should monitor a platelet control 1 and 2 weeks after hospital discharge, even if it was well tolerated previously [3]. This study underlines the importance of pharmacovigilance investigations with the realization of the medical history.

References:

• 1. Jbara M, Bhogal S, Bajaj K. Abciximab-induced delayed profound thrombocytopaenia. BMJ Case Rep 2017; https://doi.org/10.1136/bcr-2017-219379. (abstract only)

• 2. Giupponi L, Cantoni S, Morici N. Delayed, severe thrombocytemia after abciximab infusion for primary angioplasty in acute coronary syndromes: Moving between systemic bleeding and stent thrombosis. Platelets 2015;26:498–500

• 3. Rasti M, Blostein M. Delayed immune-mediated thrombocytopenia after re-exposure to abciximab therapy. Can J Cardiol 2011;27:869.e13–e14

• 4. McCorry RB, Johnston P. Fatal delayed thrombocytopenia following abciximab therapy. J Invasive Cardiol 2006;18:e173–4.

• 5. Curtis BR, Divgi A, Garritty M and Aster. Delayed thrombocytopenia after treatment with abciximab: a distinct clinical entity associated with the immune response to the drug. J Thromb Haemost 2004;2:985–92

• 6. Jenkins LA, Lau S, Crawford M. Delayed profound thrombocytopenia after c7E3 Fab (abciximab) therapy. Circulation 1998;97:1214-5.

Disclosure of Interest: None declared.

122 ISoP18-1171 Cox Selectivity and Chemical Subgroup of Non-steroidal Anti-inflammatory Drugs and Frequency of Spontaneous Reporting of Hypersensitivity Reactions

122.1 O. Klungel^*1, M. Bakhriansyah¹, R. Meijboom¹, P. Souverein¹, A. de Boer¹

122.1.1 ¹Pharmacoepidemiology & Clinical Pharmacology, Universiteit Utrecht, Utrecht, The Netherlands

Background/Introduction: Use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with many adverse events, including hypersensitivity reactions (HSRs), such as angioedema and urticaria. However, no studies have investigated whether cyclooxygenase (COX) enzyme selectivity and/or chemical subgroups are associated with a difference in HSRs.

Objective/Aim: to describe and compare the frequency of HSRs among NSAIDs based on cyclooxygenase selectivity and chemical subgroups.

Methods: A case/non-case study was performed using data from the World Health Organization global database of Individual Case Safety Report (ICSR), VigiBase, containing over 13 million ICSRs submitted by the participating member states enrolled under WHO’s international drug monitoring program by June 2016. This study was nested among ICSRs where NSAIDs were a suspected drug. Cases were ICSRs mentioning HSRs (urticaria, angioedema, anaphylactic shock, anaphylactic reaction, anaphylactoid shock, and anaphylactoid reaction), whereas non-cases were all ICSRs without HSRs. Based on the ratio of inhibitory concentration 80% of COX-1/COX-2, NSAIDs were categorized into coxibs, non-coxib NSAIDs with COX-2 preference, NSAIDs with poor selectivity, and NSAIDs with unknown selectivity. Only ICSRs with complete information on age and sex, and NSAIDs with first market authorization from 1978 onward were included. RORs and 95% confidence intervals (95% CIs) to assess the association between NSAIDs and the reporting of HSRs were calculated using logistic regression analysis.

Results: We identified 16,289 HSR cases and 160,319 non-cases among ICSRs involving NSAIDs. Non-coxib NSAIDs with COX-2 preference, NSAIDs with poor selectivity, and NSAIDs with unknown selectivity were all associated with an increased reporting of HSRs (age- and sex-adjusted ROR 1.70, 95% CI 1.61–1.79, age- and sex-adjusted 2.19, 95% CI 2.11–2.77, and age- and sex-adjusted 1.26, 95% CI: 1.03–1.54, respectively) compared to coxibs.

Conclusion: HSRs were more often reported for NSAIDs with poor selectivity, non-coxib NSAID with COX-2 preference, and NSAIDs with unknown selectivity compared to coxibs.

Disclosure of Interest: O. Klungel Grant/Research support from: GSK HTA methodology research, Other: Educational lecture on unobserved confounding for Roche, M. Bakhriansyah: None declared, R. Meijboom: None declared, P. Souverein: None declared, A. de Boer: None declared.

123 ISoP18-1172 The Impact of Antihypertensive Drugs on Serum Potassium and Sodium Levels in Patients Electively Admitted to a Tertiary Hospital

123.1 O. Klungel^*1, P. Cornu², F. Alharbi¹, M. de Groot³, A. Dupont², J. Weyler⁴

123.1.1 ¹Pharmacoepidemiology & Clinical Pharmacology, Universiteit Utrecht, Utrecht, The Netherlands; ²Research Group Clinical Pharmacology & Clinical Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium; ³Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands; ⁴Epidemiology & Social Medicine, University of Antwerp, Antwerp, Belgium

Background/Introduction: Abnormal serum potassium and sodium levels may lead to serious cardiovascular and neurological conditions.

Objective/Aim: To investigate the association between the use of different antihypertensives and the risk of developing disturbances in potassium and sodium serum levels.

Methods: A cross-sectional study was conducted in antihypertensive users, electively admitted to the University Medical Center Utrecht between January 2013 and September 2016. Data on patient characteristics, antihypertensives, and electrolyte levels where extracted from the Utrecht Patient Oriented Database. The association between the use of different antihypertensives and the electrolyte level was studied using linear and logistic regression.

Results: A total of 6369 elective admissions were included in this study. The most frequent electrolyte disorder was hyponatremia (29.5%), followed by hypokalemia (20.5%). Hyperkalemia (3.4%) and especially hypernatremia (0.1%) were less common. In comparison to the use of monotherapy of beta-blockers, use of monotherapy of calcium antagonists (adj. OR 3.08; 95% CI 2.13, 4.46), thiazide or thiazide-like (adj. OR 2.08; 95% CI 1.14, 3.82) and loop diuretics (adj. OR 1.92; 95% CI 1.13, 3.28) was significantly associated with higher odds of hypokalemia. Most combinations of antihypertensives with thiazide or thiazide-like or loop diuretics were significantly associated with lower potassium serum levels compared to monotherapy of beta-blockers. None of the antihypertensive therapies were significantly associated with hyperkalemia. Monotherapy of potassium sparing diuretics (adj. OR 2.72; 95% CI 1.11, 6.66) and angiotensin receptor blockers (adj. OR 1.63; 95% CI 1.01, 2.63), and some of the combinations with a thiazide or thiazide-like or loop diuretic were significantly associated with higher odds of hyponatremia.

Conclusion: Monitoring of serum potassium and sodium levels should be encouraged in patients with antihypertensive drugs especially antihypertensives inducing hyponatremia or hypokalemia to avoid possible severe consequences of abnormal serum potassium and sodium levels.

Disclosure of Interest: O. Klungel Grant/Research support from: GSK HTA methodology research, Other: Educational lecture on unobserved confounding for Roche, P. Cornu: None declared, F. Alharbi: None Declared, M. de Groot: None declared, A. Dupont: None Declared, J. Weyler: None declared.

124 ISoP18-1173 Vaccine Safety Surveillance in Pregnancy Using Gaia Definitions for Neonatal Conditions: A Feasibility Assessment in Low- and Middle-Income Countries

124.1 A. L. Stuurman^*1, M. Riera ¹, S. Lamprianou ², S. Perez-Vilar ³, S. A. Anderson ³, P. Mangtani ⁴, H. Devlieger ⁵, T. Verstraeten¹, P. Zuber ², C. Guillard Maure ²

124.1.1 ¹P95 Epidemiology and Pharmacovigilance Consulting and Services, Leuven, Belgium; ²Department of Essential Medicines and Health Products, World Health Organization, Geneva, Switzerland; ³Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, United States; ⁴Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom; ⁵Department of Development and Regeneration, KU Leuven, Leuven, Belgium

Background/Introduction: Global efforts to adequately monitor the safety of new vaccines targeted for use by pregnant women in low and middle-income countries (LMICs) are needed. The Global Alignment of Immunization Safety Assessment in pregnancy project (GAIA) recently published case definitions based on levels of diagnostic certainty for pregnancy and neonatal outcomes and maternal immunization.

Objective/Aim: As a preliminary step to evaluate the applicability of the GAIA case definitions in LMICs, we aimed to select candidate sites and conduct a feasibility assessment to evaluate their ability to identify selected neonatal outcomes [preterm birth, neonatal death, neonatal invasive bloodstream infection (NI-BSI), stillbirth] and the maternal immunization status, with sufficient information to enable their classification by level of diagnostic certainty. The long-term goal of this work is to assess the feasibility of conducting well-designed collaborative observational studies to monitor the safety of new vaccines targeted for use in pregnant women in LMICs as part of the WHO Global Vaccine Safety Initiative.

Methods: Candidate sites were initially screened using a questionnaire. For each neonatal outcome, screened sites were asked to retrospectively identify and collect information for up to three individuals born in 2016. Sites were selected to participate in the MCCS if at least one subject per outcome could be assessed for diagnostic certainty using the GAIA definitions, demonstrating minimum diagnostic capacity and data access. Feedback on the data collection process was collected.

Results: Fifty sites were screened and 32 participated in the feasibility assessment. Twenty-four sites that identified at least one case per outcome were eventually selected. The majority (80%) of preterm births, neonatal deaths, and NI-BSI subjects, but only 50% of stillbirths, could be assessed for diagnostic certainty. The main reasons for cases not being classified as stillbirths were insufficient information to distinguish between antepartum and intrapartum stillbirth (29%) and that level of diagnostic certainty was not the same across all data elements provided (35%). Vaccination status could be assessed in 56% of mothers, with 49% considered vaccinated and 6% not-vaccinated. Sites indicated that retrospective subject identification restricted ascertainment of maternal immunization status and was resource-intensive due to the need to manually search archives.

Conclusion: GAIA case definitions for four neonatal outcomes and maternal immunization were successfully piloted in 24 sentinel sites across four WHO regions. The modification of the GAIA stillbirth definition could help avoid potential misclassification in LMICs. Vaccine safety monitoring in LMICs will benefit from systematic recording of all immunizations administered during pregnancy.

Disclosure of Interest: None declared.

125 ISoP18-1174 A Comparison of Safety-Related Label Changes for Medicines With and Without Major Objections at Time of Marketing Authorisation

125.1 L. Bloem^*1,2, M. Karomi¹, J. Hoekman³, H. Leufkens¹, O. Klungel^1,4, A. Mantel-Teeuwisse¹

125.1.1 ¹Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands; ²Dutch Medicines Evaluation Board, Utrecht, The Netherlands; ³Innovation Studies, Copernicus Institute of Sustainable Development, Utrecht University, The Netherlands; ⁴Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands

Background/Introduction: Previous research identified several product- and procedure-related factors associated with safety-related label changes, but none of these studies focused on concerns expressed during the marketing authorisation (MA) process of medicines. During this process, the European Medicines Agency (EMA) may raise major objections regarding clinical study data. We hypothesise that these are associated with more safety-related label changes post-approval.

Objective/Aim: To associate safety-related label changes with presence of major objections regarding phase III data at MA.

Methods: We performed a retrospective cohort study of innovative medicines that were approved by the EMA in 2009 and 2010, excluding influenza vaccines. For these medicines, we identified changes to all clinical sections of the label during the drug life cycle, i.e., between MA and 31 Oct 2017. We assessed whether changes were efficacy- or safety-related and whether they had a positive or negative impact on the benefit–risk. Major objections regarding phase III data at MA were identified in a previous study [1]. Label changes were extracted from the history of procedural steps available in European Public Assessment Reports. For the sections concerning warnings and precautions (section 4.4) and undesirable effects (section 4.8), we calculated the median number of label changes and interquartile ranges (IQRs) and compared their distribution between medicines with and without major objections at time of MA using the Wilcoxon Rank Sum test.

Results: We identified 40 medicines. Of these, the EMA raised major objections regarding phase III data for 23 medicines and they did not for 17. For the 40 medicines overall, we identified 503 changes to the clinical sections of the label, of which 66 (13%) were efficacy-related and 194 (39%) were safety-related. The remaining 243 changes mostly concerned risk management and study results that did not impact the benefit–risk. Of the 194 safety-related changes, 55 (28%) concerned the warnings and precautions section (n = 52 with negative impact) and 114 (59%) the undesirable effects section (n = 112 with negative impact). Their distribution did not differ between medicines with and without major objections at time of MA (Table 1). The results did not change when we omitted safety-related changes with a positive impact on the benefit–risk from the analysis. Furthermore, of 42 label changes concerning risk management, 28 (67%) concerned the warnings and precautions section, and none the undesirable effects section.

Conclusion: During a 7–9 year follow-up period, more safety-related than efficacy-related label changes occurred for innovative medicines approved by the EMA. Safety-related changes to the warnings and precautions section and the undesirable effects section do not seem to be associated with the presence of major objections regarding phase III data at MA. This may indicate that potential risks associated with these objections were adequately minimised peri or post-approval.

References:

1. Putzeist M, Mantel-Teeuwisse AK, Aronsson B, Rowland M, Gispen-de Wied CC, Vamvakas S, et al. Factors influencing non-approval of new drugs in Europe. Nat Rev Drug Discov 2012;11:903–4

Disclosure of Interest: None declared.

126 ISoP18-1175 Weight Change After Anti-psychotic Drug Treatment: Long-Term Evidence from a Retrospective Study Using Electronic Health Records

126.1 J.C. Bazo-Alvarez^*1,2, I. Petersen¹, T. Morris³, J. Carpenter^3,4

126.1.1 ¹Department of Primary Care and Population Health, University College London, London, United Kingdom; ²Instituto de Investigacion, Universidad Catolica Los Angeles de Chimbote, Chimbote, Peru; ³MRC Clinical Trials Unit, University College London, United Kingdom; ⁴Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, United Kingdom

Background/Introduction: Immediate weight gain, approximately over the first 6 weeks, is a known problem among patients treated with antipsychotic drugs. However, further evaluation over long term periods is needed, especially from real-life contexts. Electronic health records, such those routinely obtained in general medical practice, are useful sources for obtaining this kind of information.

Objective/Aim: Our main aim was to compare weight change 4 years before and 4 years after initiation of antipsychotic drug treatment, analysing men and women separately.

Methods: The study sample comes from The Health Improvement Network (THIN), a large UK primary care database from which we observed patients with a diagnosed psychotic disorder, between 2005 and 2015. Three retrospective cohorts where constructed, one per drug treatment: Olanzapine, Quetiapine and Risperidone. We modelled weight change over time using linear splines with random effect models, from which three slopes of weight change were estimated for: (i) − 4 years to baseline (pre-treatment), (ii) baseline to + 6 weeks (short-term), (iii) + 6 weeks to + 4 years (long-term).

Results: Results showed that pre-treatment weight change was null for Quetiapine (males and females) and Risperidone (males) cohorts, and slightly negative for the rest of groups. Conversely, all drugs were significantly associated with weight gain after treatment initiation, especially Olanzapine. Using Olanzapine, the short-term weight gain for males was 0.54 kg/week whereas for females was 0.37 kg/week. Later, the long-term weight gain for males was 0.007 kg/week whereas for females was 0.013 kg/week. Women consuming Quetiapine were more affected than men, in both the short and long term. In contrast, men consuming Risperidone were slightly more affected than women.

Conclusion: Although the average weight gain per week for long-term is minor than for short-term, it is continual, so patients do not lose the weight they have gained during the first 6 weeks of treatment. Differences in how women and men weights are affected by these antipsychotics can inform decisions to prescribe. Our next research will be focused on the effect of different doses and exposure periods on weight gain, in similar populations.

Disclosure of Interest: None declared.

127 ISoP18-1176 Antihypertensives Prescribed for Pregnant Women in Japan: Prevalence and Timing Determined from a Database of Health Insurance Claims

127.1 T. Ishikawa^*1, T. Obara^2,3,4, H. Nishigori^3,5, K. Miyakoda⁴, M. Ishikuro^3,4, H. Metoki^4,6, T. Ohkubo⁷, J. Sugawara^4,5, N. Yaegashi^3,4,5, M. Akazawa⁸, S. Kuriyama^3,4,9, N. Mano^1,2

127.1.1 ¹Laboratory of Clinical Pharmacy, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan; ²Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan; ³Environment and Genome Research Center, Tohoku University Graduate School of Medicine, Sendai, Japan; ⁴Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan; ⁵Department of Gynecology and Obstetrics, Tohoku University Graduate School of Medicine, Sendai, Japan; ⁶Division of Public Health, Hygiene and Epidemiology, Tohoku Medical and Pharmaceutical University Faculty of Medicine, Sendai, Japan; ⁷Department of Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan; ⁸Department of Public Health and Epidemiology, Meiji Pharmaceutical University, Tokyo, Japan; ⁹International Research Institute for Disaster Science, Tohoku University, Sendai, Japan

Background/Introduction: Hypertensive disorder of pregnancy is one of the most common medical complications that arise during pregnancy. Thus, treatment with antihypertensive agents is common [1–4]. Due to potential fetal adverse outcomes of drug exposure, the potential toxicity of antihypertensives to the fetus is important to determine. However, little is known about prescribing antihypertensive agents to pregnant women in Japan.

Objective/Aim: To evaluate the status of prescriptions for antihypertensives primarily during pregnancy, and also before and after pregnancy using a large claims database in Japan.

Methods: We extracted data from a large database of health insurance claims. Dates for the pregnancy onset and delivery were identified from the database using reported algorithms [5]. We also determined birth month and year from the database. The prevalence and timing of prescribed antihypertensives during pregnancy were descriptively evaluated. Time trends of prescriptions for antihypertensives were evaluated using multivariate logistic regression analyses. The prevalence of prescribed antihypertensives was evaluated for 180 days before pregnancy and 180 days postpartum among pregnant women who were members of the health insurance societies during the entire period.

Results: At least one antihypertensive agent was prescribed for 1144 of 41,694 pregnant women (274 per 10,000 deliveries), including 715 (171) and 605 (145) who were prescribed with oral and injectable antihypertensives. At least one antihypertensive was prescribed for 95 (23), 146 (35) and 1055 (253) women during the first, second and third trimesters, respectively. The most frequently prescribed oral antihypertensive during pregnancy was nifedipine (67), followed by methyldopa (66), hydralazine (36) and furosemide (19). Renin inhibitors, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers were prescribed for 1, 2 and 19 pregnant women, respectively. Nicardipine was the most frequently prescribed injectable antihypertensive during pregnancy (62), followed by furosemide (48), hydralazine (20) and nitroglycerin (19). Yearly prescription trends remained similar except for a significant decrease in prescriptions for oral and injectable furosemide (both P < 0.001) and an annual increase in organic nitrate prescriptions (P = 0.0011). Based on an evaluation of 33,942 pregnant women, the number of prescriptions for antihypertensives increased particularly during the third trimester, and then decreased from 91 to 180 days postpartum.

Conclusion: Various types of antihypertensives are prescribed for Japanese pregnant women. The effects of exposing pregnant Japanese women to these agents should be evaluated.

References:

• 1. Takagi K, Yamasaki M, Nakamoto O, Saito S, Suzuki H, Seki H et al. A review of best practice guide 2015 for care and treatment of hypertension in pregnancy. Hypertens Res Pregnancy 2015;3:65–103

• 2. Shimamoto K, Ando K, Fujita T, Hasebe N, Higaki J, Horiuchi M et al. The Japanese Society of Hypertension guidelines for the management of hypertension (JSH 2014). Hypertens Res 2014;37:253–390

• 3. Cea Soriano L, Bateman BT, García Rodríguez LA, Hernández-Díaz S. Prescription of antihypertensive medications during pregnancy in the UK. Pharmacoepidemiol Drug Saf 2014;23:1051–8

• 4. Bateman BT, Hernandez-Diaz S, Huybrechts KF, Palmsten K, Mogun H, Ecker JL et al. Patterns of outpatient antihypertensive medication use during pregnancy in a Medicaid population. Hypertension 2012;60:913–20

• 5. Ishikawa T, Obara T, Nishigori H, Miyakoda K, Inoue R, Hoshiai T et al. Development of algorithms to determine the onset of pregnancy and delivery date using healthcare administrative data in a university hospital in Japan. Pharmacoepidemiol Drug Saf 2018 (in press). https://doi.org/10.1002/pds.4444. [Epub ahead of print]

Disclosure of Interest: T. Ishikawa Employee of: Pfizer Japan, T. Obara: None declared, H. Nishigori: None declared, K. Miyakoda: None declared, M. Ishikuro: None declared, H. Metoki: None declared, T. Ohkubo: None declared, J. Sugawara: None declared, N. Yaegashi: None Declared, M. Akazawa: None declared, S. Kuriyama: None Declared, N. Mano: None declared.

128 ISoP18-1177 A Review of Benefit–Risk Assessment Over the Product Lifecycle

128.1 M. Miljkovic^*1, C. Bielen², M. Simic-Koumoutsaris³, A. Urakpo⁴

128.1.1 ¹Medical Department, PrimeVigilance, Belgrade, Serbia; ²Medical Depertment, PrimeVigilance, Zagreb, Croatia; ³PrimeVigilance, Guildford, United Kingdom; ⁴Medical Department, PrimeVigilance, Guildford, United Kingdom

Background/Introduction: The assessment of a medicinal product, which evaluates the product’s benefits and risks, is at the heart of drug approval decisions [1]. Benefit–risk assessment (BRA) is a valuable tool that takes place in multiple stages during a medicine’s lifecycle, and this assessment can be conducted in a variety of ways [1–3].

Objective/Aim: The aim was to summarize current BRA methods used during approval decisions and in post-approval settings, and to see possible future directions.

Methods: Relevant reviews, recommendations and guidelines published in medical literature and through regulatory agencies over the past 5 years [3–6] have been examined.

Results: The benefit–risk profile of a drug is dynamic and differs for different indications and patient groups. BRA implies the review of two dimensions: the dimension of benefits (determined mainly by the therapeutic efficacy) and the dimension of risks (comprises the safety profile of a drug). Regulators, industry and academia have developed various approaches, ranging from descriptive textual (qualitative) to decision-analytic (quantitative) models, to facilitate the BRA of medicines during the product lifecycle (from Phase I trials, to authorization procedure, post-marketing surveillance and health technology assessment for inclusion in public formularies). These approaches can be grouped into frameworks which are stepwise structured approaches; metrics which are measures for benefits and risks (usually endpoint specific), estimation techniques such as simulation techniques and meta-analysis, and utility survey techniques to elicit stakeholders’ preferences (utilities). All these approaches share the following two common goals: to assist this analysis and to improve the communication of decisions, but each is subject to its own specific strengths and limitations. Before using any method, its utility, complexity, the extent to which it is established, and the ease of results interpretation should be considered. Despite widespread and long-time use, BRA is subject to debate, suffers from a number of limitations, and currently is still under development.

Conclusion: The use of formal, systematic structured approaches to BRA for regulatory decision-making and quantitative methods to support BRA during the product lifecycle is a standard practice in medicine that is subject to continuous improvement and modernization, not only in methodology but also in cooperation between organizations.

References:

• 1. McAuslane N, Leong J, Liberti L, Walker S. The benefit–risk assessment of medicines: experience of a consortium of medium-sized regulatory authorities. Ther Innov Regul Sci 2017;51:635–44

• 2. Pignatti, F, Ashby, D, Brass, EP. Structured frameworks to increase the transparency of the assessment of benefits and risks of medicines: current status and possible future directions. Clin Pharmacol Ther 2015;98:522–33

• 3. Hallgreen CE, Mt-Isa S, Lieftucht A, et al. (PROTECT Benefit–Risk group). Literature review of visual representation of the results of benefit–risk assessments of medicinal products. Pharmaco-epidemiology and Drug Safety, 2016;25(3):238–250

• 4. Hughes D, Waddingham E, Mt-Isa S, et al. Recommendations for benefit–risk assessment methodologies and visual representations. Pharmacoepidemiol Drug Saf 2016;25:251–62

• 5. Hallgreen CE, van den Ham HA, Mt-Isa S, et al. Benefit–risk assessment in a post-market setting: a case study integrating real-life experience into benefit–risk methodology. Pharmacoepidemiol Drug Saf. 2014; 23:974-83

• 6. James Leong, Stuart Walker, and Sam Salek. A practical approach to communicating benefit–risk decisions of medicines to stakeholders. Front Pharmacol. 2015;6:1–9

Disclosure of Interest: None declared.

129 ISoP18-1178 Cognitive Patterns in Pharmacovigilance Assessments

129.1 D. Sartori¹, B. Grundmark^*1,2, J. Ellenius¹

129.1.1 ¹Uppsala Monitoring Centre, Uppsala, Sweden; ²Department of Surgery, Uppsala University, Uppsala, Sweden

Background/Introduction: Assessments of pharmacovigilance case report series of drug-event combinations (DECs), have historically been carried out by experienced professionals using clinical reasoning, possibly supported by decision algorithms [1]. Analysis of clinical reasoning has previously been performed in medicine, e.g., to characterize and improve decision making in surgery [2], but to our knowledge has not yet been performed in pharmacovigilance assessments.

Objective/Aim: To identify, characterise, and compare the reasoning by experienced pharmacovigilance assessors during assessments of DECs.

Methods: Seven DECs were assessed by 5 medical assessors. Their reasoning was elicited and clarified by semi-structured interviews [3], that were transcribed, coded, and analysed using inductive thematic analysis. Related similar codes were grouped into subtasks indicative of cognitive patterns. Subtasks were iteratively grouped into tasks to match actions taken by participants in assessments and macrocognitive functions [4]. For every assessment subtasks and tasks were qualitatively appraised for patterns and themes.

Results: The analysis revealed 5 tasks comprised by 20 unique subtasks (Table 1) being used by the assessors. Subtasks and tasks were arranged in a non-hierarchical assessment structure. Participants were found to transition from one task to another more than once before reaching a conclusion (indicated by “decide/choose option” subtask in Table 1). Within each task, subtasks were not carried out in any consistent order. Before consulting the case series, participants generally started with a situation assessment, in which they appraised their knowledge of a given DEC and initially formed expectations of the case report series analysis yield. In the planning/re-planning task, goals were established according to initial expectations, which could lead to gathering information, analysing the case reports, or providing a final decision. No decisions were made only based on expectations. Information gathering consisted in consulting drug labelling or publications, leading to hypotheses. Case reports analysis yielded further hypotheses, competing or compatible with initial expectations. Participants addressed only a subset of their hypotheses before reaching a final conclusion. In most cases, assessors reached similar final conclusions on the DECs. Differences were partly explained by participants’ depth of analysis [3], or choice of sources of information. 

Conclusion: These results of inter- and intra-individual variations in cognitive patterns indicate a flexible approach to assessments, and may hold potential implications in informing the design of training programmes for pharmacovigilance assessment skills and decision support tools.

References:

• 1. Agbabiaka TB, Savovic J, Ernst E. Methods for causality assessment of adverse drug reactions: a systematic review. Drug Saf. 2008;31:21–37

• 2. Jalote-Parmar A, Badke-Schaub P, Ali W, Samset E. Cognitive processes as integrative component for developing expert decision-making systems: A workflow centered framework. J Biomed Inform 2010;43:60–74

• 3. Grundmark B, Sartori D, Ellenius J. Do they all agree?: comparing expert signal assessment. Drug Saf. 2017;40:976–7.

• 4. Crandall B, Klein GA, Hoffman RR. Working minds: A practitioner’s guide to cognitive task analysis: Mit Press; 2006.

Disclosure of Interest: None declared.

130 ISoP18-1181 Penicillin-Induced Acute Generalized Exanthematous Pustulosis: The Importance of Patch Testing

130.1 N. Fathallah¹, A. Saii², S. Larif¹, B. Ouni¹, H. Hmouda³, R. Slim⁴, C. Ben Salem^*1

130.1.1 ¹Pharmacovigilance Center of Sousse, Research Laboratory, Sousse University, Tunisia; ²Amen Medical Center; ³Department of Intensive Care Unit, ⁴Pharmacovigilance Center of Sousse, Research Laboratory, Sahloul University hospital, Sousse, Tunisia

Background/Introduction: Acute generalized exanthematous pustulosis (AGEP) is a rare and potentially severe cutaneous reaction. It is usually caused by a drug reaction and its onset is 2–11 days after medication exposure. Antibiotics are the most common trigger [1].

Objective/Aim: To report a penicillin-induced AGEP case confirmed by positive patch test.

Methods: The first case is a previously healthy woman in his 40 s presented with 2 days of fever and a rash after initiation of amoxicillin for dental pain. On examination, a widespread symmetric erythematouseruption with numerous non follicular pinpoint pustules over the trunk and proximal limbs, was present. The patient was febrile (38 °C). Laboratory analysis revealed an elevated white blood cell count of 15 × 10⁹/L with 88% neutrophils. A punch biopsy of the skin lesions showed subcorneal and intraepidermalspongiform pustules. Based on the clinicopathologic features, amoxicillin-induced AGEP was suspected. The second case is a woman with psoriasis history in his 30 s presented with 2 days of fever and a rash after initiation of oxacillin for otitis.On examination, a widespread erythematous eruption, with numerous nonfollicular pinpoint pustules over the trunk and extremities, was observed. The patient was febrile (39 °C). Blood analysis showed a raised white blood cell count of22.7 × 10⁹/L, with a neutrophil count of 17.6 × 10⁹/L and C reactive protein of 28 mg/L (normal range < 7). A biopsy of the involved skin was consistent with AGEP.

Results: Drugs are incriminated in more than 90% of cases of AGEP. Medications from many different pharmacological classes, especially antibiotics such as sulfonamides, aminopenicillins, quinolones, lincosamides and pristinamycin, have been suspected in the development of AGEP. β-Lactams account for 80% of antibiotics implicated in AGEP [2].The major differential diagnosis were infections, generalized pustular psoriasis, and drug reaction with eosinophilia and systemic symptoms (DRESS). Differentiating AGEP from pustular psoriasis is important, as the management of each condition is quite distinct [2].

Conclusion: Drug patch tests have been recently confirmed to be safe, with few reported relapses or severe reactions, and helpful to assess drug imputability in AGEP, with a high proportion of positive results as compared with patients with other drug-related eruptions [3].

References:

• 1. Duong TA, Valeyrie-Allanore L, Wolkenstein P, Chosidow O.Severe cutaneous adverse reactions to drugs. Lancet 2017;390:1996–2011.

• 2. Yek C, Gupta A, Mauskar M. Fever and a pustular rash. JAMA 2017;317:637–8

• 3. Sidoroff A, Dunant A, Viboud C, Halevy S, Bavinck JN, Naldi L, et al.Risk factors for acute generalized exanthematous pustulosis (AGEP)-results of a multinational case–control study (EuroSCAR). Br J Dermatol 2007;157:989–96

Disclosure of Interest: None declared.

131 ISoP18-1182 Anti-epileptic Recurrent Drug-Induced Rash With Eosinophilia and Systemic Symptoms

131.1 N. Fathallah¹, B. Ouni¹, A. Saii², S. Larif¹, H. Hmouda³, R. Slim¹, C. Ben Salem^*1

131.1.1 ¹Pharmacovigilance Center of Sousse. Research Laboratory, Sousse University, Tunisia; ²Amen Medical Center, Tunis, Tunisia; ³Intensive Care Unit, Sahloul University Hospital, Sousse, Tunisia

Background/Introduction: Drug rash with eosinophilia and systemic symptoms (DRESS) is characterized by fever, rash and internal organ involvement after exposure to certain drugs. Most of the aromatic anticonvulsants, such as phenytoin, phenobarbital, and carbamazepine, can induce DRESS [1].

Nonaromatic drugs such as lamotrigine and valproate are known to be more safe than aromatic anticonvulsants and are less responsable of DRESS.

Objective/Aim: To report a case of DRESS following exposure to valproate and recurring after phenobarbital intake.

Methods: A 54-year-old man without previous significant medical history had been diagnosed with brain tumor. He was treated by surgery and received valproate (400 mg daily). No other medications had been taken. Three weeks later, the patient was admitted to the hospital with fever and general eruption. The patient’s face was edematous and erythematous papules were scattered over his entire body. Lymph nodes were palpable. Laboratory findings showed hypereosinophilia and elevated liver enzymes. Viral serology was negative for hepatitis A, B, and C, cytomegalovirus and Epstein–Barr virus. On suspicion of DRESS, valproate was stopped. While clinical symptoms and laboratory findings improved progressively, phenobarbital was started. The patient developed again a generalized rash and fever few days after phenobarbital administartion. The neurosurgeon decided to stop phenobarbital. Symptoms resolved few days later without complications.

Results: Drug rash with eosinophilia and systemic symptoms is a severe adverse reaction with high mortality rates. The aromatic anticonvulsants are the most frequently incriminated drugs [2]. In DRESS, discontinuation of the offending aromatic anticonvulsant is essential for improving the prognosis. In this case, valproate is usually a safe alternative for aromatic anticonvulsants. In fact, Sodium valproate is very rarely responsible for DRESS. As far as we know, DRESS syndrome cases related solely to the use of valproate have not been previously reported. Herin, we report the first case of DRESS primarily induced by sodium valproate and secondarily to phenobarbital. This case illustrates a possible cross-reactivity between valproate and phenobarbital, which are non aromatic and aromatic anticonvulsants, respectively.

Conclusion: Switching anticonvulsants is not usually safe. Clinicians should be more vigilant when adverse events occur first with non aromatic anticonvulsants.

References:

• 1. De A, Rajagopalan M, Sarda A, Das S, Biswas P. Drug reaction with eosinophilia and systemic symptoms: an update and review of recent literature.Indian J Dermatol 2018;63:30–40

• 2. Ben Salem C, Slim R, Denguezli M, Nouira R, Hmouda H, Bouraoui K.A recurrent drug rash with eosinophilia and systemic symptoms. Pediatr Dermatol 2007;24:666–8

Disclosure of Interest: None declared.

132 ISoP18-1183 The Association Between Inappropriate Medication Use and Health-Related Outcomes Among Nursing Home Residents: A Systematic Review and Meta-Analysis

132.1 P. Mongkhon^*1,2, T. Tanasombat¹, R. Jeenapongsa¹, C. Kongkaew¹

132.1.1 ¹Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Mueng, Phitsanulok, Thailand; ²School of Pharmaceutical Sciences, University of Phayao, Mueng, Phayao, Thailand

Background/Introduction: Potentially inappropriate medications (PIMs) are becoming a significant health problem affecting elderly in nursing home (NH) with a prevalence of 43 > 47% [1, 2]. Several studies reported the prevalence of PIM use among people residing in NH settings [3, 4], but only few studies investigated the association between PIM use and health outcomes. Furthermore, the published data are still inconsistent to demonstrate that the PIM use is significantly associated with negative health outcomes.

Objective/Aim: This systematic review and meta-analysis aimed to assess the relationship between PIMs and their consequences for health-related outcomes in NH residents.

Methods: Observational studies that examined the association between health-related outcomes and PIM use among NH residents were identified from the Cochrane library, CINAHL, SCOPUS, and PUBMED until October, 2017. Quality assessment was performed using the National Institute of Health (NIH) Quality Assessment Tool for Observational Cohort and Cross-sectional Studies. The outcome measures were mortality, hospitalization, emergency department (ED) visits and any adverse events association with PIM use among nursing home residents which were reported as odd ratio (OR), risk ratio (RR), or hazard ratio (HR) together with 95% confident interval (95% CI). Pooled estimates were obtained by using the DerSimonian-Laird random-effects model. All analyses were performed using STATA, v14.1.

Results: Eleven studies were included in the systematic review and 8/11 studies in the meta-analysis. The prevalence rate of PIMs among nursing home residents ranged from 11.9 > 77.2% with a median of 46.5% (Interquartile range; IQR = 32.2 > 50.3%). Our meta-analysis demonstrated that PIM users had a significant association with mortality compared to PIM non-users (OR = 1.46, 95% CI 1.24–1.72, I² 51.8%). In the United States, PIM users were more likely to be hospitalized than non-users (OR = 1.27, 95% CI 1.15–1.41, I² 0%). For health-related quality of life (HRQoL), no significant changes were observed in EuroQol-5 dimension (EQ-5D) score (p = 0.07) and EuroQoL visual analog scale (E-VAS) score (p = 0.34). However, when 15D and the psychological well-being scale were employed, quality of life was better for residents who were not PIM users after adjustment for age and gender The cost of pharmaceutical care services was positively correlated with the number of medications that inappropriately prescribed.

Conclusion: The use of PIM was substantial and associated with a higher risk of mortality among nursing home residents. But their impact on HRQoL remained inconclusive. Further studies with prospective long-term follow up are needed to establish its association.

References:

• 1. Morin L, Laroche ML, Texier G, Johnell K. Prevalence of potentially inappropriate medication use in older adults living in nursing homes: a systematic review. J Am Med Dir Assoc 2016;17:862.e1–9

• 2. Storms H, Marquet K, Aertgeerts B, Claes N. Prevalence of inappropriate medication use in residential long-term care facilities for the elderly: A systematic review. Eur J Gen Pract 2017;23:69–77

• 3. Nyborg G, Brekke M, Straand J, Gjelstad S, Romoren M. Potentially inappropriate medication use in nursing homes: an observational study using the NORGEP-NH criteria. BMC Geriatr 2017;17:220

• 4. da Costa FA, Periquito C, Carneiro MC, Oliveira P, Fernandes AI, Cavaco-Silva P. Potentially inappropriate medications in a sample of Portuguese nursing home residents: Does the choice of screening tools matter? Int J Clin Pharm 2016;38:1103–11

Disclosure of Interest: None declared.

133 ISoP18-1185 Process Characteristics and Time to Follow-Up of Adverse Drug Reaction Reports from a Single Center: A Retrospective Analysis

133.1 M. Ganso^*1, S. P. Lenhart², A. Said¹, M. Schulz¹

133.1.1 ¹Drug Commission of German Pharmacists, Department of Medicine, Federal Union of German Associations of Pharmacists, Berlin, Germany; ²Department of Pharmacy, Kbo-Isar-Amper-Klinikum München-Ost, Munich, Germany

Background/Introduction: Spontaneous adverse drug reactions (ADR) reports may be incomplete or may require supplementary information for scientific evaluation. Follow-up methods should be optimized in ways that encourages the reporter to submit missing information of a particular safety concern [1]. This includes the preparation of specific follow-ups without a delay.

Objective/Aim: Evaluation of follow-up characteristics and duration to initiate a follow-up by marketing-authorization holders (MAHs) in comparison to the national pharmacovigilance center Drug Commissions of German Pharmacists (AMK).

Methods: Generated as part of an ADR project, spontaneous reports provided by a clinical pharmacist working on acute psychiatric wards and using the AMK ADR-form were analyzed retrospectively. As usual, the AMK assessed all reports and followed up, if needed. The reports, including the request for additional information, were forwarded to the responsible MAH, who could follow up the reports likewise. The median (range) duration in days (d) was calculated for each process step and compared by paired sample Wilcoxon test (RStudio v 1.1.453). A significance level alpha = 0.05 was chosen.

Results: Between July 2016 and July 2017, the AMK received 42 ADR reports to 70 medicinal products marketed by 25 different MAHs. For 25 reports, the AMK sent a specific follow-up within 6d (1–15) to the reporter. 37 reports were forwarded to the MAH within 5d (1–14), including follow-ups. After receipt of the reports, 10 different MAH sent 22 follow-ups (19 reports) within 17d (5–28) to the reporter. In 8 out of 22 follow-ups, the MAH only sent blank forms. The reporter replied by email to all follow-up requests within 11d (2–31) to the AMK and predominantly by mail within 12d (0–40) to the various MAHs. In total, 12 reports were identified which were followed by both AMK and eight different MAHs. In this subset, the duration to initiate a follow-up by AMK vs. MAH differed statistically significant: median difference 9d [95% confidence interval (− 13.5 to − 4.5); p = 0.002].

Conclusion: The AMK followed up initial ADR reports from a single center significantly faster than the responsible MAH. Regarding the study size and considering a potential impact on MAH follow-ups by AMK’s first handling of reports, results should be interpreted with caution.

References:

• 1. Guideline on Good Pharmacovigilance Practices (GVP)—Module VI (Rev 2), EMA/873138/2011 Rev 2, 28 July 2017

Disclosure of Interest: None declared.

134 ISoP18-1187 Contribution of Patient’s Reports in Signal Detection: Experience of a Pharmacovigilance Center

134.1 C. Le Beller¹, N. AsgariI¹, A. Lillio-Le Louet^*1

134.1.1 ¹Pharmacovigilance Hopital Européen Georges Pompidou, Paris, France

Background/Introduction: Along with statistical data mining in the French Database (FDB), traditional approaches for signal detection are still under way in France. The French Drug Medicine Agency (ANSM) has asked the pharmacovigilance regional centers (CRPVs) to review individual cases in this perspective. Several criteria must be taken into account and formalized in 2016: seriousness, expectedness, vulnerable populations and cluster. Since June 2011 [1], patients can report adverse drug reactions (ADRs) and contribute to signal detection both in case-by-case review and statistical methods [2].

Objective/Aim: To assess the contribution of patient’s reports in manual signal detection.

Methods: Each ADRs report is analysed by the CRPV’s team as a potential signal, and if requirements are met, the cases are transmitted to the ANSM. We retrospectively analysed all cases of potential signal from patients transmitted to the ANSM from June 2011 to December 2017, and more specifically the case descriptions (patient, sex, age, ADRs, drugs involved) and criteria of transmission.

Results: During the study, 9519 spontaneous reports were registered in the FDB, including 1677 patients’ reports (17.6%). We transmitted 125 cases, 16 (12.9%) being directly reported by patients. Half of these cases involved children (1F, 5M, 2 unknown) aged from 7 months to 4 years. In 7 cases out of 8, a vaccine was suspected: 6 cases with meningitis vaccine, in a media context (legal complaints after withdrawal for quality defect) and one narcolepsy with influenza type A H1N1 vaccine. The last case concerned a lack of information about casein, an excipient with risk allergy. Eight patients were adults (5F, 3M), aged from 19 to 66 years. Two cases involved finasteride use in men: an irreversible sexual dysfunction and a misuse in a patient with a history of breast cancer. Other cases transmitted were: hepatic metastasis 24 years after a clear cell carcinoma of the uterine cervix, after in utero exposition to diethylstilbestrol, a malaise with Decontractyl^® (mephenesine) with withdrawal procedure ongoing in France, risk of allergy linked to excipients, early onset of intense headaches with tenofovir alafenamide, mania crisis related to venlafaxine and myelitis after HPV vaccine.

Conclusion: In our CRPV, 17.6% of ADRs collected since 2011 have been patient reports, and a close proportion (12.9%) was transmitted to the ANSM as potential signals, with a high proportion of vaccine-related pediatric cases, in a context of media coverage. Furthermore, some cases meet other criteria: unexpectedness; seriousness or misuse.

References:

• 1. European Directive 2010/84/EU. https://ec.europa.eu/health//sites/health/files/files/eudralex/vol-1/dir_2010_84/dir_2010_84_fr.pdf

• 2. Watson S, Chandler RE, Taavola H, Härmark, Grundmark B, Zekarias A, et al. Safety concerns reported by patients identified in a collaborative signal detection workshop using VigiBase: results and reflections from Lareb and Uppsala monitoring centre. Drug Saf 2018;41:203–12

Disclosure of Interest: None declared.

135 ISoP18-1188 Meningiomas and Progestins: Querying Brest CHRU Data Warehouse

135.1 L. El Aridi¹, C. Le Guillou², H. Jantzem^*1, Y. Audouard-Marzin¹, A. Happe², D. Carlhant-Kowalski¹, J.-M. Cauvin²

135.1.1 ¹Centre Régional de Pharmacovigilance, ²Département d’Information Médicale, CHRU de Brest, Brest, France

Background/Introduction: The hypothesis of an increased risk of meningioma in patients treated with high doses of cyproterone acetate has been validated by the french authority Agence Nationale de sécurité des médicaments et des produits de santé (ANSM) and the European Medicines Agency (EMA) [1, 2]. The role of other progestin treatment, used outside contraception, in the occurrence and/or growth of meningiomas remains to be clarified. The Pharmacovigilance Center of Brest questioned the hospital database in order to evaluate this signal.

Objective/Aim: Bring clinical cases to strengthen the signal with cyproterone and try to quantify this signal with the other progestins.

Methods: The methodology used is that of the HOPIPRAC project. It involves questioning the clinical data warehouse of the University Hospital of Brest since 2003 until June 4th 2017, and to cross two queries, one concerning the drug (progestins used in a hormonal treatment and/or hormone replacement therapy: cyproterone, nomegestrol, chlormadinone…) and the other concerning the clinical reaction: meningioma. This second query combines a text research for the word meningioma in the patients different documents, as well as searching by code D32 (ICD-10 code corresponding to meningiomas).

Results: The drug query counts 8834 patients exposed to progestins, and that of the clinical reaction counts 2585 patients for whom a diagnosis of meningioma was established. Crossing the two requests allows to obtain a sub-warehouse with 150 patients and 1544 documents. These are the patients whose documents contain the drug name and/or the clinical reaction. Based on chronological arguments, reading of these documents allowed us to retain 64 potential cases of meningioma with the different progestins and not notified to the pharmacovigilance center: 37.5% with cyproterone acetate, 25% with nomegestrol, 9.4% with chlormadinone, 9.4% with progesterone, 7.8% with dydrogesterone, 7.8% with progestin contraceptives, and 3.1% with promegestone.

Conclusion: Querying the hospital data warehouse allows to palliate undernotification and to reinforce the signal. Returning to patients medical records and a discussion with clinicians will add additional information regarding the quantification of meningioma risk in terms of dose threshold, duration of treatment and the role of a cumulative exposure to progestins for the same patient in the occurrence of a meningioma.

References:

• 1. Compte-rendu du Comité technique de pharmacovigilance (CTPV) du 18/03/2014: http://ansm.sante.fr/var/ansm_site/storage/original/application/6259701b30dc0177bdccfb40e2c0c874.pdf

• 2. Phamracovigilance Working party (PhVWP) November 2009: http://www.ema.europa.eu/docs/en_GB/document_library/Report/2009/12/WC500016972.pdf

• 3. HOPIPRAC, PRAC signals validation sentinel system, from a hospital data warhouse

Disclosure of Interest: L. El Aridi Shareholder of: none, Grant/Research support from: none, Consultant for: none, Employee of: none, Paid instructor: none, Speaker bureau of: none, Other: none, C. Le Guillou: None declared, H. Jantzem: None Declared, Y. Audouard-Marzin: None declared, A. Happe: None Declared, D. Carlhant-Kowalski: None declared, J.-M. Cauvin: None declared.

136 ISoP18-1189 Example of Using Pharmacogenetics for Drug Safety: Prevalence of the Cyp2c19*2 Polymorphism and Clopidogrel Resistance in Moroccan Population

136.1 A. Lamzouri¹, F. Z. Laarabi², J. Lyahyai³, N. Adadi^2,3, A. El Rherbi¹, A. Tebaa^*1, R. Soulaymani Bencheikh¹, A. Sefiani^2,3

136.1.1 ¹Pharmacology, Moroccan Anti Poison and Pharmacovigilance Center, Rabat, Morocco; ²Medical Genetics, National Institute of Health, ³Human Genomic Center, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco

Background/Introduction: Pharmacogenetics is the study of the genetic variation between individuals that affects their response to drugs, both in terms of therapeutic effect as well as adverse effects. Since the beginning of this century, information on pharmacogenetics appears in the summary of product characteristics of drugs. Pharmacogenetic tests particularly concern the enzymes involved in the metabolism of drugs, among which P450 cytochromes. One of the best-known examples is the association of genetic variants of CYP2C19 with Clopidogrel resistance.

Clopidogrel is an antiplatelet agent used as a basic treatment among patients with Acute Coronary Syndromes (ACS) or undergoing percutaneous coronary intervention (PCI). Although its widely described effectiveness, Clopidogrel exhibits a large inter-individual variability of response. This medicine is administrated as an inactive prodrug that requires several biotransformation steps in order to be active. This process takes place via two sequential hepatic reactions of oxidation, catalyzed by the Cytochrome P450 system especially the CYP2C19 located on chromosome 10.

CYP2C19 is a highly polymorphic locus, with almost 27 variants currently reported. The CYP2C19*1 allele corresponds to the normal allele with a complete functional metabolism, and the most described CYP2C19 abnormal variant is CYP2C19*2 (681G > A), its frequencies vary from ~ 15% among Caucasians and Africans, to ~ 29–35% among Asians.

Patients are classified as extensive metabolizers (EMs) if they carry double copy of the wild type allele *1 (*1/*1), intermediate metabolizers (IMs) when carrying one copy of the normal allele and one of the deficient one (*1/*2), and poor metabolizers (PMs) when carrying double copy of a deficient allele (*2/*2).

As the Clopidogrel effectiveness depends essentially on its activation by CYP2C19, therapeutic recommendations based on CYP2C19 genotyping were published, recommending the use of an alternative antiplatelet agent (prasugrel or ticagrelor, if no contraindication) among PMs and IMs patients, as they have reduced platelet inhibition, increased residual platelet aggregation, increased risk for adverse cardiovascular events.

Objective/Aim: The aim of this study was to determine, for the first time, the CYP2C19*2 allele frequency in Moroccan population and explain interest of testing for the CYP2C19*polymorphism in patients being treated with clopidogrel.

Methods: In this study, we used a reliable TaqMan(^®) real-time polymerase chain reaction to detect the CYP2C19*2 allele in 200 unrelated Moroccan newborns. DNA was extracted from umbilical cord blood with maternal consent.

Results: Genotyping of CYP2C19 gene, by real-time polymerase chain reaction using TaqMan probes, revealed a frequency of 18% for CYP2C19*2 allele among 200 Moroccan studied group.

Conclusion: The CYP2C19*2 allele play a vital role in Clopidogrel responsiveness among patients with ACS or after PCI, and Moroccan population has a high prevalence of this allele when compared with other African and Caucasian populations. Hence, testing for the CYP2C19*2 variant is very important for selecting the appropriate anti-platelet agent to treat a cardiac patient, and would be a step towards personalized medicine in morocco.

References:

• 1. Scott SA, et al. Clinical pharmacogenetics implementation consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol 2013;94:317–23

• 2. Saydam F, et al. The CYP2C19*2 and CYP2C19*17 polymorphisms play a vital role in clopidogrel responsiveness after percutaneous coronary intervention: a pharmacogenomics study. Basic Clin Pharmacol Toxicol 2017;121:29–36

• 3. Roden DM. Cardiovascular pharmacogenomics: the future of cardiovascular therapeutics? Can J Cardiol 2013;29:58–66

• 4. Simon T, et al. Genetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects. Clin Pharmacol Ther 2011;90:287–95

Disclosure of Interest: None declared.

137 ISoP18-1191 Pregnancies Associated with Etonogestrel Implants: Comparison of Two Five-Year Reporting Periods

137.1 S. Rowlands¹, M. Harrison-Woolrych^*2, E. Cornforth³

137.1.1 ¹Bournemouth University, Bournemouth, United Kingdom; ²ISoP, ³MHRA, London, United Kingdom

Background/Introduction:

Etonogestrel implants are a highly effective contraceptive method licensed to be used for a period of 3 years. Pregnancies are rare but continue to be reported to the British Yellow Card Scheme. Publications in 2005 were the first to identify the issue of the missing implant [1, 2]. There is little information reported so far on failures of Nexplanon, a modified device introduced towards the end of 2010.

Objective/Aim: (1) To identify pregnancies associated with use of the implants Implanon and Nexplanon in the UK during two five-year reporting periods. (2) To classify the reasons for device failure for each implant. (3) To examine any differences between reasons for pregnancies associated with these products.

Methods: Extraction of data from the UK spontaneous reporting system for adverse drug reactions in relation to the etonogestrel implants. All reports indicating pregnancies occurring after insertion of the device were assessed. The years of interest were 2005–2009 (Implanon) and 2012–2016 (Nexplanon). Reasons for failure of the method were placed into one of eight pre-determined categories.

Results: There were 544 cases (280 Implanon and 264 Nexplanon) out of a total of 752 pregnancy reports (363 Implanon and 389 Nexplanon) with sufficient information to make them suitable for analysis. Of the 544 cases, 233 (43%) were considered to be true method failures, 31 (6%) drug–drug interactions, 75 (14%) were already pregnant at the time of insertion, 35 implants were not inserted in accordance with the manufacturers’ instructions, 2 implants were extruded/expelled and 1 placebo device had been inserted in error. There were no reports of self-removal. There were 120 cases (22%) in which the implant was missing: 68 after Implanon insertion and 52 with Nexplanon. In all categories of case there was no clear difference in frequency of pregnancy when the two time periods were compared.

Conclusion: These results are similar to previous Australian and French postmarketing surveillance studies [1–3]. One intended benefit of modification of the device in 2010 was a reduction in the risk of non-insertion but missing implant cases were reported in the second 5-year period in similar proportion to the first. Our assessment suggests that missing implant cases are cases of implant non-insertion: failure to insert the implant and failure to recognise that this has happened. We note that these insertion failures continue despite modification of the device.

Please note that this Abstract does not represent the views of the UK Medicines and Healthcare products Regulatory Agency.

References:

• 1. Harrison-Woolrych M, Hill R. Unintended pregnancies with the etonogestrel implant (Implanon): a case series from postmarketing experience in Australia. Contraception 2005;71:306–8

• 2. Bensouda-Grimaldi L, Jonville-Bera AP, Beau-Salinas F, et al. Insertion problems, removal problems and contraception failures with Implanon^® [in French]. Gynécologie Obstétrique & Fertilité 2005;33:986–90

• 3. Simon C, Agier MS, Béné J, et al. Safety profile of etonogestrel contraceptive implant (Nexplanon and Implanon) reported in France [in French]. Journal de Gynécologie Obstétrique et Biologie de la Reproduction 2016;45:1074–82

Disclosure of Interest: None declared.

138 ISoP18-1192 A Framework for Identifying and Validating Cognitive Services within Pharmacovigilance

138.1 R. Mockute^*1, S. Desai¹, B. Assuncao¹, K. Danysz¹, N. Tetarenko¹, D. Abatemarco¹, M. Widdowson¹, N. Fornaratto¹, S. Beauchamp¹, S. Cicirello¹, E. Mingle¹

138.1.1 ¹Global Drug Safety and Risk Management, Celgene Corporation, Summit, United States

Background/Introduction: The responsibility of pharmacovigilance is to detect, assess, understand and prevent adverse events and any other drug-related problems [1]. To do it effectively it is imperative to collect, collate, evaluate and act upon adverse events. The volume of Individual Case Safety Reports (ICSR’s) describing adverse events has been increasing year on year. Despite this, it is estimated that more than 90% of ADR’s go unreported [2]. To address the evolving landscape, it will be necessary to embrace assistive technologies at scale.

Objective/Aim: Our study outlines a framework for identifying and validating cognitive services for pharmacovigilance, with an aim to set a standard for ensuring appropriate use.

Methods: We developed a framework to validate 40 different cognitive services ranging from information extraction to complex decision making such as ICSR validity, reporter causality, seriousness etc. This framework addresses the following shortcomings: (1) Matching predictions to ground truth needs subject matter expertise (2) Inconsistencies with ground truth (3) Automated validation of prediction can miss context (4) Auto-labeling can lead to inaccurate F1 scores.

The method consists of the following steps: (1) Assessment of cognitive workload (2) Determination of case management decision points where AI can be applied (3) Definition of the training corpus (4) Identification and standardization of PV knowledge elements (5) Cognitive service development (6) Subject Matter Expert (SME) review and validation of cognitive services using the ANSI z1.4 Acceptable Quality Limits standard.

Results: We identified, developed, and validated 40 cognitive services using a corpus of 20,000 ICSR’s. Through the application of this framework, we were able to: (1) Identify decision points that can be candidates for AI (2) Standardize the process to make PV knowledge explicit (3) Preserve PV knowledge and context by embedding SME’s throughout the development process. (4) Standardize the approval process by using established quality inspection principles.

Conclusion: The necessity of AI within PV has been well established, however, its introduction needs the assurance of quality, consistency, and standardization before it can be adopted in a regulated environment. Within PV this is a foundational framework which the industry can use to identify and validate services. More broadly, this framework could be applied to the creation and tuning of cognitive services to be used in a regulated environment.

References:

• 1. Pharmacovigilance [Internet]. World Health Organization. World Health Organization; 2015 [cited 2018Jun1]. Available from: http://www.who.int/medicines/areas/quality_safety/safety_efficacy/pharmvigi/en/

• 2. Nikfarjam A, Sarker A, O’Connor K, Ginn R, Gonzalez G. Pharmacovigilance from social media: mining adverse drug reaction mentions using sequence labeling with word embedding cluster J Am Med Inform Assoc 2015;22:671–81

Disclosure of Interest: R. Mockute Shareholder of: Celgene Corporation, Employee of: Celgene Corporation, S. Desai Shareholder of: Celgene Corporation, Employee of: Celgene Corporation, B. Assuncao Shareholder of: Celgene Corporation, Employee of: Celgene Corporation, K. Danysz Shareholder of: Celgene Corporation, Employee of: Celgene Corporation, N. Tetarenko Shareholder of: Celgene Corporation, Employee of: Celgene Corporation, D. Abatemarco Shareholder of: Celgene Corporation, Employee of: Celgene Corporation, M. Widdowson Shareholder of: Celgene Corporation, Employee of: Celgene Corporation, N. Fornaratto Shareholder of: Celgene Corporation, Employee of: Celgene Corporation, S. Beauchamp Shareholder of: Celgene Corporation, Employee of: Celgene Corporation, S. Cicirello Shareholder of: Celgene Corporation, Employee of: Celgene Corporation, E. Mingle Shareholder of: Celgene Corporation, Employee of: Celgene Corporation.

139 ISoP18-1193 Safety Profile of Immune Checkpoint Inhibitors: An Analysis of Italian Spontaneous Reporting System Database

139.1 P.M. Cutroneo^*1, V. Isgrò², V. Ientile³, M. Santarpia⁴, N. Pellegrino¹, E. Matarangolo⁵, E. Spina^1,2, G. Trifirò⁶

139.1.1 ¹Sicilian Regional Pharmacovigilance Center, University Hospital of Messina, Italy; ²Dept. of Clinical and Experimental medicine, University of Messina, Messina, Italy; ³Unit of Clinical Pharmacology, University Hospital of Messina, Messina; Italy; ⁴Dept. of Adult and Developmental Human Pathology “Gaetano Barresi”, University of Messina, Messina, Italy; ⁵Italian Medicines Agency, Pharmacovigilance Office, Rome, Italy; ⁶Dept. of Biomedical and Dental Sciences and Morpho-functional Imaging, University of Messina, Messina, Italy

Background/Introduction: Immune Checkpoint Inhibitors (ICIs) have significantly changed the treatment of a wide range of malignancies, including melanoma and non-small-cell lung cancer. Several ICIs, most commonly targeting programmed death-1 receptor (PD-1), its ligand (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) have been approved. As a result of their mechanism of action, ICIs may induce immune-related adverse events against normal tissue in multiple organs. These adverse effects have not been though yet fully characterized. Spontaneous ADR reporting system represents the cornerstone for the detection of safety signals and to explore in general safety profile of all marketed drugs including ICIs in clinical practice.

Objective/Aim: To provide an overview of ICI safety data using the Italian Spontaneous ADR Reporting System (SRS).

Methods: We selected all the ADR reports attributed to ICIs in the Italian SRS from January 2011 to December 2017. Study drugs included ipilimumab (anti-CTLA-4), nivolumab, pembrolizumab (anti-PD-1), atezolizumab (anti-PD-L1), all currently marketed in Italy. Descriptive frequency analyses of ADR reports for ICIs as a whole class as well by individual products have been conducted. Reporting odds ratio (ROR) with 95% confidence intervals (CIs) was used as a measure of disproportionality for ADRs associated with the ICI group as compared with all other suspected drugs (reference group), taking into account Standardized MedDRA Queries (SMQs).

Results: Out of a total of 249,457 ADR reports collected in the Italian SRS till end of December 2017, 1461 (0.5%) were related to ICIs. Nivolumab was indicated as a suspected drug in 1066 (73%) reports, followed by ipilimumab (n = 298; 20.4%), pembrolizumab (n = 63; 4.3%) and atezolizumab (n = 28; 1.9%). ICI-related ADR reports mostly involved male patients (63.3%). The mean age (± SD) of ICI users was 63.8 (± 12) years. ICIs were associated with a higher frequency of serious ADR reporting than for reference group (46.8 vs 34.8%; p < 0.001). The most commonly reported serious ADRs were diarrhoea (n = 78), pneumonia (n = 77), lack of efficacy/disease progression (n = 63). The frequencies of general, gastrointestinal, hepatobiliary and respiratory disorders, infections, neoplasms were significantly higher for ICIs than for reference group (p < 0.001). Analysing SMQs, ICIs resulted disproportionally associated with unexpected adverse reactions, such as ischemic heart disease, cardiac failure and ocular motility disorders.

Conclusion: The analysis of ICI-related ADR reports showed that the most frequently reported events concerned general, gastrointestinal and respiratory disorders, of a possible immune-related origin. Potential safety signals, including cardiac and ocular reactions, were detected, requiring further investigation.

Disclosure of Interest: None declared.

140 ISoP18-1195 Cohort Event Monitoring of Newest Antidiabetic Agents Using Patient Reported Outcomes

140.1 A.-M. Van Gorp¹, S. Vorstenbosch^*1, L. Rolfes¹

140.1.1 ¹Netherlands Pharmacovigilance Centre Lareb, Den Bosch, The Netherlands

Background/Introduction: In recent years, several new antidiabetic agents have been marketed, namely the GLP1-agonists, DPP4-antagonists and SGLT2-antagonists. After new drugs enter the market, little is known about characteristics of adverse drug reactions (ADRs), like the time course, management and outcomes.

Objective/Aim: To study the safety profile, including occurrence and characteristics of ADRs, of the new antidiabetic agents.

Methods: We performed a prospective, observational cohort study including 2 GLP1-agonists, 4 DPP4-antagonists and 2 SGLT2-antagonists. New users of these antidiabetic agents were recruited through local pharmacies and asked to participate in this study between 1 February 2008 and 1 January 2016. Participants were invited to complete six web-based questionnaires over a period of 1 year after start.

Results: A total of 818 patient were included, of which 119 users of GLP1-agonist (male/female 38/62%), 624 DPP4-antagonist (57/43%) and 75-SGLT2 (57/43%). The mean age of 60 years was comparable between the groups. 42% (341) of the patients experienced an ADR during the study period. For GLP1-agonist users the percentage of patients that experienced an ADR was the highest with 62% (74), followed by SGLT2-antagonist users with 60% (45), and DPP4-antagonist users with 36% (222). The top 5 reported ADRs (Table 1) and its incidence are comparable with the description in the drugs’ Summary of Product Characteristics (SPC). However, for the SLGT2-antagonists, the incidence seems to be slightly higher in this study compared to the SPC. 26% (47) of ADRs that were reported for GLP1-agonist recovered without withdrawal of the drug. For ADRs reported for DPP4-antagonists and SGLT2-antagonists, this was respectively 22% (90) and 11% (9). Respectively 6.6% (9), 8.8% (55), and 12% (9) of GLP1-agonist, DPP4-antagonist and SGLT2-antagonist users reported withdrawal of the drug due to the occurrence of an ADR.

Conclusion: This study gives insight in the safety profile and characteristics of ADRs of the new antidiabetic agents. This is valuable information that is mostly lacking from premarketing clinical trials.

Disclosure of Interest: None declared.

141 ISoP18-1196 Development and Evaluation of a Digital Recruitment Method of Patients for Lareb Intensive Monitoring

141.1 A.-M. Van Gorp¹, S. Vorstenbosch^*1

141.1.1 ¹Netherlands Pharmacovigilance Centre Lareb, Den Bosch, The Netherlands

Background/Introduction: Before new drugs are marketed, their safety profile is explored. Nevertheless, after market entry of drugs, little is known about characteristics of adverse drug reactions (ADRs), like the time course, management and outcomes. Netherlands Pharmacovigilance Centre Lareb has developed a web-based intensive monitoring system (LIM) which aims to capture data on these topics. Participants for LIM are recruited through pharmacies by an information leaflet. The inclusion rate for LIM studies is low, in 2015 < 1% of the first-time users of non vitamin K anticoagulantia (NOACs) was included for LIM.

Objective/Aim: To increase the number of inclusions for LIM by facilitating pharmacies to send a digital invitation to potential participants.

Methods: During this project a digital method was developed to alert the pharmacy technician about a first-time user and to invite the patient directly for LIM by e-mail. To test this application we performed a 6 months pilot in 30 pharmacies throughout the Netherlands. The number of inclusions was monitored and compared with the number of inclusions of the same pharmacies in the past, when recruitment was through the information leaflet. Furthermore the number of inclusions was compared with the number of inclusions by 30 other pharmacies during the same 6 months period by using the information leaflet method. During and after the pilot the new digital recruitment method was evaluated with the pharmacists of the pilot pharmacies.

Results: The digital application to alert the pharmacy and send an e-mail invitation to first time NOAC users was developed during the first 3 months of the project. Subsequently, this application was introduced by the 30 pilot pharmacies.

During the 6 months pilot the inclusion number for the LIM NOACs study was 58 participants. This is a quadrupling compared to the average number of inclusions over the past 3 years of the same pharmacies. Compared to the 30 pharmacies during the same period, using the leaflet method, the number increased even sevenfold.

Evaluation with local pharmacists provided insight in the practical bottlenecks of the new application. Some technical issues were solved during the pilot period. Other suggestions were mainly about the implementation of the method in the daily practice of the pharmacies.

Conclusion: Using a digital recruitment method to invite patients in local pharmacies led to an increase of the number of inclusions for the LIM NOACs study. The method will be implemented on large scale in the Netherlands.

Disclosure of Interest: None declared.

142 ISoP18-1197 Training an Augmented Intelligent System for Pharmacovigilance: Practical Considerations and Guidance

142.1 D. Abatemarco^*1, S. Desai¹, B. Assuncao¹, N. Tetarenko¹, K. Danysz¹, R. Mockute¹, M. Widdowson¹, N. Fornarotto¹, S. Beauchamp¹, S. Cicirello¹, E. Mingle¹

142.1.1 ¹Global Drug Safety and Risk Management, Celgene Corporation, Summit, United States

Background/Introduction: Regulations are increasing the scope of activities that fall under the remit of drug safety. Currently, individual case safety report (ICSR) collection and collation is done manually, requiring pharmacovigilance professionals to perform many transactional activities before data is available for assessment and aggregated analyses. For a biopharmaceutical company to meet its responsibilities to patients and regulatory bodies regarding the safe use and distribution of its products, improved business processes must be implemented to drive the industry forward in the best interest of patients globally.

Objective/Aim: In this study, we seek to build an augmented intelligent machine-learning system for use across pharmacovigilance. This machine-learning system will handle all pharmacovigilance activities from ICSR intake through signal detection.

Methods: A consortium of 10 cognitive computing services was identified and trained to augment the initial processing of ICSRs for Celgene products. Models were trained using Celgene data and results reviewed by pharmacovigilance subject-matter experts. To be considered adequately trained and functional, each cognitive service was required to reach a threshold of F₁ score ≥ 75%.

Results: All 10 cognitive services have reached an F₁ score ≥ 75% for spontaneous ICSRs.

Conclusion: Cognitive services can augment pharmacovigilance professionals’ decisions and provide efficiency in managing the overwhelming amount of data otherwise manually curated and monitored for ongoing drug surveillance requirements. Cognitive solutions will be key to an organization’s transformation to the real-time and supported decision making needed to meet regulatory requirements and usher in the future of pharmacovigilance as a patient-centered business function.

Disclosure of Interest: D. Abatemarco Shareholder of: Celgene Corporation, Employee of: Celgene Corporation, S. Desai Shareholder of: Celgene Corporation, Employee of: Celgene Corporation, B. Assuncao Shareholder of: Celgene Corporation, Employee of: Celgene Corporation, N. Tetarenko Shareholder of: Celgene Corporation, Employee of: Celgene Corporation, K. Danysz Shareholder of: Celgene Corporation, Employee of: Celgene Corporation, R. Mockute Shareholder of: Celgene Corporation, Employee of: Celgene Corporation, M. Widdowson Shareholder of: Celgene Corporation, Employee of: Celgene Corporation, N. Fornarotto Shareholder of: Celgene Corporation, Employee of: Celgene Corporation, S. Beauchamp: None Declared, S. Cicirello: None Declared, E. Mingle Shareholder of: Celgene Corporation, Employee of: Celgene Corporation.

143 ISoP18-1198 Cognitive Services for Pharmacovigilance Transformation

143.1 S. Bao^*1, S. Perera¹, C. Ramakrishnan¹, R. Routray¹, B. Assuncao², N. Tetarenko², D. Abatemarco², R. Mockute², K. Danysz³, M. Widdowson³

143.1.1 ¹IBM Watson Health, San Jose, CA, United States; ²Pharmacovigilance Innovation, Celgene Corp, Summit, NJ, United States; ³Global Drug Safety, Celgene Corp, Boudry, Switzerland

Background/Introduction: Today, the pharmacovigilance (PV) process is heavily dependent on people throughout each step. With ever-increasing volumes of safety reports, traditional manual approaches of growing in-house teams and outsourcing are becoming unsustainable. Cognitive computing offers capabilities to help handle enormous amounts of information, both structured and unstructured. It improves the ability to understand large volumes of data that humans can’t handle or analyze on their own.

Objective/Aim: Transform PV process with cognitive computing technologies to fully embrace ever-increasing volumes of safety reports. With timeliness and quality of safety operations as critical as ever, cognitive services are designed and integrated to add speed and consistency to the entire pharmacovigilance process from AE intake, triage (event prioritization), evaluation and reporting, to signal detection and assessment.

Methods: Cognitive Services are designed, developed and evaluated based on the following methodologies.

• By design, cognitive services are built on the deep partnership between PV experts and cognitive technology experts, from development to operation. PV experts not only impart expertise via the training data for cognitive service model development but also provide human oversight during production to confirm all evaluations and actions.

• Cognitive services are built on multiple modular components following a micro-services paradigm. Each service is configurable and trainable separately to understand the context of different types of safety reports such as spontaneous reports, clinical trials, and medical literature.

• Cognitive service accuracy is evaluated and validated by following two layers of quality processes. In the first layer, PV experts ensure the high quality of training data and in the second layer, PV experts double check the worst tolerable error cases of each cognitive service by following the Acceptable Quality Limits (AQL) process.

Results: Over 10,000 safe reports have been manually curated and annotated as training data for cognitive model training, and over 40 cognitive services (e.g., adverse event detection, MedDRA coding and ICSR classification) have been identified, trained and approved using AQL process to extract and classify data relevant to each safety report through a comprehensive analysis of the end-to-end PV process focusing on where cognitive technologies can contribute most significantly.

Conclusion: This development accomplishment demonstrates the feasibility and effectiveness of using cognitive computing technologies to transform the pharmacovigilance process with PV expert in the loop.

References:

• 1. Argentinis E, Roberts L, Fraser H. Scaling safety expertise in life sciences: A turning point in pharmacovigilance. IBM Institute for Business Value 2017. https://www-935.ibm.com/services/us/gbs/thoughtleadership/scalingsafety/

• 2. Micro Services: https://en.wikipedia.org/wiki/Microservices

• 3. Acceptable Quality Limit: https://en.wikipedia.org/wiki/Acceptable_quality_limit

Disclosure of Interest: None declared.

144 ISoP18-1199 Augmented Intelligence and the Future of the Drug Safety Professional

144.1 K. Danysz^*1, S. Cicirello², E. Mingle², B. Assuncao², N. Tetarenko², R. Mockute², D. Abatemarco², M. Widdowson², S. Desai²

144.1.1 ¹Global Drug Safety and Risk Management, Celgene, Boudry, Switzerland ; ²Global Drug Safety and Risk Management, Celgene, Summit, United States

Background/Introduction: Automation and augmented intelligence (AI) in the field of pharmacovigilance (PV) will result in the transformation of the drug safety (DS) professional’s work life. A machine-learning (ML) system that will become the new AI-assisted PV database, will impact working practices and processes in the PV industry [1]. The new envisioned work environment promises to address current challenges, such as time pressures, strained resources, and ever-increasing financial restrictions as PV moves from a volume-based business model to a value-based one, better serving the DS professional, the PV industry and ultimately, patients [2]. There is a school of thought that believes use of artificial intelligence will not result in humans losing their jobs with widespread redundancy but instead will create jobs [3].

Objective/Aim: To understand the sentiment of DS professionals towards AI in PV, to envision potential future roles for the DS professional in the new work environment and to ascertain what skills will be required.

Methods: A group of DS employees at Celgene’s Global Drug Safety and Risk Management Department (GDSRM) was interviewed to gain an understanding of their work experience, educational backgrounds, attitudes toward the anticipated changes, hopes for future roles with the ML system, thoughts on support required to adapt their skills to the new environment and the envisioned new roles.

Results: The DS professionals showed interest in development aligned with their own skills, passions, and interests. There was a general need for acquiring new proficiencies in basic computer science, as to understand concepts of natural language processing, ML, and cognitive computing as well as skills in statistics for better data analysis. In their understanding of how the ML system would function, the DS professionals suggested new approaches to daily work and visions for career pathways. A future DS specialist role would focus more on verification of information as suggested by the ML system and may potentially increase their productivity and/or utilize their time accordingly in other work activities. Some other examples of envisioned roles included working in the field of pharmacoepidemiology and focusing on a higher involvement with other functions in the company or with external stakeholders such as regulatory bodies. The DS professionals could potentially bring value in the form of new insights from PV data and be able to assist with company decisions and strategies for patient care and safety. The transcription of non-machine-readable documentation is also required if administrative work is desired.

Conclusion: The DS professionals interviewed were optimistic and enthusiastic about their job roles changing when the ML system for PV was implemented. The vision of all interviewees was one in which PV resources, time, and skills were better used and applied to ultimately achieving better patient outcomes. Managerial implications include transitioning the staff who will engage with the new solution for PV data uptake and analysis. There are opportunities to educate and develop the PV professional through training modules. With the appropriate steps taken, the future of harnessing and utilizing PV talent is promising in the environment where DS professionals are assisted in their daily work by AI.

References:

• 1. Leaf C. Here’s the surprising reason IBM is partnering with Celgene. Time Magazine website. http://time.com/4552874/ibm-watson-health-celgene-partnership/.

• 2. Botsakos G. The future of pharmacovigilance: five imperatives that will drive improved business outcomes. Cognizant Business Consulting website. https://www.cognizant.com/industries-resources/life_sciences/The-Future-of-Pharmacovigilance-Five-Imperatives-that-Will-Drive-Improved-Business-Outcomes.pdf.

• 3. Marr B. Instead of destroying jobs artificial intelligence (AI) is creating new jobs in 4 out of 5 companies. Forbes website. https://www.forbes.com/sites/bernardmarr/2017/10/12/instead-of-destroying-jobs-artificial-intelligence-ai-is-creating-new-jobs-in-4-out-of-5-companies/#58d27da7120d

Disclosure of Interest: K. Danysz Employee of: Celgene, S. Cicirello Employee of: Celgene, E. Mingle Employee of: Celgene, B. Assuncao Employee of: Celgene, N. Tetarenko Employee of: Celgene, R. Mockute Employee of: Celgene, D. Abatemarco Employee of: Celgene, M. Widdowson Employee of: Celgene, S. Desai Employee of: Celgene.

145 ISoP18-1202 Reporting of Qt Interval Prolongation and Torsade De Pointe for Hiv-Antiretrovirals in Vigibase: Focus on Potential Drug–Drug Interactions

145.1 A. Simon^*1,2, C. Marzolini^2,3,4, F. Vanobberghen^1,2, C. Burri^1,2, A. Kuemmerle^1,2

145.1.1 ¹Swiss Tropical and Public Health Institute, Basel, Switzerland; ²University of Basel, Basel, Switzerland; ³Department of Infectious Diseases & Hospital Epidemiology and Department of Clinical Research, University Hospital Basel, Basel, Switzerland; ⁴Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom

Background/Introduction: QT interval prolongation and Torsade de Pointes (QT/TDP) are rare but serious cardiac events that can lead to sudden cardiac death. The prevalence of QT/TDPs in the general population is difficult to determine but people living with HIV have 7–8 times higher risk for QT prolongations compared to the general population, possibly related to administered drugs [1, 2]. Several HIV-antiretrovirals (ARV) and various non-HIV drugs such as methadone, domperidone, haloperidol, and azithromycin have the potential to prolong the QT interval particularly in the context of drug–drug interactions (DDI).

Objective/Aim: Assess the frequency of potential DDIs in individual case safety reports (ICSR) reporting QT/TDPs together with ARVs, and registered in VigiBase, the WHO global database.

Methods: The WHO Collaborating Centre for International Drug Monitoring, Uppsala Monitoring Centre provided an extract of VigiBase including all ICSRs with ARVs considered as suspected or interacting reported by member countries since 1987 until January 2018. The following adverse events (coded as MedDRA Preferred Term) were defined as QT/TDP events: electrocardiogram QT prolonged, long QT syndrome and torsade de pointes. DDIs with ARVs were screened using the Liverpool HIV Drug Interactions database and categorized as deleterious (red), of potential clinical relevance (amber), of weak clinical relevance (yellow) or not interacting (green) [3]. Analyses were descriptive and performed using Stata^® 15 (2017).

Results: Of 180,626 ICSRs, 205 (0.1%) ICSRs mentioned QT/TDPs. Of these, 156 reported at least one co-medication. The five most frequently reported co-medications were methadone, sulfamethoxazole–trimethoprim, fluconazole, lorazepam, and azithromycin. Most frequently observed drug-pairs with red DDI potential involved saquinavir together with methadone, cocaine, or haloperidol. For the amber drug-pairs, atazanavir–methadone, ritonavir–methadone and saquinavir–clindamycin were the most frequently involved. Drug-pairs of the yellow and green categories mainly included co-medication combined mainly with non-nucleoside reverse transcriptase inhibitors (NRTI) with low propensity for metabolic DDI or QT/TDP.

Conclusion: Overall, QT/TDP reporting was low in VigiBase. The number of drug-pairs associated with a higher risk for QT/TDPs was substantial within ICSRs reporting QT/TDP. ARV included boosted atazanavir or saquinavir and co-medications such as methadone, haloperidol, fluconazole, and clindamycin (known risk for QT/TDP), and sulfamethoxazole–trimethoprim (risk for patients with congenital long QT syndrome) [4].

References

• 1. Reinsch N, Arendt M, Geisel MH, Schulze C, Holzendorf V, Warnke A, et al. Prolongation of the QTc interval in HIV-infected individuals compared to the general population. Infection 2017;45:659–67

• 2. Reinsch N, Buhr C, Krings P, Kaelsch H, Neuhaus K, Wieneke H, et al. Prevalence and risk factors of prolonged QTc interval in HIV-infected patients: results of the HIV-HEART study. HIV Clin Trials 2009;10:261–8

• 3. Liverpool Uo. HIV Drug Interactions Tables 2018 [cited 2018 01 March]. Available from: https://www.hiv-druginteractions.org/.

• 4. CredibleMeds. Search for drugs that prolong QT & induce Torsades de Pointes (TdP) [Cited on April 16th, 2018]. Available from: https://crediblemeds.org/index.php/drugsearch.

Disclosure of Interest: None declared.

146 ISoP18-1204 Adverse Effects in Elderly Subjects: Experience of the National Pharmacovigilance Center of Morocco

146.1 S. Yanisse^1,2, A. Tebaa^*1, I. Daoudi^1,2, R. Soulaymani ¹

146.1.1 ¹Antipoison and Pharmacovigilance Center of Morocco, Ministry of Health, Rabat, Morocco; ²Faculty of Medicine and Pharmacy, Rabat, Morocco

Background/Introduction: Adverse drug reactions (ADRs) in the elderly are relatively frequent. This vulnerability to ADR is explained by the physiological and/or pathological aging that leads to pharmacokinetic and pharmacodynamic changes. All these modifications can be responsible for an accumulation of active principles associated with an increased sensitivity to drug treatment, to these elements is added the polypathology responsible for a polymedication which is sometimes necessary for the patient but consequently increases drug interaction risks and therefore the risk of ADR (1, 2).

Objective/Aim: To Describe adverse drug reactions (ADRs) and imputed drugs to subjects aged over 65 in Morocco during the period 2014–2018.

Methods: A retrospective study was conducted on the BDD Database of the CNPV (National Center for Pharmacovigilance). The ADRs were coded according to the Medical Dictionary for Regulatory Activities (MedDRA version 20.1) and grouped into the system organ class (SOC). Each notification was reviewed and analyzed by qualified CAPM medical staff before being recorded in the database. The suspect drugs were coded as International Nonproprietary Names (INN) and classified according to the Therapeutic and Chemical Anatomical Classification (ATC). The analysis is done on vigilyse.

Results: 1830 subjects over the age of 65 were included in the study, of which 973 (53%) are female and 800 (44%) male and 57 (3%) are unknown sex. 24087 ADRs have been detected. The most frequently reported ATC classes were Anti-infectious (24.5%), antineoplastic (22%), and systemic Cardiovascular (21.5%).

In the ADRs, the predominantly imputed drugs were anti-tuberculosis drugs (Ethambutol, Isoniazid, Pyrazinamide, Rifampicin) (18%), beta-lactam antibacterial [Amoxicillin (1.9%), Amoxicillin-clavulanic acid (1.6%)], and others, antineoplastic agents [Rituximab (2.5%), Docetaxel (2%), Cisplatin (1.8%)…], Cardiovascular System [Amlodipine (2.2%), Furosemide (1.8%)…], Acetylsalicylic Acid (4.5%).

The most commonly reported ADRs were skin and subcutaneous tissue disorders (pruritus, rash, urticaria…) (19.9%), gastrointestinal disorders (vomiting, diarrhea, abdominal pain…) (17.9%), general disorders and site administration condition (asthenia) (15.2%)…

Conclusion: The occurrence of ADRs in elderly people patients is a real public health problem. The analysis of the different dimensions such as the quality of the prescription, the transcription, the dispensing, the administration as well as the therapeutic observance of these patients will make it possible to identify and implement corrective measures in order to reduce the avoidable part of occurrence of adverse drug reactions.

References:

• 1. Ankri J. Le risque iatrogène médicamenteux chez le sujet âgé. Gérontologie et société 2002;25:93–106.

• 2. Kanagaratnam L, Taam MA, Heng M, De Boissieu P, Roux M-P, Trenque T. Les effets indésirables médicamenteux graves et leur évitabilité chez des sujets âgés de plus de 65 ans. Thérapie 2015;70:477–84

Disclosure of Interest: None declared.

147 ISoP18-1207 Antibiotics Induced Adverse Drug Reactions in Hospitalized Pediatric Patients: Interim Results from a Prospective Observational Study

147.1 N. B. Bulik¹, A. Farcas², C. Bucsa^*2, I. Cazacu³, A. Slavcovici⁴, O. Oniga¹

147.1.1 ¹Department of Pharmaceutical Chemistry; ²Drug Information Research Center; ³Department of Pharmacology, Physiology and Pathophysiology, Faculty of Pharmacy; ⁴Department of Medical Specialties, Infectious Diseases, University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca, Romania

Background/Introduction: Antibiotics are therapeutic agents widely prescribed in pediatric patients. Therefore, their safety profile is an important issue [1].

Objective/Aim: To assess the ADRs of antibiotics in hospitalized children and to identify the risk factors that lead to ADRs.

Methods: We conducted a prospective observational study in the pediatric department of a Hospital for Infectious Diseases. We enrolled all children with antibiotic therapy prescribed at hospital admission or during hospitalization. Participants were aged up to 18 years and all had bacterial/viral infections. For each child, we collected demographic characteristics, medical treatment, and laboratory findings from their medical chart. The occurrence of new symptoms was assessed through a face-to-face interview with the parent.

Results: Here we present the interim results on the identified adverse events (AEs) for the first 125 participants. The median age of children was 3 years [0–17] and 52% of them were male. The median length of hospitalization was 5 days [2–22]. Penicillin G (31%) was the most frequently prescribed antibiotic, followed by ceftriaxone (27%) and cefuroxime (25%). Dual antibiotic therapy was prescribed to 20 children. A total of 47 (36.7%) children experienced at least one AE. The most frequent AEs were neutropenia (n = 10), vomiting (n = 9) and diarrhea (n = 7). Two cases of rash were reported. The causality, severity and preventability of AEs will be further evaluated and until then these results should be interpreted with caution.

Conclusion: The interim results of our study highlighted the importance of monitoring the safety of antibiotics in the pediatric patients.

References:

• 1. Buccellato E, Melis M, Biagi C, Donati M, Motola D, Vaccheri A. Use of antibiotics in pediatrics: 8-years survey in Italian Hospitals. PloS One 2015;10:e0139097

Disclosure of Interest: None declared.

148 ISoP18-1208 Incidence, Prevalence and Risk Factors of Hypoglycaemia in Diabetes Patients: Systematic Review and Meta-analysis of Observational Studies

148.1 H. Alwafi^*1, A. Alsharif¹, L. Wei¹, A. Naser¹, S. Bell², J. Ilomaki², G. Fang³, M. Al Metwazi⁴, I. Wong^1,5

148.1.1 ¹University college London, London, United Kingdom; ²Monash university, Melbourne, Australia; ³University of North Carolina, Chapel Hill, United States; ⁴King Saud University, Riyadh, Saudi Arabia; ⁵The University of Hong Kong, Hong Kong, Hong Kong

Background/Introduction: Diabetes forms a global health concern and is associated with serious complications and multiple comorbidities [1]. Hypoglycaemia is a major challenge in the treatment of diabetes [2].

Objective/Aim: To review the existing literature for articles that investigated the incidence, prevalence and risk factors of hypoglycaemia in type 1 and type 2 diabetes patients.

Methods: PubMed, Embase and Cochrane library databases were searched up to July 2017. Search strategy was conducted using keywords and MeSH terms. Two reviewers independently screened articles, extracted data and assessed the quality of included studies. Observational studies including patients from all age groups, any study design related to the incidence, prevalence and risk factors of hypoglycaemia in diabetes were included in the review and meta- analysis was conducted where appropriate. Pooled estimate for the incidence and prevalence of hypoglycaemia in type 1 and type 2 diabetes patients were calculated using random effect model with 95% CI.

Results: Our search strategy generated 31,288 articles, of which only 225 studies matched our inclusion criteria and were included in the systematic review. For the meta-analysis, only 88 studies were included. The pooled estimate of the prevalence of hypoglycaemia was 23.17% (95% CI 22.47–23.86), comprising a total of 743,055 patients with diabetes. The pooled episodes rate for hypoglycaemia was 47.47 per 1000 patient-years (95% CI 472.09–477.32), involving 45,083,541 diabetes patients. The pooled episodes rate estimate for hypoglycaemia stratified by type of diabetes was 149.19 episodes per 100 patient-years (95% CI 145.53–152.85) and 136.98 per 100 patient-years (95% CI 132.96–141.01) for T1DM and T2DM, respectively. The pooled episodes estimate stratified by treatment regimen was 184.62 (95% CI 180.60–188.64) for insulin-based therapy and 153.23 episodes per 100 patient-years (95% CI 142.90–163.55) for patients receiving a combination of insulin and oral therapy. The pooled incidence estimate of new cases of hypoglycaemia was 5.99 per 100 patient-years (95% CI 4.17–7.82), involving 148,609 participants. History of previous hypoglycaemia, old age, chronic kidney disease, intensive anti-diabetic therapy, insulin therapy and sulfonylureas were the main risk factors associated with hypoglycaemia.

Conclusion: Hypoglycaemia is very common among patients with diabetes. Further studies are needed to investigate hypoglycaemia-associated risk factors.

References:

• 1. Guariguata L., et al., Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014. 103:137–49

• 2. Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabetes Care. 2003;26:1902–12

Disclosure of Interest: None declared.

149 ISoP18-1210 Physician Attitudes Toward Pharmacists Advice on the Appropriateness of Prescribing

149.1 L. Garza Ocañas^*1, M. Galvan-Cantu², M. Rodríguez-Almendariz², J. D. Torres-Garza³, A. Pérez-Garza², E. Pérez-Rodríguez¹

149.1.1 ¹Facultad de Medicina y Hospital Universitario “Dr. José E. González”, Nuevo León, Mexico; ²Hospital Universitario “Dr. José E. González”, Universidad Autónoma de Nuevo León, Nuevo León, Mexico; ^;3Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, Mexico

Background/Introduction: Medication Errors (ME) is a well-documented problem in pharmacovigilance. The analysis of the 2016 ME in our University Hospital shows that the most common ME are related to the prescription process (66%). The pharmacist advice on the appropriateness of the prescription is an important activity to reduce the number of prescription ME. Acceptance of the physician to pharmacist intervention on drug related problems is an activity that has been not studied previously in our Hospital.

Objective/Aim:

To describe the pharmacist interventions given as the number of interventions in all prescription reviewed during the study period as well as response of physicians toward pharmacists interventions on drug related problems.

Methods:

The study was conducted at Hospital Universitario “Dr. José E. González”, Monterrey, Nuevo León, México, from January to December 2017. The surveillance on the appropriateness of the prescription was made at the Internal Medicine, Pediatrics, Surgery and Ginecology and Obstetrics Departments. Age, sex, type of problem (drug, dose, frequency, route of administration), intervention and outcome (physiciansattitudes) were prospectively recorded.

Results:

Of a total of 719 interventions, the overall acceptance rate was 67%. Most of the interventions were made in prescriptions ordered by surgeons, followed by internal medicine physicians and pediatricians. Antibiotics and analgesic were the most common drug involved. The most common drug related problem were the improper prescription and dosage problem. The main pharmacist interventions were dose adjustment (24%) and optimization of routes and frequency of administration (23%).The type of drug related problem influenced physician attitude, with pharmacist participation being most acceptable for errors involving dose.

Conclusion:

The study indicates that most of the physicians accepted pharmacist counseling with respect to potential adverse drug reactions, related to medication errors due to inappropriate prescription. Training courses are required for further motivation of physicians on importance of pharmacist advice to reduce the number of medication errors due to potentially inappropriate prescription.

Disclosure of Interest: None declared.

150 ISoP18-1211 Analysis of Adverse Drug Reactions Using Patient Safety Network (Psn) Severity Score Method Compared to Naranjo Algorithm

150.1 F. A. Al-Braik^*1, M. M. Tashtoush¹, R. Saad¹, M. Y. Hasan²

150.1.1 ¹Pharmaceutical Department, Abu Dhabi Health Services, Abu Dhabi, United Arab Emirates; ²College of Medicine & Health Silences, UAE University, Al Ain, United Arab Emirates

Background/Introduction: Voluntary reporting is a recognised method of recording adverse drugs reactions (ADRs) in patients. ADRs can be reported utilizing Patient Safety Network (PSN) system available for healthcare professionals at facilities accredited by Joint Commission¹.

Objective/Aim: This study examined incidents of ADRs at Abu Dhabi Health Services (SEHA) a government healthcare network adopted PSN as part of patient records. The study assessed ADRs using PSN Severity score method compared to Naranjo Algorithm.

Methods: 264 ADRs cases were reported during 2017.A Taskforce was assigned for assessing causality and evaluating outcomes through two different methods calculating severity score of PSN and probability score of Naranjo Algorithm.

Results: Highest class involved were: antibacterials (n = 85, 32.2%), anticancer (n = 39, 14.8%), iron (n = 36, 13.6%), NSAIDs (n = 27, 10.2%), opioids (n = 15, 5.7%), anti-nausea (n = 11, 4.2%), vaccines (n = 7, 2.7%) and autoimmune drugs (n = 6, 2.3%). 10 most common medications were: Ferric Carboxymaltose (n = 34, 27.6%), Ceftriaxone (n = 16, 13%), Ciprofloxacin (n = 10, 8.1%), Moxifloxacin (n = 10, 8.1%), Vancomycin (n = 10, 8.1%), Piperacillin + Tazobactam (n = 9, 7.3%), Amoxicillin- Clavulanate (n = 8, 6.5%), Oxaliplatin ((n = 9, 7.3%) and Carboplatin (n = 8, 6.5%).

187 reports were assessed comparing Naranjo Algorithm with PSN Severity Score. According to Naranjo 158(84.5%) cases classified probable, 22(11.8%) possible, 6(3.2%) highly probable and 1(0.5%) doubtful. As per PSN-Severity Score 46(25.1%) cases classified mild, 101(55.2%) moderate, 34(18.6%) sever and 1 case (1.1%) life threating. 5 cases were not identified. Using PSN-harm Score analysis 1(0.5%) case of unsafe condition (harm score = 1), 1(0.5%) case of near miss (Harm Score = 2), 24 (12.8%) cases of no harm evident, physical or otherwise (Harm score = 3), 34 (18.1%) cases of emotional distress or inconvenience (harm score = 4), 123 (65.4%) cases required additional treatment (Harm score = 5) and 5 (2.7%) cases classified as temporary harm (Harm score = 6).Most common outcome was hypersensitivity reported with Antibacterials. Shortness of breath and hypersensitivity reactions such as itching and skin rashes were reported with chemotherapy agents and Ferric medications.

Conclusion: A similar severity assessment result was obtained comparing Naranjo Algorithm with PSN Severity Score [2]. Using PSN added a further dimension of measuring harm score. Majority of ADRs are preventable through improved health professions education and prescribing monitoring [3,4]. Monitoring the trend of ADR and severity and implementing measures for rational use of medicines to improve patient safety is a vital measure

References:

• 1. Madan A, Borckardt D, Borckardt JJ, Herbert J, Cooney H. A new approach to tracking the harmfulness of medical errors in health care systems. Qual Manag Health Care 2010;19:298–303

• 2. Murayama H, Sakuma M, Takahashi Y, Morimoto T. Improving the assessment of adverse drug reactions using the Naranjo Algorithm in daily practice: The Japan adverse drug events study. Pharmacol Res Perspect 2018;6(1) https://doi.org/10.1002/prp2.373

• 3. Angamo MT, Chalmers L, Curtain CM, Bereznicki LR. Adverse-Drug-Reaction-Related hospitalisations in developed and developing countries: a review of prevalence and contributing factors. Drug Saf 2016;39:847–57

• 4. 4-Ganesan S, Sandhiya S, Reddy KC, Subrahmanyam DK, Adithan C. The impact of the educational intervention on knowledge, attitude, and practice of pharmacovigilance toward adverse drug reactions reporting among health-care professionals in a tertiary care hospital in South India. J Nat Sci Biol Med 2017;8:203–9

Disclosure of Interest: None declared.

151 ISoP18-1212 Risk Factors of Major Bleeding in Patients Prescribed Rivaroxaban in Primary Care in England: Based on a Modified-Prescription Event Monitoring Study

151.1 D. Roy^1,2, S. Dhanda^1,2, L. Wise¹, S. Shakir^*1,2

151.1.1 ¹Drug Safety Research Unit, Southampton, United Kingdom; ²University of Portsmouth, Portsmouth, United Kingdom

Background/Introduction: Clinical trials and observational studies have reported bleeding risk in patients taking oral anticoagulants. It is valuable to understand the predictors for major bleeding in patients prescribed rivaroxaban in primary care in England.

Objective/Aim: Multivariable logistic regression (MLR) analyses to explore potential risk factors for major bleeding within gastrointestinal (GI), urogenital (UG) and intracranial (IC) sites.

Methods: A case/non-case design was used to study the association between clinical risk factors and major bleeding in a cohort of rivaroxaban patients (N = 17546) in a single-arm Modified-Prescription Event Monitoring study identifying patients from dispensed prescriptions in England (2012–2016), followed for 12 months. Clinical risk factors for bleeding and bleeding outcomes were collected from prescribing general practitioners via questionnaires sent at ≥ 3, and ≥ 12 months observation. Univariate and multivariable logistic regression analyses were performed to examine the association for each different site. Multivariable analyses models were based on 2 different clinical approaches; Clinical Risk Factors Selection (CS) model and HAS-BLED (HB) model. The CS model included all reported clinical risk factors for bleeding. The HAS-BLED model included the HAS-BLED clinical risk score categories (low, moderate or high risk) and gender. Statistically significant (p < 0.05) associations from the MLR models are presented in the results section.

Results: Risk factors for Major GI bleed (n = 176).

CS Model: Age 65–74 vs < 65 years: OR = 2.4 [95% CI 1.3, 4.6]; Age ≥ 75 years vs < 65 years: OR = 4.2 [95% CI 2.3, 7.5]; Predisposition to or history of bleeding: OR = 4.8 [95% CI 3.1, 7.5].

HB Model: Moderate vs low: OR = 4.0 [95% CI 2.1, 7.6]; High vs low: OR = 8.9 [95% CI 4.0, 19.9].

Risk factors for Major UG bleed (n = 36).

CS Model: Age 65–74 years vs < 65 years: OR = 0.2 [95% CI 0.1, 0.7]; Females vs males: OR = 2.9 [95% CI 1.4, 6.1]; Malignancy: OR = 2.6 [95% CI 1.1, 6.3].

HB Model: Females vs males: OR = 2.7 [95% CI 1.3, 5.6].

Risk factors for Major IC bleed (n = 57).

CS Model: Age ≥ 75 years vs < 65 years: OR = 2.8 [95% CI 1.1, 6.9]; History of cerebrovascular accident/transient ischaemic attack (CVA/TIA) (including haemorrhagic CVA): OR = 2.2 [95% CI 1.3, 3.9]; Predisposition to or history of bleeding: OR 2.6 [95% CI 1.0, 6.7].

HB Model: Moderate vs low: OR = 3.3 [95% CI 1.2, 9.1]; High vs low: OR = 9.0 [95% CI 2.5, 31.9].

Conclusion: Use of the case/non-case design to explore risk factors for bleeding in rivaroxaban patients using the CS model identified age ≥ 65 and history of bleeding or predisposition as statistically significant prognostic factors for major GI bleeds. For major UG bleeds, age group 65–74 years, female gender (which may be related to vaginal bleeding including menorrhagia) and malignancy were statistically significant in the CS model. For major IC bleeds, age ≥ 75 years, history of CVA/TIA and history of bleeding or predisposition to bleeding were identified as statistically significant risk factors in the CS model. The HB model showed that moderate and high risk scores were statistically significant risk factors for major GI and IC bleeds and gender statistically significant for major UG bleeds. Overall, findings from the CS model and the HB model are in keeping with known clinical risk factors for bleeding.

Disclosure of Interest: D. Roy Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications. S. Dhanda Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications. L. Wise Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications. S. Shakir Other: The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU has received funding from Bayer, the manufacturer of Xarelto^®. The DSRU makes the final decision on the publication of external communications.

152 ISoP18-1215 Drug Safety: In Vitro Study of Physicochemical Incompatibilities of Infusion Medications Linked to pH Variation

152.1 I. Bennani¹, Z. El Asil², A. Cheikh³, H. Mefetah⁴, M. Draoui¹, M. Bouatia^*1

152.1.1 ¹Laboratory of analytical chemistry Faculty of Medicine and Pharmacy of Rabat, University Mohamed V, Rabat, Morocco; ²Faculty of Medicine and Pharmacy of Rabat, University Mohamed V, Rabat, Morocco; ³Faculty of Pharmacy, Abulcasis University, Rabat, Morocco; ⁴Pediatrics Hospital, CHIS, Rabat, Rabat, Morocco

Background/Introduction: The administration of incompatible products could indeed cause the appearance of a precipitate or the inactivation of one or other of the active ingredients considered. PH changes in infusion medications after contact with other acidic or basic drugs (or solutions) may lead to the formation of a precipitate which can obstruct the pathway and hinder the passage of the drug to the patient; In addition, if the precipitate enters the bloodstream without being solubilized, it can obstruct the blood vessels and cause various problems in the more or less long term.

Objective/Aim: The aim is to detect and investigate the visible physicochemical incompatibilities of injectable drugs commonly used in a resuscitation service with other acid or basic drugs in an infusion, by a simulation model to test the behavior of these drugs. Drugs with respect to the pH change.

Methods: We carried out this in vitro experimental study at the laboratory of analytical chemistry at the Faculty of Medicine and Pharmacy of Rabat, and at the Children’s Hospital of Ibn Sina University Hospital in Rabat.

We selected 31 parenteral drugs most commonly used at the children’s hospital of Ibn Sina University Hospital in Rabat.Powder drugs are prepared using the exact amounts of water for injection required for preparations for injection.Mixtures of these test drugs were then made with a solution of hydrochloric acid (HCl) and sodium hydroxide solution (NaOH) to reveal drug incompatibilities via the formation of precipitates by visual inspection, or by infrared spectrophotometry to identify their nature.

Results: The most important results obtained are summarized in the following table:

Conclusion: This study allowed us to reveal several physicochemical incompatibilities of injectable drugs related to pH, it also allowed us to establish a recommendation that prevents the simultaneous administration to the patient by the same route an acid drug with a basic drug.

Disclosure of Interest: None declared.

153 ISoP18-1216 Pharmacovigilance in Bioequivalence Studies: Is there a Difference in the Prevalence of Adverse Events Between Original and Generic Medicines?

153.1 A. Cheikh¹, M. Bouatia^*2, M. R. Ajaja¹, E. A. Faouzi¹, A. Bouklouze³, A. Benomar¹, Y. Cherrah¹

153.1.1 ¹Bioequivalence Center, Abulcasis University, Rabat, Morocco; ²Chemistry, ³Bioequivalence Center, Mohammed V University, Faculty of Medicine and Pharmacy, Rabat, Morocco

Background/Introduction: Bioequivalence studies are conducted to demonstrate that the pharmacokinetic profile of the original and generic drugs is the same, which could conclude that the pharmacodynamic effect would be the same. These studies can also provide insights into the safety profile of original and generic drugs through the collection of adverse events reported in clinical trials.

Objective/Aim: Our aim trought this study was to assess the prevalence of adverse events in bioequivalence studies conducted in our bioequivalence center. Also, we aimed to compare the prevalence of adverse events notified with generic and original medicines used in bioequivalence studies.

Methods: We calculated the prevalence of adverse events reported in bioequivalence studies conducted in 1 year. We studied all adverse events notified by investigators in bioequivalence studies in our center. The French method was applied to study the imputability between notified adverse events and the administered molecules. Chi² test was used to compare between adverse events notified by using generic and original medicine. Statistical analysis were performed with SPSS 13.0.

Results: 49 adverse events were notified in the 10 bioequivalence studies involving 196 volunteers with the frequency of 4.9 per study and 0.125 per volunteer. The prevalence of adverse events was about 12.5% in our studies population. The prevalence was different depending on the therapeutic class. The prevalence was 58.3% for bisphosphonates, 26.7% for antidepressants, 0% for statins, 0% for betablockers, 4.4% for antihypertensives, 20% for analgesics, 0% for anivirals and 0% for non-steroidal anti-inflammatory medicines. There is no significant differnce in prevalence of adverse events with generic and original medicines (p  = 0.271). All adverse events reported in all studies were reported in the Summary of Product Characteristics for the administered molecules.

Conclusion: This study showed that even with a single dose of each drug, the volunteers saw adverse events whose frequency and severity differed from one molecule to another and from one volunteer to another. Our results were different from those found in other foreign studies [1,2].

Generics should provide pharmaceutical quality similar to the originator drug framed by regulatory guidelines [3,4]. Because generic drugs do not undergo Phase I, II and III clinical trials, bioequivalence testing may be an important opportunity to detect and report adverse events in relation to the administration of generic medicines.

References:

• 1. Gurer C, Pehlivanli AC, Demircigil GC. Pooled bioequivalence study database from Turkey: characterization of adverse events and determination of split points based on Gini Index as a promising method. Springer Plus 2016; 5:709

• 2. Sibille M, Deigat N, Janin A, Kirkesseli S, Durand DV. Adverse events in phase-I studies: a report in 1015 healthy volunteers. Eur J Clin Pharmacol 1998;54:13–20

• 3. United States Food and Drug Administration (2003) Guidance for Industry, Bioavailability and bioequivalence studies for orally administered drug products—General Considerations. http://www.fda.gov/ohrms/dockets/ac/03/ briefing/3995B1_07_GFI-BioAvail-BioEquiv.pdf. Accessed 15 Nov 2015

• 4. European Medicines Agency (2010) Guideline on the investigation of bioequivalence. http://www.ema.europa.eu/docs/ en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf. Accessed 15 Oct 2015

Disclosure of Interest: None declared.

154 ISoP18-1217 Material Vigilance in a Hospital

154.1 H. Bechar¹, A. Tebaa^*2, R. Soulaymani²

154.1.1 ¹National Institute of Oncology, ²Ministry of Health’s Poison Control and Pharmacovigilance Center, Rabat, Morocco

Background/Introduction: Materiovigilance is a necessity to monitor medical devices after they are placed on the market and during their life cycle in order to avoid any incident resulting from their use.

Objective/Aim: 1. Describe the frequency of materiovigilance declarations.

2. Evaluate the activity within all the services of the National Institute of Oncology of Ibn Sina hospital in Rabat.

Methods: This is a retrospective study of notifications reported by INO services between January 2017 and December 2017 using the notification forms provided by the national pharmacovigilance center. The results were analyzed according to their severity and their impact on the patient.

Results: During these 12 months, 276 notifications were collected by the pharmacovigilance unit. The prominent cases of these declarations have been classified according to their frequency and severity.

Examples of significant cases:

• 1. Elastomeric diffusers: leakage of cytotoxic products (after contact with the company, it was decided to remove the lot and replace it)

• 2. Venous catheter (intranule): perforation of the vein and hematoma.

After investigation which demonstrated the bad technique of use: user training.

Conclusion: Spontaneous notification has enabled health professionals to become aware of the risks associated with medical devices. The early declaration of any incident can reinforce the safety of the patient hence the interest to sensitize the health professionals to notify all the noticed events.

Pharmacovigilance Register of the National Institute of Oncology.

Disclosure of Interest: None declared.

155 ISoP18-1219 Dress Syndrome Associated with Diclofenac

155.1 O. Charfi^*1, S. Kastalli¹

155.1.1 ¹National Centre of Pharmacovigilance of Tunisia, Tunis, Tunisia

Background/Introduction: Drug rash with eosinophilia and systemic symptoms (DRESS syndrome) is a rare and severe potentially life-threatening condition with a mortality rate of about 10%. Most frequent drug associated with DRESS syndrome include anti epileptic drugs, allopurinol and sulfonamid. Non steroidal anti inflammatory drugs (NSAID) had been rarely associated with this syndrome.

Objective/Aim: Herein, we report the first case of diclofenac induced DRESS syndrome.

Methods: A 53-year-old woman was prescribed for back pain diclofenac 50 mg daily. Ten days after starting the treatment, she presented with fever, cough and multiple lymphadenopathy. She stopped diclofenac and was prescribed amoxicilline, paracetamol, mefenamic acid and cetirizine. One day following the first intake of these drugs, she developed generalized rash involving the trunk and the members. She was admitted to the hospital.

Clinical examination revealed temperature at 39.5 °C, generalized maculopapular pruritic rash, cervical, axillary and inguinal lymph nodes.

Blood tests showed high eosinophils count 1830/mm³. Plasmatic creatinine level was increased at 213 µmol/l. Liver enzymes were normal.

Serology for Epstein Barr virus (EBV), Cytomegalovirus (CMV) and human immunodeficiency virus (HIV) were negative.

Histological findings were compatible with DRESS syndrome.

DRESS syndrome was confirmed and all the medications were stopped except cetirizine.

Skin condition improved slowly and laboratory parameters returned to normal level in about 16 days.

Results: The diagnosis of DRESS syndrome was made in this patient based on the criteria adopted by the European group RegiSCAR. In our case, the RegiScar score was 5 (probable case):

Generalized skin rash (1), eosinophilia (2), kidney involvement (1) enlarged lymph nodes (1).

Diclofenac was suspected to be the responsible drug for the DRESS syndrome in this case based on the French method of imputability. The score for diclofenac was I2 (possible).

In the literature, NSAI drugs have been rarely reported with DRESS syndrome as a causative agent. It was associated with piroxicam, ibuprofen and celecoxib. All the patients presented with liver involvement. In our case the patient had a normal hepatic enzymes but she developed a renal involvement.

Conclusion: To our knowledge, this is the first case of DRESS syndrome induced by diclofenac.

Disclosure of Interest: None declared.

156 ISoP18-1220 Doxycycline Induced Generalized Bullous Fixed Drug Eruption: 2 Case-Reports

156.1 O. Charfi^*1,2,3, G. Lakhoua³, S. Ben Hammamia³, A. Zaiem³, I. Aouinti³, S. El Aidli³, S. Kastalli²

156.1.1 ¹Service de Recueil et d’analyse des Données, ²National Centre of Pharmacovigilance of Tunisia, Tunis, Tunisia; ³Service de Recueil et analyse des Données, National Centre of Pharmacovigilance of Tunisia, Tunis, Tunisia

Background/Introduction: Fixed drug eruption (FDE) is a cutaneous drug reaction that typically recurs in the same site on re-exposure to the culprit drug. Usually it presents as a single plaque on erythematous background. On re-exposure to the culprit dug, old lesions reappear and widespread bullous eruptions rarely occur. Generalized bullous FDE is an extremely uncommon variant, characterized by widespread blisters and erosions mimicking Stevens-Johnson syndrome and toxic epidermal necrolysis.

Objective/Aim: Herein we report 2 exceptional cases of doxycycline induced generalized bullous fixed drug eruption.

Methods: Case report n°1

A 44-year-old woman presented with a 3 days history of multiple itchy erythematous and bullous lesions. These lesions appeared 4 h after the first intake of doxycycline 200 mg. This drug was prescribed for a genital infection.

Physical examination revealed multiple well-defined bullous and erosive lesions over the lower back, the arms and the face. Lesions size varied from 3 to 6 cm. Oral and genital mucosae were not involved.

Medical questioner revealed a history of erythematous lesions involving the same localization few hours following the first intake of doxycycline 2 years ago. These lesions healed without hyperpigmented sequelae.

The patient was prescribed anti histaminic drug. Skin condition improved within 10 days.

Case report n°2

A 62-year-old woman developed less than 1 h after the first intake of docycycline, multiple erythematous and bullous lesions involving left leg, the buttock and upper members. The size of the lesions ranged from 4 to 7 cm.

The patient noticed a history of erythematous lesions involving the same localization few hours following the first intake of doxycycline 1 year ago. These lesions healed with hyperpigmented sequelae.

Skin condition improved in 15 days following drug withdrawal.

Results: The responsibility of doxycycline in inducing bullous fixed drug eruption was evaluated according to the French method of imputability as very likely in both cases because of the suggestive delay and the positive rechallenge.

Generalized bullous FDE is a relatively rare skin condition. Exceptional cases were associated to mefenamic acid, naproxen, cetrizine, and nicotinic acid.

In literature, only 2 cases of doxycycline induced Generalized bullous FDE were reported.

In both cases, lesions appeared few hours after the first drug intake and the patients had history of fixed drug eruption following doxycycline intake.

Conclusion: Present cases highlight an uncommon reaction to a commonly used drug with positive rechallenge. Physicians should be more careful on patient’s medical history to avoid such events.

Disclosure of Interest: None declared.

157 ISoP18-1221 Drug Sefty: In-Vitro Study of Physicochemical Incompatibilities of Injectable Antibiotics Used in Pediatrics with Other Drugs in an Infusion

157.1 I. Bennani¹, Z. El Asil², H. Attjioui¹, A. Cheikh³, H. Mefetah⁴, M. Draoui¹, M. Bouatia^*1

157.1.1 ¹Laboratory of Analytical Chemistry, Faculty of Medicine and Pharmacy of Rabat, Rabat, Morocco; ² Faculty of Medicine and Pharmacy of Rabat, University Mohamed V, Rabat, Morocco; ³Departement of Pharmacy, Abulcasis University, Rabat, Morocco; ⁴Departement of Pharmacy, Pediatrics Hospital, Rabat, Rabat, Morocco

Background/Introduction: Drug incompatibilities are physical and chemical reactions that occur in vitro when two or more drug solutions are combined in one syringe, even infusion fluid, or in the same tube or bottle. During the preparation or administration of the medication.

Objective/Aim: the aim is to detect and investigate visible physicochemical incompatibilities of injectable antibiotics commonly used in pediatrics with other drugs in an infusion.

Methods: We carried out this in vitro experimental study at the laboratory of analytical chemistry at the Faculty of Medicine and Pharmacy of Rabat, and at the Children’s Hospital of Ibn Sina University Hospital in Rabat.We selected 31 parenteral drugs most commonly used at Children’s Hospital of Rabat University Hospital Ibn Sina including antibiotics. form of powder are prepared using the exact amounts of water for injection required for the preparations intended for injection.After mixing of these drugs with the antibiotics to be tested to reveal the drug incompatibilities by visual inspection, and cases of formation of precipitates will be analyzed by infrared spectrophotometry to identify their nature.

Results: The mixture of Amoxicillin/Clavulanic acid with the drugs allowed us to detect 13 drug incompatibilities for example with: Adrenaline and Noradrenaline Cefixime and Cefuroxime, Imipenem/Cilastatin, Trimethoprime, Vancomycin, Furosemide, Ganciclovir, Hydrocortisone, Midazolam, Omeprazole, and with Sugammadex.

The mixture of ceftriaxone with the 30 drugs allowed us to reveal 8 drug incompatibilities, the combination of cefuroxime with the drugs allowed us to detect 13 drug incompatibilities, the mixture of Ganciclovir with the drugs allowed us to detect 17 drug incompatibilities, trimethoprime revealed 6 drug incompatibilities, and Vancomycin revealed 10 drug incompatibilities.

Conclusion: This study allowed us to reveal several physicochemical incompatibilities of injectable drugs, it also allowed us to show the validity of the recommendation that prevents the administration of drugs simultaneously infusion.

Disclosure of Interest: None declared.

158 ISoP18-1222 In Vivo Tests for Investigating Immediate Hypersensitivity to General Anesthetics

158.1 N. Amdouni ¹, M. Bouhlel^*1, S. El Aidli¹, R. Daghfous ¹, S. Kastalli¹, A. Zaiem ¹

158.1.1 ¹Tunisian National Centre of Pharmacovigilance, Tunis, Tunisia

Background/Introduction: Immediate hypersensitivity (IHS) to general anesthetics (GA) can be life threatening for patient ongoing medical procedure. On the other hand, considering a general anesthesia in a patient with history of IHS to general anesthetics must multiply the measures of prevention of recurrence of such an event. In this context anesthesiologist and allergist should collaborate.

Objective/Aim: To study the clinical and epidemiological characteristics of patients suspected of having presented IHS to general anesthetics and who had benefited from in vivo allergic tests as well as the contribution of these tests.

Methods: Retrospective study of the files of patients suspected of having presented IHS to general anesthetics, who were referred to the national pharmacovigilance center of Tunis between January 2009 and December 2017 and in whom in vivo allergic tests were performed.

Results: Twenty-two patients were selected, the sex ratio m/f was 0.29, the age ranged from 1 year to 71 years with a median of 42.5 years. Nine patients were referred by the attending physician. Twelve patients have had at least one prior general anesthesia. Six patients had a history of drug hypersensitivity. In 6 patients the nature of the anesthetic was unknown. The time to perform skin tests ranged from 18 days to 20 years with a median of 4 months. GA used before the event were: morphine 54%, hypnotic 25% and curare 21%. Of the 22 patients tested, only four patients were positive to GA: three to cisatracurium and one to atracurium. The follow-up of 13 patients showed that nine patients were anesthetized without problems. For the other nine patients we had no feedback.

Conclusion: In vivo allergic tests to GA, are interesting for the orientation of the choice to the anesthetic to which they are negative, and for the determination of the responsible agent when they are positive. However, these tests remain limited and would be better interpretable by associating them with the results of the pharmacovigilance survey and biological assays.

Disclosure of Interest: None declared.

159 ISoP18-1224 Comparison of 4 Commonly Prescribed Antipsychotics Patient Information Leaflets of Indian Companies with the Original Smpc from Innovator Companies

159.1 P. Biswas^*1, H. Biswas¹

159.1.1 ¹Symogen Limited, Bourne End, United Kingdom

Background/Introduction: In recent times there have been several safety issues with antipsychotic drugs and cardiovascular ADRs, including withdrawal of thioridazine. In an era where consumer awareness is at an all-time high and rapidly increasing, information available to patients and prescribers for safe and efficient use of medicines is still an area of concern.

Objective/Aim: Compare the PILs of the most commonly prescribed antipsychotics of the Indian manufacturers with that of the SmPCs from the Innovator manufacturers and review if the package inserts adhere to standard guidelines.

Methods: PILs for the Indian manufacturers and SmPCs from the Innovator manufacturers were obtained from the internet. Both the documents were then compared for each section and the missing information specifically in respect to cardiovascular ADRs. The drugs for which the SmPC and PIL were compared were Olanzapine; Quetiapine; Clozapine and Aripiprazole.

Results: Review and analysis of the PILs and SmPCs showed standard labeling guidelines were not adhered and details not updated in the PILs. Discrepancies were found in the undesirable effects section, contraindication, special warnings and precautions for use and interaction with other drugs. Serious adverse reactcions, i.e., QTc prolongation, Ventricular tachycardia/fibrillation, fatal myocardial infarction; cardiac arrest and bradycardia were missing in the PIL for drugs manufactured by the Indian companies when compared with the innovator companies.

Conclusion: Our research has highlighted that Indian companies do not have proper mechanism or process for development of package inserts with important sections on safety of these drugs missing with several discrepancies. Provision of good quality patient information is intended to supplement the prescribers and patients and not replace the advice given to patients by health professionals. As these drugs are used globally for the treatment of patients with schizophrenia and bi-polar disease, it would be beneficial to have globally harmonized information to be incuded in the PIL and SmPCs for consistency and accurate guidance to prescibers for patient safety.

Disclosure of Interest: None declared.

160 ISoP18-1226 Development and Validation of a Model Predictive of Case Inclusion in Pharmacovigilance Reviews

160.1 M. Munoz^*1,2, G. Dal Pan¹, J. Wei², C. Delcher³, H. Xiao², C. Kortepeter¹, A. Winterstein^2,4

160.1.1 ¹Office of Surveillance and Epidemiology, US Food and Drug Administration, Silver Spring, Maryland United States; ²Department of Pharmaceutical Outcomes and Policy; ³Department of Health Outcomes and Biomedical Informatics; ⁴Department of Epidemiology, University of Florida, Gainesville, Florida, United States

Background/Introduction: The rapidly expanding size and complexity of the FDA Adverse Event Reporting System (FAERS) database requires data-driven pharmacovigilance practices. Techniques to systematically identify and distinguish higher utility individual case safety reports (ICSRs) from lower utility ones will support improved management of safety signals.

Objective/Aim: We aimed to develop and validate a model predictive of an ICSR’s pharmacovigilance utility (PVU).

Methods: We used a retrospective cohort of FDA pharmacovigilance reviews completed in 2016 to determine the association between PVU and ICSR features. PVU was operationalized as an ICSR’s inclusion in a case series supporting a recommendation to modify product labeling. Characteristics of ICSRs included in a case series and those excluded were compared using univariate analyses. Next, we developed multivariable logistic regression models to examine likelihood of case inclusion based on: all available variables, completeness variables only, and a parsimonious model using backward elimination. Of these models, we selected the best performing model for bootstrapping validation based on fit, discriminative ability, and calibration. As a sensitivity analysis, we evaluated the validated model’s performance across subgroups of reviewed safety issues.

Results: For model development, we identified 69 pharmacovigilance reviews containing 10,381 ICSRs, of which 2115 ICSRs were included in a case series. The parsimonious model was selected for validation as it had the best discriminative ability with a C-statistic of 0.71. The strongest predictors of ICSR inclusion were reporting of a designated medical event (OR 1.93, 95% CI 1.54–2.43), positive dechallenge (OR 1.67, 95% CI 1.50–1.87), and reason for product use provided (OR 1.60, 95% CI 1.40–1.83). The strongest predictors of ICSR exclusion were death reported as the only outcome (OR 2.72, 95% CI 1.76–4.35), > 3 suspect products (OR 2.69, 95% CI 2.23–3.24), and > 15 events reported (OR 2.69, 95% CI 1.90–3.82). Our sensitivity analysis demonstrated heterogeneity in model performance by review issue. The correct classification of ICSRs was similar to the overall results when the model evaluated hypersensitivity reactions and drug-induced liver injury (C-statistic of 0.70 and 0.74, respectively); however, less discriminative ability was demonstrated with cardiovascular events and events without acute life-threatening outcomes (C-statistic of 0.64 and 0.58, respectively).

Conclusion: Our model demonstrated the feasibility of predicting the PVU of an ICSR. The model’s modest discriminative ability highlights opportunities for further enhancement and suggests algorithms tailored to particular safety issues may be beneficial.

Disclosure of Interest: None declared.

161 ISoP18-1227 Pharmacists’ Role in Risk Communication on Self-Medication: Pilot Study from Bulgaria

161.1 H. V. Lebanova^*1, R. Staynova², V. Getova²

161.1.1 ¹Department of Pharmaceutical Sciences and Social Pharmacy, Faculty of Pharmacy, Medical University-Pleven, Pleven, Bulgaria; ²Department of Pharmaceutical Sciences, Faculty of Pharmacy, Medical University—Plovdiv, Plovdiv, Bulgaria

Background/Introduction: Self-medication is defined as the selection and use of medicines by individuals (or a member of the individuals’ family) to treat self-recognized or self-diagnosed conditions or symptoms [1]. Appropriate self-medication has many benefits but it is also linked to potential risks such as incorrect diagnosis, delays in seeking medical advice when needed, infrequent but severe adverse reactions, dangerous drug interactions, incorrect manner of administration, incorrect dosage, incorrect choice of therapy, masking of a severe disease and risk of dependence and abuse [2].

Objective/Aim: The aim of the study was to assess pharmacists’ attitudes and previous experience with risk communication on self-medication in community pharmacies in Bulgaria.

Methods: An anonymous, questionnaire-based, descriptive study was performed. A prevalidated close-ended questionnaire was distributed among random sample of community pharmacists in Bulgaria. Data was analyzed using SPSS v.19.

Results: A total of 99 questionnaires were collected. 60.6% of the responders claim that patients very often consult them about their self-medication practices but rarely about possible adverse drug reactions and other drug-related problems such as drug interactions. 51.5% of pharmacists consider presenting information about risks as a mandatory part of the pharmaceutical consultation and the majority of them (87.9%) believe that it could affect patients’ decisions. According to 18.2% of the responders up to 80% of self-medicating patients do not use their over-the-counter medicines as recommended in the patient leaflet. 63.6% of the responders believe that over-the-counter medical products have high potential for drug misuse and abuse and 12.1% consider them with a substantial potential for drug interactions.

Conclusion: Data suggests that patients consider over-the-counter medicines safe and rarely seek information about possible risks. The conducted pilot study showed that pharmacists should be the primary and pro-active source of information about risks of self-medication products.

References:

• 1. Hughes CM, McElnay JC, Fleming GF.Benefits and risks of self medication. Drug Saf 2001;24, 1027–37

• 2. Ruiz ME. Risks of self-medication practices. Curr Drug Saf 2010;5:315–23

Disclosure of Interest: None declared.

162 ISoP18-1228 Rebound Effect after Discontinuation of Denosumab: Case Evaluation of the Regional Pharmacovigilance Center Bern in Switzerland

162.1 S. Banholzer^*1,2, M. Haschke^1,2, I. Scholz^1,2

162.1.1 ¹Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, Bern, Switzerland; ²Institute of Pharmacology, University of Bern, Bern, Switzerland

Background/Introduction: Denosumab is a human monoclonal antibody that binds with high affinity and specificity to the receptor activator of NF-κB ligand, which is important for the maturation of osteoclasts. As a result denosumab reduces bone resorption and increases bone mass and strength [1]. The effect of the therapy is limited to the duration of treatment and discontinuation of denosumab is associated with a rapid loss of bone mass [2].

Objective/Aim: To describe the frequency and variety of rebound cases after discontinuation of denosumab reported to our regional pharmacovigilance center (RPVC), to the regulatory authorities in Switzerland, in Europe and worldwide.

Methods: Retrospective analysis of reported rebound cases in Switzerland, Europe and using the WHO-Pharmacovigilance database in the time period between January 2013 and May 2018 [3]. Detailed characterization of the cases reported to the RPVC Bern within the same time span. In particular, we are interested in the following points (1) reported fractures (2) osteoporosis treatment after discontinuation of denosumab (3) reported bone-damaging co-medication.

Results: The number of all reported cases in the WHO-Pharmacovigilance database [3] and from our RPVC are shown in the table. From 116 cases reported to the RPVC Bern, 94 cases were found regarding “rebound effect” after discontinuation of denosumab. 35% of these cases were related to bone fractures of any location [vertebral fractures (85%), vertebral and non-vertebral fractures (12%) and non-vertebral fractures (3%)].

In 26% of the cases, no follow-up treatment was performed after discontinuation of denosumab and in 74% of the cases a follow-up treatment with bisphosphonates (64.4% zolendronat, 24.3% ibandronat, 10.0% alendronat, 1.4% risedronat) is documented. In 24.5% (23 of 94) of the cases a bone-damaging comedication was documented (most frequent: 38% proton pump inhibitors, 16% aromatase inhibitors, 16% systemic glucocorticoids).

Conclusion: Our data show that 90% (124 of 138) of all ‘rebound effects’ worldwide have been reported in Switzerland and that 68% (94 of 138) originated from our RPVC in Bern. There seems to be an accumulation in Switzerland or an underreporting outside of Switzerland. To prevent future adverse drug reactions, controlled prospective studies are necessary to determine optimal therapy duration and follow-up treatment.

References:

• 1. Arzneimittelinformation-Publikationssystem (AIPS), (electronic version). Swissmedic, Bern, Switzerland. Available at: http://www.swissmedicinfo.ch/. [Internet]. Available from: www.swissmedicinfo.ch.

• 2. Meier C, Uebelhart B, Aubry-Rozier B, Birkhauser M, Bischoff-Ferrari HA, Frey D, et al. Osteoporosis drug treatment: duration and management after discontinuation. A position statement from the SVGO/ASCO. Swiss Med Wkly 2017;147:w14484

• 3. VigiLyze. Uppsala Monitoring Center—WHO individual case safety report (ICSR) database system. Available from: https://vigilyze.who-umc.org/.

Disclosure of Interest: None declared.

163 ISoP18-1231 The Purchase of Health Products via the Internet: Health Issues and Perspectives

163.1 H. Attjioui¹, Z. Aliat², A. Cheikh³, A. Tebaa⁴, I. Bennani¹, H. Mefetah⁵, M. Bouatia^*1

163.1.1 ¹Mohamed V University—Faculty of Medicine and Pharmacy, ²Mohamed V University- Faculty of Medecine and Pharmacy, CHIS, ³Mohamed V university—Faculty of Medicine and Pharmacy, Abulcasis university, ⁴Antipoison and Pharmacovigilance Center of Rabat, Ministry of Health, Rabat, Morocco; ⁵Paediatric Hospital, Pharmacy, Rabat, Morocco

Background/Introduction: The rise of the Internet and e-commerce is disrupting access to health products, and the offerings of these products on the Internet are often attractive from the point of view of the customer. However, it contributes significantly to the expansion of falsified drug trafficking internationally. According to the WHO, 62% of medicines bought on the internet are counterfeit products and 42% of these products manufactured worldwide are distributed in Africa.

Objective/Aim: To take stock of the significant growth of internet sales of health products with the health challenges encountered and to propose actions and perspectives adapted to public health issues.

Methods: We made a summary of the elements extracted from websites offering health products, data from the drug management and the national pharmacovigilance center, the data collected allowed us to identify the problem and study the courses of action. To consider to secure the purchase of drugs.

Results: Counterfeit medicines have many victims in Morocco, since they are the second largest source of poisoning (25%) after food in the country according to the Anti-poison and Pharmacovigilance Center of Morocco (CAPM).

The most common purchases include so-called “comfort” drugs. Indeed, the products intended to treat the sexual problems, the products against the obesity, the food supplements, are the products most concerned. Generic drugs and medical devices (lenses, breast implantations, etc.) are not spared from this problem, just like cosmetics. In addition, the counterfeiting of anti-cancer products is even more serious and widespread, especially because of their high cost in the conventional circuit. These products may contain compounds of inactive principles, others are over or under dosage, or composed of harmful ingredients.The majority of falsified health products are imported from producing countries (India, China, Turkey and Russia) and then resold at lower cost in other countries.

The online purchase of health products is not the main source of fake drug trafficking in Morocco. Indeed, the illegal importation of contraband drugs also constitutes a serious health risk for the population because these means of acquisition of drugs are doubtful.

Conclusion:

The sanitary dramas related to falsified medicines show that counterfeiting of medical products is not to be taken lightly, as it continues to make victims around the world. For that, it is necessary to set up adapted and responsible actions which begins by creating a regulatory framework governing the purchase of these products on Internet.

In this perspective, prevention campaigns must be implemented to raise the awareness of health professionals and the public by encouraging them to give priority to official distribution channels, to double their vigilance in the face of abnormally low prices and the presence of spelling errors, or grammar on the box and/or on the site, the quality of the packaging, or unusual packaging .

Disclosure of Interest: None declared.

164 ISoP18-1232 The Experience of using Khartoum Medicines Information Center (Khmic) as a Focal Point to Enhance Pharmacovigilance In Sudan

164.1 T. Yousef^*1, A. Abbas², T. Ali¹, A. Abdelghadir¹

164.1.1 ¹Medication Safety Department, Ministry of Health Khartoum State, Khartoum, Sudan; ²Pharmacy Department, Countess of Chester Hospital NHS Foundation Trust, Chester, United Kingdom

Background/Introduction: Introduction: Under reporting of adverse drug reactions (ADRs) and medication errors (MEs) is a major health concern globally [1–2]. Sudan has been a full member of the WHO International Drug Monitoring Program via the Uppsala Monitoring Center since 2008. However, reporting of ADRs via Vigiflow system has been consistently poor over the years for many reasons including time constraints, misconception about spontaneous reporting, bureaucratic reporting procedures and lack of knowledge and awareness [3]. KhMIC is located within Khartoum State Ministry of Health and works closely with its Medication Safety (MS) department. Due to KhMIC ‘s location in the capital of Sudan with access to resources, it answers enquiries from other states regarding all clinical and non-clinical  medication issues including ADRs, management of MEs and poisoning. Furthermore, in November 2017, KhMIC collaborated with UK colleagues to deliver training in pharmacovigilance and medication safety to representative of medicines information centres from other states thereby forming an active network for ADR data collection similar to the Yellow Card Scheme regional centres in the UK.

Objective/Aim: To use nationally collated data processed via KhMIC service for ADRs and ME detection.

Methods: All enquiries received at KhMIC via different methods (telephone, personal and electronically) between December 2017 and May 2018 were screened to select enquiries related to ADRs and MEs. Data was analysed and adverse reaction reports were submitted to the Sudan National Medicines and Poisons Board.

Results: Of a total of 3676 enquiries received between Dec 2017 and May 2018, 13 ADRs and 40 MEs were reported compared to 20 ADRs reports received directly from hospitals by regular pathways during the same period.

Conclusion: Sudan requires financial resources and electronic systems to enhance pharmacovigilance and medication safety activities. However, using KhMIC as a focal reporting centre may be another promising new channel to increase the number of reported ADRs and MEs and ultimately detect signals at national level.

References:

• 1. Pirmohamed M, James S, Meakin S, Green C, Andrew K. Adverse Reactions as a Cause of admissions to hospital: prospective analysis of 18,820 patients. BMJ 2004;329:15

• 2. Mansur JM. “Medication System and the Important Role of Pharmacists. Drugs Aging 2016;33:213–21

• 3. Elnour AA, Ahmed AD, Yousif MA, Shehab A. Awareness and Reporting of Adverse Drug Reactions Among Health Professionals in Sudan. Jt Comm J Qual Patient Saf 2009;35:324–9

Disclosure of Interest: T. Yousef: None declared, A. Abbas: None declared, T. Ali: None declared, A. Abdelghadir Employee of: employees at the Department of Health—Ministry of State Khartoum.

165 ISoP18-1233 Sulfasalazine-Induced Dress Complicated by Hemophagocytic Lymphohistiocytosis in an Adult Ulcerative Colitis Patient

165.1 N. Fathallah¹, B. Ouni¹, S. Larif¹, A. Saii², H. Hmouda³, R. Slim¹, C. Ben Salem^*1

165.1.1 ¹Pharmacovigilance Center of Sousse, Research Labratory, Sousse University, Sousse, Tunisia; ²Amen Medical Center, Tunis, Tunisia; ³Intensive Care Unit, Sahloul University hospital, Sousse, Tunisia

Background/Introduction: Drugs are a rare cause of Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) and also of macrophage activation syndrome (MAS) and extremely rare cause of DRESS complicated with MAS.

Objective/Aim: To report the first case of sulfasalazine-induced DRESS complicated by MAS in an adult ulcerative colitis patient.

Methods: A 45-year-old male was diagnosed with ulcerative colitis, he was started treatment with oral sulfasalazine. Six weeks after drug initiation, the patient developed pruritic skin eruption associated with severe liver failure, so he was admitted to intensive care unit. He was diagnosed with DRESS associated of MAS.

Results: Drug hypersensitivity syndrome is among the most severe drug hypersensitivity reactions and in rare cases it may progress to hemophagocytic lymphohistiocytosis MAS is rare and severe complication of DRESS and often misunderstood [1].

MAS has been observed in immunocompromised patients, regardless of the cause of immunosuppression: pharmacologic, infectious, or neoplastic [2].

To date, the pathogenesis of MAS is not totally known. It is considered as ineffective immune response with activation and uncontrolled proliferation of T lymphocytes, macrophages and natural killer (NK) cells and the ingestion of cellular blood components and their precursors by these macrophages, and secretion of high levels of pro-inflammatory cytokines [2].

To the best of our knowledge, only one case of sulfasalazine induced MAS associated with has been reported [2] and this is the first case of sulfasalazine-induced DRESS complicated by hemophagocytic lymphohistiocytosis .

Conclusion: The most offending drugs incriminated in the developpement of DRESS complicated with MAS are Vancomycine, phenobarbitol, lamotrigine. Clinicians should be aware of this risk.

References:

• 1. Korbi M, Youssef M, Ben Brahim H, et al. DRESS à l’allopurinol compliqué d’un syndrome d’activation macrophagique Ann Dermatol Venereol 2015;142:767–70.

• 2. Klotz U, Maier K, Fischer C, Heinkel K. Therapeutic efficacy of sulfasalazine and its metabolites in patients with ulcerative colitis and Crohn’s disease. N Engl J Med 1980;303:1499–502

Disclosure of Interest: None declared.

166 ISoP18-1234 Immediate Hypersensitivity Reaction to Acetylsalicylic Acid with Positive Skin Tests

166.1 B. Ouni¹, N. Fathallah¹, S. Larif¹, A. Brahim², R. Slim¹, C. Ben Salem^*1

166.1.1 ¹Pharmacovigilance Center of Sousse, Research Laboratory,Tunisia, Sousse University, Sousse, Tunisia; ²Post-Operatory Care Unit, Farhat Hached University Hospital, Sousse, Tunisia

Background/Introduction: Immediate hypersensitivity reactions to acetylsalicylic acid are classified as allergic reaction (immunoallergic) and pseudo-allergic reaction (pharmacological).

Objective/Aim: To report a case of immediate hypersensitivity reaction following oral acetylsalicylic acid administration with positive rechallenge with positive prick skin test.

Methods: A 55-year-old female patient with a medical history of cervical arthritis treated with Sertraline. In 2013, and after taking one tablet of Acetylsalicylic Acid, 2 h later, she developed a generalized urticaria, dyspnea and wheezing. Her hemodynamic state was stable treated in emergency with corticosteroids and oxygen. In 2014 and after taking one dose of acetylsalicylic acid, 1 h later, the patient developed the same symptomatology requiring her hospitalisation in the emergency department and she received corticosteroids with oxygen. The evolution was favorable. Skin prick tests performed (after obtaining informed consent from the patient) returned positive for acetylsalicylic acid and negative for Ketoprofen and Piroxicam. For that reason, we contre-indicated the use acetylsalicylic acid.

Results: Immediate hypersensitivity reactions to NSAIDs arise from 2 pathophysiological mechanisms: immunological or pharmacological. Clinical pattern included urticaria, angioedema and possibly anaphylactic shock. In our case, the association between the chronological and clinical arguments and positive skin prick tests (SPT) results suggests an Ig-E mediated mechanism and allowed us to retain the responsibility for acetylsalicylic acid.  SPT have been successfully applied in the assessment of IgE-mediated immunological drug reactions [1].

Conclusion: In immediate hypersensitivity reactions induced by drugs, it is recommend to perform skin tests in patients with adverse reactions to these drugs before exposing them to an oral challenge.

References:

• 1. Rebelo Gomes E, Geraldes L, Gaspar Â, Malheiro D, Cadinha S, Abreu C, et al. Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs among adults: clinical features and risk factors for diagnosis confirmation. Int Arch Allergy Immunol 2016;171:269–275

Disclosure of Interest: None declared.

167 ISoP18-1237 Allopurinol-Induced Overlapping Dress and Toxic Epidermal Necrolysis

167.1 N. Fathallah¹, S. Mokni², B. Ouni¹, I. Ben Saida³, S. Larif¹, N. Ghariani², R. Slim¹, C. Ben Salem^*1

167.1.1 ¹Pharmacovigilance Center of Sousse, Research Labratory, Sousse University, Sousse, Tunisia; ²Department of Dermatology, ³Intensive care Unit, Farhat Hached University Center, Sousse, Tunisia

Background/Introduction: Drug-induced cutaneous adverse reactions are varying from 2 to 3% of all hospitalized patients. Severe cutaneous adverse reactions (SCARs) represent 2% of the overall adverse cutaneous reactions. Although the diagnosis criteria between the different SCARs seems to be specific, DRESS and toxic epidermal necrolysis (TEN) can share some features, raising the hypothesis of overlap syndromes [1].

Objective/Aim: To report a case of overlapping DRESS and Toxic epidermal necrolysis induced by allopurinol.

Methods: A 35-year-old male, diagnosed in 2002 with chronic renal failure, was initiated with allopurinol for hyperuricemia. Four weeks later, he developed a generalized erythematous drug eruption associated with fever and cervical lymphadenopathy. The mucosae were not involved and no skin detachment was noted. Biological tests showed creatinine levels of 175 µl likely due to his previousely known chronic renal failure and hyperuricaemia. Hemogram showed hypereosinophilia of 1600/mm³. Screening for viral serology was negative. Allopurinol-induced DRESS was probable according to the Regiscar. Allopurinol was stopped and the patient received supportive local treatment. The evolution was marked by a general spread of the eruption to the whole body associated with skin detachment and positive Nikolsky sign, associated with mucosal involvement.

The histopathological findings revealed a necrotic epidermis with spongiosis, necrotic keratinocytes, and rare eosinophils, compatible with SJS. In our patient, the clinical picture fulfilled “probable” score for both DRESS and TEN according to the RegiSCAR criteria. In our patient, our final diagnosis was an overlapping DRESS/TEN.

Results: In some cases, the initial presentation of SCARs can be confusing making the diagnosis more challenging. In fact, although the skin lesions in SJS/TEN are different from those in DRESS, there is some confusion regarding the diagnosis of DRESS syndrome vs TEN. The pathogenesis of SCARs is not fully understood. SCARs are a Type IV reactions mediated by T cells. In the recent classification of Gell and Coombs, distinct T-cell functions led to different clinical phenotypes. T cells recruit and activate different blood cells such as monocytes, eosinophils or neutrophils. For instance, granulysin is the dominant cytokine inducing the destruction of epidermis in SJS-TEN and eotaxine and IL5 in DRESS. Therefore, delayed adverse drug hypersensitivity reaction may be primary based on the preferential activation of drug-specific T cells. However, these complexe immune reactions are not specific and many reactions may be associated. So, an overlap of immune reactions is possible, even if one type of drug-activated specific cells is dominant, explaining clinical ambiguities among SCARs [2].

Conclusion: Clinician should be awer of the risk of overlapping DRESS and Toxic epidermal necrolysis induced by allopurinol.

References:

• 1. Casagranda A, Suppa M, Dehavay F, Del Marmol V. Overlapping DRESS and Stevens-Johnson Syndrome: case report and review of the lLiterature. Case Rep Dermatol 2017;9:1–7

• 2. Horcajada-Reales C, Pulido-Pérez A, Suárez-Fernández R.Severe cutaneous drug reactions: do overlapping forms exist? Actas Dermosifiliogr 2016;107:23–33

Disclosure of Interest: None declared.

168 ISoP18-1239 A Pediatric Case of Severe Rhabdomyolysis in Acute Asthma Crisis

168.1 C. Ladhari¹, N. Fathallah¹, B. Ouni¹, A. Tej², S. Larif¹, J. Bouguila², R. Slim¹, C. Ben Salem^*1

168.1.1 ¹Pharmacovigilance Center of Sousse, Research Labratory, Sousse University, Sousse, Tunisia; ²Department of Pediatry, Farhat Hached University Hospital, Sousse, Tunisia

Background/Introduction: Corticosteroids and β-Agonists are the first line of treatment for severe acute asthma. Adverse drug reactions related to the use of these medications include hyperglycemia, hypertension and nausea. Rhabdomyolysis associated with severe acute asthma is an uncommon complication not well known by clinicians.

Objective/Aim: To present a case of severe rhabdomyolysis occurring after severe acute asthma in an 11 year-old infant.

Methods: An 11-year-old boy with history of asthma controlled with short-acting β2-agonist upon request, had developed coughing and dyspnea after dust’s exposure. Respiratory function had worsened and he was transferred to the pediatric department. The diagnosis of severe acute asthma was retained and the infant was mechanically intubated and ventilated. He received salbutamol 0.25 mg/h, solumedrol 80 mg intravenous then 40 mg intravenous every 6 h. Respiratory signs improved gradually. However, at the biological test, an increased CPK at 1626 UI/ml was noticed. Otherwise, his renal and liver function were in normal ranges. Potassium level was of 5.74 mmol/L and sodium level was of 137 mmol/L. Blood gas measurements showed respiratory acidosis. Rhabdomyolysis secondary to high doses of corticosteroids was suspected. A decrease in doses of solumedrol was recommended. The monitoring of CPK values revealed a decrease in CPK values (1478 then 800). CPK levels returned to normal ranges 1 week later.

Results: This infant had developed a rhabdomyolysis in the course of severe acute asthma. The association of rhabdomyolysis and asthma has been described at the first time by Chud et al. [1] however; the problem consists to determine the cause of rhabdomyolysis occurring in such cases. In the literature, some hypothesis suggest that theophylline intoxication, hypokalemia secondary to excessive use of β2-agonists or infection with legionella pneumophila and Mycolpasma pneumonia are likely to induce rhabdomyolysis.  Yet, the most common cause seems to be hypoxia, acidosis and intensive muscular work of respiratory muscles [2]. In our case, rhabdomyolysis is most likely to be induced by high doses of corticosteroids since decreasing of CPK values when clinicians decreased doses of corticoids given to this infant. Moreover, his potassium blood rate was within normal range. High doses of corticosteroids may induce myopathy which is related to rhabdomyolysis [2].

Conclusion: Close monitoring of CPK in severe acute asthma remains necessary due to the risk of occurrence of rhabdomyolysis. Rapid management of rhabdomyolysis is primordial to aboid severe complications.

References:

• 1. Chugh KS, Singhal PC, Khatri GK. Rhabdomyolysis and renal failure following status asthmaticus. Chest 1978;73:879–80

• 2. Goh AY, Chan PW. Acute myopathy after status asthmaticus: steroids, myorelaxants or carbon dioxide? Respirology 1999;4:97–9

Disclosure of Interest: None declared.

169 ISoP18-1241 Side Effects of Targeted Therapies

169.1 N. Fathallah¹, C. Ladhari¹, B. Ouni¹, S. Larif¹, K. Baccouche², R. Slim¹, C. Ben Salem^*1

169.1.1 ¹Pharmacovigilance Center of Sousse, Research Labratory, Sousse University, Sousse, Tunisia; ²Department of Rheumatology, Farhat Hached University Hospital, Sousse, Tunisia

Background/Introduction: Targeted therapies have nowadays significantly changed the treatment of cancers and inflammatory diseases. Targeted therapies are generally better tolerated than traditional chemotherapy, but they are associated with several adverse effects.

Objective/Aim: To report the adverse effects reported with targeted therapies.

Methods: This retrospective study was carried out on reports of adverse reactions related to targeted therapies. Reports were notified to the Regional Centre of Pharmacovigilance of Sousse from the 1st January 2015 to 31th December 2016. The causality assessment was evaluated by Naranjo’s method of imputability.

Results: This case series included 8 notifications of adverse reaction imputed to targeted therapies. The sex ratio H/F was 1.66 and the median age was 40.6 years (from 17 to 69 years). The culprit drugs were as following: etanercept (N = 1), certolizumab (N = 1), sorafenib (N = 1), natalizumab (N = 1), imatinib (N = 2), Tocilizumab (N =), infliximab (N = 1). Targeted therapies were Indicated to treat cancers in 3 cases [hepatocellular carcinoma (N = 1) and myeloid leukemia chronic (N = 2)]. Inflammatory diseases were as following: rheumatoid arthritis (N = 2), juvenile arthritis (N = 2) and Multiple Sclerosis (N = 1). Side effects noticed were hypersensitivity reactions (anaphylactic reaction), cutaneous lesions, leuconeutropenia, and muscular involvement. The delay of onset was variable from few minutes after administration to 4 months. The outcome was favorable in all cases.

Conclusion: Targeted therapies act at specific sites and are monoclonal antibodies (in our case series: infilixamb, natalizumab, cetrolizumab and tocilizumab) and fusion proteins (etanercept). Receptor tyrosine kinase inhibitors (imatinib and sorafenib) could be included as targeted therapies as they are biological drugs. Concerning adverse reactions, the true incidence is unknown. However, the Spanich Society of Rheumatology Biobadaser database recorded a total of 16361 adverse reactions in 6754 patients treated with monoclonal antibodies until 2012 [1]. Cutaneous adverse reactions are the most reported adverse reactions. Our patients had severe anaphylactic reactions, prurigo and fixed drug eruption. However, in the literature, other cutaneous side effects are reported including: hand-foot syndrome, acneiform eruption, psoriasiform eruption, cutaneous infection, vasculitis, cutanous carcinoma… [2]. Hematologic disorders (leuconeutropenia in our case series) cause recurrent infections and lead to drug withdrawal. Muscular disorders are also reported with target therapies.

Adverse effects to targeted therapies may be severe and may lead to drug cessation. Some measures may be proposed to avoid occurrence of side effect such as hydration and calcium and magnesium supplementation.

References

• 1. Biobadaser. Regitro espanol de acontecimientos adversos de terapia biologica en enfermedades reumaticas. Informe enero 2013

• 2. M. Helloa, S. Barbarotb, J. Connaulta. Skin manifestations of new targeted treatments. Rev Med Interne. 2012;33:273–8

• 3. A. Leroux, N. Clere. Prévention et prise en charge des effets indésirables induits par les thérapies ciblées. Actualités Pharmaceutiques, 2015

Disclosure of Interest: None declared.

170 ISoP18-1242 Skin Testing in Antibiotic Allergic Patients with Immediate and Delayed Hypersensitivity Reactions

170.1 N. Fathallah¹, C. Ladhari¹, S. Mokni², B. Ouni¹, S. Larif¹, K. Baccouche³, N. Ghariani², R. Slim¹, C. Ben Salem^*1

170.1.1 ¹Pharmacovigilance Center of Sousse, Research Labratory, Sousse University, Sousse, Tunisia; ²Dermatology Department, ³Department of Rheumatology, Farhat Hached University Hospital, Sousse, Tunisia

Background/Introduction: Skin tests are performed to investigate cutaneous adverse drug reactions (CADR) in both immediate and delayed hypersensitivity reactions [1]. Sensitivity of skin tests seems to vary according to the tested drugs and the type of CARD.

Objective/Aim: To report the results of skin tests in antibiotic allergic patients with immediate and delayed hypersensitivity reactions.

Methods: A retrospective study was carried out on patients who developed a CARD secondary to antibiotics. These patients were investigated by skin tests in the Regional Pharmacovigilance Centre of Sousse, Tunisia from January 2009 to February 2016. Skin tests including prick tests and intradermoreactions with immediate readings for immediate hypersensitivity reactions and patch tests for delayed hypersensitivity reactions. The results of the tests were performed according to the European Network for Drug Allergy recommendations.

Results: Fifty-eight skin tests to antibiotics were performed in our case series. Previous history of drug reaction was found in 17 patients (29%). CADR were immediate hypersensitivity reactions (urticaria and anaphylactic choc) in 34 cases and were delayed hypersensitivity reactions in 24 patients (including maculopapular eruption, fixed drug eruption and acute generalized exanthematous pustulosis). Tested drugs were amoxicillin (22 cases, 13 Prick tests, 9 patch tests), penicillin G (7 Prick tests), oxacillin (7cases, 4 Prick tests, 3 patch tests), amoxicillin/calvulanate (1 patch test), ampicillin (1 Prick test), cefotaxime (3 cases, 2 Prick tests, 1 patch test), Cefazolin (3 Prick tests), Ceftriaxone (2 patch tests), Cefuroxime (1 patch test), lincomycin (2 patch tests), cotrimoxazole (2 cases, 1 Prick test, 1 patch test), ciprofloxacin (1 Prick test), rovamycine (1 Prick test) and 1 patch test to clarithromycin, vancomycin, pristinamycin, fusidic acid and vibramycin, respectively. Performed skin tests were positive to amoxicillin in 53%, to penicillin G in 43%, to oxacillin in 57.1% and to cefazolin in 33.3% of cases. Skin tests performed toward ciprofloxacin and rovamycin were also positive. Four patients experienced cross reactivity among betalactamins. Indeed, cross reactivity was noticed among amoxicillin and oxacilline in 2 cases, penicillin G and oxacilline in one case, amoxicillin and penicillin G in one case, amoxicillin, oxacillline and ampicillin in one case.

Conclusion: The most frequent tested drugs in our case series were betalactams. Our results confirm those reported in many studies. In fact, hypersensitivity to betalactams is the most reported drug allergy and positivity of skin tests in this class of antibiotics is also most frequent [3]. Drug hypersensitivity investigation in betalactam hypersensitivity is actually well established. Concerning the others drugs, there is no clear strategy to explore CADR [1]. False positive test could be seen toward quinolones due to their non specific histaminoliberation. Skin tests seems to be a safe and rapid method that should be carried out as frequently as possible to establish drug allergy especially among betalactamin antibiotics.

References:

• 1. Barbaud A. Skin testing in delayed reactions to drugs. Immunol Allergy Clin North Am 2009;29:517–35

• 2. Bursztejn AC, Rat AC, Tréchot P, Cuny JF, Schmutz JL, Barbaud A. Results of skin tests to assess drug-induced allergy. Ann Dermatol Venereol 2010;137:688–94

• 3. Matheu V, Pérez E, González R, Poza P, De La Torre F, Sánchez-Machín I, et al. Assessment of a new brand of determinants for skin testing in a large group of patients with suspected beta-lactam allergy. J Investig Allergol Clin Immunol 2007;17:257-60

Disclosure of Interest: None declared.

171 ISoP18-1243 Lichenoid Eruption Induced by Methotrexate

171.1 R. Slim¹, N. Fathallah¹, B. Ouni¹, S. Larif¹, S. Mokni², C. Belajouza², C. Ben Salem^*1

171.1.1 ¹Pharmacovigilance Center of Sousse, Research Labratory, Sousse University, Sousse, Tunisia; ²Dermatology Department, Farhat Hached University Hospital, Sousse, Tunisia

Background/Introduction: Methotrexate, a folate antagonist, has been used in dermatology to treat psoriasis and collagen vascular diseases. Cutaneous adverse reactions attributed to methotrexate therapy are uncommon.

Objective/Aim: Herein, we report a rare case of lichenoid eruption associated with methotrexate.

Methods: A 40-year-old man presented to dermatology department with 2 month history of a widespread pruritic eruption. He had a history of psoriasis treated with methotrexate therapy (10 mg/week) started 8 months before onset of the eruption. Physical examination revealed lichenoid plaques on the abdomen, anterior side of forearms and thighs. The oral and genital mucosae were not involved.

Based on the clinical and histologic findings, a diagnosis of lichenoid drug eruptions (LDE) induced by methotrexate was suspected and the medication was withdrawn. A significant improvement was noted after 2 weeks of treatment with prednisone and potent topical steroid. There was no recurrence of the lichenoid eruption during a 9-month follow-up period.

Results: LDE are uncommon dermatoses that can occur after administration of various medications and chemicals [1]. The diagnosis is often challenging and it can be difficult to distinguish these eruptions from idiopathic lichen planus because both clinical and histological similarities. Furthermore, several findings are more typical of specimens of LDE and include focal parakeratosis, presence of eosinophils and plasma cells, and a deeper perivascular and periadnexal infiltrate [2].

Our patient had most of clinical and histopathological features suggestive of LDE. In addition, the diagnosis of a LDE is favored over idiopathic lichen planus because of the closely linked onset of occurrence of clinical symptoms and the complete resolution after withdrawal of methotrexate. 

Several mucocutaneous adverse reactions have been reported with methotrexate in the treatment of psoriasis, including oral ulceration, erythroderma, and bullous eruption [3].

To the best of our knowledge, this is the first lichenoid drug eruption due to intake of methotrexate following treatment of psoriasis.

The latency period for starting medication and occurrence of LDE ranged from 10 days to several years. LDE normally cleared spontaneously within a few weeks to a few months after withdrawal of the causative drug [1].

Conclusion: As the frequent use of methotrexate in dermatology, clinicians should be aware of the possibility of LDE occurring as a rare adverse effect.

References:

• 1. Ellgehausen P, Elsner P, Burg G. Drug-induced lichen planus. Clin Dermatol 1998;16:325–32

• 2. Van den Haute V, Antoine JL, Lachapelle JM. Histopathological discriminant criteria between lichenoid drug eruption and idiopathic lichen planus: retrospective study on selected samples. Dermatologica 1989;179:10–3

• 3. Sako EY, Famenini S, Wu JJ. Bullous drug eruption in a patient with psoriasis after a test dose of methotrexate. J Am Acad Dermatol 2013;69:e264–5

Disclosure of Interest: None declared.

172 ISoP18-1244 Sulfasalazine Induced Dress Syndrome with Fulminant Hepatitis

172.1 R. Slim¹, N. Fathallah¹, B. Ouni¹, S. Larif¹, H. Hmouda², C. Ben Salem^*1

172.1.1 ¹Pharmacovigilance Center of Sousse, Research Labratory, Sousse University, Sousse, Tunisia; ²Intensive Care Unit, Farhat Hached University Hospital, Sousse, Tunisia

Background/Introduction: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe and potentially life-threatening disease that can lead to acute liver failure.

Objective/Aim: We report a rare case of favourable issue of a fulminant hepatitis associated with sulfasalazine DRESS syndrome.

Methods: A 35-year-old man had been taking sulfasalazine for 3 weeks when he experienced symptoms consistent with a viral infection.

He was admitted to hospital on day 6. Physical examination found fever, widespread erythematous macules and cervical lymphadenopathy. Investigations revealed hypereosinophilia and hepatic cytolysis. Abdominal ultrasonography was normal. Viral and autoimmune antibodies were not detected. A skin biopsy was compatible with drug-induced toxicity. Sulfasalazine was stopped, and methylprednisolone was initiated. The immediate evolution was characterized by major hepatic cytolysis (aminotransaminases over 2498 IU/l), and cholestasis (total bilirubin at 9 N). Signs of liver failure occurred, with factor V at 37% and prothrombin at 27%. Consequently, the patient was proposed for emergency liver transplantation. However, aminotransferases rapidly decreased as well as the factor V and prothrombin index were assessed. The decision regarding liver transplantation was therefore postponed. Symptomatic intensive care and corticosteroid therapy were maintained. The patient was discharged on day 25. His liver function tests returned to normal levels in 2 month.

Results: Liver involvement in DRESS is common and may range from a transitory increase in liver enzymes to liver necrosis with fulminant hepatic failure [1].

Sulfasalazine, is a sulfamid currently used for treating inflammatory bowel diseases. Side effects include gastrointestinal symptoms, headaches, and hemolytic anemia. Immunoallergic reactions to sulfasalazine, including DRESS syndromes, have been reported and they describe cases of mild hepatitis, but acute liver failure resulting in death or liver transplantation can also occur [2–3]. Classical management requires immediate withdrawal of the suspected drug. Liver transplantation is usually proposed in emergency situations, but the prognosis remains poor. According the Naranjo probability scale sulfasalazine-induced DRESS syndrome with fulminant hepatitis was probable in our patient [4].

Conclusion: Even though sulfasalazine DRESS is rare, clinicians increase in awareness enables early recognition and treatment so as to reduce morbidity in these patients.

References:

• 1. Husain Z, Reddy BY, Schwartz RA. DRESS syndrome: Part I. Clinical perspectives. J Am Acad Dermatol 2013;68:693.e1–14; quiz 706–8

• 2. Michel F, Navellou JC, Ferraud D, Toussirot E, Wendling D. DRESS syndrome in a patient on sulfasalazine for rheumatoid arthritis. Joint Bone Spine 2005;72:82–5

• 3. Besnard M, Debray D, Durand P, Cezard JP, Navarro J. Sulfasalazine-induced fulminant hepatitis in pediatric Crohn’s disease: report of two cases. J Pedriatr Gastroenterol Nutr 1998;26:119–20

• 4. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239–45

Disclosure of Interest: None declared.

173 ISoP18-1246 Signals Detection in Pharmacovigilance Based on the Seriousness of Adverse Drug Reactions, Moroccan Pharmacovigilance Database, 2008–2017

173.1 I. Talibi¹, A. Tebaa², A. Khattabi¹, R. Soulaymani-Bencheikh^*2

173.1.1 ¹Ecole Nationale de Santé Publique; ²Centre Anti Poison et de Pharmacovigilance du Maroc, Rabat, Morocco

Background/Introduction: Adverse drug reactions (ADRs) constitute a significant burden for public health. They represent major concerns in terms of individual outcomes and public health expenditures [1–4]. The risk factors for developing serious ADRs are not yet studied in Morocco. We propose a new approach for signal detection in pharmacovigilance based on the measure of the disproportionality for developing the serious ADRs cases.

Objective/Aim: To identify risk factors associated to serious ADRs and to detect pharmacovigilance signals in Moroccan Pharmacovigilance Database (MPD).

Methods: We carried out a retrospective observational study of ADRs in MPD for the period from January 2008 to December 2017. We included in this study only spontaneous cases with the scores of WHO Causality Assessment certain, probable or possible, and excluded the vaccine cases. We used the Anatomical Therapeutic Chemical classification for drugs, WHO Adverse Drug Reaction Terminology and the ICH E2A guidelines to classify the seriousness of cases. Descriptive statistics and logistic regression using Epi Info 7 were undertaken.

Results: Among all the reported ADRs included in our study (n = 9283), 39.3% referred to serious ADRs (n = 3648). The majority of these serious ADRs (73.1%) were caused by drugs belonging to J (32.8%), L (21.3%) and N (19.0%) ATC groups. Cases reported by health professionals were more associated with seriousness than those reported by patients [Odds Ratio = 6.53, 95% CI (5.32–8.02)]. Patient demographics were explored as well as disproportionate reporting signals.

Conclusion: This study has identified factors that associated to developing serious ADRs in Morocco and proposed a new approach to detect signals in pharmacovigilance. We recommend using this data to develop of risk management plans, to generate alert and to implement the risk minimization actions for improving the safety of drug use in Morocco.

References:

• 1. Lazarou J, et al. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998; 279:1200–5

• 2. Kongkaew C, et al. Hospital admissions associated with adverse drug reactions: a systematic review of prospective observational studies. Ann Pharmacother 2008;42:1017–25

• 3. van der Hooft CS, et al. Adverse drug reaction-related hospitalisations: a population-based cohort study. Pharmacoepidemiol Drug Saf. 2008;17(4):365–71

• 4. Moore N, et al. Frequency and cost of serious adverse drug reactions in a department of general medicine. Br J Clin Pharmacol 1998;45:301–8

Disclosure of Interest: None declared.

174 ISoP18-1250 Contribution Of Patients To Pharmacovigilance—The Views Of European Patient Organizations

174.1 C. Matos^*1,2, G. Weits³, F. van Hunsel³

174.1.1 ¹Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain, ²Department of Pharmacy, Coimbra Health School-IPC, Coimbra, Portugal, ³Netherlands Pharmacovigilance Centre Lareb, ‘s Hertogenbosch, Netherlands

Background/Introduction: Patients’ involvement in actively reporting adverse drug reactions (ADRs) is a key to build better drug safety practices, and growing pharmacovigilance initiatives from consumer organizations are being recognized as potentially valuable sources of information.

Objective/Aim: The objective of this study is to understand the role of European patient organizations as stakeholders to optimize patient involvement in pharmacovigilance.

Methods: A descriptive-correlational study was conducted investigating patient organizations’ opinions and attitudes regarding patient involvement in pharmacovigilance and their initiatives to support drug safety through a web-based questionnaire during March and April 2018. 

Results: A total of 1898 patient organizations were invited to participate in the survey, including 89 pan-European organizations. In total, 297 completed answers (15.65%) were collected from 31 countries. Most organizations stated that would like to increase awareness of patients to specific ADRs related to their medicines (43.19%, n = 130). However, 38.54% declare don’t have any goal in Pharmacovigilance (n = 116). Barriers found to the support in Pharmacovigilance activities include lack of resources to be involved in pharmacovigilance activities (43.77%, n = 130) or don’t receive any support from National Competent Authorities in their countries (33.33%, n = 99).

Table 1. Contribution of the patients to pharmacovigilance

In what way do you think patients can contribute to pharmacovigilance? Total of respondents: 301	Strongly Disagree or Disagree	Neutral	Agree or Strongly Agree
Patients can provide different information from the healthcare professionals	5.64% (17)	14.95% (45)	76.08% (229)
Patients can contribute to the detection of new adverse drug reactions	3.32% (10)	5.32% (16)	89.70% (270)
Patients give more information on the impact of the adverse drug reaction on quality of life	2.66% (8)	6.31% (19)	88.04% (265)
Patients can be useful in describing the severity of reported reactions	4.65% (14)	7.31% (22)	86.38% (260)
Patients can report information that is useful, even without medical confirmation	6.64% (20)	12.29% (37)	79.40% (239)
Patients describe information based on their experience with medicines	3.32% (10)	5.98% (18)	89.37% (269)

1. “Not Answered”/“Not Relevant” answers were not present in the table

Organizations inform patients that they are allowed to report adverse drug reactions (40.40%; n = 120) or communicate them if an important new ADR appears for a specific medicine (40.07%; n = 119), or when a new drug is marketed (30.98%; n = 92); however, more than one-third admitted that never had any involvement in Pharmacovigilance (34.68%; n = 103). Activities related with pharmacovigilance include spread information on how to report (for instance on their websites, newsletter, email, conferences) (28.57%, n = 86), organizing activities (seminars, campaigns, workshops, courses) to help patients to be aware of drug safety (28.57%, n = 86), or have a direct link on patient organization website for patients to report adverse drug reactions (6.64%, n = 20).

Conclusion: Bringing pharmacovigilance stakeholders and patient organizations together could create awareness among patients. However, greater communication by patient organizations on pharmacovigilance topics and facilitation of the reporting is necessary to enable their members to be more active in pharmacovigilance.

Disclosure of Interest: None declared.

175 ISoP18-1252 Present Status and Future Prospects of Pharmacovigilance in Nepal

175.1 R. Karki^*1

175.1.1 ¹Pharmacy, Pokhara University, Pokhara, Nepal

Background/Introduction: Nepal, one of the low income country had started pharmcovigilance program from the year 2004 and become full member of the International Drug Monitoring Programme since 2006. The drug regulatory body of the country, Department of Drug Administration (DDA) is the national pharmacovigilance centre that coordinates 11 regional centres situated in several hospitals across the country.

Though ADR reporting is mandatory in Sweden, France and Italy [1, 4], it is not in Nepal. The current trend suggests high rate of underreporting [2] of ADR in Nepal which might be due to lack of awareness and educational intervention among healthcare professionals [3].

The present study is an attempt to present the current status and future prospects to improve the ADR reporting programme in Nepal.

Objective/Aim: The primary objective was to find out the current status of pharmacovigilance programme since its beginning, to assess the knowledge and perception of final year pharmacy students regarding ADR reporting and pharmacovigilance in Nepal.

Methods: A retrospective analysis of suspected ADR reports from the National Pharmacovigilance Centre, online website was conducted. Similarly, a cross sectional study using pretested questionnaire (cronbach’s alpha:0.77) was performed using census sampling technique.

A total of 27 final year pharmacy students were enrolled in the study. The data collection was done after getting approval from the institution and informed consent from the participants. SPSS version 16 was used for data entry and analysis.

Results: Since 2004, a total of 547 ADRs were reported to the Uppsala Monitoring Center, Sweden from Nepal. The top 10 drugs reported causing ADR were Carbamazepine, Phenytoin, Ciprofloxacin, Amoxicillin, Diclofenac, Isoniazid, Ibuorofen, Paracetamol,Tramadol and Cotrimoxazole. The maximum number of ADR reported in the year 2008 (209) which then reduced gradually and become only 2 suspected ADR reports in the year 2017.Out of 27 participants majority were female (74.9%). The knowledge assessment have showed all participants were known about ADR classification, Post Marketing Surveillance and Hypersensitivity reactions. Only 37% were known about how to report ADR in Nepal. Majority (81.5%) of participants reported pharmacovigilance as not well covered topic in their curriculum.The perception towards pharmacovigilance have showed that 77.8% participants strongly agreed to make ADR reporting compulsory and 81% strongly agreed about teaching on reporting of ADR to pharmacy students. They strongly agreed on counselling about ADR while dispensing (92.6%). However student were not aware about the purpose of spontaneous ADR reporting.

Conclusion: Pharmacovigilance is still in infancy in case of Nepal despite of 14 years of its establishment in Nepal. This study highlights the need of inclusion of pharmacovigilance in the curriculum of pharmacy students as well as pre service training about ADR reporting especially in those places which lack regional pharmacovigilance centre.

References:

• 1. Avong Y. Prospects and Challenges of providing pharmacovigilance services in resource limited countries Pharmaceut Reg Affairs 2015;4:53

• 2. Santosh KC, Tragulpiankit P, Gorsanam P, Edwards IR, Alam K. Strengthening the pharmacovigilance programme in Nepal. Nepal J Epidemiol 2013;3:230–5

• 3. Palaian S, Ibrahim MI, Mishra P. Health professionals knowledge, attitude and practice towards pharmacovigilance in Nepal. Pharma Practa (Granada) 2011;9:228–35

• 4. Olsson S, Pal SN, Dodoo A. Pharmacovigilance in resource limited countries. Expert Rev Clin Pharmacol 2015;8:449–69

Disclosure of Interest: None declared.

176 ISoP18-1254 Adverse Drug Reaction Reports Following a “Brand Switch”. The New Zealand experience

176.1 R. Braund^*1, M. Tatley¹

176.1.1 ¹NZPhvC, University of Otago, Dunedin, New Zealand

Background/Introduction: Internationally the use of generic medicines is increasing. There is growing interest in the “patient experience” of using generic medicines, particularly in relation to risk of adverse drug reactions (ADRs) and therapeutic equivalence. Recently this has focused on ADRs experienced by a patient when switching from the innovator brand of a specific medicine to its generic “equivalent” [1, 2]. Questions have been raised about the impact of generic medicines on the public and health providers and whether this may be increasing the report frequency [3]. Subsidised medicines are available to New Zealanders procured through a tender process which can result in brand changes, typically to generics over time in long-term users. This provides a unique opportunity to evaluate the ADR reporting profile following a “brand switch”.

Objective/Aim: To use a series of “brand switch” examples as case studies to identify the ADR reporting profiles and characteristics.

Methods: Specific “brand switch” examples were identified that provided an opportunity to compare the reporting profiles. These provided an opportunity to determine the potential influence of parameters such as brand-attributed ADRs, user-perceived loss of therapeutic effect, formulation differences or factors such as social media influence of user perceptions. The time course of reports subsequent to the change was determined, the number of reports and type of reactions reported were investigated.

Results: There is a delay following new brand availability before reactions begin to be reported, most likely due to the delay in exhaustion of the previous brand supply. Reports of loss of therapeutic effect tend to predominate. A smaller proportion of reports document mild hypersensitivity reactions, including rash and gastrointestinal disturbances. Some reports of loss of therapeutic effect document return of efficacy on dose re-titration which may reflect individual variations in bioavailability. Reports submitted for generics produced by the same innovator, supports the suggestion that there is an influence of the users perceptions of generic medicines.

Conclusion: When a brand switch occurs there is a predictable spectrum of reactions reported. Some of these may reflect perception of generics rather than the medication, However, there are some reactions reported that do reflect individual responses to either altered bioavailability or formulation factors (i.e. excipients).

References:

• 1. Desari RJ et al. Differences in rates of switchbacks after switching from branded to authorized generic and branded to generic drug product: cohort study. BMJ 2018;361:k1180

• 2. Singh S. The safety of generic prescription drugs in the United States. Drug Saf 2018;41:325–8

• 3. Faasse K et al. The effect of a apparent change to a branded or generic medication on drug effectiveness and side effects. Psychosom Med 2013;75:90–6

Disclosure of Interest: None declared.

177 ISoP18-1256 Acetylsalicylic Acid Adverse Events: A Survey of General Practitioners in Democratic Republic of Congo

177.1 O. M. Mboma^*1, E. S. Tambwe², W. M. Mampuya³, T. N. M. Mpiempie⁴, F. B. Makila⁵, G. K. Mesia⁶

177.1.1 ¹Clinical Pharmacology and Pharmacovigilance Unit and National Pharmacovigilance Centre, University of Kinshasa, The Democratic Republic of the Congo; ²Basis Science, University of Kinshsa, Kinshasa, The Democratic Republic of the Congo; ³University Hospital Centre, University of Sherbrooke, Sherbrooke, Canada ; ⁴National Pharmacovigilance Centre, National Pharmacovigilance, ⁵Centre Nationale de Pharmacovigilance, Centre National de Pharmacovigilance, ⁶Faculty of Pharmaceutical Sciences, Universty of Kinshasa, Kinshasa, The Democratic Republic of the Congo

Background/Introduction: Acetylsalicylic acid (ASA) remains essential in the management of cardiovascular disease both in primary and secondary prevention. It is one of the key measures to reduce embolic strokes incidence [1], the major cause of disability all over the world [2]. According to the World Health Organization (WHO), in the World, cardiovascular diseases (CVD) are responsible for 17.3 million deaths per year, 9% in the Democratic Republic of the Congo (DRC) [3].

Objective/Aim: Identify the various adverse events (AE) of ASA as reported by the prescribing general practitioners (GPs).

Methods: We administered a questionnaire to GPs who had prescribed ASA at least once from October to December 2017, for which patients had complained of AEs.

Results: Questionnaires completed by 280 GPs were analyzed. In total, 66 AEs were reported following the use of ASA, of which 64 were benign and 2 were severe. The severe cases included thrombocytopenia and disseminated intravascular coagulation (DIC). Thirty-three percent of these AEs led to treatment modification. The most commonly reported AEs were edemas (12.1%), gastrointestinal disorders (33.3%), bleeding (42.4%) and allergic reactions (4.6%). Edemas included facial edema (12.5%), lower extremity edema (25%) and unspecified edemas (62.5%). Gastrointestinal disorders included vomiting (4.5%), epigastralgia (9.1%), abdominal pain (4.5%), diarrhea (13.7%), dyspepsia (4.5%), acute gastritis (45.5%) and unspecified gastrointestinal disorders (18.2%). Bleeding (42.4%) included hematemesis (14.3%), gingivorrhagia (10.7%), epistaxis (7.1%), gastrointestinal hemorrhage (7.1%), thrombopenia (3.6%), bleeding at the injection site (3.6%), petechiae (3.6%), hemoptysis (3.6%), metrorrhagia (3.6%) and rectorrhagia (3.6%), unspecified bleeding (32.1%) and unspecified hemorrhages (7.1%). Anemia (4.6%) included unspecified anemia (66.7%) and DIC (33.3%).  Allergic reactions included pruritus (50%) and unspecified allergic reactions (50%).

Conclusion: This study shows that the use of ASA in the DRC is associated with multiple AEs that lead to a change in therapy in 33% of the cases. Bleedings and gastrointestinal disorders are the most prevalent AEs of ASA. Deepened studies on the rational use of ASA are ongoing.

Key words: Acetylsalicylic acid, Aspirin, Adverse events, DR Congo.

References

• 1. Patrono C, et al. Eur Heart J 2011; 32:2922–32

• 2. The Lancet, Volume 385, Issue 9963, 117–171

• 3. WHO 2013

Disclosure of Interest: None declared.

178 ISoP18-1261 Development, Validation and Implementation of an Active Electronic Pharmacovigilance System in Hospitalized Patients

178.1 A. Ceschi¹, P. Hitz¹, L. Müller¹, R. Bertoli^*1, V. Piffaretti²

178.1.1 ¹Institute of Pharmacological Sciences of Southern Switzerland, Division of Clinical Pharmacology and Toxicology, Ente Ospedaliero Cantonale, Lugano, Switzerland; ²Area Information and Communications Technology, Ente Ospedaliero Cantonale, Lugano, Switzerland

Background/Introduction: Spontaneous reporting of adverse drug reactions (ADRs) is the foundation of pharmacovigilance systems worldwide. One of the main limitations is underreporting, which is significant and widespread, and has been estimated to approach a median rate of 94% [1].

Objective/Aim: To develop, validate and subsequently introduce into routine practice a novel, easy to adapt, active electronic pharmacovigilance system in hospitalized patients.

Methods: In close collaboration with the ICT of our hospital network, we developed an electronic system that actively and continuously screens all electronic medical records searching for words and word combinations which we defined as related to ADRs. We subsequently modified the list of words in order to improve the positive predictive value of the system. Chi square and post hoc tests were performed.

Results: With the first word list we obtained 40 and 60% true and false positives, respectively. A subsequent list generated an error message. After adding further words and combinations, we obtained 60 and 40% true and false positives, respectively, and a further revision of the list provided 96.7 and 3.3% true and false positives, respectively. There was a significant improvement of the positive predictive value of the system (p < 0.001) and the third and fourth word lists contributed significantly to this result (p < 0.001 and p = 0.001, respectively). During the subsequent test phase of 51 days the system generated 365 alerts for potential cases. Of these, 283 (77.5%) were true ADRs and 160 (56.5%) were subject to mandatory reporting according to the Swiss law on therapeutic products. Of these reportable ADRs, 140 (87.5%) were serious, 19 (11.9%) medically important and 1 (0.6%) due to medication abuse. Of the 140 serious ADRs, 85 (60.7%) required hospitalization and 55 (39.3%) increased the length of stay. Among the 160 ADRs subject to mandatory reporting, only 14 (8.8%) cases were reported spontaneously to our pharmacovigilance centre. The underreporting rate was therefore 91.2%. There was a significant correlation between seriousness of the ADR and reporting to the centre (p = 0.024).

Conclusion: We developed and tested an easy to adapt active electronic pharmacovigilance system in hospitalized patients, which was able to detect a large number of relevant ADRs which would have gone unnoticed as they were not reported spontaneously to our centre although subject to mandatory reporting. The system was then successfully introduced into routine practice reducing underreporting and therefore contributing to increase medication safety.

References:

• 1. Hazell L, Shakir SA. Under-reporting of adverse drug reactions: a systematic review. Drug Saf 2006;29:385–96

Disclosure of Interest: None declared.

179 ISoP18-1262 Opinion of Costa Rican Pharmacists Regarding a New Adverse Drug Reaction Reporting Platform, 2017

179.1 V. Hall Ramirez^*1

179.1.1 ¹Pharmaceutical Care and Clinical Pharmacy Department, Pharmacy Faculty, University of Costa Rica, San José, Costa Rica

Background/Introduction: The importance of Pharmacovigilance for safe medicines and their safe use has increasingly been recognised during the last few years [1]. As part of the curriculum in the Pharmacy career of the University of Costa Rica, several aspects related to Pharmacovigilance are studied.

Objective/Aim: Describe the results of a survey to community pharmacists in Costa Rica during the second half of 2017, regarding to a new Adverse Drug Reaction reporting platform.

Methods: We performed a descriptive, cross-sectional study.

Application of a data collection instrument to preceptor pharmacists by the Pharmaceutical Care I course students. The data were managed in a group, confidential and anonymous way. The data obtained was analyzed by Microsoft Excel.

Results: Information was collected from 41 community pharmacies. The first question of the instrument was related to the pharmacist’s experience in reporting an Individual Case Safety Report (ICSRS) through the new Regional Online Platform to Report Adverse Drug Reactions (NOTI-FACEDRA) [2], three months after it was release in June, 2017. All the pharmacist (100%) mentioned that they have not reported any ICRS in this period.

Even if they had not used the platform to make a report, they were encouraged to visit the website along with their student, so they can explore NOTI-FACEDRA and after that, give a valuation of the platform.

The pharmacists said that the report is filled quickly (22.53%), the platform is simple and accessible (21.12%) and it is easy to generate statistical information (21.12%), it can bring regional information (12.67%) and allows to make the report in real time (11.27%).

Conclusion: Although the existence of a new website to report online the adverse drug reactions by the health professionals, it is important to make a campaign to ensure not only that the professionals knows how to use it, but also to empower the patient to visit their pharmacist so they can tell all the possible adverse drug reactions they can be experimenting in order to report them and also to manage the reactions by different pharmaceutical interventions.

References:

• 1. Beckmann J, Hagemann U, Bahri P et al. Teaching pharmacovigilance: the WHO-ISoP core elements of a comprehensive modular curriculum. Drug Saf 2014;37:743–59

• 2. Secretaria Ejecutiva de COMISCA. Portal Regional de Notificación en línea de Sospecha de Reacciones Adversas a Medicamentos de uso humano [Internet] [Accessed on June 4th, 2018]. Available in http://www.notificacentroamerica.net/Pages/mapa.aspx#no-back-button

Disclosure of Interest: None declared.

180 ISoP18-1263 Patient Reporting of Adverse Drug Reactions in Romania-Pilot Phase of a Cross-Sectional Survey

180.1 C. Bucsa^*1, I. Cazacu¹, C. Mogosan¹, N. Bulik¹, B. Axente¹, A. Farcas¹

180.1.1 ¹Drug Information Research Center, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania

Background/Introduction: Patient reporting of adverse drug reactions (ADRs) in Romania is possible since 2012, once the new European legislation on pharmacovigilance was introduced. However, 4 years later the level of patient reporting is still very low [in 2016 only 26 ADR reports coming from patients were registered to the Romanian National Agency for Medicines and Medical Devices (NAMMD)] [1].

Objective/Aim: To test a questionnaire designed for patients, to investigate their perception and knowledge on ADR reporting.

Methods: A questionnaire was designed in a panel of 5 pharmacists specialized in pharmacovigilance activities. The patients participating to a health campaign on the importance of health monitoring, during 3 days in July 2017 in Cluj-Napoca, were invited to fill-in the questionnaire. Of the 18 total questions, 17 were referring to demography (age, sex, education, occupation), health status (chronic diseases, medicine use, frequency of physician visits, concern for own health), the source of information on medicines, the ability to recognize ADRs and the perception and knowledge on ADR reporting. The last question contained 13 subheadings on the most recent ADR (if the case).

Results: Of the 59 patients who completed the questionnaire, 42 were women and the median age was 57 years [range 22–78].  The great majority of patients (54) knew that every medicine may induce ADRs. For 17 patients the leaflet was the main source of information for identifying ADRs. 20 patients knew about the possibility of reporting ADRs to NAMMD. Nevertheless, of the 24 patients who described an ADR, only 15 reported the ADR, and all to the attending physician. The main reason for reporting ADRs for 10 of the 15 patients was altruism: the importance of knowing about the ADR for other patients/authorities. Four patients filled-in an ADR report form to NAMMD after completing the questionnaire. Following this pilot phase of the study, 7 questions of the questionnaire were reworded to increase clarity. We also added one question to investigate the reason why patients prefer to report ADRs only to the physician and not directly to NAMMD.

Conclusion: Although most of the patients were aware about the risk of ADRs and the possibility to report the ADRs to the NAMMD, they preferred to report to the attending physician only. The study will continue on-line with the questionnaire adapted accordingly.

References:

• 1. Romanian National Agency for Medicines and Medical Devices. Romanian National Agency for Medicines and Medical Devices 2016 activity report [Romanian language only]. Available from https://www.anm.ro/agentie/rapoarte-de-activitate/. Accessed 29 May 2018

Disclosure of Interest: None declared.

181 ISoP18-1264 Adherence to Treatment of Chronic Patients in General Practitioner Office-First Results of a Cross-Sectional Survey

181.1 C. Bucsa^*1, N. Bulik¹, S. Iurian², S. Muresan³, I. Muresan⁴, G. Feher⁵, C. Mogosan¹

181.1.1 ¹Drug Information Research Center, ²Department of Pharmaceutical Technology and Biopharmaceutics, “Iuliu Hatieganu” University of Medicine and Pharmacy, ³Sandra Muresan medical practice, ⁴Ioan Muresan medical practice, ⁵Gabriella Feher medical practice, Cluj-Napoca, Romania

Background/Introduction: Patients’ adherence to chronic treatment plays an important role in preventing disease complications and adverse drug reactions (ADRs). The impact of poor adherence grows as the burden of chronic disease grows worldwide [1].

Objective/Aim: To investigate how patients’ and health system’s characteristics may influence aspects of adherence to treatment in chronic Romanian patients.

Methods: We developed an in-house questionnaire which comprised aspects of patient’s demography and social status (sex, age, marital status, education, occupation, income, medication cost), source of information on medicines, use of medication reminders, choice of pharmacy and discussion with the pharmacist and several questions to investigate the patient’s forgetfulness (4 questions: sometimes, during past month, past 2 weeks and 1 day before the interview) and intentional omission of taking medicines (in case the health status improves or worsens). The questionnaire was applied to chronic patients in 3 general practitioners (GPs) offices by a trained pharmacist before the GP consultation. The questions targeted the month before the interview timeframe.

Results: We present here the results of the first 100 questionnaires. The median age of the patients was 63 years, most of them (66) were females and married (29). The medium income was approximately 257 euro/month and the medium amount spent on medication was 23 euro/month. The medium number of chronic diseases was 2.45 and the medium number of medicines 4.07. The great majority of patients (95) followed only advice of doctor/pharmacist related to their medication.  Most of the patients took their medicines always from the same pharmacy (48), only 6 of them because they preferred a personal pharmacist and 19 because of the convenient location. 66 of the patients did not use a reminder system for taking their medicines. A great part of the patients (45) did not forget to take their medicines during the past month (answered NO to all 4 questions), 34 patients answered YES once, 15-twice and 6-3 times. 20 patients did not take their medication on own initiative when they felt worse and 16 when they felt better. 23 patients had at least one event of forgetfulness and one intentional omission during last month.

Conclusion: First results of our study showed that forgetfulness and intentional omission of taking medicines in chronic patients were present in a high number of patients. Association between the findings will be tested further.

References:

• 1. Sabaté E (editor). Adherence to long-term therapies: evidence for action. 2003 World Health Organization

Disclosure of Interest: None declared.

182 ISoP18-1266 Evaluation of Drug-Related Health Problems by Diagnosis in Children

182.1 A. Akici^*1, N. I. Kirmizi¹, N. Akici², F. İsli³, M. Aksoy³

182.1.1 ¹Department of Pharmacology, Marmara University, Istanbul, Turkey; ²Department of Pediatrics, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey; ³Turkish Medicines and Medical Devices Agency, Ministry of Health, Ankara, Turkey

Background/Introduction: Drug-related health problems (DRHP) are one of the major reason for hospitalization in worldwide [1]. Children that more vulnerable to these problems represent a highly critical population [2]. As pediatricians are more likely to face DRHPs in children, addressing the extent of these problems in diagnosed by pediatricians can provide more information about DRHP in children.

Objective/Aim: This study aimed to investigate the diagnosis-based distribution of DRHPs in children.

Methods: Diagnoses prescribed to children (< 18-year-old) by pediatricians in Turkey were examined. The diagnoses in the prescriptions registered between 2015 and 2016 in the Prescription Information System of the Turkish Medicines and Medical Devices Agency were analyzed retrospectively. The details of the diagnoses containing DRHPs were examined according to the ICD-10 coding system (F11, F13, F15, F16, F19, T36–T50, Y40–Y59, X40–X44, X60–X64).

Results: A total of 11,642,110 diagnoses were found to be registered during the two-year study, where 838 DRHPs were identified (0.01%). It was detected that 77.3% of these diagnoses belonged to “Y40–Y59” codes (drugs, medicaments, and biological substances causing adverse effects in therapeutic use), which was followed by “X40–X44” coded-diagnoses (accidental poisoning by and exposure to noxious substances-excluding alcohol, gases etc.) with 16.3%. When we examined the details of the 648 diagnoses belonging to the codes of “Y40–Y59”, we observed the most common codes are “Y57” (other and unspecified drugs and medicaments, 29.0%), “Y59” (other and unspecified vaccines and biological substances, 28.7%), and “Y44” (agents primarily affecting blood constituents, 17.0%).

Conclusion: It was the first study to describe various DRHPs experienced by pediatric patients in Turkey. Available findings may shed light on the prevention of DRHPs, especially the most common ones, and on the development of respective pharmacovigilance strategies.

References:

• 1. Shehab N, Lovegrove MC, Geller AI, Rose KO, Weidle NJ, Budnitz DS. US emergency department visits for outpatient adverse drug events, 2013–2014. JAMA 2016;316:2115–25

• 2. Bouvy JC, De Bruin ML, Koopmanschap MA. Epidemiology of adverse drug reactions in Europe: A review of recent observational studies. Drug Saf 2015;38:437–53

Disclosure of Interest: None declared.

183 ISoP18-1267 An Online Collaborative, Open Access Pharmacovigilance Platform for Resource-Limited Countries

183.1 E. Allen^*1, C. Pace²

183.1.1 ¹University of Cape Town, Cape Town, South Africa ; ²Liverpool School of Tropical Medicine, Liverpool, United Kingdom

Background/Introduction: It can be particularly challenging to evaluate drug safety in low-resourced settings for a variety of reasons, including a lack of infrastructure, sometimes weak regulatory environments and poor access to training and education. Although there are good online and on-the-ground options for researchers working in pharmacovigilance in these settings, some may yet be unaffordable. More could be done to pull together existing free or low-cost resources, and develop new such resources, for those with limited acess to funds.

Objective/Aim: To sustain an online pharmacovigilance platform that is accessible to all, interactive, comprehensive, practical and responsive to users, thereby increasing the capacity for high quality drug safety evaluations in low-resourced settings.

Methods: Global Pharmacovigilance (https://globalpharmacovigilance.tghn.org) was launched mid-2016 with seed funding through the ACT Consortion (http://www.actconsortium.org), a global collaboration of researchers answering key questions about artemisinin-based combination therapies for malaria. Since its inception the website, which is not restricted to malaria, has provided links to a range of pharmacovigilance resources, including notices of events, training and education opportunities, special interest groups, and news items and articles on a diverse range of related topics.

Results: Coordinated voluntarily, the platform has grown to be consistently in the top 6 most accessed sites that form The Global Health Network (https://tghn.org), an online science park of 36 specialist health research-related professional member areas. Twitter and RSS feeds have been added and the focus has broadened to include non-drug interventions. As other member areas of TGHN have grown, so this one has drawn in their safety-related resources in a cost-effective and efficient way through its inter-connected infrastruture (and vice versa, raising the profile of pharmacovigilance across the TGHN membership of over 400,000 researchers). The focus going forward is encouraging those working or otherwise engaged in pharmacovigilance to contribute short articles, career advice and potentially mentorship, to ensure content and advice is of a high quality (as it is authored by experts), reflects current thinking, and showcases efforts being made globally to improve the safe use of medicines and other interventions.

Conclusion: The outputs hosted through Global Pharmacovigilance are expected to contribute to improving the practice of safety evaluations in resource-poor settings. We call on those involved in pharmacovigilance to support this platform by sharing their experiences and expertise so that those in under-resourced settings, and their patients, may benefit.

Disclosure of Interest: None declared.

184 ISoP18-1268 Pharmacovigilance Teaching to Undergraduates of Medicine and Surgery School: the Experience of Verona University

184.1 L. Magro^*1, U. Moretti¹, E. Arzenton¹, R. Leone¹

184.1.1 ¹Department of Diagnostics and Public Health, Section of Pharmacology, University of Verona, Verona, Italy

Background/Introduction: Teaching pharmacovigilance (PV) to undergraduates of Medicine and Surgery School is an educational objective of great importance. Their acquisition of theoretical bases and practical skills in detecting and reporting adverse drug reactions (ADRs) is an essential pre-requisite for their future contribution to pharmacovigilance activities. Unfortunately, at national level pharmacovigilance is not compulsory within the Degree Course of Medicine and Surgery (MD) in Italy and its introduction within the course of Pharmacology depends on the individual initiative of some professors.

Objective/Aim: Pharmacovigilance teaching to undergraduates of Medicine and Surgery School at University’s Verona, Italy.

Methods: The teaching methods included 15 h of frontal teaching, problem based learning (PBL) and problem solving (PS). The course aimed to the development of pharmacovigilance knowledge and skills and focused on basis of pharmacovigilance, regulatory aspects and benefit/harm assessment. With regard to PBL and PS, students, divided into groups with the presence of a tutor, were trained on drug–drug interactions, medical diagnosis, recognizing, managing and reporting ADRs through the analysis of a clinical case report. At the end of the course the students’ knowledge was assessed through an oral exam.

Results: At the University of Verona pharmacovigilance has been taught within the Degree Course of MD for at least 20 years, since the professors of Pharmacology are involved in the activities of the Regional PV Centre. Until last year the teaching of pharmacovigilance was only among the training objectives of the Pharmacology course, whereas, starting from the academic year 2017–2018, the course has been divided into two modules: General/Special Pharmacology (8 Educational Credits-ECTS) and Pharmacovigilance (1 ECTS), both carried out during the fourth year of education (120 students). At the conclusion of the PV module students:

> were able to understand the mechanisms of ADRs,

> were able to understand the classification of ADRs,

> knew the epidemiological data on ADRs,

> were able to fill in a reporting form.

Conclusion: Teaching PV is particularly important for MD students, since their knowledge on PV can influence their future ability to prescribe and monitor drug therapies. As a matter of fact, a physician who has the ability to identify ADRs and the habit of reporting them, will certainly pay attention to all aspects related to the patient’s health and consequently to both positive and negative effects of a drug therapy.

Disclosure of Interest: None declared.

185 ISoP18-1269 Exploring the Association Between Monoclonal Antibodies and Depression and Suicidal Ideation and Behavior: A Vigibase Study

185.1 L. Minnema^*1,2, T. Giezen^2,3, P. Souverein¹, T. Egberts^1,4, B. Leufkens¹, H. Gardarsdottir^1,5

185.1.1 ¹Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht, the Netherlands; ²Medicines Evaluation Board, Utrecht, ³Foundation Pharmacy for Hospitals in Haarlem, Haarlem, the Netherlands; ⁴Department of Clinical Pharmacy, University Medical Centre Utrecht, Utrecht, the Netherlands, ⁵Department of Pharmaceutical Sciences, School of Health Sciences, University of Iceland, Reykjavik, Iceland

Background/Introduction: Recently, exposure to monoclonal antibodies has been associated with neuropsychiatric effects, e.g., depression, and suicidal ideation and behavior. So far, little is known about any differential risk between individual monoclonal antibodies and the potential underlying mechanism.

Objective/Aim: To quantify and characterize spontaneously reported adverse drug reactions (ADRs) of monoclonal antibodies related to depression and suicidal ideation and behavior. Furthermore, to explore the association between the mechanism of action of the monoclonal antibodies and these ADRs.

Methods: ADRs reported until December 2017 in VigiBase, the WHO global database of Individual Case Safety Reports, were included. Reports related to depression and suicidal ideation and behaviour (MedDRA standardized search) for monoclonal antibodies were extracted. Monoclonal antibodies that had been authorised by any global regulatory authority (e.g. FDA, EMA) for at least 3 years were included. Associations were tested by estimating reporting odds ratios (RORs) for the monoclonal antibodies separately (using bevacizumab as a reference) as well as grouped on their influence on the immune system (not influencing the immune system (reference), suppressing the immune system, and stimulating the immune system). Monoclonal antibodies suppressing the immune system were further stratified according to their intended indication (autoimmune diseases, cancer).

Results: A total of 44 monoclonal antibodies were included for which a total of 2924,319 adverse drug reactions were reported. For these 44 monoclonal antibodies, 9455 (0.3%) reports related to depression and 1770 (0.1%) reports related to suicidal ideation and behaviour were analysed. For both depression and suicidal ideation and behaviour, natalizumab and belimumab showed the highest ROR relative to bevacizumab, i.e. for depression 5.7 (95% CI 5.0–6.4) and 5.1 (95% CI 4.2–6.2), for suicidal ideation and behaviour 12.0 (95% CI 7.9–18.3) and 20.2 (95% CI 12.4–33.0) respectively. Monoclonal antibodies suppressing the immune system showed higher ROR relative to monoclonal antibodies not influencing the immune system, i.e. for depression 1.9 (95% CI 1.8–2.0) and for suicidal ideation and behaviour 3.6 (95% CI 3.0–4.4). This difference was only seen in the monoclonal antibodies suppressing the immune system that are used for treating autoimmune diseases.

Conclusion: Adverse neuropsychiatric effects are seen in patients exposed to monoclonal antibodies. Two antibodies peaked relative to bevacizumab (i.e. natalizumab, belimumab) regarding reporting of depression and suicidal ideation and behaviour. Furthermore, monoclonal antibodies used for treating autoimmune diseases showed higher RORs compared to monoclonal antibodies not influencing the immune system. For the interpretation of these data the indications for use and other population characteristics need further consideration.

Disclosure of Interest: None declared.

186 ISoP18-1272 Comparison of Reported Adverse Events of Premature and Term Born Infants Following Childhood Vaccinations in the Netherlands

186.1 L. van Balveren^*1, F. van Hunsel¹, E. van Puijenbroek¹

186.1.1 ¹Netherlands Pharmacovigilance Centre Lareb, ‘s-Hertogenbosch, The Netherlands

Background/Introduction: Most reported common adverse events (AEs) following infant vaccination are well-known. In The Netherlands infants receive two different vaccines; a pneumococcal vaccine and a diphtheria, tetanus, pertussis (acellular, component) hepatitis B, poliomyelitis and Haemophilus influenzae type b vaccine (DTaP/IPV/Hib/HepB) at the gestational age of 2, 3 (only DTaP/IPV/Hib/HepB), 4 and 11 months. Some of the reports on AEs received concerned premature babies. This raised the question whether or not there was a difference between reported AEs of preterm and term born babies.

Objective/Aim: To determine differences between the pattern of reported AEs of spontaneous reports following infant vaccinations between premature and term born babies.

Methods: Retrospective analysis of reported AEs to pharmacovigilance centre Lareb of reports following infant vaccinations between a premature and term born babies. Reports concerning AEs after infant vaccinations between December 2011 and May 2017 were selected. The AEs were listed for premature and term born babies. Odds ratios were calculated to compare the AE pattern for both groups.

Results: The most reported well known AEs in both methods were comparable. Table 1 shows the frequencies of occurrence of these reported AEs in spontaneous reports of term and preterm babies. Statistically significant differences were found for apnoea (OR = 90; 95% CI 36–224), apnoeic attack (OR 109; 95% CI 51–232), decreased oxygen saturation (OR = 86; 95% CI 30–249) and syncope (OR = 2.8; 95% CI 1.5–5.1), which were more frequently reported for premature babies.

Conclusion: This study shows that the pattern of reported AEs is comparable between both groups for well-known common AEs. Apnoeic attacks and comparable symptoms like bradycardia and a decreased oxygen saturation are events also known to occur in premature born babies not being vaccinated. These events are described as rare AE in the SmPC, especially in premature children.

Disclosure of Interest: None declared.

187 ISoP18-1274 Gynecomastia and Galactorrhea: Unlabeled Adverse Drug Reactions of Retinoids used in Dermatology

187.1 M. Atzenhoffer^*1, S. Pierre¹, F. Bellet², S. Pinel³, L. Javot⁴, T. Vial¹, B. Kassai¹, M. Auffret¹

187.1.1 ¹Centre Régional de Pharmacovigilance, Service Hospitalo-Universitaire de Pharmacotoxicologie, Hospices Civils de Lyon, Lyon, France; ²Centre Régional de Pharmacovigilance, Centre-Hospitalo-Universitaire de Saint-Etienne, Saint-Etienne, France; ³Centre Régional de Pharmacovigilance Paris Fernand-Widal, Hôpital Lariboisière-Fernand Widal—APHP, Paris, France; ⁴Centre Régional de Pharmacovigilance, Service Hospitalo-Universitaire de Pharmacologie Clinique et de Toxicologie, CHRU de Nancy, Nancy, France

Background/Introduction: Gynecomastia and galactorrhea are rare adverse drug reactions (ADRs) mainly associated with exogenous estrogens, antiandrogens, 5 alpha-reductase inhibitors, spironolactone and cimetidine. Several case reports of gynecomastia and galactorrhea have been reported in the literature with retinoids [1, 2]. However, these ADRs are not listed in the Summary of Product Characteristics of retinoids.

Objective/Aim: The aim of this study was to describe cases of gynecomastia and galactorrhea concomitant with the use of retinoids in the French Pharmacovigilance database (FPVD).

Methods: All cases corresponding to the MedDRA term “breast disorder” (High Level Group Term) and associated with oral or topical retinoid use for a dermatological purpose were extracted from the FPVD between 1985 and May 2018. Cases were excluded if another drug- or non-drug etiology was finally retained based on the French method for causality assessment.

Results: Thirty-one cases were included. Among them, there were 22 cases associated with oral isotretinoin use (14 cases of gynecomastia, 6 of galactorrhea and 2 of both gynecomastia and galactorrhea), 8 cases of isolated gynecomastia with oral acitretin use and one case of gynecomastia with topical tretinoin use. The indications were mostly acne and psoriasis. Patients’ median age was 22 years [Interquartile range (IQR) 19–35]. Gynecomastia and/or galactorrhea were unilateral for almost half of the cases with known clinical description (7/15). The median time of onset was 90 days (IQR 39–347, n = 26). The outcome was known for 27 patients and a total recovery after withdrawal of retinoid was observed for 63% of them. There were two cases of positive rechallenge. Only two cases were considered as serious: one hospitalization and one case that needed surgery.

Conclusion: Gynecomastia and/or galactorrhea could be associated with the retinoid treatment for cutaneous disease. Physicians should be aware of these potential ADRs and inform their patients. For most of the cases, gynecomastia and galactorrhea resolved after withdrawal of the treatment.

References:

• 1. Larsen GK. Iatrogenic breast discharge with isotretinoin. Arch Dermatol 1985;121:450-1

• 2. Carmichael AJ, Paul CJ. Reversible gynaecomastia associated with etritinate. Br J Dermatol. 1989;120:317

Disclosure of Interest: None declared.

188 ISoP18-1275 Reactogenicity and Safety of the Measles–Mumps–Rubella Vaccine: A Prospective Observational Real World Study

188.1 C. Bucsa^*1, N. Bulik², A. Farcas¹, S. Muresan³, I. Muresan⁴, O. Oniga²

188.1.1 ¹Drug Information Research Center, ²Pharmaceutical Chemistry Department, “Iuliu Hatieganu” University of Medicine and Pharmacy, ³Sandra Muresan medical practice, ⁴Loan Muresan Medical Practice, Cluj-Napoca, Romania

Background/Introduction: Measles outbreaks are spreading in many European countries due to parents’ refusal to vaccinate their children. The highest number of measles cases in Europe during 2017 was reported in Romania [1].

Objective/Aim: To assess the reactogenicity and safety of MMR vaccine as reported by parents of vaccinated children, in real-world general practice.

Methods: Children vaccinated with MMR according to the national immunization schedule (1st dose at 1 year old and 2nd dose at 5 years old) in 2 general practitioners’ (GPs) offices from Romania during March 2016–May 2017 were followed-up for 6 months. Demographic characteristics, medical history, history of adverse events (AEs) after previous vaccination and prior use of medication were recorded. We collected the solicited symptoms (Table) within 4 days after vaccination via an online questionnaire, and any AEs urging medical visit within 6 months after vaccination via follow-up phone calls.

Results: A total of 216 children, 123 aged 9–17 months (Group 1) and 93 aged 4–7 years (Group 2) received 219 MMR vaccine doses alone or together with other pediatric vaccines. 3 children in Group 1 received 2 MMR vaccine doses (at 9 and 12 months) due to change in the national vaccination schedule. The incidence of solicited symptoms is presented in the Table 211 AEs urging medical visit were recorded during the 6 months after vaccination in Group 1 and 49 AEs in Group 2. The most frequent unsolicited AEs urging medical visit were upper respiratory tract infections, tonsillitis, bronchiolitis, diarrhea and otitis media. No death was reported.

Conclusion: Incidences of both solicited and unsolicited AEs were generally higher in 9–17 months age group, as expected. Likewise, incidence of solicited general symptoms was higher when MMR vaccine was co-administered with other vaccines.

References:

• 1. European Centre for Disease Prevention and Control. Measles in the EU/EEA: current outbreaks, latest data and trends—January 2018. Available from https://ecdc.europa.eu/en/news-events/measles-eueea-current-outbreaks-latest-data-and-trends-January-2018 [AccessedJuly 2018]

Disclosure of Interest: None declared.

189 ISoP18-1276 What is Risky about Risk Communications: a Case Study on Dengue Vaccine

189.1 K. Y. Hartigan-Go^*1, H. Larson²

189.1.1 ¹Zuellig School of Development Management, Asian Institute of Management, Makati, Philippines; ²Vaccine Confidence Project, London School of Hygiene and Tropical Medicine, London, United Kingdom

Background/Introduction: Dengue is a tropical disease that affects large populations and creates a heavy burden of disease. While there are public health strategies like vector control, intensive surveillance, clinical monitoring and intervention, these approaches are often inadequate in hyper-endemic areas. In late 2015, the first Dengue Vaccine was made available and became part of a critical intervention for poputlations at risk. The Philippines licensed this vaccine in December 2015 and adopted it for a pilot public health intervention in three regions of the country with heavy burden of disease. The cases of dengue were particularly high and rising since 2012. In some localities, a state of calamity was declared. There were brewing objections about this immunization program by some quarters. On the 29th November 2017, Sanofi Pasteur informed the Philippine government of their retrospective analysis that those with seronegative status and vaccinated woudl have a trend risk for sever dengue and increased hospitalization after 3 years of protection.

Objective/Aim: Lessons and recommendations will be discussed in the spirit of improving risk management and communications in a setting of public health, politics, culrture, media manipulation, poor understanding of science and benefit–risk even by health professionals, and anti-vaccine lobby.

Methods: Review of the government records, interviews and analysis of the socio-political-health events will describe the evolution of damage caused by false narratives in social media, news and investigations.

Results: A perfect storm of events followed leading to product withdrawal and stoppage of immunization. Social media was weaponized and false narratives were made including allegations that vaccine killed a number of children. The vaccine was labelled as dangerous. Fear was created among parents and children as media continually reported a sensational and bias news, leaving both public health insitutions and workers’ reputation damaged.

Conclusion: The Dengue Vaccine scare led to an unintended consequence. It created a loss of vaccine confidence. As a result, cases of measles went up due to poor adoption of vaccines more broadly in both the public programs and private clinics.

Disclosure of Interest: K. Hartigan-Go Other: The issue is a subject of investigation for which the author is involved. H. Larson: None declared.

190 ISoP18-1277 Anaphylactic Shock Secondary to Blue Patent Administration with Positive Skin Tests

190.1 B. Ouni¹, N. Fathallah¹, O. Kaabia², A. Brahem³, S. Larif¹, R. Slim¹, S. Haydar², C. Ben Salem^*1

190.1.1 ¹Pharmacovigilance Center of Sousse, Labratory of Research, Sousse University, Sousse, Tunisia; ²Department of Gynecology, ³Reanimation Care Unit, Farhat Hached University Hospital, Sousse, Tunisia

Background/Introduction: Patent Blue is commonly used for selective localisation of the lymphatic system before sentinel lymph node biopsy, but is known to induce severe anaphylaxis. The prevalence of anaphylactic reactions to patent blue is reported to be 1.8% (0.6–2.8%) [1].

Objective/Aim: To report a case of anaphylactic shock secondary to patent blue administration with positive skin tests.

Methods: A 50-year-old female patient without history of allergic diseases or any drug, food or latex allergies, was diagnosed with breast cancer (T2, N0, Mx). She underwent lymph node dissection with tumorectomy, panectomye. About 5 min after patent blue injection, the patient developed dyspnea, agitation and generalised skin eruption. The patient’s oxygen saturation was 71%, his blood pressure was 70/50 mmHg with tachycardia. The diagnosis of anaphylactic shock was retained. The patient was recieved adrenaline and fluids. Thereafter, the patient symptoms improved and she fully recovered without apparent complications. Skin prick tests performed (after obtaining informed consent from the patient) returned very positive for patent blue. For that reason, we contre-indicated the use of patent blue.

Results: Patent Blue is commonly used to identify the lymph node before sentinel lymph node biopsy, but is known to induce severe anaphylaxis mediated by IgE. The prevalence of anaphylactic reactions to patent blue is reported to be 1.8% (0.6–2.8%) [1]. The skin test (skin prick or intradermal) is used seems to be the ideal test with high sensitivity and specificity to identify patients with hypersensitivity to patent blue. Our patient had a hypersensitivity reaction grade II which evolved satisfactorily without sequelae with positive skin prick test [2].

Conclusion: Both anaesthetists and surgeons should be aware of severe anaphylactic reactions when administering Patent Blue.

References:

• 1. Parvaiz MA, Isgar B. Anaphylaxis and blue urticaria associated with Patent Blue V injection. Anaesthesia 2012;67:1275–6

• 2. Maranhão MV, da Nóbrega DK, Anunciação CE, Maia Bde A, Mariano PV. Allergic reaction to patent blue dye in breast surgery—case report. Braz J Anesthesiol 2016;66:433–6

Disclosure of Interest: None declared.

191 ISoP18-1279 Serious Adverse Drug Reaction Reports in the Nigerian Vigiflow Database from September 2004 to December 2016

191.1 A. Ibrahim^*1, C. K. Ogar¹, A. S. Abiodun¹, M. C. Adeyeye², H. Nosiri¹, E. Amadi¹

191.1.1 ¹PV/PMS Directorate, Wuse-Abuja, Nigeria; ²Director General, NAFDAC, FCT, Nigeria ³Director General, NAFDAC, FCT, Nigeria

Background/Introduction: Adverse drug reactions (ADRs) are a source of concern in healthcare delivery as they negatively affect patients. Serious adverse drug reactions (SADRs), which may occur during clinical care of patients, have greater impact on patients and the health system; both in terms of morbidity and financial burden. Documenting and sharing reports of serious ADRs help to generate critical data that provide evidence of how the healthcare system can be improved.

The Nigerian National Pharmacovigilance Centre collects spontaneous reports on ADRs experienced by patients using the Adverse Drug Reaction Reporting Forms. A review of the reports submitted between September 2004 to December 2016 was carried out to identify all ICSRs classified as serious in the VigiFlow database.

Objective/Aim: This study aimed to identify all ICSRs classified as serious in the VigiFlow database and profile patients with SADRs, the medicines most implicated in SADRs and indications for their use; describe the SADRs and their classification; document outcome of such reactions and the system organ classes affected by SADRs; and sources of the reports.

Methods: We retrospectively assessed all ICSRs received by the NPC in Nigeria and entered into the VigiFlow database as SADR reports between September 2004 and December 2016.

Results: A total of 11,222 ADR reports were entered into the VigiFlow database within the period under review, of which 298 (2.7%) were classified as SADR reports. A total of 283 (2.5%) ICSRs were considered valid reports. The mean age at onset of SADR was approximately 35 ± 15.7 years. Adults were the most affected by SADR (86%), while neonates were the least affected (1%).The mean number of medicines per report was 3.3 ± 1.5. Nevirapine(10.7%) and Zidovudine (10.4%) as single entities were the most frequently reported medicines. Human Immunodeficiency Virus (HIV) infection affected 55.2% of those who experienced SADRs, followed by unspecified malaria (17.7%). There was no statistically significant difference between gender of the patients, age group, number of medicines in a report and the number of reactions per report. The mean time to onset (TTO) of reaction was 68.51 days.

Hospitalization was the highest reason for classifying a report as serious (53.4%) and death was reported in 29 reports (10.2%). Skin and appendages disorder (24.5%) was the most frequently affected SOC, while anaemia (9.6%) was the most frequently reported reaction. Many patients (39%) made a full recovery.

Pharmacists (52%) submitted the highest number of reports while consumers submitted the least number of reports (5%).

Conclusion: This study found that SADRs reports accounted for 2.5% of valid reports in the NPC VigiFlow database as at December 2016. Many patients recovered fully from the SADRs showing that if SADRs are detected early and promptly managed, patients are likely to make a full recovery. In addition, we found that a large number of ICSRs had information on critical data elements required for analysis of the data. The use of standardized and validated data management software such as VigiFlow is advocated to ensure proper collection and use of homegrown data.

Disclosure of Interest: None declared.

192 ISoP18-1280 Nurses’ Experiences, Attitudes and Perspectives About ADRs and Reporting in the Netherlands

192.1 G. Weits^*1, A. Kant¹

192.1.1 ¹Netherlands Pharmacovigilance Centre Lareb, ‘s-Hertogenbosch, The Netherlands

Background/Introduction: Nurses are directly involved in patients’ medication management. They assist patients in the correct use of medicine and sometimes also prescribe medicines themselves. Nurses are therefore well-placed to monitor patients’ responses to drugs including adverse drug reactions (ADRs). Nevertheless, the number of ADRs reported by nurses to the Netherlands Pharmacovigilance Centre is low.

Objective/Aim: Explore nurses’ experiences, attitudes and perspectives on ADRs and reporting in the Netherlands.

Methods: A web-based questionnaire was used, containing: respondent characteristics, encountering ADRs in daily practice, familiarity with reporting and motives for reporting ADRs. Questions about motives for reporting, reasons for not reporting and familiarity with reporting ADRs were not mandatory and multiple answers were possible. The questionnaire was distributed by e-mail to nurses, specialist nurses, home health nurses, student nurses, advanced nurse practitioners and nurse practitioners. Nurses were invited to participate at nurse congresses, on websites and through newsletters. Answers were analysed using descriptive statistics.

Results: 442 valid questionnaires were received (Table 1). 76.9% (n = 273) of the respondents indicated that they were confronted with ADRs at least a few times a month and 25.1% (n = 89) even daily. Of the latter group, 71.0% (n = 22) were nurses working in mental healthcare. 52.1% (n = 171) of the respondents is not aware that ADRs can be reported. 24.2% (n = 38) of the respondents ever reported an ADR. The main reason for those who never reported an ADR, was because the ADR was described in the product’s Summary of Product Characteristics (SPC) (77.7%, n = 87). Motivation for nurses to report ADRs were: contributing to healthcare (74.4%, n = 244) and that Pharmacovigilance Centre Lareb can pay attention to the reported ADR (41.2%, n = 135). The willingness to report ADRs is high among nurses who did not know Pharmacovigilance Centre Lareb and never reported ADRs (71.9%, n = 115).

Conclusion: This study confirmed that nurses are in a unique position to signal ADRs. They are regularly confronted with patients that experience ADRs in daily practice. The nurses have a high willingness to report. This also applies to the nurses who were unfamiliar with the possibility to report ADRs prior to this questionnaire. To encourage a more active role in pharmacovigilance, increasing awareness for reporting ADRs is important. Also, a clear explanation of what can be reported is desirable.

Disclosure of Interest: None declared.

193 ISoP18-1282 The Impact of Facilitated Reporting of Adverse Drug Reactions by Health Care Professionals as a New Source of ADR Information

193.1 J. van Lint^*1, N. Jessurun¹, W. Hermens²

193.1.1 ¹Netherlands Pharmacovigilance Centre Lareb, ‘s-Hertogenbosch, the Netherlands; ²Jeroen Bosch Hospital, ‘s-Hertogenbosch, The Netherlands

Background/Introduction: Adverse drug reaction (ADR) reports from health care professionals in hospitals contain valuable information for improving knowledge for pharmacovigilance since most severe ADRs occur in hospitals or are a cause for admittance to a hospital. Pharmacovigilance centre Lareb facilitates reporting in hospitals to increase awareness of the occurrence of ADRs in hospitals and to stimulate ADR reporting [1, 2]. Facilitated reporting of ADRs was established in the Jeroen Bosch hospital in ‘s Hertogenbosch (2015) by the clinical pharmacology department. An email-address was created for health care professionals to report suspected ADRs by sending a patient identification number, the suspect drug and the ADR to this email address. The inbox was maintained by clinical pharmacologists in training who further elaborated the cases with standard, requested information from the electronic health record and sent reports to Lareb. Interesting cases were presented in multidisciplinary meetings with participating assessors from Lareb. Facilitated reporting was initially introduced in two selected departments, internal medicine and geriatrics, and was later expanded to the entire hospital.

Objective/Aim: To measure the impact of introducing facilitated reporting in a hospital on ADR awareness.

Methods: ADR awareness was measured by calculating the increase in number of reports received by Lareb from Jeroen Bosch hospital in the years after introducing facilitated reporting. This was compared to the number of reports received in the year before introducing the strategy. The number of publications in peer reviewed journals that facilitated reporting has contributed to, was also measured.

Results: The number of reports increased from 46 in the year before introducing facilitated reporting to 106 in the first year after introducing the method, which is an increase of 130%. Lareb received 70 reports from Jeroen Bosch hospital in the second year, which is an increase of 52%. So over a period of 2 years after the intervention the number of reports almost doubled. Since 2015 the strategy has resulted in 3 publications of drug-ADR associations [3–5].

Conclusion: Facilitated reporting of ADRs in the clinical pharmacology department is a feasible method to increase the number of reports from hospitals and thus increase awareness of ADRs. Since introduction in the Jeroen Bosch hospital, facilitated reporting was adopted in more hospitals in the Netherlands. The impact in other hospitals should be explored in further research.

References:

• 1. Ribeiro-Vaz I, Sliva AM, Costa Santos C et al. How to promote adverse drug reaction reports using information systems—a systematic review and meta-analysis. BMC Med Inform Decis Mak 2016 1;16:27

• 2. Goldstein LH, Berlin M, Saliba W et al. Founding an adverse drug reaction (ADR) network: a method for improving doctors spontaneous ADR reporting in a general hospital. J Clin Pharmacol 2013;53:1220–5

• 3. Dautzenberg L, Jessurun N, Dautzenberg PL, Keijsers CJ. Reversible methotrexate-induced dementia: a case report. J Am Geriatr Soc 2015;63:1273–4

• 4. Jessurun N, Marum van RJ, Hermens W, Puijenbroek van EP. Advanced age and female sex as risk factors for high anion gap metabolic acidosis after a drug interaction between paracetamol and flucloxacillin: a case series. J Am Geriatr Soc 2016 64:e90–e93

• 5. Rouw de HJA, Jessurun NT, Masen-Poos LJP, Derijks HJ. Muscle spasms: an unexpected adverse drug reaction of pemetrexed? Ther Adv Med Oncol 2017;9:138–141

Disclosure of Interest: None declared.

194 ISoP18-1283 Geant Blue Urticaria Secondary to Blue Patent Administration with Positive Skin Tests

194.1 B. Ouni¹, N. Fathallah¹, A. Brahim², S. Larif¹, L. Lassoued³, M. Haj Khalifa², R. Slim¹, C. Ben Salem^*1

194.1.1 ¹Pharmacovigilance Center of Sousse, Labratory of Research, Sousse University, Sousse, Tunisia; ²Reanimation Care Unit, Farhat Hached University Hospital, Sousse, Tunisia ³Gynecology Department, Farhat Hached University Hospital, Sousse, Tunisia

Background/Introduction: Patent Blue is commonly used to identify the lymph node before sentinel lymph node biopsy, but is known to hypersensitivity reactions mediated by IgE with an average incidence of 1.8% (0.1–2.8%). This reaction ranged from skin changes to severe and prolonged cardiovascular depression [1].

Objective/Aim: To report a case of geant blue urticaria secondary to blue patent administration with positive skin tests.

Methods: A 37-year-old female patient without history of allergic diseases or any drug, food or latex allergies, was diagnosed with breast cancer (T2, N0, M0). She underwent lymph node dissection with tumorectomy and panectomy. About 1 h after patent blue injection, the patient developed geant and generalised urticaria-like plates (bluish) without respiratory or hemodynamic disorders. The diagnosis of hypersensitivity reaction was retained. The patient was recieved corticosteroide. Thereafter, the patient symptoms improved and she fully recovered. Skin prick tests performed (after obtaining informed consent from the patient) returned very positive for patent blue. For that reason, we contre-indicated the use of patent blue.

Results: Patent Blue is commonly used to identify the lymph node before sentinel lymph node biopsy, but is known to hypersensitivity reactions mediated by IgE with an average incidence of 1.8% (0.1–2.8%) [1]. Three grades of severity have been described: grade 1 (69–87%), characterised by urticaria, pruritus, blue hives and generalised rash; grade 2 (3.2–8%), by transient hypotension (systolic blood pressure.

Conclusion: Both anaesthetists and surgeons must remain constantly vigilant for severe anaphylactic reactions when administering patent blue.

References:

• 1. Maranhão MV, da Nóbrega DK, Anunciação CE, Maia Bde A, Mariano PV. Allergic reaction to patent blue dye in breast surgery—case report. Braz J Anesthesiol 2016;66:433–6

• 2. Parvaiz MA, Isgar B. Anaphylaxis and blue urticaria associated with Patent Blue V injection. Anaesthesia 2012;67:1275–6

Disclosure of Interest: None declared.

195 ISoP18-1284 Ototoxicity Induced By Antineoplastic Therapy In Children—Review

195.1 C. Matos^*1,2, J. Joaquim^2,3, J. Marques², C. Silva⁴, M. Loureiro⁵

195.1.1 ¹Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain, ²Pharmacy, Coimbra Health School, Coimbra, Portugal, ³Faculty of Pharmacy, University of Salamanca, Salamanca, Spain, ⁴Audiology, Coimbra Health School, Coimbra, Portugal, ⁵Audiology Department, Brighton and Sussex University Hospitals NHS Trust, Brighton, United Kingdom

Background/Introduction: Cancer treatment using antineoplastic agents, such as platinum derived drugs, could have a relationship with ototoxicity, which has as a main symptom permanent hearing loss. Ototoxicity is characterised by damage to the cochlear or vestibular systems of the inner ear resulting from exposure to chemicals. This symptom is quite harmful to children as it impairs their linguistic ability, which is still developing. Drugs derived from platinum are the ones that cause most ototoxicity, which usually results in a permanent hearing loss. The prevalence of ototoxicity varies between 13% and 96% since it depends on several factors, such as the drug used or combinations, gender, age, genetic polymorphisms, neoplasia severity, and cumulative dose.

Objective/Aim: The objective of this study was to review and characterise the pattern of ototoxicity caused by antineoplastic drugs in children.

Methods: A structured literature search on two scientific databases, B-on^® and PubMed^®, and in Google Scholar was performed over the past 10 years. The studies were collected using keywords in different combinations. After the selection of the articles from the title and abstract, taking into account the inclusion and exclusion criteria, bibliographical references were also analysed to obtain other articles relevant to the present study.

Results: A total of 23 articles were analysed. Among the antineoplastics used in paediatric patients, cisplatin is the drug that causes more ototoxicity. There was evidence that, in males and at younger ages, the frequency of ototoxicity caused by cisplatin was higher. There was also evidence of increased toxicity in concomitant use with aminoglycosides, other antineoplastic agents and furosemide.

Conclusion: Methods of audiometric surveillance in risk groups, development of equally effective and less ototoxic therapeutic strategies than cisplatin, development of personalized strategies based on genetic susceptibility, and notification of toxicity data by health professionals to the responsible entity, are measures that should be adopted so that episodes of ototoxicity are less frequent or have no consequences for children’s’ futures.

Disclosure of Interest: None declared.

196 ISoP18-1286 Drug-Related Questions from General Practitioners Submitted to a Regional Pharmacovigilance Centre

196.1 J. Jacquot¹, H. Bagheri¹, C. de Canecaude¹, J. L. Montastruc^*1, G. Durrieu¹

196.1.1 ¹Service de Pharmacologie Médicale et Clinique, Centre de PharmacoVigilance, de Pharmacoépidémiologie et d’Informations sur les Médicaments, Pharmacopôle Midi-Pyrénées, Centre Hospitalier Universitaire et Faculté de Médecine de l’Université de Toulouse, Toulouse, France

Background/Introduction: Toulouse University PharmacoVigilance Centre (TUPV), in south- western of France, set up regular visits by one Clinical Research Assistant (CRA) to its PharmacoVigilance GP network (called PharmacoMIP-MG) involving 165 general practitioners (GPs) among a total of 3565 GPs located in the region. Previous papers have shown an increase in the number of adverse drug reaction reports using this approach [1, 2]. We now investigated the possibility to use this network to promote independent information on medicines.

Objective/Aim: The aim of this study was to analyze questions about drugs asked by the network to the TUPV during the period 2015–2017.

Methods: All questions asked by GPs to TUPV during this 3 year-period were reviewed. The questions were classified into two groups: “general” and “related to a patient”. The last group was divided in three groups: “Adverse Drug Reaction”, “Drug–Drug Interactions” and “Drug Management”. Drugs were classified according to Anatomical Therapeutic Chemical (ATC) classification system.

Results: During the study period, TUPV answered to 4050 questions, 622 (15.3%) being asked by GPs. The CRA collected 289 questions from the 165 GPs of the PharmacoMIP-MG network (1.75 question/year/GP). Simultaneously, other GPS (3400 GPs, not involved in the network) spontaneously asked 333 questions (0.09 question/year/GP). ATC categories most often involved in the questions were N: Nervous system (27.9%), J: Antiinfectives for systemic use (14.8%) and C: Cardiovascular system (13.0%). Most of the questions were classified in the “related to a patient” category (74.9%) with 339 “Adverse Drug Reaction” (54.5%), 39 “Drug–Drug Interactions” (6.3%) and 88 “Drug Management” (14.1%).

Conclusion: Regular visits of GPs by a CRA allowed to increase by 20 fold the number of pharmacovigilance questions. CRA visits are a new mean to promote independent information on drugs.

References:

• 1. Durrieu et al. Improving adverse drug reaction reporting by general practitioners through clinical research assistants visits. Therapie 2017;72:351–355

• 2. Driot D et al. Satisfaction of a pharmacovigilance declaration support network in general practice. Thérapie 2018; in press

Disclosure of Interest: None declared.

197 ISoP18-1287 Hypersensitivity Reaction Following l-Asparaginase Administration: Skin Tests may be Helpful to Confirm Diagnosis

197.1 B. Ouni¹, N. Ben Sayed², N. Fathallah¹, H. Regaieg², A. Brahim³, S. Larif¹, Y. Ben Youssef², R. Slim¹, C. Ben Salem^*1

197.1.1 ¹Pharmacovigilance center of Sousse, Labratory of Research, Sousse University, Sousse, Tunisia; ²Clinic Haematology Department, ³Reanimation Care Unit, Farhat Hached University Hospital, Sousse, Tunisia

Background/Introduction: l-asparaginase (derived from Escherichia coli) is important agent used in treatment of pediatric acute lymphoblastic leukemia (ALL). However, up of 30% of patients develop a hypersensitivity reaction [1].

Objective/Aim: To report a case of a child who developed hypersensitivity reaction following l-asparaginase administration confirmed with skin tests (skin prick test intradermal test).

Methods: A 04-year-old child patient without history of allergic diseases or any drug allergies was newly diagnosed with ALL type B. The patient was treated with chemotherapy according to EORTC-AR protocol. After the third injection of l-asparaginase, the patient experienced hypersensitivity reaction including generalized urticaria with pruritis without respiratory or hemodynamic instability. The patient was recieved corticosteroid and fluids, thereafter, the patient symptoms improved and he fully recovered. The patient continued his chemotherapy protocol without incident and l-asparaginase was remplaced by crisantaspase. SPT with l-asparaginase was performed and showed negative results. However, IDT with l-asparaginase (1/100 dilution) was positive. According to the information currently available, the diagnosis of hypersensitivity to l-asparaginase was retained. According to the Narnjo causality assessment, the causal relationship between adverse event and l-asparaginase was “probable”.

Results: l-asparaginase is an active antileukemia agent in the treatment of childhood ALL. Hypersensitivity reactions that can be seen in up to 30% of patients [1]. The mechanism of hypersensitivity reaction is linked to neutralizing anti-asparaginase antibodies that can form with or without an associated clinical allergic reaction. The risk of development of clinical allergy and silent inactivation may influenced by several factors including the formulation preparation of asparaginase, the route of administration, the schedule of administration, the line of treatment and the concurrent use of other chemotherapeutic agents including corticosteroids [2]. Monitoring of specific antibody to l-asparaginase to confirm diagnosis of hypersensitivity was not performed in the context of routine clinical care in our country. Skin prick tests (SPT) and intradermal test (IDT) could be helpful to confirm hypersensitivity [1].

Conclusion: Positive results of skin tests (SPT and IDT) could be use to confirm the diagnosis of hypersensitivity to l-asparaginase.

References:

• 1. Lynda M,et al. Erwinia Asparaginase after allergy to E. coli asparaginase in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 2010;54:199–205

• 2. Inge M, et al. Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation. Haematologica 2016;101:279–85

Disclosure of Interest: None declared.

198 ISoP18-1290 Sulfasalazine Induced Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)

198.1 B. Ouni¹, N. Fathallah¹, N. Belasfar², A. Brahim³, S. Larif¹, W. Hachfi², R. Slim¹, C. Ben Salem^*1

198.1.1 ¹Pharmacovigilance center of Sousse, Labratory of Research, Sousse University, Sousse, Tunisia; ²Department of Infectious Diseases, ³Reanimation Care Unit, Farhat Hached University Hospital, Sousse, Tunisia

Background/Introduction: DRESS syndrome is recognised as a hypersensitivity syndrome presenting with severe cutaneous eruption, fever, lymphadenopathy, hepatitis, haematologic abnormalities with eosinophilia, atypical lymphocytes and may involve other organs. Sulfasalazine is known to induce DRESS syndrome [1].

Objective/Aim: We describe a case of sulfasalazine-induced DRESS.

Methods: A 31-year-old woman with a medical history of type 1 diabetes, hypothyroidism, prolactine adenoma, osteoporosis and nephritic syndrome (all diseases were stable), was hospitalized for generalised maculopapular rash, fever, bilateral lymphadenopathies on cervical chain. Symptoms appeared 3 weeks after the initial of sulfasalazine treatment for chronic diarrhea. Initial laboratory tests were as follows: hyperleucocytosis (24 × 103/μL), hypereosinophilia (5%, 1200) increase transaminases (AST:168 U/L, ALT: 130 U/L), total bilirubin 28 mg/dl (NR 0.2–1), alkaline phosphatase (ALP) 269 U/L (NR < 140), gamma GT (186 U/L < 50). All test results for viral and autoimmune hepatitis were negative. DRESS syndrome to sulfasalazine was suspected. The patient was treated with corticosteroid. All symptoms improved after discontinuation of sulfasalazine and 4 weeks of corticosteroid. Skin biopsy showed a spongiotic epidermatitis with a many lymphocytic infiltrate and many necrotic keratinocytes. In the dermis, biopsy showed important extravasation of red blood cells with inflammatory eosinophilic infiltrate suggestive of immunoallergic purpuric capillaritis. The diagnosis of DRESS syndrome to sulfasalazine was retained. The pach test was negative.

Results: Sulfasalazine is a compound consisting of sulphapyridine (a sulphonamide) and 5-aminosalicylic acid. Sulfasalazine is known to induce DRESS syndrome [2]. DRESS syndrome is a hypersensitivity syndrome. It presents with severe cutaneous eruption, fever, lymphadenopathy, hepatitis, haematological abnormalities with eosinophilia, atypical lymphocytes and may also involve other organs. The multi-organ involvement differentiates this entity from other common drug eruptions. DRESS has been associated with higher morbidity and mortality compared to other adverse drug reactions [1].

Conclusion: Sulfasalazine is known to induce DRESS syndrome. Early diagnosis and treatment can reduced morbidity and mortality.

References:

• 1. Teo L, Tan E. Sulphasalazine-induced DRESS. Singapore Med J 2006;47:238

• 2. Poland GA, Love KR. Marked atypical lymphocytosis, hepatitis and skin rash in sulfasalazine drug allergy. Am J Med 1986;81:707–8

Disclosure of Interest: None declared.

199 ISoP18-1292 Adverse Drug Events Observed in Elderly Patients: Restrospective Study During Six Years

199.1 S. Bennis¹, L. Yachi¹, H. Benhaddou¹, M. Bouatia^*2, L. Ait Moussa³, A. Tebaa³, R. Soulaymani Bencheikh³

199.1.1 ¹Mohammed V University-Faculty Of Medicine And Pharmacy- Rabat- Morocco; ²Mohammed V University-Faculty Of Medicine And Pharmacy- Paediatric Hospital- Rabat- Morocco; ³Poison Control And Pharmacovigilance Center- Rabat- Morocco Background/Introduction: The elderly constitute a particularly heterogeneous population, due to the considerable variability associated with the aging process

The characteristics of geriatric patients suggest that a large number of adverse events should occur in this population.

Objective/Aim: The purpose of our study is to enumerate the adverse events occurring in patients over 65 years old and to classify them according to NCC MERP Index for Categorizing Medication Errors. This work also aims to list the therapeutic classes involved in the occurrence of these adverse effects.

Methods: This is a retrospective study, from January 2010 to September 2016. The method used to collect the adverse effects was spontaneous notifications. These data are subsequently entered on the database of the Moroccan Poison Control and Pharmacovigilance Center.

Results: On a total of 16,323 cases reported between 2010 and 2016, 990 notifications correspond to adverse events observed in geriatrics, that is represented 6%. The median age is 72 years.

A total of 1491 side effects were reported,because each notification contains one or more adverse events. 75% (n = 743) of the study population have multidrugs. Nausea and vomiting,qualified category A, were the most observed with 20.8% (n = 206) followed by skin rash, category C, representing 19.1% (n = 189), and third, general disorders with 15.5% (n = 155); who required hospitalization are qualified category F.

The main therapeutic classes are anticancer drugs with 26.1% (n = 258),knowing that the therapeutic dose was respected, followed by cardiovascular system drugs with 23.8% (n = 236) represented mainly by antithrombotic agents and antihypertensives drugs with 22% (n = 218).

Of the total cases, 26.5% (n = 303) were considered severe, of which 59 cases had evolved towards death.

Conclusion: The heterogeneity of the elderly population resulting in particular from a polymedication and a large polymorbidity is responsible for a very variable therapeutic response according to the individuals, leading to therapeutic failures or to the occurrence of adverse events.

With effective pharmacovigilance based on spontaneous notification, however, it will be possible to sensitize doctors to problematic drug classes to enable rapid detection of a potential adverse effect in these population.

Disclosure of Interest: None declared

200 ISoP18-1297 Impact of the Doctor-Patient Relationship on Non-compliance with Pharmacological Medical Prescription in Chronic Disease. A Cross-Sectional Study

200.1 M. I. B. Ribeiro^1,2,3, L. M. Nascimento⁴, A. Aragão⁵, F. Roque^*1,6

200.1.1 ¹Health Sciences School, Polytechnic of Guarda, Guarda, Portugal; ²Department of Exact and Social Sciencies, Agriculture School, Institute Polytechnic of Braganca, Braganca, Portugal; ³Mountain Research Center, Bragança, Portugal; ⁴Department of Diagnostic and Therapeutic Technologies, Health School, Institute Polytechnic of Bragança, Portugal; ⁵Department of Life Sciences and Public Health, Health School, Institute Polytechnic of Bragança, Bragança, Portugal; ⁶Research Unit for Inland Development, Guarda, Portugal

Background/Introduction: In developed countries chronic disease is currently the main reason why people betake to health care [1]. Negative effects of non-compliance with medical prescription reduce the clinical benefits of the medication, leading in most cases to the use of unnecessary treatments, hospitalization and death [2]. Factors associated with non-compliance with medical prescription may be related to: the doctor-patient relationship, the treatment, the health system, the health condition and the socioeconomic situation.

Objective/Aim: To assess the impact of the doctor-patient relationship on non-compliance with pharmacological medical prescription in chronic disease.

Methods: A cross-sectional design was developed based on a random sample of 141 patients with pathologies covered by Portuguese Exceptional Legislation. To collect the data, it was applied a questionnaire by interview between July 2017 and April 2018. The questionnaire included a list of non-compliance factors associated to doctor-patient relationship, developed by Cabral & Silva (2010) [3]. The IBM SPSS 24.0 software was used to analyse the data. Besides descriptive statistics, the data analysis involved the estimation of a logistic regression model, at a confidence level of 95%.

Results: Chronic patients were aged between 20 and 95 years old, with a mean age of 65.3 years (SD = 19.39). Most were female (51.8%), married or lived in marital cohabitation (62.4%), retired (55.3%), and had up to the 3rd cycle of schooling (61%) and an income up to € 1000 (62.4%). These patients suffered from Chronic Renal Insufficiency (CRI) (63.1%), Rheumatoid Arthritis (RA) and Psoriatic Arthritis (PA) (20.6%), Multiple Sclerosis (MS) (10.6%), Amyotrophic Lateral Sclerosis (ALS) (2.1%), Hepatitis C Virus (HCV) (2.1%), Hepatic disease (HD) (0.7%) and Gaucher Syndrome (GS) (0.7%).  The active substances most dispensed were: ferrous sulphate (76.6%), folic acid (73.8%), calcium polysterenonosulfonate (53.2%), alfacalcidol (48.9%), epoetin β (43.3%), complex B (26.2%) for CRI; adalimumab (8.5%), etarnecept (7.1%) and Ustecinumab (4.3%) for RA and PA; interferon B (8.5%) for MS. Modal treatment time was 24 months. The main reason for non-compliance associated to doctor-patient relationship dimension was “the doctor prescribes too many medicines” (35%). The second most mentioned reason was “the fear to ask questions” (18.4%), followed by “I do not understand what doctors say” (17.5%) and the “lack of confidence in doctors” (6.8%). A patient who does not consider that “the doctor prescribes too many medications” has a lower risk of non-compliance with the therapeutic prescription [OR = 0.262; CI (95%) 0.112–0.617].

Conclusion: The doctor-patient relationship is fundamental for compliance with the prescribed therapy and consequently for the improvement of the clinical benefits of medication and well-being of the patient.

References:

• 1. Dowrick C, Dixon-Woods M, Holman H, Weinman J. What is chronic illness? Chronic Illness 2005;1:1–6

• 2. Bugalho A, Carneiro A. Intervenções para aumentar a adesão terapêutica em patologias crónicas. Lisboa Centro de Estudos de Medicina Baseada na Evidência—Faculdade de Medicina de Lisboa, 2004

• 3. Cabral M, Silva P. A adesão à terapêutica em Portugal: Atitudes e comportamentos da população portuguesa perante as prescrições médicas. APIFARMA, 2010.

Disclosure of Interest: None declared.

201 ISoP18-1298 CAST Analysis of UK Pregnancies Reported During/After Isotretinoin Administration. Proposal for Application in a Global Safety Study

201.1 S. Trantza¹, B. Edwards^*2, I. Dokas³, S. Webley¹

201.1.1 ¹University of Hertfordshire, Hatfield, United Kingdom; ²NDA Regulatory Science LTD, London, United Kingdom; ³Democritus University of Thrace, Xanthi, Greece

Background/Introduction: Isotretinoin, a retinoid derivative of Vitamin A, is an oral medicine first approvedin the US in 1982 that is prescribed for the treatment of acne when other treatments do not work. Within a few years after launch, it became apparent that exposure to isotretinoin during pregnancy carried a greatly increased risk of foetal malformation. Numerous standard risk management approaches based on labelling and education have failed to adequately prevent women becoming pregnant whilst using this medicine. Several strategies, based on pregnancy prevention programmes (PPPs), have helped reduce the number of pregnancies in women receiving retinoids by mouth, but the number of pregnancies remains unacceptably high. Indeed, a recent analysis of the effectiveness of PPPs supported the widespread suspicion that they are not being followed in practice and that there is enormous inconsistency globally. Because isotretinoin is a valuable medicine for disfiguring acne, there is a need to intensify efforts to control pregnancy in exposed women and develop a common model which can be understood and applied internationally.

Objective/Aim: The aim of this original research was to apply Causal Analysis using System Theory (CAST) based on Systems Theoretic Accident Model and Processes (STAMP) ¹to analyze the spontaneous events of pregnancies that have reported during or after the administration of isotretinoin in the UK and to identify vulnerabilities and flaws in the safety management system.

Methods: The post-authorization spontaneous cases were obtained from the EudraVigilance database of the European Medicines Agency (EMA) via the Medicines and Healthcare Products Regulatory Agency (MHRA). The data concerned cases of pregnancies that had been reported to the MHRA in the United Kingdom during the period 01 January 2005 to 30 September 2017.

Results: The results included important failures of the controllers and of the physical component of the system, revealing failures in two control loops in the safety control structure of the system. Based on the unsafe control actions that were revealed, we have advised some changes in the Pregnancy Prevention Program with several recommendations for the controllers of the system.

Conclusion: CAST revealed important failures and system complacency across the different levels. Furthermore the easy application of CAST might well be an important way for investigating systems future failures concerning teratogenic drugs and pregnancy cases. CAST showed that such spontaneous reports of pregnancy can contribute real value in causal analysis when the information is pooled systematically.

References:

• 1. Levenson NG. Engineering: a safer world. January 2012, MIT press

Disclosure of Interest: None declared.

202 ISoP18-1299 Factors of Non-adherence to Therapy in Chronic Patients with Pathologies Covered by Specific Legislation in Portugal

202.1 M. I. B. Ribeiro^1,2,3, L. M. Nascimento⁴, A. Aragão⁵, F. Roque^*1,6

202.1.1 ¹Health Sciences School, Polytechnic of Guarda, Guarda, Portugal; ²Department of Exact and Social Sciencies, Agriculture School, Institute Polytechnic of Braganca, Portugal; ³Mountain Research Center, Bragança, Portugal; ⁴Department of Diagnostic and Therapeutic Technologies, Health School, Institute Polytechnic of Bragança, Portugal; ⁵Department of Life Sciences and Public Health, Health School, Institute Polytechnic of Bragança, Bragança, Portugal; ⁶Research Unit for Inland Development, Guarda, Portugal

Background/Introduction: Medication adherence is a multidimensional phenomenon determined by the interaction of factors of diverse nature. The World Health Organization classified in five groups the reasons for non-adherence to therapy, related to, patient, disease, therapy, health system and socioeconomic factors [1].

Objective/Aim: To identify the most prevalent extrinsic and intrinsic factors for non-adherence to therapy and to verify the existing differences taking into account the socioeconomic variables.

Methods: A random probabilistic sample of 141 outpatient suffering from pathologies covered by specific legislation with dispensing medicines at the hospital pharmacy, treated at the Local Health Unit of the Northeast in Portugal, was selected. The sample included patients with Chronic Renal Insufficiency (n = 89), Rheumatoid Arthritis and Psoriatic Arthritis (n = 29), Multiple Sclerosis (n = 15), Amyotrophic Lateral Sclerosis (n = 3), Hepatitis C Virus (n = 3), Hepatic disease (n = 1) and Gaucher Syndrome (n = 1). To collect the data, was applied a questionnaire, by interview, that included socioeconomic variables and a list of non-adhesion factors adapted from Cabral and Silva [2], between July 2017 and April 2018. The list of factors for non-adherence to the therapy consisted of 35 factors that were later aggregated into three dimensions. The first dimension “extrinsic factors”, consisted of 11 reasons that could lead patients not to follow completely the indications recommended by the doctor. The second dimension “intrinsic factors” was constituted by 20 factors related to the characteristics of the medicines and the therapeutics. The SPSS 24.0 software was used to analyse the data. The internal consistency was analysed through Alpha Cronbach. For the comparison of groups, the non-parametric Mann–Whitney test was used at a significance level of 5%.

Results: In the “extrinsic factors” dimension, the three most prevalent factors were “patient does not like to have the trips to go to consultations” (39%), “patient does not like to take medications” (37.6%) and “patient does not like to think he is ill “(31.9%). It was the female patients with the lowest level of education and the lowest income who were most likely to leave the treatment. The “intrinsic factors” that stand out were: “the schedule of the shots” (36.9%), “drugs were difficult to take” (29.8%) and “treatment duration was long” (29.1%). It was women, aged 65 years old or more, without professional occupation, with lower levels of income and schooling who were less compliant with medical indications. 

Conclusion: The socioeconomic variables are differentiated from the non-compliance by the medical indications.

References

• 1. World Health Organization. Adherence to long-term therapies: Evidence for action. Geneva: World Health Organization; 2003. [Accessed May, 2017]. Available from:http://www.who.int/chp/knowledge/publications/adherence_report/en/

• 2. Cabral M, Silva P. A adesão à terapêutica em Portugal: Atitudes e comportamentos da população portuguesa perante as prescrições médicas. APIFARMA, 2010

Disclosure of Interest: None declared.

203 ISoP18-1300 An Evaluation of Postmarketing Reports from Industry-Sponsored Programs in Drug Safety Surveillance

203.1 L. Harinstein^*1, D. Kalra¹, C. Kortepeter¹, M. Munoz¹, E. Wu¹, G. Dal Pan¹

203.1.1 ¹Food and Drug Administration, Silver Spring, United States

Background/Introduction: Industry-sponsored programs (ISPs), such as Patient Support Programs, involve direct contact with customers (e.g., patient, healthcare professional) to provide support on disease management, aid medication adherence, or share other information. Adverse events identified via ISPs have contributed to the rise in individual case safety reports (ICSRs) in the FDA Adverse Event Reporting System (FAERS) database.

Objective/Aim: To characterize ICSRs from ISP and non-ISP sources and determine their usefulness in the identification of safety signals.

Methods: ICSR reference numbers for six drugs and biologics were obtained from four manufacturers and matched to ICSRs in the FAERS database. Randomly selected ICSRs, distributed evenly across the six products, were assigned for comparison to either non-ISP (n = 510) or ISP (n = 510) report groups. We conducted a manual evaluation to identify the presence of data elements in the report narratives to classify reports by their utility in assessing drug-adverse event causality, referred to as “useful.” Other data evaluated included report descriptive characteristics, including serious outcome, and the presence of: data elements in structured fields, information identifying the report as originating from an ISP, and manufacturer documented causality assessment in ISP reports. Serious outcomes per regulatory definition (CFR 314.80) include death, life-threatening, hospitalization, disability, congenital anomaly, and other serious important medical events.

Results: Compared to non-ISP reports, ISP reports were more likely to be associated with a serious outcome (51.4 vs. 58.8%, p = 0.02), including a fatal outcome (9.6 vs. 23.7%, p < 0.01). ISP reports contained more words in the report narrative (169 vs. 217) and tended to contain more data elements (i.e., age, sex, indication for use) that may be valuable when evaluating a case report.

Our manual evaluation revealed that 30.8% (157/510) of non-ISP reports compared to 28.5% (145/510) of ISP reports met our definition of “useful” (p = 0.42).

Of the 510 ISP reports, 454 (89%) contained documentation that the report came from an ISP; 102 (20%) contained documentation of a causality assessment in the report narrative, of which 12 reported that the event was possibly related to the product and 90 reported it was unlikely related to the product.

Conclusion: Our review of non-ISP and ISP postmarketing adverse event reports in the FAERS database demonstrated that reports obtained from ISPs contain more data elements to suggest it would be a good case report, but are no better than non-ISP reports for being “useful” in signal detection. Future investigations into which ISPs generate more useful reports may be important.

Disclosure of Interest: None declared.

204 ISoP18-1302 Undergraduate Pharmacovigilance Education: Moroccan Experience

204.1 S. Serragui^*1, D. Soussi Tanani², R. Soulaymani^1,3, Y. Cherrah¹

204.1.1 ¹Pharmacology and Toxicology, Faculty of Medicine and Pharmacy, Rabat, Morocco; ²Pharmacology, Faculty of Medicine and Pharmacy, Tanger, ³Centre Anti Poison et de Pharmacovigilance, Rabat, Morocco

Background/Introduction: Under-reporting of adverse drug reactions is a global problem. Increased awareness of health professionals with a strengthening of their competence in Pharmacovigilance is essential. Currently, another solution is being set up in different countries. It’s about the teaching of Pharmacovigilance during the university course. It is in this context that we decided to do this work within the laboratory of Pharmacology and Toxicology of the Faculty of Medicine and Pharmacy of Rabat in Morocco.

Objective/Aim: Promote the Pharmacovigilance to the students of the pharmacy section of the Faculty of Medicine and Pharmacy of Rabat.

Methods: The Pharmacovigilance teaching of the first cycle students of the pharmacy section at the Faculty of Medicine and Pharmacy of Rabat has always been based on 4 h of lectures. In order to reinforce the teaching of this science for our future pharmacists, some activities have been led between February and May 2018.

Results: The first activity consisted of multiple sessions of working group. For each session, the students were divided into 6 groups. The working group was devoted to define all the contributing factors to the emergence of ADRs. Each group had to present a factor and answer the questions of the students of the other groups until they had finished all the factors. We only intervened when the explanations were false or mis-explained. We tried to create a competitive atmosphere between the students. This interactive teaching method allowed to consolidate their knowledge on the ADRs. We ended the session by talking to them about the national system of PV and the importance of notifying ADRs. Each student received his notice form.

The second activity was to propose the price of the best notifier during the pharmaceutical days organized by the students from all the levels. Moreover, a presentation has been done in the PV, the notification of ADRs and how to win the prize. During these days, the students were only talking about the notification and how to win the prize which made it memorable.

The last activity consisted of setting up in the Laboratory of pharmacology and toxicology a teaching and research unit in PV. The reference terms as well as the functioning of these units are in the validation process by the administration.

Conclusion: Other activities are being validated to strengthen the teaching of pharmacovigilance in our faculty.

Disclosure of Interest: None declared.

205 ISoP18-1303 Consideration of Benefit–Risk Assessment and Risk Management in Clinical Research of Traditional Medicines

205.1 L. Zhang^*1, J. L. Cong¹, J. K. Huang¹, X. H. Yang¹

205.1.1 ¹Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China

Background/Introduction: Traditional medicine (TM) plays an important role in global healthcare system. With its wide application, efforts on TM drugs (TMDs)’ research and development are increasingly strengthened. Clinical studies of new varieties have been carried out successively in some countries. In addition, pharmaceutical regulatory agencies have also publicized the relevant laws and guidelines to strengthen supervision. Key issues facing companies, scientific research institutions, and regulators are how to formulate risk identification and control strategies fitting characteristics of TMDs, and improve the clinical research quality and the technical level of benefit–risk assessment of drugs.

Objective/Aim: To put forward key strategies for potential risk management of the clinical research and improving the data quality fitting the characteristics of TM.

Methods: Reviewing typical cases of serious adverse events caused by Chinese herbal compound preparation clinical trials, combined with the status of clinical trials in China in recent years, this thesis analyzes and summarizes the main factors affecting the risk–benefit assessment of clinical trials of TMDs.

Results: Compared with chemical drugs, the basic research of TMDs is relatively fewer. Factors that influence benefit–risk assessment of TMDs include: [1] Drug factors such as the reasonability of the compound preparation group, different extraction process and composition changes as well as drug interactions; [2] Top-level design of clinical protocols such as identification of potential risk signals in previous studies and reasonability of evaluation indicators designed in clinical investigation protocols; [3] Quality control of investigation processes including the immediacy and completeness of data reporting, the rigor and reasonability of ethics review, consistency of quantitative and semi-quantitative data collection and evaluation criteria related to subjective judgments of physicians and quality of CRO monitoring, etc.

Conclusion: Fully combining the characteristics of TMDs and strengthening basic research related to safety can provide reference for clinical research. Establishing a scientific and reasonable clinical investigation protocols, obtaining true and complete data about safety and effectiveness, and strengthening the quality control of the research process are prerequisites for the scientific and objective assessment of the risks and benefits of TMDs. At the same time, there are such effective ways to achieve scientific data standardization of TMDs and improve the quality of clinical research as considering introducing and innovating the Data and Safety Monitoring Boards monitoring model, strengthening the whole-process data monitoring and regularly assessing accumulated data.

References:

• 1. Wang T, Dong RS. Thinking about serious adverse events of traditional Chinese medicine: one case in clinical trial. Chinese Journal of New Drugs 2008;17:1185–7

• 2. Jing L. 65% self check withdrawal rate, self check and on-site withdrawal data analysis. Med Econ News 2017-07-13(003)

• 3. Zhang L, Yan JB, Liu XM, et al. Pharmacovigilance practice and risk control of traditional Chinese medicine drugs in China: Current status and future perspective. J Ethnopharmacol 2012; 140:519–25

Disclosure of Interest: None declared.

206 ISoP18-1307 Understanding Paediatric Patients’ Pharmaceutical Needs Post Discharged from a Hospital: an Exploration Study

206.1 S. V. Gunnlaugsson¹, S. Tomlin^2,3, A. N. Rashed^*2,3

206.1.1 ¹Faculty of Pharmaceutical Science, School of Health Sciences, University of Iceland, Reykjavík, Iceland; ²Pharmacy Department, Evelina London Children’s Hospital, Guy’s & St Thomas’ NHS Foundation Trust, London, United Kingdom; ³Institute of Pharmaceutical Science, King’s College London, London, United Kingdom

Background/Introduction: Parents/carers’ perspectives, understanding medication instructions, and readiness for post-discharge care can have an impact on a patient´s health outcome after the transition from hospital to home; medication errors occurrence and readmission rate [1, 2].

Objective/Aim: To explore paediatric patient´s pharmaceutical needs after the transition of care from hospital to the community; when taking long-term medications.

Methods: Semi-structured telephone interviews were conducted with parents/carers and their children aged 0–18 years, who were discharged from Evelina London Children’s Hospital on long-term medications. Two telephone interviews were conducted with each parent/carer; 5 days after the child was discharged and then after the parents had obtained resupply of the child’s medication from their general practitioner (GP) and/or community pharmacy (CP). Issues related to medications, discharge and resupply process were discussed. Quantitative and qualitative thematic analyses were carried out.

Results: Nineteen participants [median age 2 years (IQR 0.2–13.2), 68% male] were included. Mean number (± SD) of medications per patient: at admission 4.1 ± 4.6, at discharge 6.3 ± 3.8, after resupply 5.7 ± 4.5. A total of 119 medications were prescribed at discharge and 91 after resupply. Majority of patients (90%, n = 17/19) were prescribed unlicensed medications at discharge and liquid formulations (63%, 75/119) were the most frequently prescribed.

Only 21% (4/19) of parents/carers said they did not receive any information regarding their child’s medication before discharge “just handed the bag with medication”.

A total of 22 drug-related problems (DRPs) affected 58% (11/119) patients, were reported by parents/carers. Drug forms (27%, 6/22), and drug administration (36.3%, 8/22) problems were the most reported. Majority of identified DRPs (95%, 21/22) were deemed preventable.

Out of those (n = 16) who obtained medication resupply, 63% (10/16) said that they got different medication formulation to what was given upon discharged home. Half (50%, 8/16) of them experienced problems getting resupply from GP compared to 37.5% (6/16) from CP.

Conclusion: This study identified that parents experience various issues related to their children’s medications during the transition from hospital to community, particularly around acceptability to the child and administration. A future study to evaluate and bridge the gap that seems to be between the community and hospital setting is important in order to improve the safe transition from hospital to home for children.

References:

• 1. Solan LG, Beck AF, Brunswick SA, et al. The Family Perspective on Hospital to Home Transitions: A Qualitative Study. Pediatrics 2015;136:e1539–49

• 2. Husain NR, Davies JG, Tomlin S. Supply of unlicensed medicines to children: semi-structured interviews with carers. BMJ Paediatrics Open 2017;1:e000051

Disclosure of Interest: S. V. Gunnlaugsson: None declared, S. Tomlin: None declared, A. Rashed Grant/Research support from: Neonatal and Paediatric Pharmacists Group.

207 ISoP18-1308 Hypersensitivity Adverse Drug Reactions in a Portuguese Hospital: 5-Year Retrospective Study

207.1 D. Mendes^*1,2, C. Alves^1,3, M. Loureiro^2,4, A. Fonte^2,4, F. Batel-Marques^1,2,3

207.1.1 ¹CHAD, AIBILI, ²Drug Safety and Effectiveness Research Network, ³Laboratory of Social Pharmacy and Public Health, School of Pharmacy, University of Coimbra, Coimbra, Portugal; ⁴Centro Hospitalar de Entre o Douro e Vouga, Santa Maria da Feira, Portugal

Background/Introduction: Hypersensitivity adverse drug reactions (ADRs) are associated with considerable morbidity and mortality. They may include benign (e.g. urticaria, maculopapular eruptions) or severe clinical manifestations (e.g. angioedema, bronchospasm, anaphylaxis, shock, or other systemic syndromes) [1]. Hypersensitivity ADRs are described to affect up to 20% of inpatients and ≈ 7% of the general population [2].

Objective/Aim: The aim of this study is to identify cases of drug-induced hypersensitivity reported in a Portuguese hospital over 5-years period of time.

Methods: Data was extracted from electronic health records (EHR) of patients through a module used by healthcare professionals to record hypersensitivity ADRs, known as the Portuguese catalogue of allergies and other adverse reactions (CPARA). Data recorded between 2013 and 2017 within the CHEDV hospital (“Centro Hospitalar de Entre o Douro e Vouga”) were considered. The hospital has 397 beds and hosts ≈ 20,300 inpatients/year. The Medical Dictionary for Regulatory Activities (MedDRA^®) classification was used to codify ADRs. The Anatomical Therapeutic Chemical (ATC) classification system was used to codify suspected drugs. Since a single patient may experience more than one hypersensitivity ADR in association with a single suspected drug, the concept of individual case safety report (ICSR) was considered for performing data analyses. Descriptive statistics were used to analyse data with Microsoft Excel^® 2013.

Results: The database contained 484 ICSRs; 20 duplicates were identified. The 464 valid cases corresponded to a total of 380 patients and 559 hypersensitivity ADRs. Most patients were female (n = 254; 66.8%); the median age was 55 years (range 2–98). Of the cases, 330 (71.1%) were considered serious and 134 (28.9%) non-serious, according to the by the healthcare professional evaluation. On average, each patient used ≈ 1.2 suspected drugs and experienced ≈ 1.5 hypersensitivity ADRs. At least ≈ 0.4% inpatients have experienced hypersensitivity ADRs over the study period. 245 cases (52.8%) were associated with the use of antibacterials for systemic use, mainly beta-lactam antibacterials. The majority of hypersensitivity ADRs were skin and subcutaneous tissue disorders (n = 266; 47.6%), such as urticaria (n = 106; 21.9%) and angioedema (n = 61; 12.6%), or immune system disorders (n = 231; 41.3%), namely anaphylactic reactions (n = 209; 45.0%).

Conclusion: This registry contains data on cases of hypersensitivity ADRs that is relevant for the Portuguese Pharmacovigilance System (PPS). However, none was reported to the PPS. Authorities and health care providers should pay attention to this problem. Furthermore, the present results reinforce the fact that antibacterials for systemic use deserve particular attention from clinicians since these therapies are implicated in most cases of hypersensitivity ADRs.

References:

• 1. Pichler WJ, Hausmann O. Classification of drug hypersensitivity into allergic, p-i, and aseudo-allergic forms. Int Arch Allergy Immunol 2016;171:166–79

• 2. Gomes ER, Demoly P. Epidemiology of hypersensitivity drug reactions. Curr Opin Allergy Clin Immunol 2005;5:309–16

• 3. Catálogo Português de Alergias e Outras Reações Adversas (CPARA), V3.1.1. (31-08-2017). Available from http://www.ctc.min-saude.pt/2017/08/31/cpara-v3-1-1/, Accessed on 04-06-2018.

Disclosure of Interest: None declared.

208 ISoP18-1309 Apipuncture Induced Urticaria with Recurrence Following Honey Contact

208.1 O. Charfi^*1, I. Aouinti², A. Zaiem¹, G. Lakhoua¹, S. El Aidli¹, R. Daghfous¹, S. Kastalli¹

208.1.1 ¹Service de Recueil et Analyse des Données, Tunis, Tunisia; ²Serice de Recueil et analyse des Données, National Centre of Pharmacovigilance of Tunisia, Tunisia, Tunisia

Background/Introduction: Apipuncture is an alternative medicine that combines acupuncture with bee venom. It is indicated primarily in musculoskeletal conditions and autoimmune diseases.

Adverse effects are usually simple skin disorders but can be serious such as anaphylactic shock.

Objective/Aim: Herein, we report a particular case of urticaria occurring after apipuncture with recurrence during a subsequent contact with honey.

Methods: This case was notified on January 2018 and was analyzed according to the French updated method for the causality assessment of adverse drug reactions.

Results: A 23-year-old patient was treated with apipuncture for 2 years for polycystic ovarian syndrome. During the last 6 months, she received regularly a cure per week (8–12 punctures per session). The number of injections gradually increased to reach 18–19 punctures per session at the end of December 2018.

On 28/12/2017, 1 h after the last injection, she developed urticaria at the neck, trunk and inguinal region with facial edema and slight dyspnea. She consulted in the emergency room where she received an injection of corticosteroid. The evolution was favorable in 2 h for urticaria and 48 h for facial edema.

A week later and 1 h after she applied a honey-based formula cream, the patient developed acute urticaria over the face and the chest.

The next day, she took paracetamol for flu syndrome. Urticaria persisted and she developed hoarse voice for which she took ibuprofen and desloratadine.

She presented few hour later dyspnea and bronchospasm. The evolution was favorable in a few hours.

Conclusion: Discussion/conclusion.

The main venom allergens are high molecular weight glycoproteins that are responsible of enzymatic activity. Phospholipase A2 is the major allergen of bee venom. Other major allergens are hyaluronidase and acid phosphatase.

Honey is composed of flower nectar, pollen and several other compounds secreted by bees. However, the allergenic part of honey is not yet identified.

In literature, cross-reactivity has not been reported in the literature between these 2 products of the hive.

Are IgE serum against bee venom in allergic patients able to fix honey proteins?

Disclosure of Interest: None declared.

209 ISoP18-1310 Evaluation of Pharmacovigilance System in Sudan Using WHO Indicators

209.1 M. Elsidig¹, H. Elkheir^*1, A. Osman¹

209.1.1 ¹Omdurman Islamic University, University of Science & Technology, Omdurman, Sudan

Background/Introduction: Assessment of Pharmacovigilance (PV) is very important in order to promote PV systems in developing countries. PV system was assessed in India, Uganda and South Africa with reference to WHO’s minimum requirements. All three countries had the same problems mainly insufficient funding and inadequate number of trained staff [1].

Objective/Aim: To evaluate the PV system in Sudan using WHO indicators.

Methods: Qualitative study design was done by a direct interview form during the period from March to May 2017. The study assessed the three PV centers in Sudan; the national, Khartoum State and public health program PV centers. A direct interview was done with persons responsible for PV in the centers. WHO Structure and Process indicators were used in the assessment.

To assess the inclusion of PV in the curricula of medical schools a direct interview was done with dean of faculty of medical schools or their delegates, the list of medical schools was obtained from Sudan Medical council last update 2015 (27 schools).

Results: The national PV center was established since 2006. It has a well-structured accommodation and a national policy and legislation do exist. This center is currently under the umbrella of the National medicine and poison board, Sudan. Financial support for the center is irregular and only two pharmacists are working in the center. There is a national adverse reaction (ADR) form for health care providers and ADR application which can be used by both health care providers and the public. There is no clear process for collection, recording and analysis of ADR reports.  With regard to the PV center at Khartoum State, it is included as a part of the Medicine Information Center at Khartoum State Ministry of health. The other center is part of public health programs. Each center has one pharmacist responsible for all PV activities.

PV was included in the curricula of all undergraduates and post graduate pharmacy schools included in the study. On the other hand all Medicine and Dentistry schools included in the study had no PV curricula.

Conclusion: Instability of financial funding and improper inclusion of PV in the medical schools are the main reasons for the poor PV status in Sudan.

References:

• 1. Maigetter K, Pollock AM, Kadam A, Ward K, Weiss MG. Pharmacovigilance in India, Uganda and South Africa with reference to WHO’s minimum requirements. Int J Heal Policy Manag 2015;4:295–305

Disclosure of Interest: None declared.

210 ISoP18-1311 Qualitative Method to Detect Signals and Manage Alerts in Pharmacovigilance “From Identification to Actions”

210.1 H. Sefiani^*1, R. Soulaymani²

210.1.1 ¹Pharmacovigilance Centre; ²CAPM, R.CC, Rabat, Morocco

Background/Introduction: The performance of all pharmacovigilance systems is measured by their ability to detect signals and manage alerts to ensure patient safety. Typically, the quantitative methods available are applicable for large databases. In countries with limited resources [1], the evaluation of pharmacovigilance systems has highlighted the need for methods adapted to their contexts: Starting pharmacovigilance systems, small databases and especially special contexts of use of health products.

Objective/Aim: The objective of this work is to conceptualize and implement a qualitative model to detect a signal, to validate a signal into alert, and to manage alert in pharmacovigilance. This integrated and reactive method aim to identify and minimize the risk due to medicinal products. This model is adapted to pharmacovigilance systems that do not have large databases.

Methods: This method was carried out at the CAPM Rabat collaborating center; we adapted all pharmacovigilance tools and methods to analyze signals. In addition, statistical methods for detection of signals were used to support the qualitative method.

Results: We propose to pharmacovigilance systems, a qualitative method in 7-steps describing a systematic way for signal detection and alert management : 1/Identification and definition of signal 2/Cases analysis: causality assessment, preventability assessment [2] and contributing factors assessment 3/Extrinsic evaluation: SPC, PSUR, publications 4/Data analysis: quantitative methods [3] 5/Root cause analysis and the proposition of actions to minimize the identified risk 6/Actions validation: technical committee and national commission 7/Evaluation of actions put in place. Through an example of application at national level, we presented the added value of the use of the method for early signal detection and for alert management in specific context to ensure patient safety and the rational use of medicines.This method is a decision-support tool for reducing and/or preventing the risks identified as related to adverse drug reactions. It is a contribution for the identification and the minimization of the risks related to ADRs. Its integration into pharmacovigilance curriculum as skill for countries would promote patient safety at public health level.

Conclusion: This method is a decision-support tool for reducing and/or preventing the risks identified as related to adverse drug reactions. It is a contribution for the identification and the minimization of the risks related to ADRs. Its integration into pharmacovigilance curriculum as skill for countries would promote patient safety at public health level.

References:

• 1. Olsson S, Pal SN, Stergachis A. Couper M. Pharmacovigilance activities in 55 low- and middle-income countries a questionnaire based analysis. Drug Saf 2010;33:689–703

• 2. Benkirane R, Soulaymani R, Khattabi A, Benabdallah G, Alj L, Sefiani H et al. Assessment of a new instrument for detecting preventable adverse drug reactions. Drug Saf 2015;38:383–3

• 3. Bate A, Linquist M, Edwards IR, et al. A Bayesian neural network method for adverse drug reaction signal generation. Eur J Clin Pharmacol1998;54:315–21

Disclosure of Interest: None declared.

211 ISoP18-1312 Safety of BRAF and MEK Inhibitors for Treatment of Metastatic Melanoma: Disproportionality Analysis in Vigibase

211.1 M. Rousset^1,2, A. Gouverneur^1,2, G. Miremont^*2, M. Molimard²

212 ¹University of Bordeaux, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, Bordeaux, France; ²Pharmacology, CHU de Bordeaux, Bordeaux, France

Background/Introduction: Bitherapy with BRAF-inhibitors (BRAFi) and MEK-inhibitors (MEKi) offer significant benefits in BRAFV600^mut metastatic melanoma patients; however adverse drug reactions (ADRs) occur in 90% of treated patients in clinical trials. ADRs have been well studied in clinical trials, but few is known in real life setting. Does the WHO international pharmacovigilance database provide arguments for new signals detection?

Objective/Aim: We aimed to detect new ADRs signals of BRAFi (vemurafenib, dabrafenib) and MEKi (cobimetinib, trametinib) used to treat metastatic melanoma in the WHO international pharmacovigilance database, VigiBase.

Methods: The PRR was calculated for each targeted therapy associated with metastatic melanoma as indication in comparison to all other anticancer drugs (ATC classification code L01 “antineoplastic agents”), and considering ADRs at the High Level Term. Drug-ADR associations were considered statistically significant if PRR was > 2, lower boundary of the 95% CI was > 1 and if number of ADR was > 3. The Uppsala Monitoring Centre performed disproportionality analysis.

Results: Up to January the 3^rd, 2018, we retrieved 6675 drug-reaction pairs. Of these, 268 had PRR > 2 and lower boundary of the 95% CI > 1. We analysed 42 reactions, according to their statistical and clinical relevance. Significant disproportionality appeared for vemurafenib associated with “breast signs and symptoms” PRR [3.29 (1.90–5.69)], “noninfectious pericarditis” PRR [3.01 (1.78–5.10)] and “lumbar spinal cord and nerve root disorders” PRR [2.31 (1.04–5.18)]. “Chronic polyneuropathies” PRR [6.57 (3.11–13.89)], “delusional symptoms” PRR [4.00 (1.49–10.73)] and “spinal fractures and dislocations” PRR [2.49 (1.29–4.80)] were associated with dabrafenib. The association between “acute polyneuropathies” and BRAFi was statistically significant. For cobimetinib, “hepatocellular damage and hepatitis not elsewhere classified (NEC)” PRR [3.57 (2.46–5.18)], “cholestasis and jaundice” PRR [3.45 (2.21–5.39)] and “renal failure impairment” PRR [2.73 (2.11–3.54)] were detected as signals. We found potential signals related to trametinib and “retinal bleeding and vascular disorders (excl retinopathy)” PRR [2.32 (1.25–4.32)] and “structural brain disorders NEC” PRR [2.28 (1.14–4.57)]. For both drugs of the bitherapy with dabrafenib + trametinib “seizures and seizure disorders NEC” emerged as a signal.

Conclusion: New drug-ADR combinations have been highlighted in VigiBase. These signals may be of interest in clinical practice for the prevention, identification and monitoring of unobserved ADRs in the clinical trials of BRAFi and MEKi.

The authors would like to thank the Uppsala Monitoring Center (UMC) for providing and giving permission to use the data analyzed in this study. The authors are responsible to the national pharmacovigilance centers that provided the data. The opinions and conclusions of this study are not necessarily those of the different centers or WHO.

Disclosure of Interest: None declared.

213 ISoP18-1313 A Model-Based Analysis on Direct Costs of Adverse Drug Events and Related Cost-Savings Achievable by their Prevention in Tuscany, Italy

213.1 I. Convertino^*1, S. Salvadori², A. Pecori², M.T. Galiulo¹, S. Ferraro¹, M. Parrilli³, T. Corona³, G. Turchetti⁴, C. Blandizzi^1,3,5, M. Tuccori^1,3,5

213.1.1 ¹Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; ²Institute of Clinical Physiology, National Research Council, Pisa, Pisa, Italy; ³Tuscan Regional Centre of Pharmacovigilance, Florence, Italy; ⁴Institute of Management, Sant’Anna School of Advanced Studies, Pisa, Italy; ⁵Unit of Adverse Drug Reactions Monitoring, University Hospital of Pisa, Pisa, Italy

Background/Introduction: Adverse drug events (ADEs) may represent an important cost item for healthcare systems, since the recall, repair or rework of faults from ADEs and their management are costly and time consuming [1–3]. Their prevention could result in a relevant cost-saving.

Objective/Aim: To simulate the annual economic burden for ADEs in Tuscany (Italy) and the potential cost-savings related to avoidable ADEs.

Methods: A systematic review was performed, according to PRISMA [4] and MOOSE [5] statements, on observational studies published from 2006 to 2016 in Medline and EMBASE, focusing on direct costs of ADEs in the inpatient setting from high-income Countries. All the included studies were assessed for their methodological quality through the Newcastle–Ottawa Scale. The mean probability of preventable ADEs was estimated over the included studies. The mean ADE cost was calculated by means of Monte Carlo simulation. Then, we extrapolated the Tuscan spontaneous reports of inpatient ADEs in 2016 from the Italian Pharmacovigilance database, and we assumed for Tuscan ADEs the same costs and preventability probability obtained in the systematic review. Finally, we simulated the possible costs of ADEs and the potential cost-savings by using the estimated preventable ADEs in Tuscany. Three sensitivity analyses were performed also to test the robustness of the results [6].

Results: Out of 11,936 articles initially selected, 12 observational studies were included. Four studies were performed in North America and eight in Europe. The mean cost reported for a single ADE ranged from $2620 to $5373 in the American studies, and from €970 to €5461 in the European ones. All the included studies were classified at low risk of bias. The estimated mean ADE cost was €2471.46 (standard deviation (SD): ± €1214.13). The mean probability of preventable ADEs was 45% (SD: ± 21). The simulated Tuscan expenditure for ADEs was €3406,280.63 per million inhabitants [95% confidence interval (CI): €1,732,910.44–€5,079,664.61] and the potential cost-saving was €1,532,760.25 per million inhabitants (95% CI: €779,776.1–€2,285,750.60). The sensitivity analyses confirmed the robustness of our results.

Conclusion: The present simulation showed that the management of inpatient ADEs could have a relevant economic impact on the Tuscan healthcare system and the prevention would result in important cost-savings. These findings could be likely extended to other healthcare systems.

References:

• 1. Bouvy JC, De Bruin ML, Koopmanschap MA. Epidemiology of adverse drug reactions in Europe: a review of recent observational studies. Drug Saf 2015;38:437–53

• 2. Lundkvist J, Jonsson B. Pharmacoeconomics of adverse drug reactions. Fundam Clin Pharmacol 2004;18:275–80

• 3. Lindquist M. Data quality management in pharmacovigilance. Drug Saf2004;27:857–70

• 4. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ 2015;349:g7647.

• 5. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology- a proposal for reporting. JAMA 2000;283:2008

• 6. Drummond M, Barbieri M, Cook J, Glick HA, Lis J, Malik F, et al. Transferability of economic dvaluations across jurisdictions: ISPOR good research practices task force report. Value Heal 2009;12:409–18

Disclosure of Interest: None declared.

214 ISoP18-1314 Pharmacovigilance Software Support for Belgian Community Pharmacists

214.1 D. Van Broeck¹, D. De Meestere¹, J. Saevels^*1

214.1.1 ¹Association of Pharmacists in Belgium, Brussels, Belgium

Background/Introduction: European pharmacovigilance legislation introduced back in 2012 new concepts such as inverted black triangles, direct healthcare professional communications and risk minimization activities [1]. Healthcare professionals need to familiarize themselves with these new notions in order to comply with their obligations such as risk mitigation and reporting of adverse drug reactions (ADRs). Yet the information comes to healthcare professionals in many forms, respects differing timeframes and is disseminated through various channels. To the practitioners, the exact products concerned, the reason for the measures, what they imply, or who is exactly involved is not always available when interacting with a patient.

Objective/Aim: Belgian community pharmacists have always had wide and legal responsibilities in regard to the quality of the products and the advice they deliver. Studies reveal that pharmacists show willingness to report ADRs and consider ADR reporting as part of their professional responsibility. However, a number of barriers to ADR reporting have been identified, such as the lack of knowledge about reporting guidelines and policies and establishing ADR causation with suspected drug [2]. Pharmacists need to be optimally supported in taking clinical responsibility in the early detection of adverse drug reactions and other drug-related problems as well as monitoring the effectiveness of medicines.

Methods: For this reason, the Association of Pharmacists in Belgium constructed an inventory database containing relevant pharmacovigilance information for all medicines on the Belgian market. A summary was made and for each of the materials it was indicated whom they were intended for. All information was subsequently linked to the product code included in a scientific database. Finally, a web service was developed, making it possible to link the information to the pharmacy dispensing software.

Results: The number of available and dispensed medicines with black triangle or additional risk minimisation activities has increased significantly since July 2014. During July 2017, each pharmacy dispensed around 120 packs with risk minimisation obligations and around 70 with a black triangle, clearly illustrating the relevance of having all information at hand.

Conclusion: Building on other innovative features in Belgium such as shared patient records, clinical decision support, the concept of family pharmacist, and having relevant safety information available at the moment of dispensing, pharmacists can now focus on complying with their pharmacovigilance activities by accessing relevant information directly from their software while dispensing.

References:

• 1. Pharmacovigilance EU legal framework. 2013. http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000491.jsp. Accessed 25 May 2018

• 2. Hadi MA, Neoh CF, Zin RM, Elrggal ME, Cheema E. Pharmacovigilance: pharmacists perspective on spontaneous adverse drug reaction reporting. Integr Pharm Res Pract 2017;6:91–8

Disclosure of Interest: None declared.

215 ISoP18-1315 Ten Years of Experience in Graduate and Postgraduate Education in Pharmacovigilance

215.1 N. Mirošević Skvrce^*1, Ž. Margan Koletić¹, D. Krnić¹, S. Prpic¹, K. Gvozdanović¹, I. Mucalo², S. Vladimir-Knežević³, N. Božina⁴, S. Marušić⁵, I. Mudnić⁶, M. Klarica⁷, S. Tomić⁸

215.1.1 ¹Department for Pharmacovigilance and Rational Pharmacotherapy, Agency for Medicinal Products and Medical Devices, Zagreb, Croatia; ²Centre for Applied Pharmacy,; ³Department of Pharmacognosy, Faculty of Pharmacy and Biochemistry, University of Zagreb, Croatia; ⁴Department of Pharmacology, University of Zagreb, Croatia; ⁵University Hospital Dubrava, Zagreb, Croatia; ⁶Department of Pharmacology, School of Medicine, University of Split, Split, Croatia; ⁷Department of Pharmacology, School of Medicine University of Zagreb, Croatia; ⁸Agency for Medicinal Products and Medical Devices, Zagreb, Croatia

Background/Introduction: Need for education in pharmacovigilance and adverse drug reactions (ADRs) is increasingly recognized worldwide. Pharmacovigilance system is based on reports from healthcare professionals and patients. In addition, safe use of drugs is dependent on successful implementation of risk minimization measures. Croatian Agency for Medicinal Products and Medical Devices participates in pharmacy and medical students’ education for the last 10 years, hence takes part in shaping future generations of healthcare professionals.

Objective/Aim: To describe the experience gained in graduate and postgraduate education in pharmacovigilance during the last 10 years.

Methods: Comparison of content and number of hours spent in pharmacovigilance teaching in graduate and postgraduate courses were studied for the period between 2009 and 2018. In addition, questionnaires about student satisfaction and needs for additional content were also analyzed. On average, 300 students per year were involved in pharmacovigilance classes.

Results: Number of hours of teaching pharmacovigilance is growing for both medical and pharmacy students; from 1 h per year in 2009 to 4 h per year in 2018 as part of obligatory graduate courses and 20 h for postgraduate courses. Additionally, an elective course Pharmacovigilance and Pharmacoepidemiology was introduced at the Faculty of Pharmacy and Biochemistry University of Zagreb in 2017 (20 h). Furthermore, a big shift in the content is being noticed; the focus is moving from causality assessment, ways of reporting and clinical importance of ADRs to the awareness of risk minimization measures and importance of their implantation as to increase safe medicine use. Students are very satisfied with pharmacovigilance education (4.7 on the 5-point Likert scale on average for the last 9 years). There is a growing need for education in pharmacoepidemiology, regulatory aspects of pharmacovigilance, medication errors and pharmacogenomics predisposition for ADRs development, as recognized by the students.

Conclusion: There is a growing importance of teaching pharmacy and medical students in the field of pharmacovigilance.

Disclosure of Interest: None declared.

216 ISoP18-1316 Comparison of Drug-Induced Stevens–Johnson Syndrome/Toxic Epidermal Necrolysis in French and Vietnamese Database (2010–2015)

216.1 K.-D. Nguyen^1,2,3, H.-A. Nguyen², J.-L. Montastruc^*1,3, L. Chebane^1,3, H. Bagheri^1,3

216.1.1 ¹Centre Midi-Pyrénées de PharmacoVigilance, de Pharmacoépidémiologie et d’Information sur le Médicament de l’UMR INSERM 1027, Centre Hospitalier Universitaire, Toulouse, France; ²The National Centre of Drug Information and Adverse Drug Reaction Monitoring, Hanoi University of Pharmacy, Hanoi, Viet Nam, ³Laboratoire de Pharmacologie Médicale et Clinique, Equipe de Pharmacoépidémiologie de l’UMR INSERM 1027, Faculté de Médecine de l’Université Paul-Sabatier, Toulouse, France

Background/Introduction: Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) induced by drugs are rare (1–2/million inhabitants/year) but life-threatening reactions (with mortality rate of about 1–40%). In addition, SJS/TEN are genetic dependence disorders and the risk differs between populations.

Objective/Aim: The aim of this study is to compare the characteristics of the drug-induced SJS/TEN in French and Vietnamese pharmacovigilance database in the period 2010–2015.

Methods: All spontaneous adverse drug reaction (ADR) reports from January 2010 to December 2015 in Vietnamese and French databases containing 2 Preferred Terms “Stevens–Johnson syndrome” and “toxic epidermal necrolysis” were retrospectively analyzed. Demographic data, suspected drug according to Anatomical Therapeutic Chemical (ATC) classification were compared between 2 countries.

Results: Over a 6-year period, among a total of 28,698 and 229,481 spontaneous reporting respectively registered in Vietnamese and France database, 136 (0.47%) and 576 (0.25%) concerned respectively the cases of drug-induced SJS/TEN reports. The male/female ratio of SJS/TEN patients were significantly different between 2 countries (Vietnam = 0.58, France = 0.41, p = 0.001). SJS/TEN mainly occurred in adult patients (18-65 years) in 2 nations but Vietnamese SJS/TEN patients were younger than French ones with mean age of 42.48 (± 22.95) and 48.59 (± 25.38) respectively (p = 0.011). Concerning the suspected drugs induced SJS/TEN, we mainly found cotrimoxazole (n = 69, 1.3%), lamotrigine (n = 59, 1.11%), allopurinol (56, 1.06%) in French database and carbamazepine (n = 25, 18.38%), paracetamol (n = 20, 14.71%), allopurinol (n = 15, 11.03%) in Vietnamese database. Antiepileptics (N03A) are most reported in SJS/TEN in Vietnam (n = 33, 16.1%) and France (n = 132, 2.49%). For beta-lactam antibiotics, cephalosporins and carbapenems group (J01D) was the most reported in Vietnam (n = 24, 11.71%) and penicillin groups (J01C) was mostly reported in France (n = 82, 1.55%).

Conclusion: These data show some differences for the characteristics of cases of drug-induced STJ/TEN between France and Vietnam. The suspected drugs seem similar in 2 countries, except for antibiotics. Outside the diseases pattern, geographic location, lists of marketed drugs, the differences could be explained by the genetic variation (HLA-B), the knowledge and attitude of healthcare workers about ADR reporting, the overuse of antibiotics in Vietnam. Further analysis is required to fully discuss on social pharmacology aspect.

Disclosure of Interest: None declared.

217 ISoP18-1317 Pregnancy Exposure Registry/Birth Defects Surveillance Programme in the Western Cape, South Africa: A Model for Low- and Middle-Income Countries

217.1 E. Kalk^*1, U. Mehta¹, A. Slogrove², N. Jacob¹, L. Myer¹, M.-A. Davies¹, A. Boulle^1,3

217.1.1 ¹Centre for Infectious Diseases Epidemiology & Research, University of Cape Town, South Africa; ²Department of Paediatrics, Stellenbosch University, Stellenbosch, South Africa; ³Health Impact Assessment, Provincial Government of the Western Cape, Cape Town, South Africa

Background/Introduction: Pharmacovigilance presents specific challenges in low- and middle-income countries. In Southern Africa, the mass treatment campaigns for HIV and tuberculosis and the introduction of new therapeutic regimens have highlighted the need for improved surveillance systems especially during pregnancy and breastfeeding. As part of a larger project aimed at evaluating the vertical transmission of HIV prevention programme, we established a Pregnancy Exposure Registry/Birth Defects Surveillance programme (PER/BDS) to determine the rates of adverse pregnancy outcomes (maternal and fetal), and their associations with any medicine exposure during conception and pregnancy in the Western Cape Province, South Africa.

Objective/Aim: To adapt and implement an integrated PER/BDS in the Western Cape, South Africa.

Methods: We adapted the National PER/BDS protocol for use in the Western Cape. Limited obstetric and neonatal data and information on all antenatal prescriptions, immunizations, alcohol, cigarette and recreational drug use as recorded in the clinical stationery are digitized using the existing Provincial primary care electronic medical records platform by clerical staff embedded in the facilities. Since we rely on routine clinical notes, on-going system strengthening and training to optimize neonatal examination and record-keeping are required. Data are sent to the Western Cape Provincial Health Data Centre where they are compared and consolidated with those obtained from other electronic sources (e.g. pharmacy dispensing data and the Perinatal Problem Identification Programme records), as well as in-house departmental databases, e.g., Fetal Medicine, Medical Genetics.

Results: The PER/BDS is being piloted at two primary care obstetric units in Gugulethu (01 Sept 2016; urban) and Worcester (05 Feb 2018; rural) and their referral hospitals. Antenatal data are collected prospectively in the primary care sites and retrospectively after birth for those women transferred to hospital. Pregnancy losses, including termination of pregnancy, are included as well as placental histology and post-mortem reports. Since congenital disorders are rare, this pooled dataset encompassing five facilities from primary to tertiary care and including pregnancy losses will establish a sufficiently large cohort to determine rates with reasonable precision. To date, 8482 pregnancies have been included with 4997 outcomes: 4721 live births and 276 pregnancy losses.

Conclusion: The routine systematic collection of pregnancy exposures and birth outcomes will enable us to determine the background rates of congenital disorders in our cohort and any associations with antenatal medicine exposures. By integrating the PER/BDS into clinical services, we have established an active surveillance system to monitor the impact of any future treatment guideline changes (e.g. antiretroviral therapy) on pregnancy outcomes.

Disclosure of Interest: None declared.

218 ISoP18-1318 Neosensitization to Multiple Drugs Following Carbamazepine Dress Syndrome

218.1 O. Charfi^*1, A. Zaiem¹, G. Lakhoua¹, I. Souilem¹, R. Daghfous¹, S. El Aidli¹, S. Kastalli²

218.1.1 ¹Service de Recueil et Analyse des Données; ²National Centre of Pharmacovigilance of Tunisia, Tunis, Tunisia

Background/Introduction: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is associated with severe skin eruption, fever, and multi-organ involvement. Aromatic anticonvulsant drugs have been frequently associated with this manifestation. There are limited cases about neosensitization related to chemically unrelated drugs following an episode of DRESS syndrome.

Objective/Aim: Herein we report a case of a patient who developed secondary neosensitization to escitalopram and amoxicillin after experiencing DRESS syndrome due to carbamazepine.

Methods: This case was notified on February 1th, 2016 and was analyzed according to the French updated method for the causality assessment of adverse drug reactions.

Results: A 38-year-old woman was treated by carbamazepine, escitalopram and levomepromazine on July 2017. Three weeks later, the patient developed a whole-body skin rash, facial edema, temperature at 39 °C, cervical and inguinal lymph nodes. Laboratory tests revealed aspartate aminotransferase (ASAT) of 322 U/L (9.4 N) and alanine aminotransferase (ALAT) of 403 U/L (7.3 N). Eosinophils count was normal.

The patient stopped all the medication and was prescribed corticoid and antihistamines. Skin condition improved slowly and laboratory parameters returned to normal level in about 20 days.

The diagnosis of DRESS syndrome to carbamazepine was made.

On September 2017, 14 days after the first event resolved, escitalopram was rechallenged. Twelve hours later, she presented with fever, generalized pruritus and erythema. Laboratory tests showed eosinophils count 760 elmts/mm³ (18.4%).

On January 2018, she was treated by amoxicilline and paracetamol for dental pain. Two weeks later she developed erythema, pruritus and mucosal involvement.

However, she became lost to follow up since then.

Conclusion: Discussion/conclusion.

The diagnosis of DRESS syndrome to carbamazepine was made in this patient based on the criteria adopted by the European group RegiSCAR. In our case, the RegiScar score was 4 (probable case).

The responsibility of escitalopram in inducing this syndrome was less suspected because of lack of cases reported with this drug.

The patient exhibited a novel hypersensitive reaction to escitalopram and then to amoxicillin.

This suggests that it is possible to develop neosensitization to multiple drugs after DRESS syndrome.

It has been reported that DRESS episode may induce a massive nonspecific activation of the immune system, which will provide the enhanced expression of costimulatory molecules and proinflammatory cytokines. The latter will allow a more efficient presentation of chemical antigens to antigen-presenting cells and consequently decrease the level of tolerance to drugs present at the time in the organism, and especially amoxicillin.

Disclosure of Interest: None declared.

219 ISoP18-1320 The Impact of Pharmacovigilance Oversight on Expanded Access Programs (EAPs) with Nivolumab in Bristol-Myers Squibb Turkey

219.1 B. Cilmi Arslan^*1, F. Yasan¹, E. Coskuncay¹, I. Reid²

219.1.1 ¹Bristol-Myers Squibb, Istanbul, Turkey, ²Bristol-Myers Squibb, Mulgrave, Australia

Background/Introduction: Expanded Access Programs (EAP) have an important role in accessing to the novel medicines and for the Health Care Professionals (HCP)’ early awareness for immuno-oncology products. In Turkey, nivolumab was approved for different indications as EAP by Turkish Health Authority (HA) for the patients who suffer from urgent-life-threatening diseases and have not been included into the scope of the clinical trials conducted in related fields. Renal cell carcinoma, melanoma, squamous and non-squamous non-small cell lung cancers (NSCLC), chronic Hodgkin Lymphoma indication based EAPs have been conducted in Turkey concurrently since 2014.

Objective/Aim: To monitor the pharmacovigilance impact on EAP data collected from Jul 2014 to May 2018.

Methods: The data which belongs to the HA-approved patients and the patients who received at least one dose of treatment during the EAPs as well as the data from safety submissions were analyzed.

Results: First EAP with nivolumab was approved in Jul 2014 by the HA. There were 977 patients who were approved for five different indication-based EAPs with nivolumab. Of the total patients, 288 (29%) were females and 689 (71%) were men. Overall, 845 patients were received at least one dose of treatment. The most common types of cancer in the patients received at least one dose of nivolumab treatment, were renal cell carcinoma [278 (33%)] and non-squamous NSCLC [245 (29%)].

Totally 865 individual cases covering all serious adverse events occurred during the execution of the program were submitted to HA within 8 calendar days per local legislation. The other safety requirement of the local legislation was preparation and submission of 3- and 6-monthly reports for each approved EAP. 3-monthly reports highlight safety phase with the related AE listings as well as 6-monthly reports highlight efficacy phase on whether the patient has benefited from the undergoing therapy or not [1]. Totally, 52 and 26 submissions were performed for 3-monthly and 6-monthly reporting, respectively.

Although the EAPs were closed, there are still 126 active patients continuing their treatment, which necessitates the maintenance of safety monitoring.

Conclusion: EAPs have vital importance to fulfill the unmet medical need of the suffering patients. The data gathered from EAPs could provide a wider aspect on the safety profile of the product. Pharmacovigilance oversight is essential to be able to monitor the safety and efficacy of the products within close collaboration of all stakeholders, including the HAs, pharmaceutical companies and HCPs.

References:

• 1. Guideline on the Compassionate Use Program, Turkey dated 01 Jan 2009.

Disclosure of Interest: None declared.

220 ISoP18-1321 Reporting Point Side Effects Medical Implants: Experiences After 1 Year

220.1 C. Molto-Puigmarti^*1,2, L. Pelzer^2,3, P. Zweers^2,3, M. Klaassen^1,2, W.H. De Jong^1,2, J. Hoebert^1,2

220.1.1 ¹RIVM, ²Meldpunt en Expertisecentrum Bijwerkingen Implantaten, Bilthoven, ³Lareb, ‘s-Hertogenbosch, The Netherlands

Background/Introduction: Implants are medical devices that are placed in the body for a medical or cosmetic purpose. An implant can cause an unexpected undesired effect, or side effect. While early signaling of side effects of implants is of utmost importance, sometimes (rare) side effects are detected only after an implant has been for a long time on the market and used in a relative large amount of patients.

Objective/Aim: To facilitate early detection of implant side effects, the Dutch Government aimed at building a central point where not only healthcare professionals but also patients could report health problems suspected to be associated with an implant.

Methods: On the 3rd of July of 2017 the Reporting Point Side Effects Medical Implants (Meldpunt Bijwerkingen Implantaten) was established in the Netherlands. This is a collaboration between the Netherlands Pharmacovigilance Center Lareb and the National Institute for Public Health and the Environment (RIVM).

Results: The health complaints are reported via an online questionnaire. These are subsequently analyzed and, when necessary, discussed with medical specialists or other relevant experts in the field. In some cases, an in depth research is performed regarding a specific implant or side effect, and a signaling is published on the website of the Reporting Point Side Effects Medical Implants.

From its start until the summer of 2018, the Reporting Point Side Effects Medical Implants has received a few hundred notifications, mostly from patients. In addition, the team has been working on several activities such as optimizing its reporting questionnaire and ICT infrastructures, to improve the quality of the information received on the one hand, and to support the work with big amounts of data on the other.

Conclusion: A Reporting Point Side Effects Medical Implants has been established in the Netherlands to report possible side effects of implants. The main objective is to facilitate the early detection of problems due to implants.

Disclosure of Interest: None declared.

221 ISoP18-1323 The Epidemic of Opioid Misuse, a Threat for Switzerland? A Pilot Study at the Geneva University Hospitals

221.1 K. Ing Lorenzini^*1, L. Wainstein¹, L. Bovet¹, M. Ramlawi², R. Khan², H. Spechbach², J. Desmeules¹, V. Piguet¹

221.1.1 ¹Clinical Pharmacology and Toxicology; ²Emergency Medicine, University Hospitals of Geneva, Geneva, Switzerland

Background/Introduction: Chronic cancer and non cancer pain are frequent, occurring in at least one-third of the adult population [1, 2]. Given the high prevalence of chronic pain, it is not surprising that the global opioid consumption has increased during the last decades. Between 2000 and 2015, the total opioid consumption (in morphine equivalence as mg/capita) increased threefold in America and Europe. A modest 1.7-fold increase was also observed In Switzerland [3].

The widespread use and misuse of opioids has resulted in a national epidemic of opioid overdoses and addictions in the US, with about two-thirds of drug-overdose deaths being attributable to opioids in 2016 [4], and a parallel increase in the rate of opioid addiction [5]. In Europe, the opioid-related morbidity also shows an increasing trend, but it seems to remain much lower than in the US [6]. However, more data are needed.

Objective/Aim: The primary aim of this pilot study is to assess the frequency and causes of opioid-related emergency department (ED) visits in a tertiary Swiss University Hospital.

Methods: We performed a prospective observational study of all adult ED visits to the Geneva University Hospital over a 1 month period (May 2018). All patients’ electronic health records were screened for opioid treatment home use and ED admissions related to opioid adverse events (overdose, adverse drug reactions (ADR), and/or inefficacy).

Results: A total of 1320 ED visits were screened. Patients age ranged from 18 to 102 (mean 50.8, standard deviation ± 21.1) years and 55.8% (n = 723) were males. In 8.0% (n = 106) of cases, patients had an opioid-based regular treatment. 2.0% (n = 27) of the total ED visits were related to opioid use. In half of the cases, insufficient efficacy was the leading cause (Table 1).

Conclusion: Based on our preliminary results in at our hospital, opioid-related morbidity and mortality does not seem to be a major issue. These results need to be confirmed by further studies. If confirmed, preventive measures and continuous monitoring should be implemented to prevent the development of opioid misuse as in the US.

References:

• 1. IASP. Unrelieved pain is a major global healthcare problem. 2013; Available from: https://s3.amazonaws.com/rdcms-iasp/files/production/public/Content/ContentFolders/GlobalYearAgainstPain2/20042005RighttoPainRelief/factsheet.pdf

• 2. van den Beuken-van Everdingen MH, de Rijke JM, Kessels AG, Schouten HC, van Kleef M, Patijn J. Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol 2007;18:1437–49

• 3. Pain & Policy Studies Group. Opioid Consumption Data. Available from: http://www.painpolicy.wisc.edu/opioid-consumption-data

• 4. Seth P, Scholl L, Rudd RA, Bacon S. Overdose deaths involving opioids, cocaine, and psychostimulants—United States, 2015–2016. MMWR Morb Mortal Wkly Rep 2018;67:349–58

• 5. Volkow ND, McLellan AT. Opioid abuse in chronic pain—misconceptions and mitigation strategies. N Engl J Med 2016;374:1253–63

• 6. Helmerhorst GT, Teunis T, Janssen SJ, Ring D. An epidemic of the use, misuse and overdose of opioids and deaths due to overdose, in the United States and Canada: is Europe next? Bone Jt J 2017;99-B:856–64

Disclosure of Interest: None declared.

222 ISoP18-1324 Retrospective Study on Cutaneous Adverse Drug Reactions Induced by Antiepileptic Drugs

222.1 L. Aït Moussa^*1, A. El Rherbi¹, K. Senouci², A. Tebaa¹, R. Soulaymani^1,2

222.1.1 ¹Center Antipoison et de Pharmacovigilance du Maroc, Rabat, Morocco; ²Faculty of Medicine and Pharmacy. Mohammed V University, Rabat, Morocco

Background/Introduction: Cutaneous adverse reactions (CADRs) to antiepileptics (AEs) are common with an incidence rate of 3% in individuals who receive AEs. They are various and can be classified into immunologic and nonimmunologic etiologies. Serious reactions are rare, but may be life threatening.

Objective/Aim: To study the epidemiological characteristics of CADRs related to AEs and identify AEs commonly involved in the cutaneous reactions.

Methods: This was a retrospective study of suspected cutaneous adverse reactions to AEs reported in the Moroccan Pharmacovigilance database between January 2003 and December 2017.

Results: A total of 848 individual case safety reports related to AEs drugs were recorded in the Moroccan Pharmacovigilance database. Skin reactions were identified in 278/848 (32.8%) patients (mean age (SD): 29.5 (20.7), 52% females). 130 out of 278 (46.8%) patients experienced Serious reactions resulted in hospital admission (106/130), death (5/130) and life threatening (8/130). The most commonly identified CADRs were Skin rashes (35.68%). Toxic epidermal necrolysis (TEN) was observed in 11.3% followed by drug rash with eosinophylia and systemic symptoms (DRESS) in 8.1%, Stevens-Johnson-syndrom (SJS) in 7.1% and acute generalized exanthematous pustulosis (AGEP) in 2.1%. Drugs most frequently involved in CADRs were phenobarbital (PB: 29%), carbamazepin (CBZ: 25.7%), valpric acid (VPA: 20.1%) and lamotrigine (LTG: 15%). STJ was more frequent with VPA and LTG (p < 0.05) whereas DRESS syndrome was more observed with PB (p < 0.05). CADRs were more common in women and adults but there was no significant gender or age effect for risk of developing skin reactions.

Conclusion: PB, CBZ, VPA and LTG were the major causative AEs for SCARs. Serious reactions including TEN, DRESS, SJS and AGEP show a high rate (28.6%). early detection and reporting can improve the management of CADRs and reduce their incidence. Furthermore, the use of non-aromatic AEs drugs could be a safe alternative for patients with aromatic AE-induced SCARs.

Disclosure of Interest: None declared.

223 ISoP18-1326 Safety Profile of Sodium-Glucose Co-Transporter-2 (Sglt2) Inhibitors: A Retrospective Study of the Portuguese Pharmacovigilance System Database

223.1 D. Mendes^*1, C. Alves^1,2, F. Batel-Marques^1,2

223.1.1 ¹CHAD, AIBILI; ²Laboratory of Social Pharmacy and Public Health, School of Pharmacy, Coimbra, Portugal

Background/Introduction: Sodium-glucose co-transporter-2 inhibitors (SGLT2) inhibitors were the latest class of antidiabetics introduced in the European market (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin). SGLT2 inhibitors reduce renal glucose reabsorption, thereby promoting urinary glucose excretion [1].

Objective/Aim: To characterize the safety profile of SGLT2 inhibitors by analysing disproportionalities of associations between adverse events (AEs) and antidiabetics in the Portuguese Pharmacovigilance System (PPS) Database.

Methods: Spontaneous reports of AEs in association with antidiabetic monotherapy received by the PPS over the last 10 years (2008–2017) were considered. AEs were classified according to MedDRA^®, v.20.1, in Preferred Terms (PT). A case/non-case approach was performed by pooling reporting odds ratio (ROR) with 95% confidence intervals (CIs) for SGLT2 inhibitors versus other antidiabetics on all AEs. Corrections were made when there were no reports of a given AE in the control group (i.e. 0.5 was added to each of those cells) in order to enable the calculation of the ROR. ROR values > 1 along with a 95% CI > 1 were considered statistically significant. Microsoft Excel 2013^® was used to perform all the calculations.

Results: There were 270 spontaneous reports. Most cases were serious (n = 159; 58.9%). The majority of patients were female (n = 145, 53.7%; male: n = 119, 44.1%; missing: n = 6, 2.2%); the median age was 66 years old (min. 19, max. 96; missing data in 46 cases). The suspected drug was a SGLT2 inhibitor in 45 cases, while other antidiabetics were cited in 225 cases (metformin, n = 107; DPP4-inhibitors, n = 50; GLP1-analogues, n = 29; sulfonylureas, n = 17; thiazolidinediones, n = 10; others, n = 12). SGLT2 inhibitors were associated with an increased risk for candida infection (ROR 51.5, 95% CI 2.8–949.8), diabetic ketoacidosis (ROR 84.8, 95% CI 4.8–1486.9), pollakiuria (ROR 7.6, 95% CI 1.2–45.8), renal injury (ROR 5.0; 95% CI 1.0–25.3), somnolence (ROR 30.4, 95% CI 1.5–610.2), urinary tract infection (ROR 7.6, 95% CI 1.2–45.8), and urosepsis (ROR 30.4, 95% CI 1.5–610.2).

Conclusion: The present results are in line with the previous knowledge about the safety profile of SGLT2 inhibitors, since an increased risk of urinary and genital tract infection, dysuria and polyuria had been identified with these drugs in premarketing clinical trials, while diabetic ketoacidosis was reported in patients taking SGLT2 inhibitors during post-marketing [1, 2]. Therefore patients under treatment with SGLT2 inhibitors should be carefully monitored for these type of adverse events.

References:

• 1. Forxiga: EPAR—Public assessment report (07/12/2012). Available from http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002322/human_med_001546.jsp&mid=WC0b01ac058001d124. Accessed on 04/06/2018

• 2. Fadini GP, Bonora BM, Avogaro A. SGLT2 inhibitors and diabetic ketoacidosis: data from the FDA adverse event reporting system. Diabetologia 2017;60:1385–9

Disclosure of Interest: None declared.

224 ISoP18-1327 A Study Regarding the Frequency of Adverse Reactions in the Infertility Treatment

224.1 A. Butuca^#*1, C. Morgovan^#1, A. Juncan^#1, L. Vonica¹, A. Muntean¹, F. Gligor¹

224.1.1 ¹ULB Sibiu, Sibiu, Romania

Background/Introduction: The follicle stimulating hormone (FSH) is a glycoprotein produced by the anterior pituitary gland and it plays an important role in the fertility regulation of men and women. The gonadotropin therapy is essential for ovarian stimulation in infertility treatments. The current gonadotropins have better quality, safety profiles and clinical efficiency than the previous ones.

An important achievement was the use of recombining technology in the manufacturing processes for obtaining FSH, luteinizing hormone (LH) and human chorionic gonadotropin (hCG).

Recently, two FSH products obtained through recombined DNA technology have been approved for marketing. Both medicines used in therapy have higher purity and guaranteed consistency between batches: follitropin alfa (FA) and follitropin beta (BF) [1].

Objective/Aim: To evaluate the adverse reactions (ADRs) reported in the European database EudraVigilance for both molecules (FA and FB).

Methods: In this study, a retrospective analysis of ADRs reported in EudraVigilance (from January 2013 to December 2017) was done for 18–65 year old women, to whom FA and FB were administrated in the controlled ovarian stimulation, which is part of the routine practice in assisted human reproduction technology. The information refers to the medical events reported following treatment with molecules authorized in the EU or EEA. According to the ICH E2A, an ADR is considered serious (SHO) if it represents a danger for life, or if it caused hospitalization or prolonged hospital accommodation.

The observational method as used and the descriptive analysis was undertaken using SigmaStat.

Results: Most of the total ADRs reported (n = 522) were for FA (86.59%). The main part of ADRs were SHO which produced complications (n = 95.21%). Also, 73.75% of the reported ADRs required prolonged hospitalization. Most SHO (n = 497, 91%) were reported for FA. In 2.1% of the reports, patients’ lives were endangered. In 2017, two patients treated with FB (0.38%) developed breast cancer. The results confirm that, even if the ovarian hyperstimulation syndrome is rarely used in assisted human reproduction technology, it has an increased risk of morbidity and mortality due to its complications [2–4].

Conclusion: The results of our analysis show that the characterization of SHO caused by the ovarian stimulating treatment using assisted human reproduction techniques aren’t different from other studies presented in scientific literature. At this moment, there isn’t enough data to show a correlation between the treatment used for ovarian stimulation and the risk of developing breast cancer.

References:

• 1. Lispi M, Bassett R, Crisci C, Mancinelli M, Martelli F, Ceccarelli D, et al. Comparative assessment of the consistency and quality of a highly purifi ed FSH extracted from human urine (urofollitropin) and arecombinant human FSH (follitropin α). Reproductive Biomed Online 2006;13:179–93

• 2. Nevesa LM, Kurobeb FMC, Drezett J, Blakeb MT, Dzikd A, Cavagnae M, et al. Ovarian hiperstimulation syndrome: incidence in a public service of assisted reproduction and literature review. Reprodclim 2013;28:10–7

• 3. Cuc Hepcal I, Toma CC, Olah N, Dehelean C, Motoc A, Ardelean S, et al. Study of the oral contraceptives’ use by women from western Romania. Farmacia 2015;63:607–12

• 4. Zreik TG, Mazloom A, Chen Y, Vannucci M, Pinnix CC, Fulton S, et al. The fertility drugs and the risk of breast cancer: a meta-analysis and review. Breast Cancer Res Treat 2010;124:13–26

Disclosure of Interest: None declared.

225 ISoP18-1328 Docetaxel Side-Effects Notified to the Tunisian National Centre of Pharmacovigilance in 2017

225.1 I. Aouinti^1,2, O. Charfi^1,2, I. Hamza¹, G. Lakhoua^1,2, N. Alaya¹, S. El Aidli^1,2, R. Daghfous^*2,3, A. Zaiem^1,2

225.1.1 ¹Service de Recueil et Analyse des Effets Indésirables, Centre National de Pharmacovigilance; ²Faculté de Médecine de Tunis, Université Tunis El Manar, Tunis, Tunisia; ³Centre National de Pharmacovigilance, Tunis, Tunisia

Background/Introduction: Docetaxel is a chemotherapeutic treatment. It is indicated in particular in breast or lung cancer. Besides its efficacy, it can induce frequent side effects as cutaneous or hematological manifestations.

Objective/Aim: To study epidemiological and clinical features of docetaxel.

Methods: Retrospective and descriptive study about docetaxel side effects notified to the Tunisian National Centr of Pharmacovigilance between January and December 2017. The imputability was assessed according to the French Method of imputability. The severity of side effects was evaluated according to the Common Terminology Criteria for Adverse Events 4.0 of the National Cancer Institute.

Results: We have collected 92 side effects cases occurred in 86 patients (81 women and 5 men). The age varied from 28 to 74 years. The indication was breast cancer in 93%, lung cancer in 3.5% and not precised in 3.5% of patients. Oral premedication was received in 20.7% of side effect and not precised in 73.9% of cases. The side effects were cutaneomucosal in 76.1% (mainly hand-foot syndrome), hematological in 31.5% (mainly febrile neutropenia), infusion related reactions in 7.6%, gastro-intestinal in 10.9%, neurological in 3.3%, general manifestations in 3.3% and hepatic in 1.1% of side effects cases. The side effects were severe in 42.4% of side effects cases. The outcome was favorable in 94.6% of side effect cases and not precised in 5.4%.

Conclusion: This study focused on the predominance of cutaneomucosal and hematological docetaxel side effects. It showed also the important frequency of severe side effects.

Disclosure of Interest: None declared.

226 ISoP18-1331 Drug-Induced Anaphylaxis in French and Vietnamese Pharmacovigilance Database 2010–2015: A Social Pharmacology Discussion

226.1 K.-D. Nguyen^1,2,3, H.-A. Nguyen³, J.-L. Montastruc^*1,2, L. Chebane^1,2, H. Bagheri^1,2

226.1.1 ¹Centre Midi-Pyrénées de PharmacoVigilance, de Pharmacoépidémiologie et d’Information sur le Médicament de l’UMR INSERM 1027, Centre Hospitalier Universitaire, Toulouse, France; ²Laboratoire de Pharmacologie Médicale et Clinique, Equipe de Pharmacoépidémiologie de l’UMR INSERM 1027, Faculté de Médecine de l’Université Paul-Sabatier, Toulouse, France, ³The National Centre of Drug Information and Adverse Drug Reaction Monitoring, Hanoi University of Pharmacy, Hanoi, Viet Nam

Background/Introduction: Drug-induced anaphylactic reactions is a severe and life-threatening Adverse Drug Reaction (ADR) and the risk differs between populations.

Objective/Aim: The aim of this study is to compare the characteristics of the drug-induced anaphylaxis between French pharmacovigilance database (FPVD) and Vietnamese pharmacovigilance database (VPVD).

Methods: Spontaneous ADR reports from January 2010 to December 2015 were collected for retrospective analysis: in FPVD, all ADRs containing High Level Term “Anaphylactic and anaphylactoid reactions” were selected; in VPVD, all ADRs meeting the anaphylaxis definition by the Second Symposium on the Definition and Management of Anaphylaxis [1] were selected. Demographic data, suspected drugs according to Anatomical Therapeutic Chemical classification were compared.

Results: Among a total of 28,698 and 229,481 spontaneous reporting respectively registered in Vietnamese and France database over a 6-year period, 3182 (11.08%) and 5279 (2.3%) concerned respectively the cases of drug-induced anaphylaxis reports. The male patients with anaphylaxis accounted for 41.8% in France and 46.7% in Vietnam (p < 0.001). Anaphylactic patients in Vietnam were younger than those in French, with mean age of 41.02 (± 25.38) and 51.91 (± 17.79) respectively (p < 0.001). Mortality rate due to anaphylaxis in VPVD are significantly lower than in FPVD (n = 79, 2.5% and n = 164, 3.1% respectively). Concerning the suspected drugs related to anaphylaxis, we mainly found anesthetic or analgesic drugs with suxamethonium (n = 1002, 18.92%), propofol (n = 672, 12.69%), sufentanyl (n = 497, 9.38%) in FPVD and antibiotics with cefotaxime (n = 627, 19.7%), ceftriaxone (n = 334, 10.5%) and ceftazidime (n = 294, 9.24%) in VPVD. In FPVD, the antibiotics reported were amoxicillin (n = 483, 9.12%), amoxicillin with enzyme inhibitor (n = 453, 8.55%) following by cefazoline (n = 214, 40.4%). Cephalosporins and carbapenems group (J01D) was the most reported pharmacological class in Vietnam with 56.8% of cases (mostly third-generation cephalosporins) whereas this group accounted only 9% in France.

Conclusion: These data show some differences for the characteristics of drug-induced anaphylaxis cases between France and Vietnam. The discrepancy of drug-induced anaphylaxis between 2 countries could be explained by the antibiotic overuse in Vietnam. The further analysis is required to fully discuss on social pharmacology aspect.

References:

• 1. Sampson HA, et al. Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin. Immunol 2006;117:391–7

Disclosure of Interest: None declared.

227 ISoP18-1334 Impact of Quality and Outcomes Framework on Prevalence of Chronic Kidney Disease in United Kingdom

227.1 M. Kaur^*1, L. Sharma²

227.1.1 ¹Patient Safety and Transformation, Cognizant Technology Solutions, London, United Kingdom; ²Patient Safety and Transformation, Cognizant Technology Solutions, Zurich, Switzerland

Background/Introduction: In April 2004, the Quality and Outcomes Framework (QOF), a comprehensive new contract was introduced in UK for General Practitioners (GPs)—a pay for performance scheme providing financial incentives for diagnosing and managing conditions. It is a voluntary part of the new General Medical Services contract; general practices can aspire to achieve all, part, or none of the points available in the QOF. The QOF contains three main components, known as domains. The three domains are: Clinical (e.g. chronic kidney disease, hypertension etc.); Public Health and Public Health—Additional Services. QOF data on Chronic kidney disease (CKD) has been included in the pay for performance system/QOF since April 2006, to improve diagnosis and management of CKD in primary care by promoting the development of a CKD register (for CKD 3–5), establishing the proportion of patients with CKD with a recorded blood pressure (BP), and promoting improved BP control.

Objective/Aim: To study the impact of QOF on prevalence of CKD in the United Kingdom (UK) by reviewing published literature.

Methods: A literature review search using PubMed search engine with the following search terms; chronic kidney disease, chronic kidney failure, Quality and Outcomes Framework, incentive* and pay for performance; was performed to find the articles reporting the prevalence or incidence of chronic kidney disease and the trends in prevalence were checked before and after introduction of QOF indicators.

Results: The prevalence of chronic kidney disease was observed to be higher after the introduction of QOF, i.e., 2–4 fold increase in prevalence of CKD was observed in reports from QOF participating practices as compared to those non-participating local practices. Population BP control was increased from the pre-QOF period to the post-QOF period.

Conclusion: The prevalence trends indicate that QOF may have increased awareness among GPs in the UK, which in turn improved the intervention and control of risks and disease progression. The prevalence and incidence of diseases or conditions included in QOF should be interpreted carefully as the introduction of QOF may have resulted in the over diagnosis. As the prevalence and incidence data of conditions is widely used in different functions of pharma industry including pharmacovigilance, health economics etc., therefore, researcher should be aware of the QOF and it’s potential impact on prevalence and incidence of disease conditions.

References:

• 1. Harvey G, Oliver K, Humphreys J, Rothwell K, Hegarty J. Improving the identification and management of chronic kidney disease in primary care: lessons from a staged improvement collaborative. Int J Qual Health Care 2015;27:10–6

• 2. Humphreys J, Harvey G, Coleiro M, Butler B, Barclay A, Gwozdziewicz M, et al. A collaborative project to improve identification and management of patients with chronic kidney disease in a primary care setting in Greater Manchester. BMJ Qual Saf 2012;21:700–8

• 3. Jameson K, Jick S, Hagberg KW, Ambegaonkar B, Giles A, O’Donoghue D. Prevalence and management of chronic kidney disease in primary care patients in the UK. Int J Clin Pract 2014;68:1110–21

• 4. Karunaratne K, Stevens P, Irving J, Hobbs H, Kilbride H, Kingston R, et al. The impact of pay for performance on the control of blood pressure in people with chronic kidney disease stage 3–5. Nephrol Dial Transplant 2013;28:2107–16

Disclosure of Interest: None declared.

228 ISoP18-1340 Exceptional Case Of Ecchymosis And Gingivorrhagia Associated With Tocilizumab

228.1 I. Souilem¹, I. aouinti¹, S. ben hammamia¹, G. Lakhoua¹, S. el aidli^*1, R. daghfous¹, S. kastalli¹

228.1.1 ¹service de recueil et d’analyse des effets indésirables, centre national de pharmacovigilance, tunis, Tunisia

Background/Introduction: Tocilizumab is a humanized monoclonal antibody that blocks the action of interleukin-6 receptors. It is used for its immunosuppressive action in rheumatoid arthritis. The most commonly reported adverse reactions (i.e., occurred in ≥ 5% of patients treated with tocilizumab alone or in combination) were: infections of upper respiratory tract, nasopharyngitis, headache, hypertension and increased ALT. 

Objective/Aim: We report herein an exceptional case of ecchymoses and gingivorrhagia probably induced by tocilizumab, in a woman treated for rheumatoid arthritis.

Methods: This case was notified on March 23th, 2018 and was analyzed according to the French updated method for the causality assessment of adverse drug reactions [1].

Results: A 53-year old women, was prescribed on June 2017 intravenous tocilizumab to treat rheumatoid arthritis (4 mg/kg every 4 weeks). 10 days after the first infusion, the patient developed spontaneous gingivorrhagia and three ecchymoses. The evolution was spontaneously favorable in few days. 1 week after her second infusion, she developed the same symptoms with the same evolution. Then, because of a surgery, tocilizumab was suspended for 2 months. During this period, ecchymoses and gingivorrhagia do not reoccurred. At the resume of the treatment at the same dose, the symptoms reappeared after 2 days of all the subsequent infusions. Ecchymoses were more numerous and gingivorrhagia more abundant. Laboratory tests showed a platelet count at 236000/µL and a bleeding time at 4 min. The treatment was stopped without recurrence of ecchymoses and gingivorrhagia.

Conclusion: The responsibility of tocilizumab was valued as likely in this case because of the recurrence of the ecchymoses and ginginvorrhagia after all the infusions with a shortening of the delay in each time. In addition, these symptoms did not reoccur when tocilizumab was suspended for 2 months. To our knowledge, this is the first case of tocilizumab-induced ecchymoses and gingivorrhagia. In fact, these manifestations were not reported in literature, and were only mentioned in phase III controlled clinical trials. In our patient, the platelet count and bleeding time were in normal range. So, the mechanism of these manifestations does not seem to be related to haematological disturbances. It could be explained by a vascular fragility which is also reported as a side effect of tocilizumab in the results of clinical trials.

References:

• 1. Arimone Y, Bidault I, Dutertre J-P, et al. Updating the French Method for the Causality Assessment of Adverse Drug Reactions. Thérapie 2013;68(2):69–76.

Disclosure of Interest: None declared.

229 ISoP18-1341 Anticoagulant Therapy in Patients with Atrial Fibrillation and Risk of Bleeding: Interim Analysis: Tyrion Study

229.1 S. Ferraro^*1, I. Convertino¹, S. Salvadori², S. Pieroni², A. Pecori², M. Franchini², I. De Carlo³, U. Kirchmayer⁴, T. Corona⁵, M. Parrilli⁵, M. Rossi⁶, A. Vannacci⁷, C. Blandizzi^1,5,8, M. Tuccori^1,5,8

229.1.1 ¹Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; ²Institute of Clinical Physiology, National Research Council, Pisa, Italy; ³Regional Center of Pharmacovigilance Marche, Teramo, Italy; ⁴Department of Epidemiology, Lazio Regional Health Authority, Rome, Italy; ⁵Tuscan Regional Centre of Pharmacovigilance, Florence, Italy; ⁶Department of Medical, Surgical and Neuroscience Sciences, University of Siena, Siena, Italy; ⁷Section of Pharmacology and Toxicology, Department of Neuroscience, Psychology, Research on Drugs and Children’s Health, University of Florence, Florence, Italy; ⁸Unit of Adverse Drug Reactions Monitoring, University Hospital of Pisa, Pisa, Italy

Background/Introduction: New oral anticoagulants (NOA) showed a lower risk of bleeding in patients with atrial fibrillation as compared to traditional oral anticoagulants (TOA). However, some studies highlighted a higher frequency of gastrointestinal bleeding related to NOA than TOA [1–3].

Objective/Aim: To assess the risk of bleeding events (i.e. overall, gastrointestinal and intracranial) in patients with NOA, as compared to TOA.

Methods: The TYRION study had a case–control design with a historical cohort and included patients of four Italian regions with at least one NOA or TOA prescription from July 1st, 2012 to December 31st, 2015. Exposure and outcome data were extracted from the regional databases of drug reimbursement claims and the regional records of hospital discharge, respectively. The databases were linked by an anonymous unique patient identification number. Cohort entry was defined by the date of the first prescription of NOA or TOA after July 1st, 2013 among patients who were free from any anticoagulant prescription in the previous year. Cases were patients with at least one record of bleeding event. The date of the first bleeding was the index date. In the primary analysis, two controls were matched for each case by year of birth, year of cohort entry, sex and duration of follow-up. In the secondary analysis, cases were stratified into intracranial and gastrointestinal bleedings, and then they were matched with two controls. In each analysis, TOA users were the reference group. The odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by conditional logistic regression for the association of NOA use with bleeding events, adjusted for region.

Results: This interim analysis included data provided by three regions (Tuscany, Lazio, Marche). The cohort included 33,314 patients. At the cohort entry, 17,263 and 16,051 patients received NOA and TOA, respectively. During the follow-up period, 537 patients switched from NOA to TOA, while 6098 from TOA to NOA. A total of 1557 cases of overall bleeding, 222 cases of intracranial bleeding and 403 cases of gastrointestinal bleeding were recorded. The adjusted ORs of NOA were: 0.54 (95% CI 0.47–0.61) for overall bleeding, 0.48 (95% CI 0.34–0.67) for intracranial bleeding, and 0.83 (95% CI 0.65–1.07) for gastrointestinal bleeding.

Conclusion: These results showed a significant protective effect of NOA, as compared to TOA, for overall and intracranial bleedings only. The final analysis is expected to confirm the results.

References:

• 1. Goette A. Novel oral anticoagulants for stroke prevention in atrial fibrillation: key trial findings and clinical implications. Trends Cardiovasc Med 2013;23:128–34

• 2. He Y, Wong ICK, Li X, Anand S, Leung WK, Siu CW, et al. The association between non-vitamin K antagonist oral anticoagulants and gastrointestinal bleeding: a meta-analysis of observational studies. Br J Clin Pharmacol2016;82:285–300

• 3. Chang H-Y, Zhou M, Tang W, Alexander GC, Singh S. Risk of gastrointestinal bleeding associated with oral anticoagulants: population based retrospective cohort study. BMJ 2015;350:h1585

Disclosure of Interest: None declared.

230 ISoP18-1345 Consumers’ Contributions to Pharmacovigilance for Herbal Medicines: Analyses of Global Reports in Vigibase^®

230.1 F. Van Hunsel^*1, S. Skalli², J. Barnes³

230.1.1 ¹The Netherlands Pharmacovigilance Centre Lareb, ‘s Hertogenbosch, The Netherlands, ²Faculty of Sciences, University Mohammed V in Rabat, Rabat, Morocco, ³School of Pharmacy, University of Auckland, Auckland, New Zealand

Background/Introduction: The important contribution that users of medicines make to pharmacovigilance is well-recognised for conventional pharmaceutical medicines. However, the contribution that consumers (including patients) make to reporting of suspected ADRs associated with herbal medicines (HMs) is less evaluated. The use of HMs and related products is commonplace, and such products are often perceived to be ‘safe’, or safer than conventional medicines. However, these products are not without risks. Typically, consumers buy, including purchases via the internet, or use these products without the involvement of health professionals (HPs), and consumers may be reluctant to report suspected ADRs associated with HMs to health professionals (HPs). Against this background, it is important to understand whether consumers of HMs themselves provide useful information on ADRs associated with their use of these products.

Objective/Aim: To investigate the global pattern for consumer ADR reports for HMs, and to compare consumer and HP reports to gain insights into potential benefits from greater consumer involvement in pharmacovigilance for HMs.

Methods: A search in Vigibase^®, the WHO international database of suspected adverse drug reaction (ADR) reports, was performed by a data-scientist of the Uppsala Monitoring Centre (UMC) on 12-02-2018. Dataset date was 01-02-2018. HMs, classified by the reporter as being a suspected or interacting substance, were identified by searching for reports relating to substances classified as UMC assigned ATC code ‘V90’: unspecified herbal and traditional medicine’. This ATC code is assigned to herbal products containing either only herbal ingredients or mixed products (non-herbal substances, including ingredients of animal origin, e.g., deer velvet; substances such as vitamins/minerals, and conventional drugs—where such substances are co-ingredients with herbal substances, e.g., paracetamol with herbal ingredients in cough/cold remedies); or by searching for reports relating only to specified herbal substances. Data were extracted on number of reports, country of origin of report, reporter type, HM used and MedDRA-coded ADRs.

Results: Overall, VigiBase^® contained 54093 reports relating to HMs. HM reports were submitted most frequently from the Republic of Korea (n = 10104), China (n = 9011) and Germany (n = 5906). In total, 14467/54093 reports (26.7%) listed ‘consumer’ as a reporter; of these, 7445 (51.5%) listed  ‘consumer’ as the sole reporter. In general, HMs reported most frequently (top 10) and ADRs reported most frequently (top 10) were similar for consumer and HPs, with the exception of terms such as substance abuse (n = 573), drug dependence (n = 291) and drug ineffective (n = 263) that appeared in the top 10 categories for consumer, but not HPs, and vice versa for urticaria (n = 1065), rash (n = 1042) and dyspnoea (n = 923).

Conclusion: There was considerable overlap among consumer-only and HP-only reports with respect to the HMs implicated in the reports and the types of ADRs reported. Notable differences were that consumer-only reports included ADR terms relating to lack of efficacy and drug dependence. This work has also highlighted issues with coding and classification of HMs implicated in ADR reports; future work needs to address these.

Disclosure of Interest: None declared.

231 ISoP18-1347 Palmar Keratoderma Induced by Amoxicillin

231.1 F. Zgolli¹, G. Lakhoua¹, O. Charfi¹, W. Kaabi¹, S. El Aidli¹, R. Daghfous^*1, S. Kastalli¹

231.1.1 ¹Tunisian National Centre of Pharmacovigilance, Tunis, Tunisia

Background/Introduction: Palmar keratodermas (PK) is a thickening of the skin of the palms caused by excessive keratin. They are a heterogeneous group of disorders that are classically grouped as either hereditary or acquired. Several drugs have been reported to cause PK, including glucan, lithium and chemotherapeutic agents. However amoxicillin has never been associated with such cutaneous eruption.

Objective/Aim: We report a case of PK associated with cheilitis induced by amoxicillin.

Methods: This case was evaluated according to the Begaud’s method of imputability.

Results: A 45-year-old man without family history of keratoderma, developed, 12 h after a self-medication with amoxicillin a PK associated with cheilitis. Skin examination showed keratic lesions on the palms associated with scally and swelling chapped lips. The rest of physical examination and laboratory tests were normal. A spontaneous resolution was observed 3 days after the treatment had been stopped.

Conclusion: In this case the responsibility of amoxicillin in inducting this cutaneous impairment was evocated because symptoms occurred 12 h after the drug intake, the regression of these disorders following the drug withdrawal (I1) [1] and the absence of other aetiology. However histopathology remains necessary to confirm this diagnosis.

References:

• 1. Bégaud B, Evereux JC, Jouglard JB, et al. Unexpected or toxic drug reaction assessment. Actualisation of the method used in France. Therapie 1985;40:111–8

Disclosure of Interest: None declared.

232 ISoP18-1348 Safety Profile Of Quinolone: The Experience Of Tunisian National Centre Of Pharmacovigilance

232.1 I. Souilem^*1, O. Charfi¹, A. Zaiem¹, S. Ben Hammamia¹, H. Zayeni¹, S. El aidli¹, S. Kastalli¹

232.1.1 ¹Service de recueil et d’analyse des effets indésirables, centre national de pharmacovigilance, Tunis, Tunisia

Background/Introduction: Quinolone represent a class of antibacterial agents widely used for several infectious diseases due to their broad spectrum of activity, high bioavailability and generally good safety profile. Reactions of the gastrointestinal tract, the central nervous system and the skin are the most often observed adverse effects. Occasionally major events such as hypersensitivity, cardiotoxicity, arthropathy and tendinitis occur.

Objective/Aim: The aim of this study was to report and analyze the adverse events reported by patients using quinolones.

Methods: We conducted a retrospective study that included all observations of adverse events into patients who used quinolones. These cases were notified to the Tunisian National Centre of Pharmacovigilance center over a period of 4 years.

These cases ware analyzed according to the frensh updated method for the causality assessment of adverse drug reactions [1].

Results: In our study, we included 33 patients who presented 36 adverse events. Patient’s age ranged from 17 to 90 years. There was a slight feminine predominance with a sex ratio Female/male of 1.35.

All the molecules used were fluoroquinolones (ciprofloxacine, levofloxacine and ofloxacine). Among these molecules, ciprofloxacin was the most frequently associated with adverse effects (48.65%). Hypersensitivity reactions were the most common adverse events and represented 41.7% of all reactions: 10 cases of facial edema, 3 cases of anaphylactic shock and 2 cases of Quincke edema.

Cutaneous disorders represented 39% mainly macula-papular skin eruption. A case of fixed drug eruption with positive rechallenge and one case of Steven Johnson syndrome were reported.

Musculoskeletal system was involved in 11.1% cases (rhabdomyolysis and dentinitis).

Liver was involved in 2 cases.

In all cases, outcome was favorable after drug withdrawal.

Conclusion: This study highlighted the characteristics of quinolone’s adverse effects. Prospective studies would be interesting torefine the safety profile of quinolones.

References:

• 1. Arimone Y, Bidault I, Dutertre J-P, et al. Updating the French Method for the Causality Assessment of Adverse Drug Reactions. Thérapie 2013;68(2):69–76.

Disclosure of Interest: None declared.

233 ISoP18-1349 Post-marketing Pharmacovigilance: Checking on Checkpoint-Inhibitors

233.1 K. Geiling^*1, I. Scholz¹, M. Haschke¹, A. Rütsche²

233.1.1 ¹Department of Clinical Pharmacology ²Inselspital Bern, Bern, Switzerland

Background/Introduction: Checkpoint inhibitors (CPI) modulate T-cell-mediated immune response. Cancer patients with melanoma, renal cell carcinoma, non small cell lung cancer and other cancer types can benefit from CPI. However, CPI treatment is associated with adverse immune-mediated reactions (IMRs), such as pneumonitis, colitis and various endocrinopathies.

Objective/Aim: To describe the frequency and characteristics of adverse drug reactions after the application of CPI in a primary care hospital in Switzerland.

Methods: Systematic database search of all patients receiving one or more CPI during their in- or outpatient treatment at the University Hospital of Bern between January 2015 and May 2018. We recorded the indication, the date of the first and last application, the type of substance, and, in case of an adverse event, the time of onset and type and categorized them according to the WHO-standards. Only adverse drug reactions (ADR) labelled as such in the medical record were included. We further checked whether the ADR had been reported to the Regional Pharmacovigilance Centre of Bern. The ADR was classified as either “known” or “unknown” according to the prescribing information.

Results: In total we assessed 157 patients who received either nivolumab (52%), pembrolizumab (32%) and/or ipilimumab (16%) as single substances or as a combination for at least one treatment period. 46% of patients were female with a mean age of 64 when receiving the first treatment; the main indications for treatment were melanoma (37%) and NSCLC (20%). The mean number of applications per patient were 7 (range 1–65). 58 adverse drug reactions occurred in 48 patients (30.5%). Types of adverse events were: hypophysitis (16%), arthritis/arthralgia (12%), pneumonitis, hepatitis and colitis/diarrhea (10% each).The mean time of onset after first application was 10 weeks (median). According to WHO-Guidelines, the causality was assessed as possible (44%), probable (10%) or certain (8%). 44% of the events were classified as “serious”. No fatal cases were observed. 16% of the events were “unknown” (i.e. not listed in the prescribing information). None of the evaluated events had been reported to the Regional Pharmacovigilance Centre of Bern.

Conclusion: These results raise the question whether our passive spontaneous postmarketing pharmacovigilance system is suited to deal with medications entering the market. More proactive strategies using data mining in available electronic hospital health records may yield better results and should be discussed and systematically evaluated.

Disclosure of Interest: None declared.

234 ISoP18-1350 Autoimmune Hepatitis with Atorvastatin?

234.1 F. Zgolli¹, G. Lakhoua¹, I. Aouinti¹, W. Kaabi¹, S. El Aidli¹, R. Daghfous^*1, S. Kastalli¹

234.1.1 ¹Tunisian National Centre of Pharmacovigilance, Tunis, Tunisia

Background/Introduction: Statins are largely prescribed drugs in the prevention of cardiovascular disease. Hepatobiliary adverse effects notified with this drug class are rare. It includes altered liver function tests and hepatitis. Statins can also be associated with an autoimmune liver failure but it is rarely reported in the literature.

Objective/Aim: We report the case of a woman who developed a drug-induced autoimmune hepatitis while taking a combination of atorvastatin and losartan/hydrochlorothiazide.

Methods: This case was notified in the 8th marsh 2018 and evaluated according to the Begaud’s method of imputability.

Results: An 85-year old woman with past medical history of high blood pressure and stroke was admitted to hospital after complaining of asthenia, nausea, vomiting and epigastric pain. The patient had been taking 40 mg atorvastatin daily for 10 years, with normal liver function tests. Losartan/hydrochlorothiazide 100/25 mg daily was added since 2 years. Other long-term drug therapies were frusemide and dl-Lysine Acetylsalicylate. Physical examination has showed epigastric tenderness. Laboratory findings have identified a hepatic impairment (Table 1) and antinuclear antibodies > 1/640. Viral serology testing showed no evidence of a recent viral infection with hepatitis B or C. No abnormalities were found by ultrasound of the hepatobiliary system. Treatment with atorvastatin and Losartan/hydrochlorothiazide was stopped few days after admission. The furosemide and the dl-Lysine Acetylsalicylate were pursued. Liver function test returned to normal levels over the subsequent 6 weeks under symptomatic treatment (cortisone). The control of antinucelear antibodies was not performed until this day.

Conclusion: The biochemical and immunological findings following onset of this illness suggest a drug induced autoimmune hepatitis. The responsibility of atorvastatin was retained in front of the compatible chronology, the favourable outcome after the medication withdrawal and the absence of autoimmune hepatitis induced losartan/hydrochlorothiazide in literature (I1) [1]. The responsibility of frusemide and DL-Lysine Acetylsalicylate is doubtful due to the favourable outcome despite their pursuit. According to the literature, autoimmune hepatitis was never described with losartan/hydrochlorothiazide. Nevertheless statins were associated with few cases of autoimmune hepatitis with possibly trigging or unmasking an autoimmune process but the exactly mechanism remains unknown.

References:

• 1. Bégaud B, Evereux JC, Jouglard JB, et al. Unexpected or toxic drug reaction assessment. Actualisation of the method used in France. Therapie 1985;40:111–8

Disclosure of Interest: None declared.

235 ISoP18-1351 Seizures following the administration of Diphtheria + Pertussis + Tetanus (DTP) containing vaccines: A case series

235.1 J. Sebastian¹, G. Parthasarathi¹, Dr. M. D. Ravi²

235.1.1 ¹Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, India; ²Department of Pediatrics, JSS Medical College and Hospital, JSS Academy of Higher Education and Research, Mysuru, India

Background: Immunization is one of the most effective public health intervention which cam save millions of life globally. Vaccines rarely cause serious adverse reactions, which can be either due to the inherent property of the vaccine product or it can be a coincidental event [1, 2]. DTP containing vaccines can cause seizures within 3 days of vaccination [3, 4]. New causality assessment algorithms helps to systematically review the details of the reported event for the causal association between the vaccine and the event [5].

Objective: To study the association between seizures following DTP containing vaccination and to identify the causal association between the vaccine and the event.

Methodology: The retrospective observational study was conducted at a multi specialty hospital where there is an active and spontaneous vaccine safety surveillance system present. A file having spontaneous reports of serious adverse events following immunization (AEFI) for a period of four years was reviewed to identify the seizure cases following DTP containing vaccination. The demographic, vaccination and reported AEFI details were collated for the analysis.

Results: The percentage of seizure with DTP containing vaccination was 78.12% among all the vaccine SAEs reported in the study and more events were reported (56%) in boys. All the cases were febrile seizures with a mean time gap of 7 hours with a standard deviation of 3.59 hours between the vaccination and first symptom onset. The incidence rate of seizures remain same (24%) for first, second, third and first booster dose of vaccination, but the incidence rate was less (4%) with the second boosted dose. The causal association with the vaccine and the event was coincidental in 28% of the cases where as 78% of events had a consistent causal association to vaccination. All the babies vaccinated with a product having a whole cell pertussis component and that could be the possible explanation of the seizures.

Conclusion: The study concluded that seizures can develop any time during the DTP containing vaccination schedule though the babies didn’t develop similar events in their previous doses. So the health care professionals should be vigilant to respond quickly to the events and also communicate effectively to the parents to maintain the public confidence in vaccines.

Keywords: Adverse Events following Immunization, Serious AEFIs, DTP containing vaccine, causality assessment.

References:

• 1. 1. Global manual on surveillance of adverse events following immunization. World health organization 2014. [Cited 2017 Feb 16] Available from http://www.who.int/vaccine_safety/publications/aefi_surveillance/en/

• 2. 2. Vaccine safety basics learning manual. World health organization 2013. [cited 2014 Dec 12] Available from http://www.who.int/vaccine_safety/initiative/tech_support/ebasic/en/

• 3. 3. Adverse events following immunization standard operating procedures. Ministry of health and family welfare, Government of India 2010. [cited 23 April 2017] available from http://www.searo.who.int/india/topics/routine_immunization/AEFI_standard_operating_procedures_SOPs_2010.pdf?ua=1

• 4. 4. Berg A T. Seizure risk with vaccination. Epilepsy Curr 2002;2(1):15–16. Available from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC320893/

• 5. 5. Causality assessment of adverse events following immunization user guide for revised WHO classification. World health organization 2013. [cited 2014 Mar 13] Available from http://www.who.int/vaccine_safety/publications/aevi_manual.pdf

Disclosure of Interest: None declared.

236 ISoP18-1352 Hallucinations Associated with Tetanus Immunization

236.1 I. Souilem¹, A. Zaiem¹, S. Ben Hammamia¹, I. Aouinti¹, S. El Aidli¹, R. Daghfous^*1, S. Kastalli¹

236.1.1 ¹Service de Recueil et d’analyse des Effets Indésirables, Centre National de Pharmacovigilance, Tunis, Tunisia

Background/Introduction: Adverse Effects Following Immunization (AEFI) associated with tetanus vaccine consists generally in local reactions. Serious reactions, including neurologic and hypersensitivity reactions, are rare. Psychological effects are not reported.

Objective/Aim: We report herein an exceptional case of hallucinations in a young woman few hours after receiving tetanus vaccination.

Methods: This is a case report that was notified on April 30th 2018 to the Tunisian National Centre of Pharmacovigilance.

Results: A 27-year old pharmacy student, were injured at work, and since her vaccination status was unknown, she received anti-tetanus serotherapy on 19th April without incident. On April 21st, she received tetanus toxoid vaccine. At night, she presented intense palpitations, cold sweats and edema at the injection site. She had no fever, headache nor stiff neck. The patient presented also scary visual hallucinations (animals, monsters, insects…) with open eyes and remained awake all the night. The symptoms resolved in the morning and only muscle soreness and pain at the injection site remained. However, the hallucinations re-occurred the two following nights.

Conclusion: The implication of tetanus immunization in our case is valued as possible because of the compatible delay (3 days after serotherapy and few hours after the vaccine) with spontaneous regression 3 days later.

Several studies have established a causal relationship between tetanus toxoid vaccine and the development of peripheral neuropathy or guillain-Barré syndrome.

The symptoms presented by our patient could not be a part of neurological trouble since hallucinations were isolated (normal neurological exam). At the best of our knowledge, visual hallucination had never been reported after tetanus immunization.

Disclosure of Interest: None declared.

237 ISoP18-1354 Reporting Immune Related Adverse Events During Checkpoint Inhibitor Therapy

237.1 A. Leuppi-Taegtmeyer^*1,2, A. Wicki³, A. Harings-Kaim², B. Zimmermanns², S. Krähenbühl^1,2, A. Raetz Bravo²

237.1.1 ¹Clinical Pharmacology & Toxicology; ²Regional Pharmacovigilance Centre, Clinical Pharmacology & Toxicology; ³Oncology, University Hospital Basel, Basel, Switzerland

Background/Introduction: Checkpoint inhibitors are a new group of anti-tumour agents. By inhibiting T-cell autoregulation, they may cause different immune-related adverse events (irAEs), which can occur at various time points during therapy. Because pharmacovigilance activities usually take place at the first manifestation of an irAE, we were interested to know whether irAE reports associated with checkpoint inhibitors generated more follow-up reports than other types of adverse drug reactions (ADRs).

Objective/Aim: To determine the number of irAEs reported to our regional pharmacovigilance centre for whom follow-up reports were submitted and to compare this proportion as well as the time elapsed between the initial and follow-up reports with other ADRs reported during the same time period.

Methods: Investigator-driven, single-centre, retrospective study of irAE pharmacovigilance reports.

Results: Twenty-one patients with a total of 35 irAEs (approximately 1.7 irAE per patient) were reported to our centre between January 2016 and May 2018. Five (24%) of the cases gave rise to follow-up reports, on average 20 weeks (5 months) after the initial reporting of the irAEs (SD 14, median 20). During the same time period, 773 cases of ADRs which did not involve checkpoint inhibitors were reported. Of these 58 (7.5%) had subsequent follow-up reports, reported on average 10 weeks later (SD 17 weeks, median 4 weeks). The latency time between initial and follow-up reporting was significantly longer for irAEs than other ADRs (p = 0.04, t-test using log transformed data). The proportion of follow-ups was also greater for irAEs than for other ADRs (p = 0.02, Fisher`s exact test).

Conclusion: irAEs due to checkpoint inhibitors appear to be more likely than other ADRs to generate follow-up reports, and these follow-up reports arrived later. This may be due to the presence of multiple irAEs in the same individual, which increases the likelihood that the final outcome was still unknown at the time of initial reporting. A further reason is a probable reporting bias for new therapies and new types of ADRs, as represented by checkpoint inhibitors and irAEs. It would be interesting to examine data from other centres to see if our findings are reproducible. If so, reporting authorities should consider adopting a standard follow-up procedure for irAEs for example, at 6 months after the initial report to ensure follow-up data is systematically gathered in a time- and cost-efficient manner.

Disclosure of Interest: None declared.

238 ISoP18-1356 Screening of Discharge Letters to Detect Adverse Drug Reactions. Can Natural Language Processing Tools be Helpful?

238.1 K. Ing Lorenzini^*1, V. Foufi², F. Tirone¹, V. Rollason¹, C. Gaudet-Blavignac², J. Desmeules¹, C. Lovis², C. Samer¹

238.1.1 ¹Clinical pharmacology and toxicology, ²Medical Information Sciences Division, University Hospitals of Geneva, Geneva, Switzerland

Background/Introduction: Adverse drug reactions (ADRs) are frequent and associated with significant morbidity, mortality and costs. Their incidence ranges from 7 to 17% in hospitalized patients [1, 2] and half of them are preventable [3]. Comprehensive detection of ADRs occurring during hospitalization can be performed retrospectively with chart reviews or prospectively through regular ward visits by a trained health professional [4]. Data mining techniques focusing on the automated identification of ADRs from the patient electronic health records (EHR) are promising tools [5]. Text-mining, including natural language processing (NLP), may be complementary to structured data analysis [6]. Most of studies have been performed in English. Therefore, studies in French are needed.

Objective/Aim: The aim of our study was to detect ADRs in discharge letters from patients hospitalized in a tertiary hospital, in whom a serious ADR occurred, based on a specialized consultation from clinical pharmacologists.

Methods: We performed a retrospective review of the EHR of the patients’ for whom a specialized consultation from clinical pharmacologists had identified the occurrence of serious ADRs. Discharge letters were manually and independently annotated by two clinical pharmacologists to assess whether the suspected ADR and causal drugs were explicitly mentioned. NLP techniques were also applied for the automatic detection of ADRs. More precisely, finite state automata were constructed for named entity recognition (e.g. drugs) and relation extraction (drugs-ADRs).

Results: Our preliminary results, based on the manual annotation by clinical pharmacologists, show that ADRs were explicitly mentioned in the discharge letter in 76% of the cases. Moreover, the first results issued by the automatic detection tools have shown on one hand that processing of free-text medical data is a demanding task and on the other hand that finite state automata constitute an effective method for recognizing complex structures in medical narratives.

Conclusion: ADRs were frequently mentioned in discharge letters even though not in all expected cases. A significant bias in our study is that the test population were patients that had already benefited from a specialized pharmacology consultation that had identified the ADR that was thereafter mentioned in the discharge letter. A similar analysis should be performed in unselected patients. Moreover, NLP techniques may be promising tools in increasing the detection of ADRs when a large number of letters have to be screened.

References:

• 1. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA.1998;279:1200–5

• 2. 2.Miguel A, Azevedo LF, Araujo M, Pereira AC. Frequency of adverse drug reactions in hospitalized patients: a systematic review and meta-analysis. Pharmacoepidemiol Drug Saf 2012;21:1139–54

• 3. Hakkarainen KM, Hedna K, Petzold M, Hagg S. Percentage of patients with preventable adverse drug reactions and preventability of adverse drug reactions—a meta-analysis. PLoS One 2012;7:e33236

• 4. Thurmann PA. Methods and systems to detect adverse drug reactions in hospitals. Drug Saf 2001;24:961–8

• 5. Trifiro G, Pariente A, Coloma PM, Kors JA, Polimeni G, Miremont-Salame G, et al. Data mining on electronic health record databases for signal detection in pharmacovigilance: which events to monitor? Pharmacoepidemiol Drug Saf 2009;18:1176–84

• 6. Warrer P, Hansen EH, Juhl-Jensen L, Aagaard L. Using text-mining techniques in electronic patient records to identify ADRs from medicine use. Br J Clin Pharmacol 2012;73:674–84

Disclosure of Interest: None declared.

239 ISoP18-1357 Effect of Ramadan Fasting on Trough Plasma Concentration of Cyclosporine in Renal Transplant Patients

239.1 E. Gaies¹, F. Zgolli¹, M. Ben Salem¹, R. Charfi¹, N. Jebabli¹, H. El Jebari¹, I. Salouage¹, R. Daghfous^*1, S. Trabelsi¹

239.1.1 ¹Department of Clinical Pharmacology, Tunisian National Centre of Pharmacovigilance, Tunis, Tunisia

Background/Introduction: Ramadan, a month of fasting, is a daily abstinence from any food, beverage, or oral drug from dawn to sunset. Several studies have shown that patients arbitrarily change the intake time and dosing of drugs without taking medical advice. This behaviour could alter the pharmacokinetics and pharmacodynamics of drugs, especially those with a narrow therapeutic index, like cyclosporine (CsA), and consequently their efficacy and tolerance.

Objective/Aim: The aim of our study was to assess trough blood levels of CsA in renal transplant patients during Ramadan fasting.

Methods: We performed a retrospective study over a period of 5 years (2012–2017) in the Department of Clinical Pharmacology in the Tunisian National Centre of Pharmacovigilance. We included 2117 samples collected from 438 adult renal transplant patients aged from 18 to 79 years old who were treated by CsA twice a day. Trough blood concentrations (C₀) were measured by an immunological method (Architect^®). We considered the therapeutic ranges (TR) for the (C₀) between 75 and 300 ng/mL.

Results:

Median age was 43 years. Sex ratio (M/F) was 2.2. The median dose of CsA was 2.7 mg/kg/day. The median C₀ was 131.2 ng/mL during Ramadan and 130.8 ng/mL for the remainder of years (p = 0.39). Distribution of C₀ according to the therapeutic range is described below (Table 1).

Conclusion: In our case, analyses have showed that there is no significant difference between median concentration during Ramadan and outside the month of Ramadan. However, median C₀ in the group in TR and under TR was higher in Ramadan than C₀ outside of this month. This may be due to the administration of CsA very early in the morning at dawn. So, education of patients regarding adherence to treatment and the respect of the half time for drug administration is very important to ensure better medical support.

Disclosure of Interest: None declared.

240 ISoP18-1359 Drug Sefty: Drug Incompatibilities in Intensive Care

240.1 I. Bennani¹, A. Cheikh², H. Attjioui¹, H. Mefetah³, M. Draoui¹, M. Bouatia^*1

240.1.1 ¹Laboratory of Analytical Chemistry, Faculty of Medicine and Pharmacy of Rabat, University Mohamed V, Rabat, Morocco; ²Departement of Pharmacy, Abulcasis University, Rabat, Morocco; ³Departement of Pharmacy, Pediatrics Hospital, CHIS, Rabat, Rabat, Morocco

Background/Introduction: The administration of incompatible products could indeed cause a change in the appearance of the drug as a precipitate or the inactivation of one or other of the active ingredients. the formation of a precipitate that can obstruct the pathway and prevent the patient from switching to the medication; In addition, if it enters the bloodstream without being solubilized, it can obstruct the blood vessels and cause various problems. As for the inactivation of one product by another, it can cause a decrease in the therapeutic effect of the drug in the presence.

Objective/Aim: The aim is to detect and study the visible physicochemical incompatibilities of injectable drugs in a perfusion commonly used in intensive care unit, by a simulation model to test the behavior of these drugs mixed in an infusion.

Methods: We carried out this experimental in vitro study at the laboratory of analytical chemistry of the Faculty of Medicine and Pharmacy of Rabat and the University Hospital of Ibn Sina Hospital in Rabat.

We selected 10 parenteral drugs most commonly used in intensive care unit. After mixing these drugs with the antibiotics to be tested to reveal the incompatibilities of the drug by visual inspection, and cases of precipitate formation will be analyzed by infrared spectrophotometry to identify their nature.

Results: After mixing the test drugs we revealed several incompatibilities:

Noradrenaline revealed 6 drug incompatibilities.

Midazolam revealed 7 drug incompatibilities.

Hydrocortisone revealed 5 drug incompatibilities.

Furosemide revealed 8 drug incompatibilities.

Diazepam revealed 4 drug incompatibilities.

Sugmmadex revealed 4 drug incompatibilities.

Atropine revealed a single drug incompatibility.

Ephedrine revealed 2 drug incompatibilities.

Neostigmine revealed a single drug incompatibility.

Neostigmine revealed a single drug incompatibility.

Conclusion: This study allowed us to reveal several physicochemical incompatibilities of injectable drugs used in intensive care, it also allowed us to show the validity of the recommendation that prevents the administration of drugs simultaneously infusion.

Disclosure of Interest: None declared.

241 ISoP18-1361 A Framework for Leveraging Emerging Technologies in Pharmacovigilance

241.1 S. Desai^*1, E. Mingle¹, B. Egan¹, R. Gulati¹, J. Freeman¹

241.1.1 ¹Global Drug Safety and Risk Management, Celgene Corp, Summit, United States

Background/Introduction: The pharmaceutical and biotech industry is challenged by continuously increasing volumes of Individual Case Safety Reports (ICSRs). Ongoing regulatory initiatives are mandating expansion in the range of activities falling within the remit of pharmacovigilance (PV) including ADR reporting, signal detection and evaluation, risk management, benefit–risk assessment and communication. Despite the fact that 95% of spontaneous ADRs are never received, there is expectation that the system of pharmacovigilance is powered to quickly identify important Adverse Drugs Reactions and to take action to minimize risk to patients. Maximizing the use of technology is required to enable our future effectiveness.

Objective/Aim: To develop a blueprint of capabilities and a framework to leverage emerging technologies across the pharmacovigilance value chain.

Methods: We conducted a review across a range of PV business processes to assess the impact of increasing ICSR volumes and identify opportunities for automation. Findings were used as input to define a vision and create a blueprint for implementing technology driven capabilities.

We used Human-centered design to refine the vision and blueprint. A cognitive psychologist conducted interviews of pharmacovigilance professionals and used cognitive task analysis (CTA) principles to validate findings from the business process review and match tasks to capabilities.

Leveraging an automation maturity model, we evaluated PV tasks and decisions against the automation spectrum. PV tasks and decisions were mapped to key classes of technologies. For example, to increase efficiency and quality of signal evaluations and automate the deduplication of ICSRs, we identified spark based machine learning as a class of technology to apply.

Results: We established an extensible multi-partner, multi-technology approach. With one partner we secured a large scale multiyear co-development agreement to build an end to end PV system. Additionally, we developed 3 novel Industry-level capabilities covering search, ICSR deduplication and annotation for machine learning in PV. We were able to inform technology selection such as machine learning, natural language generation and Robotic Process Automation, based upon assessment of cognitive load across different PV tasks.

Conclusion: Application of human centered design is a helpful way to identify the right capabilities required across the PV value chain. Automation should be viewed as a spectrum of different approaches enabled by multiple technologies. By leveraging a framework comprised of business and cognitive task analysis and an automation maturity model, it is possible to consistently determine opportunities to correctly apply new and emerging technologies.

References:

• 1. Dal Pan GJ. Ongoing Challenges in Pharmacovigilance. Drug Saf 2013;37:1–8

• 2. Smith MY, Benattia I. The Patient’s voice in pharmacovigilance: pragmatic approaches to building a patient-centric drug safety organization. Drug Saf 2016;39:779–85

• 3. Hazell L, Shakir SAW. Under-reporting of adverse drug reactions. Drug Saf 2006;29:385–96

• 4. The RUMJog Automation Maturity Model [Internet]. RUMJog Enterprises. [cited 2018 Jun 4]. Available from: http://www.rumjog.com/automation

• 5. IBM and Celgene to transform patient safety monitoring [Internet]. IBM—Archives—History of IBM—1880—United States. IBM Corporation; [cited 2018Jun4]. Available from: https://www-03.ibm.com/press/us/en/pressrelease/50927.wss

Disclosure of Interest: S. Desai Shareholder of: Celgene Corp, Employee of: Celgene Corp, E. Mingle Shareholder of: Celgene Corp, Employee of: Celgene Corp, B. Egan Shareholder of: Celgene Corp, Employee of: Employee, R. Gulati Shareholder of: Celgene Corp, Employee of: Celgene Corp, J. Freeman Shareholder of: Celgene Corp, Employee of: Celgene Corp.

242 ISoP18-1362 Ecopharmacovigilance for Better Health in Ghana

242.1 C. Amaning Danquah^*1, A. Yeboah Mensah², K. Ohene Buabeng³, A. Dodoo⁴

242.1.1 ¹Department of Pharmacology, ²Department of Pharmacognosy, ³Department of Pharmacy Practice, Kwame Nkrumah University of Science and Technology, Kumasi, ⁴Africa Collaborating Centre for Pharmacovigilance, Accra, Ghana

Background/Introduction: The twenty-first century has seen thousands of chemicals being used in everyday life, in industry and agriculture, however, massive attention is not being paid to the direct or indirect risk to human health, animal species and on the environment. Globally, an estimated 100,000 tons of antimicrobials are used annually and the world today is bedevilled with antimicrobial resistance, described by the World Health Organisation (WHO) as the single greatest challenge to the control of infectious diseases which affects both rich and poor countries. The widespread detection of a large variety of pharmaceuticals in the environment has raised concerns about the potential impact of these bioactive substances on the environment. Ecopharmacovigilance (defined as the science and activities concerning detection, assessment, understanding and prevention of adverse effects or other problems related to the presence of pharmaceuticals in the environment, that affects both human and animal species; derived from a compromise between an industrialized chemical-based society and the need for the protection of the environment) is the way forward for better health in Ghana and globally [1–4].

Objective/Aim: This research seeks to assess the potential impact of the risk of using human and veterinary pharmaceuticals on the quality of water in the Barekese Dam and catchment area, Ashanti Region of Ghana.

Methods: Analysis of the quality of water and its potential contaminants; a retrospective study of patients’ records to document disease patterns reported at health centres in the area; focused group discussions with health workers, herbal medical practitioners and the public to get first-hand information on disease epidemiology in the area.

Results: Preliminary examination of the quality of water showed the high prevalence of antibiotics, pesticides and traces of veterinary medicines and other pharmaceuticals in the water. Detailed study would inform strategy for public engagement, education and promotion of safe disposal of medicines and the promotion of rational use of drugs to reduce the volume of medicines finding their way into the ecosystem and impacting negatively on the health and life of living organisms in the environment.

Conclusion: Stepping up Ecopharmacovigilance and seeing it as an integral part of pharmacovigilance will help reduce the level of water pollution in the Barekese Dam. The data obtained would inform policy and also change the knowledge, attitude and behaviour of the public on proper disposal of Pharmaceuticals.

References:

• 1. Ternes TA. Analytical methods for the determination of pharmaceuticals in aqueous environmental samples. Trends Anal Chem 2001;20:419–33

• 2. Wise R. Antimicrobial resistance: priorities for action. Antimicrob Chemother 2002;49:585

• 3. Ye Z, Weinberg HS, Meyer MT. Trace analysis of trimethoprim and sulfonamide, macrolide, quinolone, and tetracycline antibiotics in chlorinated drinking water using liquid chromatography electrospray tandem mass spectrometry. Anal Chem 2007;79:1135–44

• 4. Jones OA, Lester JN, Voulvonis N. Pharmaceuticals: a threat to drinking water? Trends Biotechnol 2005;23:163–7

Disclosure of Interest: None declared.

243 ISoP18-1364 Thyroid Dysfunction After Long-Term Treatment by Amiordarone

243.1 I. Bennani¹, R. Soulaymani², A. Tebaa^*2

243.1.1 ¹Faculty of Medicine and Pharmacy of Rabat, University Mohamed V Rabat, Morocco; ²Pharmacovigilance Departement, Poison and Pharmacovigilance center of Morocco, Rabat, Morocco

Background/Introduction: Amiodarone is a potent antiarrhythmic drug that is used to treat ventricular and supraventricular tachyarrhythmias. It is a benzofuran-derived, iodine-rich compound with some structural similarity to thyroxine (T4). Amiodarone contains approximately 37% iodine by weight. Each 200-mg tablet is estimated to contain about 75 mg of organic iodide, 8–17% of which is released as free iodide. Standard maintenance therapy with 200 mg amiodarone can provide more than 100 times the daily iodine requirement. It is highly lipid-soluble and is concentrated in the adipose tissue, muscle, liver, lung, and thyroid gland. 

Objective/Aim: The objective of this work is to study imputability of case with Thyroid Dysfunction after prolonged treatment by amiordarone.

Methods: We report the case of a 60-year-old female patient followed for 5 years for Cardiac arrhythmia treated with amiodarone at the maximum dose of 200 mg/day, admitted to emergency for gastric malaise with convulsive seizures generalized.

The electrocardiogram demonstrated ventricular hyperexcitability and a BAV Mobitz II. Clinical examination revealed good hemodynamics, normal cardiopulmonary auscultation and normal neurological examination.Biological examinations showed an increased Serum thyrotropin (TSH) levels, moderate hypokalaemia, moderate hepatic cytolysis.

In the case of this patient, to determine the imputability of amiodarone we used the French method and that of the WHO.

Results: The timescales for the drug are compatible. Evolution is suggestive and the rechallenge was 0.

There are reliable tests to confirm drug origin: Serum thyrotropin (TSH), scintigraphy.

 In the literature Thyroid Dysfunction with amiodarone is an effect already described.

The imputability score according to the French method was I5B4. According to the criteria of the WHO method, the occurrence of this adverse effect is certainly.

However, the Cases notified at the level of the national pharmacovigilance center concerning amiodarone which are 39 cases. 35% had thyroid dysfunction, of which 63% presnted hyperthyroidism, and 27% presented hypothyroidism.

According to the literature, amiodarone causes a wide spectrum of effects on the thyroid.

Amiodarone inhibits type 1 5′-deiodinase enzyme activity, thereby decreasing the peripheral conversion of T4 to triiodothyronine (T3) and reducing the clearance of both T4 and reverse T3 (rT3). Consequently, the serum levels of T4 and rT3 increase and the serum levels of T3 decrease by 20–25%.

Amiodarone inhibits entry of T4 and T3 into the peripheral tissue. Serum T4 levels increase by an average of 40% above pretreatment levels after 1–4 months of treatment with amiodarone. This, in itself, does not constitute evidence of hyperthyroidism (thyrotoxicosis).

Inhibition of type 2 5′-deiodinase enzyme activity in the pituitary due to feedback regulation is seen in the first 1-3 months and leads to an increase in thyroid-stimulating hormone (TSH) levels. This is not an indication for T4 replacement in these patients. Serum TSH levels return to normal in 2–3 months as T4 concentrations rise sufficiently to overcome the partial block in T3 production. The response of TSH to thyroid-releasing hormone (TRH) may be reduced.

Conclusion: the decision to discontinue Amiodarone with the given adverse reactions should be based on a case-by-case assessment of the benefit/risk and benefit/cost ratio of the extended treatment.

Disclosure of Interest: None declared.

244 ISoP18-1368 Pharmacovigilance of Herbal Medicines: A Systematic Review and Meta-analysis

244.1 C. Kongkaew¹, P. Janusorn¹, P. Mongkhon^*1, C.N. Scholfield¹

244.1.1 ¹Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand

Background/Introduction: The use of herbal products is widespread and increasing rapidly because of their perceived safety. Indeed, a few reports of adverse reactions caused by herbal medicines is emerging.

Objective/Aim: This study aimed to systematically review the herbal medicine reporting mechanisms that do exist, and examine the reporting rates of adverse events (AEs) caused by consumption of herbal medicines.

Methods: The PUBMED/MEDLINE, SCOPUS, EMBASE, CINAHL were searched for relevant studies since their inception dates to 19th August 2017. Observational studies that provided information about the type of reporting systems for adverse reactions and examined the reporting rates of adverse events/experiences associated with herbal medicine were included. The risk of bias in eligible studies was assessed by two independent investigators using Crombie’s items as recommended for prevalence or for cross-sectional studies. The effect estimates with corresponding 95% confidence interval (95% CI) of each study was used to calculate the pooled estimates of reporting rates by the DerSimonian-Laird random-effects model. All analyses were performed using STATA, v14.1.

Results: Overall, 25 studies met the eligibility criteria and were included in the systematic review. Mechanisms used to report the AEs caused by herbal medicines were only spontaneous reporting system (SRS, 18 studies), an intensive monitoring program (IMP) or cohort event monitoring (CEM) only (2 studies), both SRS and IMP (3 studies), and both electronic medical record (EMR) and IMP (2 studies). AEs most commonly involved conditions of skin and appendages, the gastro-intestinal tract, and the nervous system. AEs were common with high total dose of herbal medicine, combination with other medications, and being elderly.

By meta-analytic pooling, the mean prevalence rate of AEs from SRS accounted for 0.35% (95% CI 0.27–0.44%), but highly heterogeneous (χ² = 2973; p < 0.001; d.f. 12; I² = 99.6%). For IMP or CEM methods, the pooled estimates were more prevalent (12.4%, 95% CI, 7.3–17.6%) than SRS but also very heterogeneous (χ² = 10729; p < 0.001; d.f. 3; I² = 100%). However, prevalence rates were strongly influenced by design. The quality of all studies demonstrated the Crombie’s score ranged from 4 to 7.

Conclusion: Herbal medicines were associated with a varied AEs. SRS is the most frequently used tool for signal detection due to herbal medicine consumption, but the number of reports were low and may be underreported. Public awareness and education should be raised to ensure the safe use of herbal products.

Disclosure of Interest: None declared.

245 ISoP18-1372 Serious Adverse Drug Reactions: Experience from the Moroccan Pharmacovigilance Centre

245.1 L. Aït Moussa^*1, R. Benkirane², A. Tebaa¹, R. Soulaymani^1,3

245.1.1 ¹Centre Antipoison et de Pharmacovigilance du Maroc, Rabat, Morocco; ²Ecole Nationale de Santé Publique, ³Faculty of Medicine and Pharmacy. Mohammed V University, Rabat, Morocco

Background/Introduction: Serious adverse drug reactions (ADRs) can be associated with significant morbidity and mortality. Clinical manifestations of ADRs are variable and can be caused by various drugs.

Objective/Aim: To identify and characterize the serious ADRs spontaneously reported in the Moroccan pharmacovigilance centre and to determine the most causative drugs.

Methods: Spontaneous ADRs reports enrolled in the Moroccan Pharmacovigilance database between January 2012 and December 2016 were retrospectively analyzed. A serious ADR was defined as an ADR that is fatal or life threatening, which causes hospitalization or prolongation of hospitalization, or permanent or significant disability, or congenital malformation. Causality was assessed using the WHO-Uppsala Monitoring Centre criteria.

Results: During the 5-year study period, a total of 8353 spontaneous ADRs reports were enrolled in the Moroccan Pharmacovigilance database and 2533 ADRs reports were serious. The majority of serious ADRs cases were reported for female (56.8%). Adults were more concerned (68.8%). The serious ADRs cases experienced ADRs deaths (6.3%), life threatening complications (6.8%), hospitalization (54.11%), disabling (5.5%) and congenital malformation (1.5%). Some patients suffered more than one ADR and the total number of ADRs identified was 3880. According to system organ classification, the classes most often involved were skin and appendage disorders (14.5%), neurological disorders (12.3%) and gastrointestinal disorders (11.6%). The most common classes of drugs involved in ADRs were antineoplastic agents (16.3), antivirals for systemic use (13%) and antimycobacterials (7.5%). 60.7% of the ADRs were assessed as possible. The outcome was favorable in 46.4%.

Conclusion: About 30% of the spontaneous ADRs reports identified in the study period are serious. The skin and appendage disorders were more prevalent and the antineoplastic agents were the most causative drugs involved. The high rate of serious ADRs emphasizes the importance of detecting and reporting ADRs early during treatment in order to improve their management and ensure patient safety.

Disclosure of Interest: None declared.

246 ISoP18-1375 Drug Rash with Eosinophilia and Systemic Symptoms Syndrome in Pediatric Cases

246.1 W. Kaabi¹, G. Lakhoua¹, I. Aouinti¹, F. Zgolli¹, N. Alaya¹, R. Daghfous^*1, S. El Aidli¹, A. Zaiem¹

246.1.1 ¹Service de recueil et d’analyses des effets indésirables des médicaments, Centre National de Pharmacovigilance, Tunis, Tunisia

Background/Introduction: Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is a serious and rare toxidermia in children. It is characterized by the combination of skin damage, visceral involvement, eosinophilia, fever and lymphadenopathy.

Objective/Aim: To identify the clinical and epidemiological characteristics of DRESS syndrome in children, as well as the most incriminated drugs.

Methods: This was a retrospective study of 16 children who had a DRESS syndrome and were notified to the Tunisian national center of pharmacovigilance between January 2010 and December 2017. All the files were scored according to the RegiSCAR criteria for the diagnostic of DRESS syndrome and analyzed according to the French updated method for the causality assessment of adverse drug reactions.

Results: Sixteen cases were retrieved, with a female predominance (62.5%) and an age that varied between 1 and 18 years. Four patients were epileptic. The delay between the drug intake and the occurrence of symptoms varied from 5 days to 6 weeks with an average of 3 weeks. Fever was noted in 15 cases and lymphadenopathies in 10 cases. The cutaneous lesions were found in all the patients. Eleven cases (68.75%) had maculopapular rash, 4 cases (25%) had erythematous eruption and 1 case (6.25%) had morbilliform eruption.Three cases (18.75%) had mucosal involvement. The visceral disorders found were: liver damage in 12 cases, muscle damage in one case. Laboratory findings showed eosinophilia in 10 patients and positive serology of herpes virus in 1 patient.

The DRESS score was possible in 9 cases, probable in 6 cases and definite in 1 case.

Incriminated drugs were antiepileptic drugs (11 cases), antibiotics (4 cases) and immunosuppressive drug (1 case).

We have contra-indicated the offending drugs for the 16 children.

Conclusion: Our work pointed out similar epidemiological and clinical features in DRESS syndrome between children and adults. The withdrawal of the culprit drug as soon as possible is recommended to limit the injuries.

Disclosure of Interest: None declared.

247 ISoP18-1377 Adverse Drug Reactions Arising from the Use of the Products Outside the Terms of the Marketing Authorisation

247.1 N. Mirošević Skvrce^*1, I. Mucalo², I. Galić¹, C. Pacadi³, N. Kandzija⁴

247.1.1 ¹Agency for Medicinal Products and Medical Devices; ²Centre for Applied Pharmacy, Faculty of Pharmacy and Biochemistry; ³Mandis Pharm community pharmacies, Zagreb, Croatia; ⁴Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, United Kingdom

Background/Introduction: New European (EU) pharmacovigilance (PV) legislation, introduced in 2012, widened the scope of an Adverse Drug Reactions definition so that it also includes noxious and unintended response to a medicinal product arising from the use outside the terms of the marketing authorisation (MA), whereby the use outside the MA also includes off-label use, overdose, misuse, abuse and medication errors (MEs).

Objective/Aim: To describe ADRs arising from the use outside the terms of the MA reports in the Croatian pharmacovigilance database.

Methods: A retrospective, observational study of the HALMED PV database. The outcome measure included ADRs arising from the use of the products outside the terms of the MA. An assessment was performed based on the information provided in a reference document, an SmPC, on a case-by-case basis, using predefined criteria.

Results: Among 679 ADRs included in the analysis, 162 (23.9%) ADR reports were related to the use outside of the MA, 370 (54.5%) were related to the use within the MA and 147 (21.6%) were adjudged as not-assessable. Majority were due to medication errors (N = 155). Off-label use was identified in 87 reports, while misuse and overdose were identified in 11 and 39 reports, respectively. There were no reports of abuse among the analysed reports. In only 27 out of 128 reports (21.09%), reporters recognized an ADR as a consequence of use outside MA.

Conclusion: The main observation derived from this study was a rather high proportion of ADR reports that arise from the medicinal product use outside the use of MA. Moreover, a considerable portion of ADRs outside the terms of the MA was not-assessable nor recognized by a reporter, suggesting the need for targeted education and improving reporting systems, since forms currently used were not designed for reporting ADRs outside the MA.

Disclosure of Interest: None declared.

248 ISoP18-1378 Visual Disturbances Associated with Voriconazole

248.1 S. Ben Hammamia¹, I. Souilem¹, A. Zaiem¹, G. Lakhoua¹, S. El Aidli¹, R. Daghfous^*1, S. Kastalli¹

248.1.1 ¹Pharmacovigilance National Center, Tunisia. University Tunis El Manar, Tunis, Tunisia

Background/Introduction: Voriconazole is an azole antifungal agent, used to treat or prevent invasive fungal infections. This antifungal agent is highly efficacious; however, the major limitation of voriconazole is the risk of adverse events (AE) such as hepatotoxicity and neurotoxicity. These AE lead usually to drug withdrawl and can cause therapeutic failure.

Objective/Aim: We report two cases of neurological AE which consist in visual trouble.

Methods: These cases were notified to National Center of Pharmacovigilance and were analyzed according to the French updated method for the causality assessment of adverse drug reactions [1].

Results: Case 1

A 52-year-old male treated with hematopoietic stem cell transplant on June 2015 for myeloma, was prescribed voriconazole at the dose of 500 mg per day. Few hours later, he developed visual disorders including dyschromatopsia. The evolution was marked by the regression of the symptomatology, 4 days after stopping the drug.

Case 2

A 28-year old man treated with hematopoietic stem cell transplant on December 2017 for Hodgkin’s lymphoma, was prescribed intravenous voriconazole at the dose of 340 mg twice a day to treat pulmonary aspergilosis. Thirteen days later, he reported visual disturbances: he described the occurrence of dazzling light and hallucination during the hour following the drug injection. The treatment was relayed orally, at the dose of 200 mg twice a day, but the symptoms persisted. He even had a car accident because of these symptoms. Voriconazole was stopped on 14th January and the symptoms disappeared. 

Conclusion:

Visual troubles associated with voriconazole were reported to be transient and totally reversible: They usually disappear spontaneously in 60 min and no clinically significant visual persisting effects were observed [2].

However, cases of prolonged visual adverse events have been reported, during use after marketing [4].

This effect may be dose dependant [3]. Though, dosage adjustment based on blood dosage, seems to be a good approach.

The mechanism is unknown, although the site of action is likely to be in the retina [5].

References:

• 1. Arimone Y, Bidault I, Dutertre J-P, et al. Updating the French method for the causality assessment of adverse drug reactions. Thérapie. 2013;68:69–76

• 2. Zrenner E, Tomaszewski K, Hamlin J, et al. Effects of multiple doses of voriconazole on the vision of healthy volunteers: a double-blind, placebo-controlled study. Ophthalmic Res 2014;52:43–52

• 3. Zonios DI, Gea-Banacloche J, Childs R, et al. Hallucinations during voriconazole therapy. Clin Infect Dis 2008;47:e7–e10

• 4. Mounier A, Agard E, Douma I, et al. Macular toxicity and blind spot enlargement during a treatment by voriconazole: a case report. Eur J Ophthalmol 2018;28:NP11–4

• 5. Xiong WH, Brown RL, Reed B, et al. Voriconazole, an antifungal triazol that causes visual side effects, is an inhibitor of TRPM1 and TRPM3 channels. Invest Ophthalmol Vis Sci 2015;56:1367–73

Disclosure of Interest: None declared.

249 ISoP18-1380 Reports of Adverse Events with Levonorgestrel Iud Mirena^® in France Before and After the 2017 Media Intense Coverage

249.1 C. Langlade¹, A. Gouverneur¹, P. Bosco-Lévy¹, A. Gouraud², M.-C. Pérault-Pochat³, J. Béné⁴, G. Miremont-Salamé^*1, A. Pariente¹

249.1.1 ¹CHU de Bordeaux, Bordeaux, France; ²CHU de Lyon, Lyon, France; ³CHU de Poitiers, Poitiers, France; ⁴CHU de Lille, Lille, France

Background/Introduction:

Intra-Uterine Device (IUD), amongst which levonorgestrel Mirena^®, is the second most used contraception method in France. In 2017, concerns on adverse events (AEs) associated with Mirena^® were echoed in French media, first in social networks, then in traditional medias. The media coverage peak occurred in May 2017, which resulted in a tremendous wave of reporting of AEs from patient to French Pharmacovigilance Centres. Noticeably, this reporting mainly used the newly launched web-portal for the reporting of AEs whatever the cause.

Objective/Aim: To describe AEs reported for Mirena^®, before and after the media coverage peak.

Methods: All reports involving Mirena^® (marketed in France: July 1995) recorded in the French national pharmacovigilance database were extracted on August 4th, 2017. Reports were analyzed according to two periods: before and after the media coverage peak of May 2017. AEs were analyzed by System Organ Classes (SOC), and Preferred Term (PT) according to the MedDRA classification. Disproportionality analyses were performed on reporting that preceded the media peak.

Results: Among 3224 included cases, 510 (16%) were recorded before and 2714 (84%) after the media peak. Patients median age was similar between both periods (37 vs 36 years). Most of the cases were serious: 53% before and 66% after the peak. Before the peak, 77% were reported by health professionals and 55% were considered serious because of “Caused/Prolonged hospitalization”. After it, 93% were reported by patients and 55% were considered serious because of “Other serious medical situation”. The number of PT and SOC by case increased between the two periods, with a mean of respectively 2.4 and 1.9 before vs 7.2 and 5.0 after the peak.

Before the peak, ectopic pregnancy and drug lack of efficacy were among the most frequently reported AEs. After the peak, most frequent AEs were depression (38 vs 10% before), anxiety (31 vs 5%), migraine (22 vs 5%), alopecia (29 vs 9%) or loss of libido (47 vs 7%). Disproportionalities identified 15 new signal, notably asthenia (20 cases), arthralgia (9 cases) and erythema nodosum (6 cases).

Conclusion: This study highlighted many differences of AE reports involving IUD Mirena^® before and after the peculiar media peak that occurred in May 2017 in France for this health product: nature and number of reported AEs, type of reporter, and seriousness criteria of reports. Disproportionality analyses performed in the first period led to identify 15 potential safety signals.

Disclosure of Interest: None declared.

250 ISoP18-1381 Time to Onset of Adverse Reactions Induced by Artesunate and Amodiaquine Combination in DRC

250.1 G. Nsimba^*1, P. Ntamabyaliro¹, N. Didier¹, G. Tona¹

250.1.1 ¹Clinical Pharmacology and PharmacovigilanceUnit, Kinshasa, The Democratic Republic of the Congo

Background/Introduction: Artesunate and amodiaquine combination is an artemisinin-combined therapy (ACT) that has been recommended as a first-line in the treatment of uncomplicate malaria [1, 2]. However, adverse drug reactions to this combination may affect patients health, reduce compliance and lead to therapeutic failure [3]. To determine the Time To Onset (TTO) of this combination may give to health professionnal informations of ADRs occurrence because the information is poorly documented [2].

Objective/Aim: The aim of this study is to evaluate the time to onset of adverse reactions to artesunate and amodiaquine combination from the DRC spontaneous reporting database.

Methods: Reports of adverse reactions to the artesunate and amodiaquine combination entered into Vigibase™ from January to December 2016 in DRC were indentified. ADRs were classified according MedDRA^® including the System Organ Class and Preferred Terms.

Time to onset (TTO) of was calculated as the date of ADRs occurence minus the date of drug administration.  Median of TTO ADRs occurence was calculated between the first day of starting treatment to the fourth day, median of TTO ADRs occurence was on second day. To determine TTO of ADRs gave more informations to heath professionnal to inform patients that may increased they compliance.

Results: A total of 288 ADRs were recorded of which:

• Body as a whole-general disorders (n = 86, 29.8%) of which the time to onset of 58.1% ADRs occurred on second day of treatment. Asthenia were the most frequent ADRs reported with 47 cases reports (57.3%).

• Gastrointestinal disorders (n = 75, 26%) of which the time to onset of 49.3% occurred on second day of treatment. Vomiting were the most frequent ADRs reported with 48 cases (64%).

• Skin and appendages disorders (n = 36, 12.5%) of which the time to onset of 72.2% occurred on second day of treatment. Pruritus were the most frequent ADRs reported with 25 cases (69.4%).

• Neurological disorders (n = 36, 12.5%) of which the time to onset of 61.1% ADRs occurred on second day of treatment. Dizziness were the most frequent ADRs reported with 33 cases (91.6%).

• Psychiatric disorders (n = 29, 10%) of which the time to onset of 75.8% ADRs occurred on second day of treatment. Anorexia were the most frequent ADRs reported with 20 cases (68.9%).

• Cardiovascular disorders (n = 13, 4.5%) of which the time to onset of 46.1% ADRs occurred on third day of treatment. Palpitation were the most frequent ARDs with 7 cases, 53.8%.

• Musculoskeletal disorders (n = 7, 2.4%) of which the time to onset of ADRs were equal on first, second and third day of treatment with 28.5% each one. Myalgia were the most frequent ADRs reported with 4cases, 57.1%.

• Other ADRs was less then 1% of which:Hearing, vestibular and special senses disorders (n = 2, 0.6%). Metabolic and nutritional disorders (n = 1, 0.3%), Immune disorders and infections (n = 1, 0.3), Blood disorders (n = 1, 0.3%), Reproductive disorders (n = 1, 0.3%).

Conclusion: This cases reports showed that the time to onset of the most ADRs induced by artesunate and amodiaquine combination occurred on the second day of treatment.

References:

• 1. McEwen, J. Artesunate- and amodiaquine-associated extrapyramidal reactions: a weries of 49 cases in VigiBase. Drug Saf 2012;35:667–75

• 2. Le Garlantezec P, Richard C. Treatment of imported Plasmodium falciparum malaria: role of the combination of dihydroartemisinin and piperaquine. MedSante Trop 2015;25:136–40

• 3. D’allession A, Fraschetti R, Celleno L, et al. Biologic drugs and psoriasic: the influence of adverse drug reactions on patients compliance and therapeutic. Abstract code: ISP3412-38.

Disclosure of Interest: None declared.

251 ISoP18-1385 Drug-Related Problems in Hospitalised Patients with Chronic Kidney Disease: A Systematic Review

251.1 A. Cox¹, V. Paudyal¹, W. Alruqayb^*1

251.1.1 ¹School of Pharmacy, University of Birmingham, Birmingham, United Kingdom

Background/Introduction: Inappropriate medication use may result in drug-related problems (DRPs) causing life-threatening conditions or even death [1], most of which are preventable [2]. Chronic kidney disease (CKD) is considered a worldwide public health issue due to the high percentage of global prevalence and its influence on patients. Patients with CKD are susceptible to DRPs due to polypharmacy and reduced drugs excretion [3]. Although inappropriate medication use in renal patients in the non-hospitalised setting has been investigated [4], there is no systematic review on DRPs in hospitalised patients with CKD.

Objective/Aim: To investigate the prevalence of DRP among hospital in-patients with CKD, including risk factors, patients’ characteristics and most common contributor drug classes.

Methods: A systematic review of the literature was conducted using eight databases; Medline, EMBASE, PsycINFO, Web of Science (Core Collection), CINAHL plus (EBSCO), Cochrane Library (Wiley), Scopus (ELSEVIER) and PubMed (USNLM). Studies investigated any type of DRPs in hospitalised patients (i.e. during hospital episodes) and contained data on CKD were included. Studies were excluded if investigating DRP as a cause of admission/readmission, primary focus is pharmacokinetics. Abstract only publications, grey literature, reviews, and meta-analyses were also excluded. Searches were restricted to human participants and English language. Two independent reviewers critically appraised the eligible articles for the systematic review using a tool that has been developed to examine the quality of the prevalence studies across different designs [5]. Meta-analysis will be conducted to analyse the results if similar outcomes and methods of assessment are identified. Heterogeneity level will be measured by the random effects methods, where, I² value and 95% Confidence Interval will show statistical heterogeneity. This systematic review has been pre-registered at Prospero [6].

Results: 1756 unique titles were identified. Up to now, 1220 titles have been screened and 62 abstracts have been included for full text screening. The final data synthesis from included papers will be narratively summarised by publication year, age range, prevalence of DRPs in hospitalised patients who have CKD, such as patients’ characteristics (age and gender), DRPs prevalence, stages of CKD and risk factors.

Conclusion: This review will synthesise and critically appraise the current knowledge on DRPs among hospitalised patients with chronic kidney disease.

References:

• 1. Adusumilli P, Adepu R. Drug related problems: an overview of various classification systems. Asian J Pharm Clin Res 2014;7:7–10

• 2. Patel NS, Patel TK, Patel PB, Naik VN, Tripathi C. Hospitalizations due to preventable adverse reactions—a systematic review. Eur J Clin Pharmacol 73:385–98

• 3. Levin A., Tonelli M, Bonventre J, Coresh J, Donner J-A, Fogo AB, et al.Global Kidney Health 2017 and beyond: a roadmap for closing gaps in care, research, and policy. Lancet. 2017;390:1888–1917

• 4. Dörks M, Allers K, Schmiemann G, Herget‐Rosenthal S, Hoffmann F. Inappropriate medication in non‐hospitalized patients with renal insufficiency: a systematic review. J Am Geriatr Soc 2017;65:853–62

• 5. Munn Z, Moola S, Riitano D, Lisy K. The development of a critical appraisal tool for use in systematic reviews addressing questions of prevalence. Int J Health Policy Manag 2014;3:123–8

• 6. Alruqayb W, Paudyal V, Cox A. Drug-related problems in hospitalised patients with chronic kidney disease: a systematic review protocol. PROSPERO 2018 CRD42018096364 Available from: http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018096364 (accessed on the 1st June 2018

Disclosure of Interest: None declared.

252 ISoP18-1386 Safety and Efficacy of Tolvaptan in the Suisse Adpkd Cohort

252.1 S. Russmann^*1,2,3,4, E. Grimes², D. Niedrig^1,5, V. Niggemeier⁴, M. Yilmaz⁴, A. Kaegi^4,6, H. Kovari^4,6, A. Serra⁴

252.1.1 ¹drugsafety.ch, Küsnacht, ²Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich, Zurich, Switzerland; ³Epidemiology, Boston University School of Public Health, Boston, United States; ⁴Internal Medicine and Nephrology, Clinic Hirslanden, ⁵Hospital Pharmacy, University Childrens’ Hospital, ⁶Infectious Diseases and Hospital Hygiene, University Hospital Zurich, Zurich, Switzerland

Background/Introduction: Tolvaptan is the first drug with proven efficacy in patients with autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan delays disease progression and was approved in Switzerland in April 2016. Due to rare cases of liver injury approval was granted under the requirement of monitoring hepatotoxicity. Furthermore, initial apparent decreases in estimated glomerular filtration rate (eGFR) that are reversible after stop of tolvaptan have been observed [1–3].

Objective/Aim: The aim of the current study was to report the first 1-year safety and efficacy data of tolvaptan in patients with ADPKD in clinical practice.

Methods: We identified all patients treated with tolvaptan within the SUISSE ADPKD cohort. Time course of eGFR was followed at baseline before start of tolvaptan and monthly thereafter. We calculated the delta of eGFR from baseline to the first visit after start of tolvaptan, and the slope of a simple linear regression beginning 11 weeks after start of tolvaptan. For the hepatic safety evaluation, we followed the time course of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), and total bilirubin (TB) at baseline and monthly thereafter, and we used an eDISH plot for the screening of possible drug-induced serious hepatotoxicity [4]. Data management and analysis were performed using Stata 15.0 statistical software.

Results: We analyzed 76 patients who started treatment with tolvaptan. Baseline eGFR was 68.6 ± 25.9 ml/min/1.73 m², and median follow-up time after start of tolvaptan was 35.4 weeks. The median and mean ± SD of delta eGFR from baseline to first visit 4 weeks after start of tolvaptan was − 5.8 and − 5.6 ± 0.8 ml/min/1.73 m² (95% CI − 7.1 to − 4.1], respectively. At the end of follow-up after start of tolvaptan eGFR values remained stable, i.e., the mean ± SD slope of the linear regression for eGFR was 0.005 ± 0.069 ml/min/1.73 m² (95% CI − 7.075 to 0.143). There were no patients meeting Hy’s law criteria (ALT > 5× ULN and total bilirubin > 2× ULN).

Conclusion: The efficacy and safety of tolvaptan in ADPKD patients was overall comparable to results from the pivotal clinical trials supporting favorable efficacy and hepatic safety. Nevertheless, longer follow-up of our cohort will be required to reliably evaluate the efficacy and safety profile of tolvaptan in clinical practice.

References:

• 1. Irazabal MV, et al. Imaging classification of autosomal dominant polycystic kidney disease: a simple model for selecting patients for clinical trials. J Am Soc Nephrol 2015;26:160–72

• 2. Torres VE, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med, 2012;367:2407–18

• 3. Torres VE, et al. Tolvaptan in later-stage autosomal dominant polycystic kidney disease. N Engl J Med, 2017;377:1930–42

• 4. WatkinsPB, et al., Clinical pattern of tolvaptan-associated liver injury in subjects with autosomal dominant polycystic kidney disease: analysis of clinical trials database. Drug Saf 2015;38:1103–13

Disclosure of Interest: None declared.

253 ISoP18-1387 Patch-Tests in the Exploration of Late Toxidermias

253.1 S. Ben Hammamia¹, A. Zaiem¹, I. Souilem¹, O. Charfi¹, H. Zehani¹, S. El Aidli¹, R. Daghfous^*1, S. Kastalli¹

253.1.1 ¹Pharmacovigilance National Center, Tunisia. University Tunis El Manar, Tunis, Tunisia

Background/Introduction: Pharmacovigilance analysis remain, in many cases, non-conclusive. Patch tests are of great benefit in delayed toxidermias. The safety of these tests as well as their reproducibility, makes them an essential diagnostic argument to Pharmacovigilance investigations.

Objective/Aim: To study the epidemiological and clinical characteristics of patients in whom patch tests were performed.

Methods: Our study was retrospective, performed over a period of 7 years from January 2010 to February 2017. It was based on late toxidermias cases, notified to the Pharmacovigilance Center during this period, and in whom, we practiced patch-tests. The patches were prepared and read according to the recommendations of the International Contact Dermatitis Research Group (ICDRG).

Results: The study included 92 patients: 55 women and 37 men. The median age was 42 years old.

The toxidermias notified were: fixed drug eruption (FDE) (42 cases), maculopapular exanthema (MPE) (37 cases), PEAG (4 cases), DRESS (3 cases), erythema multiforme (2 cases), eczema (2 cases) and urticaria (2 cases).

Of the 92 cases investigated, 37 tests were positive.

Of the 42 cases of FDE investigated, 14 patches were positive, mainly to paracetamol in 7 cases. For the 37 cases of MPE, 18 were positive. For the 4 cases of PEAG, 3 were found positive. For the other toxidermias (DRESS and urticaria with edema) only 2 cases were found to be positive (for carbamazepine and amoxicillin). Concerning the patients having presented erythema multiforme and eczema, the tests were negative.

In our series, the most positivities were found with paracetamol (7 cases) and amoxicillin (4 cases). The most incriminated drug classes were antibiotics (14 cases) and non-steroidal anti-inflammatory drugs (14 cases).

Conclusion: Despite the low positivity rate and the small sample size, patche-tests remain an interesting way to complement the pharmacovigilance survey in case of late toxidermias.

Other studies on these tests, complementary to ours, adapted to the Tunisian population and its specificities, remain to lead, for a better indication to these tests and thus, ensure their effectiveness.

Disclosure of Interest: None declared.

254 ISoP18-1389 Safety Profile of Ombitasvir/Paritaprevir/Ritonavir/Dasabuvir, With or Without Ribavirin, in Romania: An Analysis of Vigibase^®/WHO

254.1 I. Cazacu^*1, R. Stroe², R. Dondera², C. Mogosan¹

254.1.1 ¹Pharmacology, Physiology and Pathophysiology, Faculty of Pharmacy, University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania; ²Pharmacovigilance and Risk Management Service, National Agency for Medicines and Medical Devices, Bucharest, Romania

Background/Introduction: Direct antiviral agents (DAAs) represent a major clinical advance in the era of hepatitis C treatment by achieving sustained virologic response. DAAs therapy with ombitasvir/paritaprevir/ritonavir/dasabuvir, with or without ribavirin, for patients with chronic HCV and cirrhosis patients, is reimbursed by the national insurance system in Romania.

Objective/Aim: The aim of the present study was to review the safety profile of these DAAs in the management of hepatitis C in patients in Romania.

Methods: An extraction of WHO global individual case safety reports (ICSRs) from VigiBase was performed on 1^st February 2018, which included all adverse event (AE) reports from Romania of the suspected therapy ombitasvir/paritaprevir/ritonavir/dasabuvir. A descriptive analysis was performed on patients’ demographic data, AE according to MedDRA terminology and associated medication.

Results: A total of 1102 ICSRs were retrieved for Romania and among them, 260 were serious (23.6%) and 33 fatal (2.9%). Patients had a 64 years median age (range 24–88, unknown for 32.5% of the patients) and there were more woman (n = 761, 69%) than man (n = 314, 28.5%); the gender was unknown for 2.5% of the patients. Associated medication included ribavirin (49.5%), metoprolol (12.3%), candesartan (7.8%) and indapamide (7.4%).

There were totally 4608 AEs reported. According to System Organ Class (SOC), most frequently AE were General disorders and administration site conditions (43.8%), Gastrointestinal disorders (42%), Nervous system disorders (40.6%) and Skin and subcutaneous tissue disorders (35.6%). Most frequently Preferred Terms (PT) reported were Pruritus (27.9%), Fatigue (22.5%), Dizziness (18.0%) and Headache (15.9%).

Most frequently reported AE in women, by SOC, were Gastrointestinal disorders (46%) and General disorders and administration site conditions (44.2%). In men, General disorders and administration site conditions (43.9%) and Nervous system disorders (37.9%) were the most frequently SOC reported. With reference to age, there were 123 serious AE (22.5%) reported in patients aged < 70 years (n = 546) and 71 (35.8%) in patients ≥ 70 years old (n = 198).

Conclusion: In our study, the cases reported for the combination ombitasvir/paritaprevir/ritonavir/dasabuvir, with or without ribavirin, included serious AE, with more cases in woman than men. Gastrointestinal disorders were the most frequent AE reported in woman and nervous system disorders in men. More serious AE were reported in patients aged ≥ 70 years. Direct antiviral agents represent one of the elective therapies recommended by international guidelines, but not without serious AE that must be considered.

Disclosure of Interest: None declared.

255 ISoP18-1392 Dress Syndrome Associated with Amphotericin-B in a Kidney Transplant Patient

255.1 S. Ben Hammamia¹, O. Charfi¹, I. Souilem¹, I. Aouinti¹, R. Daghfous^*1, S. El Aidli¹, A. Zaiem¹, S. Kastalli¹

255.1.1 ¹Pharmacovigilance National Center, Tunisia. University Tunis El Manar, Tunis, Tunisia

Background/Introduction: Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a severe drug-induced hypersensitivity syndrome. It is commonly associated with aromatic antiepileptic drugs, sulfonamides, gold derivatives, cyclines and allopurinol. Liposomal amphotericin-B had been exceptionally associated with DRESS syndrome.

Objective/Aim: Herein, we report an exceptional case of DRESS syndrome associated with liposomal amphotericin-B in a kidney transplant patient.

Methods: This case was notified on March 22th 2018 and was analyzed according to the frensh updated method for the causality assessment of adverse drug reactions [1].

Results: A 31-year-old male, renal transplant on April 2014, under azathioprine and tacrolimus since then, developed visceral leishmaniasis on February 24th 2018. He was prescribed liposomal amphotericin-B, 5 mg/kg per cure (3 days in a row then 1 cure every week).

Seventeen days after starting the treatment, he presented with pruritic and purpuritic generalized maculopapular skin eruption.

The laboratory findings showed high liver enzymes level: alanine aminotransferase (ALT) at 289 U/L (5.2 N) and aspartate aminotransferase (AST) at 51 U/L (1.5 N). Renal tests and eosinophilia were at normal range.

Serologies of cytomegalovirus, varicella/zoster and Epstein Barr virus were negative. IgM and IgG of herpes simplex virus were positive.

Histological findings were compatible with DRESS syndrome.

Liposomal amphotericin-B was stopped. Skin condition improved and laboratory parameters returned to normal rates within a month.

The diagnosis of DRESS syndrome associated with amphotericin-B was made in this patient based on the criteria adopted by the European group RegiSCAR. In our case, the RegiScar score was 2 (possible case).

Amphotericin-B was suspected to be the responsible drug for the DRESS syndrome in this case based on the French method of imputation. The score was I2 (possible) in front of the suggestive delay and the favorable evolution after drug withdrawal.

To our knowledge, this is the second case of DRESS syndrome with liposomal amphotericin-B.

Indeed, a case of DRESS syndrome induced by amphotericin B with positive rechallenge was reported in literature. Symptoms appeared 45 days after starting the treatment. This patient presented with fever, skin rash and exanthema of the trunk, arms and legs, cervical and inguinal lymphadenopathy [2].

Conclusion: DRESS syndrome, although rare with Liposomal amphotericin-B, should not be overlooked. The discontinuation of the culprit drug should be considered.

References:

• 1. Arimone Y, Bidault I, Dutertre J-P, et al. Updating the French method for the causality assessment of adverse drug reactions. Thérapie 2013;68:69–76

• 2. Hagihara M, Yamagishi Y, Hirai J, et al. Drug-induced hypersensitivity syndrome by liposomal amphotericin-B: a case report. BMC Res Notes 2015;8:510

Disclosure of Interest: None declared.

256 ISoP18-1393 Massive Bilateral Pulmonary Embolism Induced by Estradiol

256.1 S. Ben Hammamia¹, I. Aouinti¹, I. Souilem¹, G. Lakhoua¹, S. El Aidli¹, R. Daghfous^*1, A. Zaiem¹, S. Kastalli¹

256.1.1 ¹Pharmacovigilance National Center, Tunisia. University Tunis El Manar, Tunis, Tunisia

Background/Introduction: Pulmonary embolism (PE), a sudden thrombosis in a lung artery, is usually caused by a blood clot migrating from deep vein thrombosis. Several risk factors predispose to thromboembolic disorders, among which we mention estrogenic treatment.

Objective/Aim: We report a case of massive bilateral pulmonary embolism in young healthy women induced by estradiol treatment.

Methods: This case was notified on May 8th 2018 and was analyzed according to the French updated method for the causality assessment of adverse drug reactions [1].

Results: A 32 year-old female, without a medical history, was treated by a hormonal treatment (dydrogesterone 20 mg per day during 5 days and β-estradiol 2 mg per day) during 2 days, for adenomyotic uterus and metrorrhagia. Six days later, the patient suffered from chest pain. She consulted the emergencies. A CT pulmonary angiogram showed proximal bilateral pulmonary embolism. She was hospitalized and treated by heparinotherapy. The outcome was favorable.

The responsibility of estradiol was suspected in this case, based on chronological, semiological, and especially bibliographic criteria. In fact, the PE occurred in our patient following the hormonal treatment and no other thromboembolic risk factors was found. Moreover, estradiol is known to induce thrombo-embolic complications; but this manifestation has not been reported with dydrogesterone.

In the published literature, similar cases have been often described, since the early sixtees, especially with combined oral contraceptives (COCs) [2].

According to most studies, the thrombo-embolic risk increases with increasing estrogen dose and is highest in the first year of use. The third generation of COCs (containing desogestrel, gestodene or norgestimate) seem to be more thrombogenic than for COCs from the second generation (containing levonorgestrel) or than for the progestogen-only pill [2, 3].

The thromboembolic risk disappears spontaneously after withdrawal of the treatment [4].

Conclusion:

We recall through our case that hormonal treatment could lead to severe thrombo-embolic complications which could be fatal. Thus, it is important that physicians prescribe hormonal treatment with the lowest possible dose of ethinylestradiol. They should also inform patients about the potential risks of estrogenic and COC treatments, and assess preexisting thrombo-embolic risk factors to detect contraindications. Moreover, physician must be aware about this complication to start therapeutic management precociously and stop hormonal treatment.

References:

• 1. Arimone Y, Bidault I, Dutertre J-P, et al. Updating the French method for the causality assessment of adverse drug reactions. Thérapie 2013;68:69–76

• 2. de Bastos M, Stegeman BH, Rosendaal FR, et al. Combined oral contraceptives: venous thrombosis. Cochrane Database Syst Rev. 2014;3:CD010813

• 3. Meier CR. Health risks of oral contraceptives. Ther Umsch Rev Ther 2011;68:345–52

• 4. Abet D, Pietri J. Portal and superior mesenteric venous thrombosis secondary to oral contraceptive treatment. Two cases. J Mal Vasc 1982;7:59–63

Disclosure of Interest: None declared.

257 ISoP18-1394 Pharmacovigilance in Sudan: An Overview

257.1 M. Mousa¹, S. Mohamed ¹, D. A.Alrhman¹, E. Mohamed Alhabib¹, W. A.alghafar¹, R. Osman¹, A. Abbas², S. Hassan^*1, M. Albashir ¹, T. Yousif³, H. Elkheir⁴

257.1.1 ¹Pharmacovigilance Center, National Medicine and Poison Board, Khartoum, Sudan; ²Countess of Chester Hospital NHS, Chester Hospital, London, United Kingdom; ³National Medicine and Poison Board,Khartoum, Sudan; ⁴Head of Pv National Committee NMPB, Omdurman Islamic University, Khartoum, Sudan

Background/Introduction: Under-reporting of Adverse Drug Reactions (ADRs) is a major public health concern globally. Sudan is a low income sub-Saharan country with limited economic resources and a high disease burden and similar to other developing countries, until recently, Pharmacovigilance was not a top priority [1]. Sudan is a full member of the WHO International Drug Monitoring Program via the Uppsala Monitoring Centre (UMC) since 2008. A campaign was started by the Sudan National Medicines and Poisons Board (NMPB) in November 2017 to increase awareness of reporting ADRs amongst healthcare professionals and the public to improve ADR reporting rates. The Suspected Adverse Drug Reaction (ADR) form was developed using the Arab Good Pharmacovigilance Practice (GVP) guidelines. These forms were then made available in health institutions in print form and also online via the NMPB website.

Objective/Aim: To demonstrate the steps taken by the Sudan NMPB towards implementing an active drug safety surveillance program aimed at enhancing detection of ADRs and potential harm from Medication Errors (MEs).

Methods: Targetted pharmacovigilance training sessions using WHO commissioned materialwere launched at 10 focal teaching governmental hospitals and 3 private hospitals. Hospital pharmacovigilance teams were formed and team champions were appointed. The aim is to stimulate benchmarking and encourage individual hospitals to monitor ADR reporting performance. This was based on a model which delivered a successful outcome in a UK hospital [2].

An intensive campaign aimed at raising awareness of the general public to report ADRs was also launched in the media. A telephone call centre service was recently operationalised to motivate the public to report directly.Specific locations for drop boxes for ADR reports to be collected by focal persons were publicised as a form of public–private partnerships. Service Level Agreements with the state medicines information centres are also considered.Contact with the UMC was re-established to initiate the Vigiflow reporting system.

Results: The number of ADR reports receivedincreased significantly and are currently being reviewed prior to uploading via Vigiflow.

Conclusion: Improvement of ADR reporting activity requires a multi-disciplinary approach incorporating the use of team champions, publicity campaigns, more efficient use of technology and periodical tailored training and feedback.

References:

• 1. Pirmohamed M, Doddo, A. Pharmacovigilance in developing countries. BMJ. 2007;335:462

• 2. Abbas A. The Chester Experience. PIPELINE, JPharma Inform Pharmacovigi Assoc, (55) 20–2

Disclosure of Interest: M. Mousa Employee of: National medicine and poison board, S. Mohamed Employee of: National medicine and poison board, D. A.alrhman Employee of: National medicine and poison board, E. Mohamed alhabib Employee of: National medicine and poison board, W. A.alghafar Employee of: National medicine and poison board, R. Osman Employee of: National medicine and poison board, A. Abbas Consultant for: National medicine and poison board, S. Hassan Employee of: National medicine and poison board, M. Albashir Employee of: National medicine and poison board, T. Yousif Employee of: National medicine and poison board branch of Khartoum state, H. Elkheir Consultant for: Omdurman Islamic University.

258 ISoP18-1396 Seizures Followings Immunization: About 27 Cases

258.1 C. Ladhari¹, G. Lakhoua¹, F. Zgolli¹, I. Aouinti¹, O. Charfi¹, I. Hamza¹, H. Zayeni¹, S. El Aidli¹, R. Daghfous^*1, A. Zaiem¹

258.1.1 ¹Centre National de Pharmacovigilance de Tunis, Tunis-Bab Souika, Tunisia

Background/Introduction: Vaccines are one of the major tools for preventing infectious and viral diseases. However, some adverse events following immunization (AEFI) may occur. In most cases, theses adverse events are not severe. However, neurological events such as seizures are possible. Clinical feature may vary from absence to tonic–clonic seizures with loss of consciousness. Consequences can be serious and acute disseminated encephalomyelitis is even possible. 

Objective/Aim: The aim of this study is to analyze the clinical and epidemiological characteristics of the cases of seizures following immunization.

Methods: This retrospective study was carried out on reports of seizures following immunization notified to the National Tunisian Centre of Pharmacovigilance between January 1999 and December 2014. The causality assessment was evaluated by the OMS-UMC probability scale.

Results: his study included 27 cases of seizures following immunization. The sex ratio M/F was 1.25. The median age was 16 months (4 months to 17 years). The age of onset of seizures following immunization was less than 2 years in 67%. The delay of occurrence of seizures was variable from 10 min to 11 days following immunization. Febrile seizures were noticed in 14 cases. Seizures lasted less than 10 min in 6 cases and more than 30 min in 3 cases. Generalized tonic–clonic seizure was observed in 6 cases. Diphtheria-tetanus-acellular pertussis (DTaP) vaccine was incriminated in occurrence of 30% of seizures. Polio vaccine was implicated 25% of seizures. The outcome was favorable in 19 cases. Neurological damage was observed in one case as acute disseminated encephalomyelitis (ADEM).

Conclusion: In view of these results, the balance benefit/risk of the vaccine remains favorable for routine immunization in early childhood. The supervision of adverse events following immunization through active pharmacovigilance remains essential.

Disclosure of Interest: None declared.

259 ISoP18-1399 What Happens to the Striking Cases Presented in the French Pharmacovigilance Technical Committees?

259.1 G. Bari^1,2, G. Miremont-Salamé^*1,2, A. Pariente^1,2, C. Pageot²

259.1.1 ¹INSERM U1219, Bordeaux University, Bordeaux, France; ²Department of Pharmacology, Bordeaux Pharmacovigilance Center, Bordeaux, France

Background/Introduction: Monitoring of Adverse Effects (AEs) of medicines after their commercialization in order to contribute to the safe use of medicines is one of the mains assignments of pharmacovigilance. Thanks to spontaneous reporting, AEs are collected, analyzed and entered by regional pharmacovigilance centers (CRPV) in France. Some of these AEs are particularly interesting because of they are unlabelled or severe: they are called “striking cases” (SCs). Each CRPV submits its SCs for the last month to the French national competent authority: ANSM. SCs will be discussed during the pharmacovigilance technical committee (CTPV). During this meeting, after SC’s presentation and discussion, decisions may be taken by ANSM (information modifying, dear doctor letters, etc.).

Objective/Aim: To describe all SCs presented by Bordeaux CRPV at the CTPV since January 2014, and to evaluate the impact and actions following these presentations.

Methods: A retrospective descriptive survey: data were collected from CTPV reports and Bordeaux CRPV records. A quantitative and qualitative assessment of all the SCs from Bordeaux CRPV presented at the CTPV from January 2014 to March 2018 was realized. We studied the proportion of SCs presented (i.e. selected by ANSM to be discussed during the CTPV) and not presented and the criteria for non-presentation, the number and the type of follow-up actions.

Results: During the study period, 69 SCs were submitted by Bordeaux CRPV to the ANSM, representing an average number of 1.4 cases per month. Among them, 54% (37 SCs) were selected to be presented during the CTPV (namely 0.95 case per month). The main non-presentation criteria were: case for information (47%), pharmacovigilance survey scheduled or on-going (22%). Among the 37 presented SCs, 27 (73%) have had repercussions and led to actions. These actions were essentially: monitoring of the AE in PSURs (periodic safety update reports) (38%) and updating of SPC (summary product characteristics) (21%).

Conclusion: The average number of presented SCs may seem low but it’s important to note that nearly 3/4 have a major impact and several follow-up actions. SC’s formal eligibility criteria were set up by ANSM in July 2016. Before this date, only the experience of pharmacovigilance team allowed to determine which case can be “outstanding” and almost all submitted SCs were presented. After July 2016 and with the application of SC’s eligibility criteria, many more cases were submitted but a small proportion were selected for presentation. This study shows that eligibility criteria of SCs may be too wide, but when a case is selected by ANSM for presention during the CTPV, this has most often an important impact.

Disclosure of Interest: None declared.

260 ISoP18-1400 Management of Individual Case Safety Reports from Multiple Source in the DRC National Pharmacovigilance Center

260.1 A. Nseka Zi Nseka^*1, P. Nsengi Ntamabyaliro¹, G. Tona¹

260.1.1 ¹National Pharmacovigilance Center, Kinshasa, The Democratic Republic of the Congo

Background/Introduction: The reporting of adverse Events (AE) remains the starting point for regular Pharmacovigilance systems. This crucial activity is however hampered by several factors in poor countries like the Democratic Republic of the Congo. DRC is the second biggest country of Africa, crossed my numerous rivers, with scarce transportation and communication systems. Strategies to improve notification rates includes multiplying the sources and means, but this raises issues about the management of these sources and means. We report here the strategy put in place by the Congolese National PV Center on this matter.

Objective/Aim: The objective of this system is to improve the notification rates and quality of ICSRs.

Methods: A system was put in place which includes reporting by phone calls, text messages, transmission by internet, Transmission of scanned copies by email and reception of hard copies. The multiplicity of sources raises two major problems: the management of the different formats and origins and the accurate detection of duplicates. To solve these issues, a service dedicated to management of ICSRs was created and has the responsibility to receive all ICSR, put them in one format: phone call and sms are written of papers, scanned documents printed as is. All ICSRs receive a code indicating the origin, the mean of transmission and the date of reception.

Results: This system will probably help to increase the number and the quality of ICSR. All reporting form may be identified by their source, date of reception and initial format.

Conclusion: An assessment of the system will be done to evaluate more its impact and possible improvements.

Disclosure of Interest: None declared.

261 ISoP18-1401 From Clinical Trial to Post-marketing Signal Management: A Continuum

261.1 M. Stam Moraga^*1

261.1.1 ¹IQVIA RDS AG, Basel, Switzerland

Background/Introduction: Numerous factors influence the way how pharmaceutical companies and CROs monitor the safety profile of an investigational medicinal product versus a marketed product, not only at the signal management process level in terms of signaling strategy, signal assessment, decision making as well as documentation and tracking, but also at the company organizational level in terms of departments and teams involved, tools used and resources allocated.

Objective/Aim: Understand what are the key elements to set the foundation for a unique signal management process throughout the lifecycle stage of a product.

Understand how the main parameters influencing signal management evolve in both settings as a tool for signal management decision making.

Methods: Review of the international signal management regulations, highlighting the main differences, specificities and focus in both the clinical trial and post-marketing settings.

Results: Whereas the regulations on signal management in the post-marketing setting are well defined, clinical trial guidances on this topic are less specific.

Safety departments will gain efficiencies in terms of processes, training, tracking tools and quality by setting a foundation of key signal management steps applicable throughout the lifecycle of a product.

Conclusion: Understanding the differences, specificities and focus in each setting will allow safety departments to more effectively allocate resources.

The more streamlined and standardized the signal management process the better the focus on the safeguarding of patients’ safety at all time.

Disclosure of Interest: M. Stam Moraga Employee of: IQVIA.

262 ISoP18-1402 Side Effects of Lipid-Lowering Agents: Case Series of 53 Patients

262.1 C. Ladhari¹, G. Lakhoua¹, F. Zgolli¹, I. Aouint¹, O. Charfi¹, A. Zaiem¹, N. Alaya¹, H. Zayeni¹, R. Daghfous^*1, S. El Aidli¹, S. Kasatlli¹

262.1.1 ¹Centre National de Pharmacovigilance de Tunis, Tunis-Bab Souika, Tunisia

Background/Introduction: Lipid lowering agents are among medications most prescribed over the worldwide [1]. Adverse effects related to liver or the musculoskeletal systems are frequently reported with these drugs. Other less specific, such as cutaneous and gastrointestinal disorders are possible [2].

Objective/Aim: The aim of this study is to analyze the clinical and epidemiological characteristics of the cases of lipid-lowering agents’ side effects.

Methods: This retrospective study was carried out on reports of adverse events related to lipid-lowring agents: Reports were notified to the National Tunisian Centre of Pharmacovigilance from the 1st January 2012 to 31th December 2015. The causality assessment was evaluated by Begaud’s method of imputability [3].

Results: This study included 53 cases of adverse effects attributed to lipid-lowring agents. The sex ratio F/H was 1.7 and the median age was 58 years (from 42 to 79 years). Adverse effects were related to statins in 29 cases (51.7%) which were atorvastatine (14 cases), rosuvastatine (8 cases), simvastatine (7 cases), pravastatine (2 cases). Fibrats were the culprit drugs in 27 cases (48.3%). Fenofibrate was the only molecule implicated in our case series. Adverse drug reactions were cutaneous (N = 30, 57%), liver injury (N = 12, 23%), muscle damage (N = 5, 9%), tendinious break (N = 1, 2%).  Cutaneous side effects were as following: pruritis (statins N = 8, fibrats N = 4), rash (statins N = 1, fibrats N = 7), photosensibility (statins N = 1, fibrats N = 5), urticaria (statins N = 4, fibrats N = 1) and eczema (fibrats N = 2). Concerning liver injury, cytolysis was seen in 5 cases and abnormalities in liver function tests in 4 cases. The others were cholestasis, isolated increasing GGT and elevated bilirubin in one case each. Concerning musculoskeletal system, increasing CPK with myalgia was noticed in 2 cases. 4/5 was due to statins. Hepatic side effects were due to statins in 9 cases. The outcome was favorable in most cases following the withdrawal of the culprit drug. No fatal injury was noticed among our patients.

Conclusion: Lipid lowering agents are responsible for a wide range of adverse effects, ranging from mild gastro-intestinal disturbances to life-threatening conditions such as rhabdomyolysis [4]. In our case series, the most frequent adverse effects noticed were cutaneous ones and were benign.

References:

• 1. Scandanavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;19;344:1383–9

• 2. Tonstad S. Statin intolerance. Tidsskr Nor Laegeforen 2017; 137, 36

• 3. Bégaud B. et al. Imputabilité des effets inattendus ou toxiques des médicaments: actualisation de la méthode utilisée en France. Thérapie 1985;40:111–8

• 4. O’Sullivan S. Statins: A review of benefits and risks. TSMJ 2007;8:52–6

Disclosure of Interest: None declared.

263 ISoP18-1404 Practical Aspects Of Developing Relevant Key Performance And Quality Indicators For Risk-Based Quality Management In Pharmacotherapy

263.1 M. A. Malikova^*1

263.1.1 ¹Surgery, Boston University, Boston Medical Center, Boston, United States

Background/Introduction: Besides being a new expectation by regulatory agencies under good clinical practices, Quality by Design (QbD) and Risk-Based Quality Management (RBQM) concepts are receiving attention world-wide. According to FDA and EMA guidelines, Key Risk Indicators (KRIs) and Critical to Quality (CTQ) metrics should focus on safety of research subjects and data integrity. (1,2) Biological products, due to their nature, can increase risks while being tested in clinical trials (3).

As the industry’s utilization of risk-based monitoring continues to increase along with the development and expansion of the area of RBQM, the need for the integration of these two concepts in pharmacovigilance becomes apparent. The premise behind RBQM is that monitoring quality can improve by leveraging existing data intelligence (1). RBQM requires development of relevant metrics, key risk and quality indicators, as well as a solid process for review/follow-up of the identified safety signals (1,2).

Objective/Aim: Develop and test relevant Key Performance and Quality Indicators (KP-QIs) for risk-based quality management in pharmacotherapy.

Methods: We have established QbD parameters and RBQM metrics and attempted to build them into our clinical operations.

We propose prioritization and risk mitigation approaches across several dimensions: protection of study subjects—rights and integrity, safety; credibility of data and results; stratified according to knowledge of investigational product. Customized approach is needed depending on: protocol complexity, therapeutic indication and nature of endpoints, population co-morbidities, concomitant medicationsAdministration of study drug (timing of drug administration, dose, formulation); nature of intervention and vulnerability of the study population.

Results: Deviations from the study protocol can lead to compromised patient safety and inaccurate data, placing the trial at risk.

Our analysis showed that many of the deviations were repetitive, where the same errors were made continuously (i.e., 96 of the 128 deviations, or 75%, were related to study procedures not performed and visit out of study protocol window that were not addressed promptly). An analysis of the number of deviations per active patient over time was conducted which provided insight into deviations trends/patterns.

Cause-Effect analysis was conducted based on the most common reasons for protocol deviations in trials with biologics.

Conclusion: Proactive assessment of safety in studies with biologics can lead to earlier mitigation of risks, quality improvement in data obtained, and increased quality of studies conducted in this field. An understanding of the frequency and types of adverse events can provide an expectation for those conducting trials in a particular indication.

References:

• 1. FDA Guidelines for Industry: Oversight of Clinical Investigations—A Risk-Based Approach to Monitoring, August, 2013. http://www.fda.gov/downloads/Drugs/…/Guidances/UCM269919.pdf.

• 2. Selema, Ramasela J. “A Risk-Based Monitoring Management Approach to Clinical Research”. Monitor 27.6 (2013):25–30.

• 3. Hougaard, P. “A Surveillance Program for Serious Adverse Events during Phase III Drug Development Studies”. Drug Information Journal 35.4 (2001):1301–314.

Disclosure of Interest: None declared.

264 ISoP18-1405 Paclitaxel Induced Photosensitivity

264.1 S. Ben Hammamia¹, S. Kastalli¹, I. Souilem¹, O. Charfi¹, N. Litaiem², S. El Aidli¹, R. Daghfous^*1, A. Zaiem¹

264.1.1 ¹Pharmacovigilance National Center, Tunisia. University Tunis El Manar, ²Dermatology Department, Charles Nicolle Hospital, University Tunis El Manar, Tunis, Tunisia

Background/Introduction: Paclitaxel (PTX) is a chemotherapy belonging to taxanes group, used in the treatment of various cancers especially in advanced breast and ovarian cancers. Some of the most frequent cutaneous adverse drug reactions that have been observed include pruritus, rash and erythema. Rare cases of paclitaxel-associated photosensitve conditions, such as onycholysis, have been reported in the literature.

Objective/Aim: We report a case of photosensitivity in a 62-year-old female probably associated with paclitaxel.

Methods: This case was notified on March 5th 2018 and was analyzed according to the French updated method for the causality assessment of adverse drug reactions [1].

Results: A 62-year-old female suffering from a mammary carcinoma with hepatic metastasis, was prescribed palliative chemotherapy with paclitaxel. She received 80 mg/m² PTX weekly. At the 12th week of treatment, she developed an erythema of the face and forearms. The skin lesions resolved, with secondary dermal desquamation, when stopping chemotherapy and avoiding the sun.

The incidence of photosensitivity appears to be inferior to 1% in patients with breast cancer treated by Paclitaxel. Some authors suggested that paclitaxel may induce variation of porphyrins biosynthesis associated with photosensitive reaction [2]. But according to others, paclitaxel inducing aberrations in porphyrin biosynthesis did not necessarily cause photohypersensitivity [3].

Conclusion: Photosensitivity induced by paclitaxel is an adverse drug reaction that can be prevented. Hence the need to raise the patient’s awareness of the importance of avoiding the sunlight and the use of sunscreen.

References:

• 1. Arimone Y, Bidault I, Dutertre J-P, et al. Updating the French Method for the Causality Assessment of Adverse Drug Reactions. Thérapie 2013;68:69–76

• 2. Cohen AD, Mermershtain W, Geffen DB, et al. Cutaneous photosensitivity induced by paclitaxel and trastuzumab therapy associated with aberrations in the biosynthesis of porphyrins. J Dermatolog Treat 2005;16:19–21

• 3. Tokunaga M, Iga N, Endo Y, et al. Elevated protoporphyrin in patients with skin cancer receiving taxane chemotherapy. Eur J Dermatol 2013;23(6):826–9

Disclosure of Interest: None declared.

265 ISoP18-1406 Lichenoid Drug Eruption Induced by Levonorgestrel

265.1 S. Ben Hammamia¹, S. Kastalli¹, I. Souilem¹, G. Lakhoua¹, N. Alaya¹, R. Daghfous^*1, S. El Aidli¹, A. Zaiem¹

265.1.1 ¹Pharmacovigilance National Center, Tunisia. University Tunis El Manar, Tunis, Tunisia

Background/Introduction: Lichen planus is a skin autoimmune disease. Different agents can trigger this condition. The exact cause isn’t always easy to determine. Sometimes, this skin eruption is associated with drug intake. When that’s the case, it’s called lichenoid drug eruption (LDE), or drug-induced lichen planus (DILP).

Objective/Aim: We report a case of LDE in a 27-year-old female probably associated with levonorgestrel.

Methods: This case was notified on February 1th, 2016 and was analyzed according to the French updated method for the causality assessment of adverse drug reactions [1].

Results: A 27-year-old female was prescribed oral contraception based on levonorgestrel. Few days after starting the medication, she developed pruritic lichenoid lesions at the extremities and the trunk.

Histopathological findings showed parakeratosis, with lymphocyte and plasmocytic infiltrate and many melanophages. Hypertrophic lichen planus was suspected. The presence of parakeratosis, pointed us towards a cutaneous adverse drug reaction.

The skin lesions resolved in 2 weeks, when stopping the drug intake and under symptomatic treatment. Erythema and edema regressed, leaving post inflammatory pigmentation.

We performed a patch-test on the back with levonorgestrel at 30% in petroleum jelly. Readings at 15 min, 48 h and 96 h were negative.

The healing following levonorgestrel removal and the fact that the condition didn’t recur in 2 years after removal, led us to exclude the possibility of idiopathic lichen planus, and to conclude that the lesion was secondary to the drug intake.

In the literature, a case of levonorgestrel-releasing intrauterine system has been implicated as the cause of LDE [2]. However, to the best of our knowledge, this is the first report of lichen planus possibly induced by levonorgestrel orally taken.

Conclusion: Awareness should be raised about the possibility of LDE, occurring as a rare adverse effect of levonorgestrel.

References:

• 1. Arimone Y, Bidault I, Dutertre J-P, et al. Updating the French method for the causality assessment of adverse drug reactions. Thérapie 2013;68:69–76

• 2. Jones A, Shuler M, Zlotoff B. Levonorgestrel-releasing intrauterine system causes a lichenoid drug eruption. Cutis. 2015;96:E13–5

Disclosure of Interest: None declared.

266 ISoP18-1408 Rhabdomyolysis Associated with the Combined Use of Levofloxacin and Colchicine in a Renal Failure Patient with Concurrent Use of Fenofibrate

266.1 S. Ben Hammamia¹, S. Kastalli¹, I. Aouinti¹, I. Hamza¹, R. Daghfous^*1, S. El Aidli¹, A. Zaiem¹

266.1.1 ¹Pharmacovigilance National Center, Tunisia. University Tunis El Manar, Tunis, Tunisia

Background/Introduction: Drug-induced rhabdomyolysis is a rare serious adverse drug reaction. Rhabdomyolysis secondary to fluoroquinolones or colchicine is even less commun [1, 2]. Rhabdomyolysis associated with the combined use of levofloxacin and colchicine has never been reported.

Objective/Aim: We report a case of rhabdomyolysis associated with the combined use of levofloxacin and colchicine in a renal failure 66-year-old woman under fenofibrate.

Methods: This case was notified on August 28th 2017 and was analyzed according to the French updated method for the causality assessment of adverse drug reactions.

Results: A 66-year-old woman, who had a history of chronic renal failure at the stage of hemodialysis and dyslipidemia under fenofibrate since 2007, was prescribed on July 14th 2017, levofloxacin at the dose of 500 mg per day for urinary infection and colchicine at the dose of 1 mg daily. Ten days after the beginning of the treatment, she developed diffuse muscular pain. The laboratory findings showed a creatinine kinase rate 8 times the upper limit of normal and myoglobulinemia rate at 8369 µg/l. Rhabdomyolysis was diagnosed. Levofloxacin and fenofibrate were withdrawn and the dose of colchicine was halved, on July 24th 2017. Clinical and biologic symptoms resolved completely 12 days later.

The responsibility of levofloxacin associated with colchicine was suspected in this case, since a delay of 10 days, compatible with a drug induced reaction and the suggestive evolution, marked by the normalization of the blood tests after stopping levofloxacin and reduction of the colchicine dosage. Moreover, the dose of 500 mg/day of levofloxacin, received by the patient, constitutes an additional risk factor for the accumulation and the toxicity of this drug. Levofloxacin being eliminated almost entirely by the kidney (85% of the dose), the recommendations, in case of chronic renal failure, even dialyzed, stipulate to give a loading dose of 500 mg the first day, then 125 mg/day before each session of dialysis. Concerning colchicine, the dose of 1 mg per day may be toxic, too, regarding the fact that it is not filtrated by dialysis. Fenofibrate is less suspected, in view of a delay of 10 years. However, it should be noted that the combination of myotoxic drugs (levofloxacin, colchicine and fenofibrate) potentiates their effects. In addition to that, renal failure, constitutes an additional risk factor. In the literature several cases of rhabdomyolysis due to a combination of colchicine and statin [2, 3] or colchicine and clarithromycin [4–6], have been reported, but there is no association of colchicine and levofloxacin.

Conclusion: Attention should be raised about the importance of not associating myotoxic drugs especially in patients with renal failure.

References:

• 1. John F, et al. Levofloxacin-induced rhabdomyolysis: a case report. J Med Case Reports 2016;10:235

• 2. Bouquié R, et al. Colchicine-induced rhabdomyolysis in a heart/lung transplant patient with concurrent use of cyclosporin, pravastatin, and azithromycin. J Clin Rheumatol 2011;17:28–30

• 3. Frydrychowicz C, et al. Colchicine triggered severe rhabdomyolysis after long-term low-dose simvastatin therapy: a case report. J Med Case Reports 2017;11:8

• 4. McKinnell J, et al. Short term treatment with clarithromycin resulting in colchicine-induced rhabdomyolysis. J Clin Rheumatol 2009;15:303–5

• 5. Celebi ZK, et al. Colchicine-induced rhabdomyolysis following a concomitant use of clarithromycin in a haemodialysis patient with familial Mediterranean fever. Clin Kidney J 2013;6:665–6

• 6. Soad H.Y, et al. Colchicine intoxication in familial Mediterranean fever patients using clarithromycin for the treatment of Helicobacter pylori: a series of six patients. Rheumatol Int. 2018;38:141–7

Disclosure of Interest: None declared.

267 ISoP18-1409 Detecting a Potential Signal of Quetiapine Abuse Using the Faers Database and Big Data Search Analytics

267.1 D. Spachos¹, S. Siafis², P. Bamidis¹, D. Kouvelas², G. Papazisis^*2

267.1.1 ¹Laboratory of Medical Physics; ²Clinical Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece

Background/Introduction: There is a growing literature of the potential misuse and abuse of quetiapine, indicated also by a recent analysis of the European Medicines Agency Adverse Drug Reactions’ Database [1]. Supplementary to spontaneous reporting system databases, big data search analytics can be an additional and valuable source of pharmacovigilance data, especially considering that Google receives more than 3.5 billion search queries every day [2]. well-known example is the 2009 H1N1 pandemic, where a Google algorithm detected the outbreak almost at real time, while the Centers for Disease Control and Prevention predicted it with a two-week lag [3].

Objective/Aim: To detect a potential signal of quetiapine abuse in the real-world use context combining two different pharmacovigilance sources.

Methods: Data regarding the United States between the first quarter of 2004 and the second quarter of 2017 were collected and analysed. To provide quantitative metrics linked to abuse liability the following indicators were used: search popularity score of abused related terms (SPS), search interest over time and search frequencies of abuse-related queries in the search analytics (SA) domain. The reporting odds ratio of abuse related adverse events in the FDA adverse events reporting system (FAERS domain) was calculated using the data analysis tool OpenVigil 2.1-MedDRA [4]. The correlation between the two domains using quarterly data from the timeline series from 2004Q1 to 2017Q2 was also assessed.

Results: Terms related to abuse had an SPS of 20, while 6.81% of the total number of quetiapine queries in the Google search engine included quetiapine abuse. In the specific timeframe, these are hundreds of million queries. In FAERS, from the 4.7 million total number of reports, 57 K included quetiapine. Drug abuse events were in 70 K reports and 3.1 K of them included quetiapine (5.55% of total quetiapine’s reports). Α disproportionality signal of drug abuse was detected for quetiapine with a ROR (95% CI) of 4.01 (3.86–4.16). As our variables were not approximately normally distributed, a Spearman’s rank-order correlation was run to assess the relationship between the domains. Based on correlation analysis, there was a significant positive correlation between FAERS and SA domains (r = 0.624; p < 0.001).

Conclusion: A potential safety signal of quetiapine abuse was detected by both search analytics and disproportionality analysis. The positive correlation between these domains suggest their combined use as a pharmacovigilance tool to detect drugs effects early. Nevertheless, signal validation and confirmation of causality require further clinical assessment.

References:

• 1. Chiappini S, Schifano F. Is there a potential of misuse for quetiapine?: Literature review and analysis of the European Medicines Agency/European Medicines Agency adverse drug reactions’ database. J Clin Psychopharmacol 2018;38:72–9

• 2. http://www.internetlivestats.com. Google Search Statistics. 2017, from www.internetlivestats.com/google-search-statistics

• 3. Ginsberg J, Mohebbi MH, Patel RS, Brammer L, Smolinski MS, Brilliant L. Detecting influenza epidemics using search engine query data. Nature 2009;457:1012–4

• 4. Böhm R, von Hehn L, Herdegen T, Klein HJ, Bruhn O, Petri H, et al. OpenVigil FDA—Inspection of U.S. American adverse drug events pharmacovigilance data and novel clinical applications. PloS One 2016;11:e0157753

Disclosure of Interest: None declared.

268 ISoP18-1410 The Trend of Reported Adverse Drug Reactions at Mbagathi Hospital’s Comprehensive Care Centre in Nairobi, Kenya

268.1 C. Wambura^*1

268.1.1 ¹Pharmacy, Mbagathi Hospital, Nairobi, Kenya

Background/Introduction: Mbagathi hospital has one of the oldest comprehensive care centres in Kenya dating back to 2003.Reporting of adverse drug reactions began in 2011 when clinicians were sensitized on pharmacovigilance and it’s importance.

Objective/Aim: To document case reports of adverse drug reactions experienced by our patients from 2011 to 2017.

Methods: All case reports that had been filed from 2011 to 2017 were entered on a microsoft excel sheet and analyzed.

Results: In total of 194 case reports from adult patients were filed.4 lipodystrophy cases were reported in 2011. In 2012 a total of 85 reports were filed of which 78 were lipodystrophy,1 gynaecomastia,1 central nervous system impairement, 2 anaemia, 2 skin rash and 1 peripheral neuropathy. 37 reports were filed in 2013 of which 21 were lipodystrophy, 6 anaemia, 2 renal toxicicty, 1 Stevens johnson syndrome, 2 central nervous system impairement, 3 peripheral neuropathy and 2 gynaecomastia. 9 reports were filed in 2014 of which 4 were lipodystophy, 3 gynaecomastia, 1 central nervous system impairement and 1 anaemia. In 2015, 23 reports were filed of which 9 were lipodystrophy, 6 gynaecomastia, 4 central nervous system impairement, 2 anaemia, 1 renal impairement and 1 swelling of the face. 24 reports were received in 2016 of which 2 were lipodystrophy, 3 renal impairement, 4 gynaecomastia, 1 central nervous system impairement, 3 anaemia, 7 hepatotoxicity, 2 rash, 1 dyslipidemia, 1 peripheral neuropathy and 1 general body swelling. 11 reports were filed in 2017 of which 2 were anaemia, 5 gynaecomastia, 1 rash, 1 central nervous system impairement, 1 hepatotoxicity and 1 lipodystrophy.

Conclusion: Adverse drug reactions occur in patients that are on antiretroviral therapy. The most common reaction reported so far in our facility is lipodystrophy.

Disclosure of Interest: None declared.

269 ISoP18-1411 Recurrent Vasculitis Induced by Different Non Steroidal Anti Inflammatory Drugs

269.1 S. Ben Hammamia¹, A. Zaiem¹, I. Souilem¹, I. Aouinti¹, R. Daghfous^*1, S. El Aidli¹, S. Kastalli¹

269.1.1 ¹Pharmacovigilance National Center, Tunisia. University Tunis El Manar, Tunis, Tunisia

Background/Introduction: Vasculitis, also known as angiitis or arteritis, is an inflammation affecting the vessel wall. It can be primary or secondary to a drug intake. In this case, it’s called Hypersensitivity vasculitis or leukocytoclastic vasculitis (LCV).

Vascularitis to non-steroidal anti-inflammatory drugs (NSAIDs) are rare in spite of their wide use. Only a few cases of hypersensitivity angiitis related to NSAIDs have been described.

Objective/Aim: We report a case of recurrent vasculitis in a 55-year-old female probably associated with NSAIDs.

Methods: This case was notified on February 17th 2017 and was analyzed according to the French updated method for the causality assessment of adverse drug reactions [1].

Results: A 55-year-old female, was prescribed ibuprofen, as symptomatic treatment for an angina. Two days later, she developed painful purpuric lesions, initially on both legs, then on the thighs, upper limbs, and abdomen. The lesions were associated with aphtoid erosions on the mucous side of the lips, without improvement under symptomatic treatment (antihistamine, local corticosteroid). Cutaneous histopathological examination was in favor of vasculitis. The evolution was marked by the regression of the symptomatology, 4 days after stopping the drug intake.

The same symptomatology reappeared in March 2017 and in November 2017, after taking niflumic acid and piroxicam, respectively, within the same delays, of about 48 h after drug intake.

The responsibility of NSAIDs was highly suspected mainly because of the recurrence of the vasculitis only after the drug intake and the regression of the symptoms after their withdrawal.

Several reports have described vasculitis associated with specific NSAIDs such as apirin, naproxen, or ibuprofen. However, no study has ever described a cross side effect between NSAIDs.

Conclusion: This cross-reaction would suggest an immuno-allergic mechanism in common between these NSAIDs, or a class effect (related to the action of NSAIDs). More studies are needed to confirm this hypothesis.

References:

• 1. Arimone Y, Bidault I, Dutertre J-P, et al. Updating the French method for the causality assessment of adverse drug reactions. Thérapie 2013;68:69–76

Disclosure of Interest: None declared.

270 ISoP18-1412 Exploring Health Professionals Perceptions About Drug Related Problems in Older Patients

270.1 F. Roque^*1, A. I. Plácido², F. Lima³, M. T. Herdeiro⁴

270.1.1 ¹Research Unit for Inland Development, Polytechnic Institute of Guarda, Guarda, Portugal; ²Research Unit for Inland Development, Polytechnic Institute of Guarda, Guarda, Portugal; ³Local Health Unit of Guarda, Guarda, Portugal; ⁴Department of Medical Sciences & Institute for Biomedicine, University of Aveiro, Aveiro, Portugal

Background/Introduction: The high prevalence of chronic diseases in the elderly population leads to a wide use of drugs by this population. Older patients use, on average, 2–5 prescription drugs daily, and about 20–40%, use more than 5 medicines. Besides the high level of prescription, elderly drugs overuse are also related to higher frequency and drug intake for longer durations than clinically indicated. Drug related problems (DRP) are frequent in these patients, leading to inefficacy of treatment and to adverse drug reactions. Primary care physicians, nurses and community pharmacists have an important role in solving DRP among older patients not institutionalized.

Objective/Aim: Explore primary care physicians´, nurses´ and pharmacists´, perceptions about drug related problems in older patients.

Methods: A qualitative research in the form of focus group was developed with primary care physicians, nurses and community pharmacists. The sessions were moderated by a researcher, following a top guide, and were audio-recorded and transcribed by another researcher. The study was developed during May 2018. Participants were informed about the aim and methodologyof the study. A signed informed consent was obtained from each one of the participants. The study was approved by the ethical committee of the Center Health Region of Portugal, and from the Portuguese Data Protection Authority.

Results: Two focus groups were conducted with primary care physicians (n = 10), nurses (n = 4) and community pharmacists (n = 7). The main problems identified were duplication of medication (physicians attributed these problems to the generic medicines dispensing in pharmacies), drug interactions, and mistakes with drugs, during self-administration. Health professionals have the perception that patients’ mistakes with drugs are frequent because sometimes packages are similar, patients´ decline of cognitive function and forgetfulness, excessive and inadequate use of medicines boxes, with exposition of medicines to the inappropriate conditions.

Conclusion: Physicians, nurses and pharmacists, recognize that drug related problems are frequent in older patients, but they tend to attribute causes to others (patients, other health professional, industry and to the health system organization).

Funding: This work was supported by Portuguese Foundation for Science and Technology (FCT/MCTES), Portugal 2020 and Centro 2020 Grants [SAICT-POL/23585/2016].

Acknowledgment: The authors wish to express their sincere thanks to all physicians, pharmacists ans nurses that participated in the study. We are also thankful to Research Unit for Inland Development, Polytechnic Institute of Guarda (UDI/IPG) and to Institute for Biomedicine (iBiMED) for supporting this project. iBiMED (UID/BIM/04501/2013—POCI-01-0145-FEDER-007628) is supported by the Portuguese Foundation for Science and Technology (FCT/MCTES) through national funds (PIDDAC), and the co-funding by the FEDER, within the PT2020 Partnership Agreement and Compete 2020.

Disclosure of Interest: None declared.

271 ISoP18-1413 Chemotherapy Induced Hand Foot Syndrome

271.1 S. Ben Hammamia¹, A. Zaiem¹, G. Lakhoua¹, O. Charfi¹, R. Daghfous^*1, S. El Aidli¹, S. Kastalli¹

271.1.1 ¹Pharmacovigilance National Center, Tunisia. University Tunis El Manar, Tunis, Tunisia

Background/Introduction: Chemotherapy drugs can be responsible of several side effects such as the hand-foot syndrome (HFS). Without proper management, it can deteriorate the quality of life of the patient, leading to a temporary or definitive stop of chemotherapy.

Objective/Aim: The aim of this work was to study the epidemiological and clinical characteristics of patients who were referred to the Pharmacovigilance Center with HFS, and to identify chemotherapy drugs which are most likely to be responsible of the occurrence of HFS.

Methods: Our study was retrospective, performed over a period of 7 years from January 2010 until April 2017. We collected the cases of HSF associated with chemotherapy drugs and notified to the National Center of Pharmacovigilance during this period. These cases were validates according to the French method of imputability. The severity of the HFS was classified according to the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) v4.0 classification.

Results: The study included 42 patients: 40 women and 2 men. The mean age was 51 years old. Docetaxel was the main drug involved in the HSF. Hands were involved in all cases and were sometimes associated with other skin surfaces apart from the feet. Erythema of the hands and/or feet was present in all patients. It was associated with edema in more than half of the cases. The distribution of different grades according to NCI-CTCAE classification among patients, was almost equal: 28% grade 1, 36% grade 2 and 36% grade 3. The regression of HFS occurred more rapidly for grade 1 and 2 compared with grade3, especially when associated with symptomatic treatment. The occurrence rate of HFS for these patients with decreased doses, spacing of cures and/or symptomatic and prophylaxis treatment, was 25%.

Our study revealed that Docetaxel was the principal drug implicated in HFS in a population composed mainly by women. The onset of the syndrome did not differ according to the grade. However, the regression depended on the grade and the prophylaxis measurements.

Conclusion: An early detection of HFS, associated with preventive measures, can be a good way to enable patients to continue their chemotherapy.

Disclosure of Interest: None declared.

272 ISoP18-1414 Lipoatrophy Complicating Panniculitis Secondary to Treatment by Beta-Interferon

272.1 S. Ben Hammamia¹, A. Zaiem¹, O. Charfi¹, I. Aouinti¹, S. El Aidli¹, R. Daghfous^*1, S. Kastalli¹

272.1.1 ¹Pharmacovigilance National Center, Tunisia. University Tunis El Manar, Tunis, Tunisia

Background/Introduction: Biopharmaceutical products in multiple sclerosis, have frequent side effects, which may lead to lack of compliance. The most common side effects of subcutaneous interferon-beta therapy include pain, inflammation, and induration at the injection site. With the actual electronic autoinjector and the education of patients with changing sites and the use of icing, the complicated forms of this adverse reaction became rare.

Objective/Aim: We report an exceptional case of complicated panniculitis in a patient treated by beta interferon since 2015.

Methods: This case was notified on December 27th 2017 and was analyzed according to the French updated method for the causality assessment of adverse drug reactions [1].

Results: A 23-year-old woman, with a multiple sclerosis history, was prescribed, since 2015, beta interferon 1-alpha, at the dose of 44 µg, three times a week. She used the interferon with the recommended electronic autoinjector and respected the sites rotation. She also used to ice the site before injection. One year after the beginning of the treatment, she developed, inflammatory lesions at the injection sites: the external side of the two arms and the anterior face of the thighs. The patient did not stop the drug and go on injections despite of two episodes of abscess in the two arms. She was treated with antibiotics and followed her interferon treatment. The inflammation and the abscess evolved into induration and fibrosis lesions, so much that the treatment does not pass anymore into the skin. The patient was referred to the National Center of Pharmacovigilance, since she was no longer able to inject her treatment because of the fibrosis.

Panniculitis induced by beta interferon is prevented by raising the patient’s awareness of the importance of the rotation of injection sites, the manual palpation and the regular examination of all injection sites. Non-steroid anti-inflammatory gels and local corticosteroids can help patients and improve their compliance [2]. Once the side effect installed, we can change the multiple sclerosis treatment using other routes of administration: intravenous, intramuscular and lately oral route.

Conclusion: Through this case, we emphasize the importance of preventive measures, to avoid this kind of side effects.

References:

• 1. Arimone Y, Bidault I, Dutertre J-P, et al. Updating the French method for the causality assessment of adverse drug reactions. Thérapie 2013;68:69–76

• 2. Lebrun C, et al. Cutaneous side-effects of immunomodulators in MS. Int MS J 2011;17:88–94

Disclosure of Interest: None declared.

273 ISoP18-1415 Patient Knowledge of Adverse Drug Reaction Reporting

273.1 K. Badyal^*1,2, P. Sharda², C. Anton¹, R. E. Ferner^1,2

273.1.1 ¹West Midlands Centre for Adverse Drug Reactions, Birmingham, United Kingdom; ²Institute of Clinical Sciences, University of Birmingham, Birmingham, United Kingdom

Background/Introduction: Patients can report adverse drug reactions (ADRs) to the Yellow Card Scheme (YCS) in the UK, and elsewhere. Studies have shown that patient reports add value and identify previously unrecognised serious adverse drug reactions. Patients have a lot of knowledge about their adverse drug reactions and the detail provided in patient reports give a unique insight into the impact on quality of life [1]. Under-reporting remains a challenge among all reporter groups and it is important to explore ways to encourage reporting [2].

Objective/Aim: To evaluate patient knowledge of the Yellow Card Scheme, establish preferred reporting methods and determine what would encourage greater reporting.

Methods: A standardised questionnaire was developed and members of the public were approached through opportunity sampling. Healthcare professionals and members of the public aged under 16 years were excluded from the intervention.

Results: 101 questionnaires were completed. 13 of the participants (13%) knew of the Yellow Card Scheme. 30 out of 101 participants had reported an ADR either directly to the YCS or to a healthcare professional. Upon learning more about the scheme 64 participants (63%) stated they would ‘definitely’ report an ADR to the YCS. Participants would have liked more information on the YCS from doctors, pharmacists and nurses at the point of prescribing.

Conclusion: The results of this study confirmed a lack of public knowledge of the YCS and their ability to report directly rather than through a healthcare professional. Increasing awareness can address low spontaneous reporting rates. The results showed that once patients are aware of the scheme they are supportive and would be engaged to report. Most patients would like to receive more information about the scheme from healthcare professionals. This suggests mobilising healthcare professionals to engage the public to report adverse drug reactions is key to increasing patient reports.

References:

• 1. Avery AJ, et al. Evaluation of patient reporting of adverse drug reactions to the UK ‘Yellow Card Scheme’: literature review, descriptive and qualitative analyses, and questionnaire surveys. Health Technol Assess 2011;15:1–234, iii–iv

• 2. Dweik AI, Stacey D, Kohen D, Yaya S. Factors affecting patient reporting of adverse drug reactions: a systematic review. Br J Clin Pharmacol 2017;83:875–83

Disclosure of Interest: None declared.

274 ISoP18-1416 Reducing Prescribing Errors Associated with In-Patient Electronic Prescribing Systems: An Investigation of Pharmacist Interventions

274.1 F. Alshahrani^*1, J. Marriott¹, A. Cox¹

274.1.1 ¹School of Pharmacy, University of Birmingham, Birmingham, United Kingdom

Background/Introduction: A reduction in medication errors is a major focus of the World Health Organisation [1]. Prescribing errors are a common type of medication error [2]. Electronic prescribing is thought to reduce medication errors, although sometimes can introduce new error types [3]. A few limited  studies have examined hospital pharmacists’ interventions in the context of an electronic prescribing system [4, 5].

Objective/Aim: To examine the number, types, and severity of prescribing errors documented by hospital pharmacists within an electronic prescribing system.

Methods: A cross-sectional retrospective review of all hospital pharmacist interventions was performed over a 1 month period (01/01/2015–31/01/2015). Interventions were retrieved from the hospital patient information system. Patients’ descriptive data (date of admission, date of ward admission, date of ward discharge, and discharge date), ward associated with the intervention, date and time of the intervention were obtained. Anonymised patient data (name, age, and gender) as well as prescribers’ data (name and speciality) was obtained. Interventions were reviewed for prescribing errors, and assigned a type of error using a modified version of the EQUIP study criteria [6]. Interventions were also classified as on admission, during hospital stay, and upon discharge. Medications involved were classified using the British National Formulary. Data was analysed using SPSS (Version 24), using descriptive data analysis. The error rate was calculated using the the total number of medication orders for the period.

Results: During the study period, a total of 1629 interventions were recorded by hospital pharmacists for 3981 patients in 131,947 medication orders. Prescribing errors accounted for 91% (n = 1481) of the interventions. The incidence of prescribing errors was 1.1%. Omission of medication was the most frequent type of intervention (42.7%) (Table 1). The majority of interventions occurred on admission (56.5%). Most interventions occurred in general medicine (61.5%). Twenty-six percent of interventions were minor, 68.5% significant, 5.1% serious, and 0.1% potentially lethal.

Conclusion: Hospital Pharmacist interventions identified important medication errors within an electronic prescribing system. Most interventions occur on admission, highlighting continuing issues on primary/secondary care.

References:

• 1. Medication Without Harm: WHO’s Third Global Patient Safety Challenge (http://www.who.int/patientsafety/medication-safety/en/) (Accessed on 1st June 2018)

• 2. Ashcroft DM, Lewis PJ, Tully MP, Farragher TM, Taylor D, Wass V, et al. Prevalence, nature, severity and risk factors for prescribing errors in hospital inpatients: prospective study in 20 UK hospitals. Drug Saf. 2015;38:833–43.

• 3. Estellat C, Colombet I, Vautier S, Huault-Quentel J, Durieux P, Sabatier B. Impact of pharmacy validation in a computerized physician order entry context. Int J QHealth Care 2007;19:317–25

• 4. Donyai P, O’Grady K, Jacklin A, Barber N,Franklin BD. The effects of electronic prescribing on the quality of prescribing. Br J Clin Pharmacol 2008;65:230–37

• 5. Abdel-Qader DH, Cantrill JA, Tully MP. Satisfaction predictors and attitudes towards electronic prescribing systems in three UK hospitals. Pharm World Sci 2010;32:581–93

• 6. Dornan T, Ashcroft D, Heathfield H, Lewis P, Miles J, Taylor D, et al. An in-depth investigation into causes of prescribing errors by foundation trainees in relation to their medical education: EQUIP study. 2009, London: General Medical Council.

Disclosure of Interest: None declared.

275 ISoP18-1417 Positive Patch-Test to Metronidazole Outside the Sequelae of Fixed Drug Eruption

275.1 S. Ben Hammamia¹, A. Zaiem¹, G. Lakhoua¹, O. Charfi¹, S. El Aidli¹, R. Daghfous^*1, S. Kastalli¹

275.1.1 ¹Pharmacovigilance National Center, Tunisia. University Tunis El Manar, Tunis, Tunisia

Background/Introduction: Fixed drug eruption (FDE) is characterized by well-defined recurrent lesions, appearing in the same place. It is almost exclusively drug induced. Metronidazole has rarely been reported as a causative agent. Allergologic tests to drug in case of FDE, are made by patch-tests at the site of the hyperpigmented sequelae.

Objective/Aim: We report the case of a patient who developed FDE associated with metronidazole, with positive patch tests on healthy skin and negative ones on hyperpigmented areas.

Methods: This case was notified on September 20th 2017 and was analyzed according to the French updated method for the causality assessment of adverse drug reactions [1].

Results: A 45-year-old patient with no significant medical history, was prescribed amoxicillin-clavulanic acid and metronidazole in 2015 for anal fistula. He developed, few hours after taking these drugs, erythematous pruriginous well-defined maculas at the palm of the hand and the mouth. The evolution was marked by the healing of the erythema in about 1 week after stopping the above-mentioned drugs, with persistent hyperpigmented sequelae. Two years later, the patient was prescribed metronidazole and cefotaxim with recurrence of the same lesions and extension to the external genitalia.

Patch-tests were performed. Two sets of patches were made. The first ones were performed with metronidazole, one on the hyperpigmented site of the palm of the hand, and another on the back, on a healthy skin zone. Forty-eight hours later, tests were positive only at the healthy skin zone. The second tests were performed with amoxicillin-clavulanic acid, and were negative. The orally reintroduction test of amoxicillin-clavulanic acid was also negative.

The imputability of metronidazole in the genesis of the FDE is ranked I6 according to the updated French method, and this considering the suggestive delay, the healing after drug withdrawal, and especially the positive reintroduction.

The negativity of the patch-test on the residual hyperpigmented lesion of the palm of the hand, could be explained by the particularities of this zone: sweating and hyperkeratosis.

Conclusion: Our case emphasizes the interest of making patches in healthy areas, too, especially when hyperpigmented areas are too much sensitive or non explorable.

References:

• 1. Arimone Y, Bidault I, Dutertre J-P, et al. Updating the French method for the causality assessment of adverse drug reactions. Thérapie 2013;68:69–76

Disclosure of Interest: None declared.

276 ISoP18-1419 Preventing Future Deaths from Medicines: Responses to Coroners’ Concerns

276.1 R. E. Ferner^1,2, T. J. Ahmad^*1, Z. Babatunde², A. R. Cox^1,2

276.1.1 ¹West Midlands Centre for Adverse Drug Reactions, Birmingham, United Kingdom; ²Institute of Clinical Sciences, University of Birmingham, Birmingham, United Kingdom

Background/Introduction: Coroners inquire into sudden, unexpected, or unnatural deaths. When future deaths in similar circumstances can be prevented, the Coroner is required to make a report to relevant parties and requests responses to the concerns raised.

Objective/Aim: We have obtained or attempted to obtain responses to Coroners’ concerns in 99 cases of death involving medicines.The aim was to analyse organisations’ responses to Coroners’ PFD reports.

Methods: We have previously identified 99 cases (100 deaths) in which Coroners in England and Wales mentioned medicines, or part of the medication process, or both in “Regulation 28 Reports to Prevent Future Deaths” (PFDs) with 160 concerns raised by coroners [1]. We identified the party or parties to whom these reports were addressed; where this was possible (names were occasionally redacted). We then sought responses, either from the Chief Coroner’s website or by making requests to the addressee under the Freedom of Information (FoI) Act 2000. We analysed the responses we obtained by theme to indicate the steps taken to prevent future deaths.

Results: A PFD could be addressed to an individual person or organisation, or to multiple organisations. We identified 187 organisations that were sent PFDs, of which 158/187 were required to respond (Table 1). The responses of 41 organisations to 28/99 (28%) PFDs were posted on the Chief Coroner’s website. We wrote to 128 addressees requesting sight of their response. Of the organizations who acknowledged our request, 63/128 (49%) provided a copy of their response to the Coroner or detailed information on the response and 48 declined to provide any information, citing various reasons or legal exemptions.

The responses we analysed described 201 separate actions proposed or undertaken. These included: staff education or training (44/201); change in processes (24/201); and altered policies (17/201). In some cases (22/201), organisations felt existing policies were sufficient.

Conclusion: Only a minority of responses by NHS bodies and others to Coroners’ Regulation 28 reports concerning medicines is in the public domain. Many remain hidden even after requests under the FoI Act. Few of the responses that we have been able to analyse suggest robust and generally applicable ways to prevent future deaths from medicines. At present there are no methods available to assess whether actions proposed by organisations are sensible, practicable or successful to address Coroners’ concerns.

References:

• 1. Deaths from medicines: a systematic analysis of Coroners’ reports to prevent future deaths. Drug Saf 2018;41:103–10

Disclosure of Interest: None declared.

277 ISoP18-1420 Multiple Drugs Neosensitization Following Dress Syndrome Induced by Cotrimoxazole

277.1 M. Bouhlel^*1, R. Daghfous ¹, S. El Aidli¹, S. Kastalli¹, A. Zaiem¹

277.1.1 ¹Tunisian National Centre of Pharmacovigilance, Tunis, Tunisia

Background/Introduction: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a rare and potentially life-threatening adverse-drug induced reaction. Its evolution is unpredictable. In fact, DRESS syndrome can induce neosensitization; which is different from cross-reactivity and flare-up reactions. Indeed, recent studies have reported the occurrence of drug hypersensitivity to chemically or antigenically unrelated drugs in patients with a history of DRESS syndrome.

Objective/Aim: We report a rare case of secondary neosensitization to multiple drugs following DRESS syndrome induced by trimethoprim-sulfamethoxazole.

Methods: A Case report.

Results: A 45-year-old woman with a past medical history of Widal syndrome, developed 4 days after she had started sulfamethoxazole + triméthoprime a pruritic and generalized cutaneous rash. Skin examination showed a purpuric eruption limited to extremities, facial oedema, duspnea, cervical lymphadenopathy and hyperthermia. Laboratory tests revealed abnormal white cell count with hypereosinophilia at 3300/ml and hepatic cytolysis. Evolution was marked by a slow improvement persistence of the signs, with even aggravation in the week following the drug withdrawal (especially dyspnea).

Six weeks later, the patient developed, immediately at the end of the first infusion of imipenem and fosfomycine acute dyspnea with thrill sensation.

Few weeks later, she initiated a treatment with metronidazole-spiramycin. Three days later, she presented a maculopapular eruption limited to the chest.

Conclusion: The DRESS syndrome was scored six (definitive case) according the European Registry Of Severe Cutaneous Adverse Reactions Study Group (RegiSCAR). In 6 weeks, our patient developed hypersensitive reaction to imipenem and fosfomycine then to metronidazole-spiramycin. These findings suggest that she had developed neosensitization to these drugs after the DRESS syndrome. According to recent studies, DRESS syndrome is considered as a high risk to induce multiple sensitization. The exact mechanism remains unknown but it seems to be related to the massive non-specific activation of the immune system which results from the enhanced expression of co-stimulatory molecules and pro-inflammatory cytokines.

Therefore, it seems highly recommended that the drugs prescribed for a patient with suspected DRESS, should be kept to a minimum to avoid multiple neosensitization.

Disclosure of Interest: None declared.

278 ISoP18-1421 Exceptional Positive Patch Test to Omeprazole to Explore Exanthema

278.1 S. Ben Hammamia¹, A. Zaiem¹, O. Charfi¹, I. Aouinti¹, S. El Aidli¹, R. Daghfous^*1, S. Kastalli¹

278.1.1 ¹Pharmacovigilance National Center, Tunisia. University Tunis El Manar, Tunis, Tunisia

Background/Introduction: Omeprazole is a proton pump inhibitor (PPI) used primarily in the treatment of gastroesophageal reflux and peptic ulcer. Although generally well tolerated, some side effects may occur, including manifestations of skin hypersensitivity. The allergic explorations by patch tests (PT) are of limited interest given the frequent false negatives with these molecules.

Objective/Aim: We report a case of generalized exanthema associated with omeprazole with positive patch test.

Methods: This case was notified on June 22th 2017 and was analyzed according to the French updated method for the causality assessment of adverse drug reactions [1].

Results: A 58-year-old man, with no chronic or atopic pathology, started taking omeprazole 20 mg daily in combination with ketoprofen 100 mg per day. The next day, he developed generalized squamous erythematous itchy rash. The treatment was stopped with slow regression of the rash. The pharmacovigilance analysis found a possible role for both drugs. Three months later, PT to the above-mentioned two drugs were performed. Reading at 48 h showed omeprazole positivity only.

The responsibility of omeprazole could be retained in the genesis of this exanthema thanks to the positive patch test. Allergological investigations are rarely positive for omeprazole and PPIs in general. Indeed, several authors consider the tests as unattractive to these molecules and do not provide significant diagnostic assistance, apart from a few isolated cases [2]. Patch tests with these products are therefore discussed on a case by case basis.

Conclusion: This case shows the interest of always performing PTs, even in cases where the drugs are reputed to be low reactogenic.

References:

• 1. Arimone Y, Bidault I, Dutertre J-P, et al. Updating the French method for the causality assessment of adverse drug reactions. Thérapie 2013;68:69–76

• 2. Otani IM, Banerji A. Immediate and delayed hypersensitivity reactions to proton pump inhibitors: evaluation and management. Curr Allergy Asthma Rep 2016;16:17

Disclosure of Interest: None declared.

279 ISoP18-1423 Agranulocytosis Induced by Voriconazole

279.1 I. Souilem¹, S. Kastalli¹, S. Ben Hammamia¹, I. Aouinti¹, R. Daghfous^*1, S. El Aidli¹, A. Zaiem¹

279.1.1 ¹Service de Recueil et d’analyse des Effets Indésirables, Centre National de Pharmacovigilance, Tunis, Tunisia

Background/Introduction: Voriconazole is the recommended agent for treatment of invasive fungal infections, especially in vulnerable populations such as patients with hematopoietic stem cell transplant as well as other immunocompromised patients. This triazole antifungal agent is highly efficacious. However, a major limitation of voriconazole is the risk of adverse events such as hepatotoxicity and neurotoxicity.

Objective/Aim: We report herein an exceptional case of agranulocytosis in a patient treated for probable pulmonary aspergillosis.

Methods: This case was notified on January 8th 2018 and was analyzed according to the frensh updated method for the causality assessment of adverse drug reactions [1].

Results: A 33-year-old patient, treated with hematopoietic stem cell transplant on August 2017 for aggressive lymphoma, was prescribed on September 7th, voriconazole at the dose of 250 mg twice a day, for probable pulmonary aspergillosis. On November 16th (approximately 2 months later), the patient was admitted urgently for non-specific respiratory symptomatology. He was not febrile and laboratory tests showed agranulocytosis (0 PNN/mm³). Voriconazole was stopped. Twelve days later, the blood count was normal. Myelogram showed hypercellular bone marrow with dysmaturity of granulocytic cells (maturation blocking aspect).

Conclusion: According to the French method of imputability and the consensus meeting on granular or platelet cytopenias to a drug, it appears that only the occurrence of isolated and reversible granular cytopenia should be considered as evoking a drug. In our case, with regard to the chronology, the delay of appearance of agranulocytosis can be considered as suggestive and evolution too, since the blood count was normal after 12 days of stopping the drug. So the implication of voriconazole was valued as likely.

However agranulocytosis has been reported in less than 2% of all patients treated with voriconazole in all therapeutic studies, clinicians should be aware and control blood count regularly even in case of a prolonged period treatement.

References:

• 1. Arimone Y, Bidault I, Dutertre J-P, et al. Updating the French method for the causality assessment of adverse drug reactions. Thérapie 2013;68:69–76

Disclosure of Interest: None declared.

280 ISoP18-1430 What Think Older Patients About Their Medicines?

280.1 F. Roque^*1, A. I. Plácido², F. Lima³, M. T. Herdeiro⁴

280.1.1 ¹Research Unit for Inland Development, Polytechnic Institute of Guarda, Guarda, Portugal; ²Research Unit for Inland Development, Polytechnic Institute of Guarda, Guarda, Portugal; ³Local Health Unit of Guarda, Guarda, Portugal; ⁴Department of Medical Sciences & Institute for Biomedicine, University of Aveiro, Aveiro, Portugal

Background/Introduction: Polypharmacy associated to the cognitive and physical functioning decline prone older patients to Drug-Related Problems. Drug-related problems are responsible for great percentage of hospitalizations and consequently increasing health care costs. Nevertheless, there are few studies exploring what older patients think about their medicines and how they are managing their medicines.

Objective/Aim: To explore how older patients are taking their medicines.

Methods: A qualitative research, in the form of focus group, was developed with older patients recruited in health primary care centers in inland region of Portugal, one of the most aged of the country. The sessions were moderated by a researcher, following a top guide, and were audio-recorded and transcribed by another researcher. The study was developed during May 2018. Participants were informed about the aim and the methodology of the study. A signed informed consent was obtained from each one of the participants. The study was approved by the ethical committee of the Center Health Region of Portugal, and from the Portuguese Data Protection Authority.

Results: Four focus groups were conducted with older patients (n = 25) taking more than five medicines. In general, all patients consider that medicines are important for them. Initially, the patients reported no problem with the management of their medicines, however, negative attitudes were revealed during the session. The main causes of incorrectly use of medicines observed was related with forgetfulness to take it, with uncertainty or lack of knowledge about the aim or function of the medicines. It was also observed that a large number of patients changes their medicines regimens (drugs being stopped, dosage modification, new drugs started). Patients revealed that they don´t report to the doctor their own alterations to the medicines regimens; the main cause of this behavior is related with forgetful, and with the fact that patient’s don’t want to see the doctor annoyed. Regarding the information on package leaflet, patients reported that they don´t like to read it, because it is very complicate to understand and they “see many contra-indications and adverse reactions”.

Conclusion: Older patients have the perception that medicines are important to improve their health. However, many of them are using their medicine incorrectly resulting in a large number of drug related problems in these population. Strategies should be developed to improve the efficient use of medicines by older adults.

Funding: This work was supported by Portuguese Foundation for Science and Technology (FCT/MCTES), Portugal 2020 and Centro 2020 grants [SAICT-POL/23585/2016].

Acknowledgment:

The authors wish to express their sincere thanks to Clinic Directors of primary care health centers and to all the patients that participated in the study. We are also thankful to Research Unit for Inland Development, Polytechnic Institute of Guarda (UDI/IPG) and to Institute for Biomedicine (iBiMED) for supporting this project. iBiMED (UID/BIM/04501/2013—POCI-01-0145-FEDER-007628) is supported by the Portuguese Foundation for Science and Technology (FCT/MCTES) through national funds (PIDDAC), and the co-funding by the FEDER, within the PT2020 Partnership Agreement and Compete 2020.

Disclosure of Interest: None declared.

281 ISoP18-1434 Acute Generalized Exanthematous Pustulosis Induced by Tenonitrozole

281.1 S. Yanisse^1,2, I. Daoudi², R. Zoubairi², H. Attjoui², A. Tebaa^*1

281.1.1 ¹Antipoison and Pharmacovigilance Center of Morocco, Ministry of Health, Rabat, Morocco; ²Faculty of Medicine and Pharmacy Rabat, Rabat, Morocco

Background/Introduction: Acute generalized exanthematous pustulosis (AGEP) is a severe form of toxin that associates a characteristic maculopustular rash, fever, and polymorphonuclear neutrophil leukocytosis [1]. It is also characterized by a delay of onset after treatment often shorter than that of maculopapular exanthemas. We report a case of PEAG induced by Tenonitrozole in a 38-year-old woman. 

Objective/Aim: The aim of this work is to determine the causality assessment between Acute generalized exanthematous pustulosis (AGEP) and the administration of the Tenonitrozole.

Methods: A 38-year-old woman developed a table of febrile exanthematous pustulosis 2 days after taking Tenonitrozole (ATRICAN^®) orally for the treatment of leucorrhea. She had no history of psoriasis. The biological assessment showed neutrophil leukocytosis, and a high CRP. The patient was hospitalized because of the effect, treatment with Tenonitrozole was discontinued and the evolution of the event was favorable.

In the case of this patient, to determine the imputability of Tenonitrozole we used the French method and that of the WHO.

Results: The intrinsic imputability score according to the French method revealed a causal relationship of I5 (C3S2) on a scale from 0 to 6, the level of informativeness was NI2… In previous studies, several cases of AGEP have been described with other drugs such as : antibacterial drugs, anticonvulsants,  and analgesics… [2, 3].

Conclusion: This article reports 1 case of AGEP related to administration of Tenonitrozole. Tenonitrozole induced AGEP is a rare but severe, extensive, and acute reaction. No specific therapy is available, and correct diagnosis generally leads to spontaneous recovery once the causative drug has been withdrawn.

References:

• 1. Brahimi N., et al. Pustulose exanthématique aiguë généralisée induite par le phloroglucinol (Spasfon^®). Ann Dermatol Vénéréol, 2017. 144:423–5

• 2. Saissi E-H, et al. Médicaments associés à la survenue d’une pustulose exanthématique aiguë généralisée. Ann Dermatol vénéréol. 2003;130:612–8

• 3. Sidoroff A, et al. Risk factors for acute generalized exanthematous pustulosis (AGEP)—results of a multinational case–control study (EuroSCAR). Br J Dermatol 2007;157:989–96

Disclosure of Interest: None declared.

282 ISoP18-1436 Planning for Implementation of a Structured Benefit–Risk Framework Within Industry

282.1 A. Cole^*1, L. Peppers¹

282.1.1 ¹Takeda Pharmaceuticals, Boston, United States

Background/Introduction: Evaluation of products’ benefits and risks is the basis of regulatory approval. Due to many factors, benefit–risk (B/R) assessments are conducted differently. This leads to variability of B/R assessments submitted to regulatory agencies as well as regulator conducted assessments. There have been several initiatives by regulators, including the FDA and EMA, IMI, PhRMA, and ICH to provide guidance and references on structured B/R assessment frameworks. Consequently, pharmaceutical industry has begun adopting these frameworks and implementing them within their companies [1–3].

Objective/Aim: To plan for implementation of a structured B/R framework within our company.

Methods: We took a stepwise approach to implementation of a structured B/R assessment framework. First was to assess the landscape, we conducted a search of published literature; attended benefit–risk conferences, seminars, and a FDA public meeting on structured B/R frameworks; and engaged in discussion with members of the pharmaceutical industry and B/R experts [1, 4–6]. We also reached out to multiple stakeholders across various functional areas in the company to assess: awareness in structured B/R assessment frameworks and possible existing frameworks within the company. Then, we drafted a multi-phase plan for implementing a framework.

Results: Our search of the published literature identified that implementing a structured B/R assessment provides improvement in the quality of B/R analyses [5]. Additionally, a structured B/R framework should be a cross-functional effort and ideally implemented early to allow refinement [6]. Based on our attendance at conferences/seminars and discussions with other companies and experts, we identified there are a various quantitative, qualitative, metric indices and visualization frameworks and tools that can be employed [1, 4]. The abundance of tools and frameworks has led to a lack of standardization among industry which poses as an early challenge in implementing a structured B/R framework. Internally, we found that awareness of B/R assessment frameworks was relatively low but interest was high. Therefore, Lunch and Learn sessions were held for members of the Medical Safety and Risk Management functions within the Global Patient Safety Evaluation department.

Conclusion: Implementing a structured framework requires proper planning and consideration before initiation. This task is further complicated due to the lack of publicly accessible information from companies that have gone through the implementation process. We have presented our approach to planning for implementation of a structured B/R framework within our company in hopes to create greater dialogue and information sharing among the pharmaceutical industry.

References:

• 1. Food and Drug Administration (US). Structured approach to benefit–risk assessment in drug regulatory decision-making. PDUFA V Plan (FY 2013–2017);2013. 1–13

• 2. European Medicines Agency [Internet]. London UK: EMA; c1995-2018. Benefit–risk methodology; [cited 2018]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/document_listing/document_listing_000314.jsp&mid=WC0b01ac0580981014

• 3. International Conference on Harmonisation. Revision of M4E guideline on enhancing the format and structure of benefit–risk information in ICH. Efficacy-M4E(R2); 2016. 4–10

• 4. Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium [Internet]. IMI Protect. Frameworks; [cited 2018]. Available from: http://protectbenefitrisk.eu/framework.html

• 5. Smith MY, Benattia I, Strauss C, Bloss L, Jiang Q. Structured benefit–risk assessment across the product lifecycle: practical considerations. Ther Innov Regul Sci 2017;51:501–8

• 6. Wang J, Wolka A, Bullok K, Anglin G, Radawski C, Noel R. Implementation of structured benefit–risk assessments in marketing authorization applications: lessons learned. Ther Innov Regul Sci 2016;50:718–23

Disclosure of Interest: None declared.

283 ISoP18-1437 Management of Medication Errors in Pharmacovigilance Centres: Case of Morocco

283.1 G. Benabdallah^*1, L. Alj¹, R. Soulaymani¹

283.1.1 ¹CAPM WHO CC, Rabat, Morocco

Background/Introduction: Since ever, Pharmacovigilance centres (PVC) collect Medication Errors (ME) within Adverse Drug Reactions (ADRs). From 2006, the Morrocan PVC collects and analyzes ME reports and implements risk minimization actions in order to avoid their recurrence and to improve patient safety. The national Moroccan ME database contains 2864 cases of MEs.

Objective/Aim: The aim of our study is to describe and analyse data related to ME collected in the Moroccan PV database to draw up MEs profile.

Methods: It is a retrospective study concerning ME data collected at the Moroccan PVC database during the year 2017.

We used Vigiflow as tool to extract and analyse MEs data from Vigibase and the National Coordinating Council for Medication Error Reporting and Prevention classification.

Results: The assessment of the ME database identified 285 cases of ME.

86% of ME reports came from health care professionals (HCP) (doctors (38%), pharmacists (22.4%), nurses (24%)) and 14% of the public.

The analysis of ME cases showed that 81% of the cases were asymptomatic ME, in which 42% were intercepted ME (detected before administration to the patient).

51 cases of ME (17.9%) were symptomatic ME causing harm to the patient. These symptomatic errors were mainly related to administration errors (50%), prescribing errors (9.8%) and concerned administration route errors (vaginal route instead of rectal route…), medication errors (suppositories for adults administered to infants…) and dose errors (taking excessive doses by forgetfulness or not understanding the dosage…)…

The most represented organ systems were the gastrointestinal system (21.5%) followed by neurological disorders (13.7%) and skin disorders (13.7%).

For asymptomatic errors, inclcuding intercepted errors, 37.6% of them were prescription errors, 68% administration errors and 6.5% self-medication errors. Errors concerned errors in doses, dosages, medications and use of expired medications… 23.5% of these cases were serious but all evolved favorably.

The most incriminated drugs with ME were antineoplastics (22.4%), antiinfectives (17.9%) and analgesics (4.1%). The analysis of ME cases enabled us to highlight flaws leading to MEs and to set up preventive actions to avoid the recurrence of them.

Conclusion: The CAPM recommended that HCP should take time to explain dosages and administration procedures to patients in order to avoid route administration errors, medication errors…, to systematically ask the patient if is known to be allergic to a given drug and to review the doses to be prescribed before any prescription.

Disclosure of Interest: None declared.

284 ISoP18-1439 Role of Patient Information on the Adverse Effects of Medicines in Oncology

284.1 H. Attjioui¹, S. Boutayeb², H. Errihani³, Z. Aliat⁴, R. Soulaymani⁵, A. Tebaa^*5, B. Meddah⁶

284.1.1 Faculty of Medicine and Pharmacy Mohamed V University, Rabat, Morocco; Faculty of Medicine and Pharmacy Mohamed V University, Rabat, Morocco; ³Faculty of Medicine and Pharmacy Mohamed V University, Rabat, Morocco; ⁵Antipoison and Pharmacovigilance Center of Rabat, Rabat, Morocco; Faculty of Medicine and Pharmacy Mohamed V University,Rabat, Morocco

Background/Introduction: Patients’ need for information and communication about treatments is important, especially the immediate and late side effects of treatments and their interactions with food.

In oncology, communication skills are the key to achieving the important objectives of patient contribution for the efficiency and quality in the treatment process.

Objective/Aim: To evaluate the potential impact of information on the side effects of cancer treatment on the safety of the patient’s therapeutic care.

Methods: We conducted a descriptive, prospective, observational study for 6 months, by interviewing patients who had startted chemotherapy at the National Institute of Oncology of Rabat.

Results: 154 patients have been identified. 65.6% were women with a mean age of 53.32 + 12.67 years. 52.3% of the treated patients were never informed of the undesirable effects of the cancer treatment, the rest of the patients. 47.7% reported receiving this information from their physician during the initial consultation. A large majority of the patients interviewed expressed their need for information. Indeed, 78% of them say they have particular questions that want their answers. The need for information on the adverse effects of cancer therapies and diet has been a constant concern and demand for a large number of patients. This need is often underestimated by practitioners. Several factors explain this conclusion: overwork, brief consultations, lack of availability of doctors and staff… Lack of information and patients’ ignorance of the adverse effects of cancer therapy can most often be life-threatening in treated patients.

Conclusion: Awareness of cancer patients about the risk of side effects will lead the patient to be more vigilant and self-report any abnormal effects, to reduce the risk of drug or food interactions. The provision of information on the therapeutic risk will improve the quality of life of the patients and will provide a better observance of the treatments.

Disclosure of Interest: None declared.

285 ISoP18-1442 Risk Management Plans: Implementation of the New Pharmacovigilance Legislation in Mexico

285.1 H. Duran^*1, R. Alatorre², O. Lara¹

285.1.1 ¹RMP Coordination, ²CEMAR, COFEPRIS, Mexico City, Mexico

Background/Introduction: NOM-220-SSA1-2012, Installation and operation of pharmacovigilance.

On July 19, 2017 the Official Mexican Standard “NOM-220-SSA1-2016, Pharmacovigilance Installation and Operation” was published in the Federal Official Gazette. Such Standard becomes effective 180 days after its publication, i.e. on January 15, 2018.

In that Standard are stablished new responsibilities of the holders of sanitary registries (marketing authorisations) and/or legal representatives in Mexico. The Risk Management Plan (RMP) is now applicable for all drugs and vaccines, but it´s related to the risk and postmarketing experience. 

Objective/Aim: Implementation of the new standar of Risk Management Plans.

Methods: According to the safety profile and risk assessment of each drug or vaccine, the RMP may have 3 categories, and the information included in it will depend on its classification, in accordance with the provisions of the Standard and the “Pharmacovigilance Guide for RMP Development”:

Category I: a. Generic drugs, including their reference drug.

Category II: Marketed medicines and vaccines, for which there is a safety concern or issue at national or international level that affects the risk/benefit ratio; New molecules, biological or biotechnological drugs with a sanitary registry issued by a regulatory authority recognized by the COFEPRIS, whose information from clinical studies allows for establishing a favorable safety profile; Orphan drugs with a sanitary registry or orphan drug acknowledgment issued by a regulatory authority recognized by the COFEPRIS; Drugs and vaccines with a well-known safety profile in other conditions and that have undergone changes that have an impact on their safety.

Category III: New molecules, biological or biotechnological drugs without a sanitary registry issued by a regulatory authority recognized by the COFEPRIS; Orphan drugs without a sanitary registry/orphan drug acknowledgment issued by a regulatory authority recognized by the COFEPRIS, whose information from clinical studies does not allow for establishing a favorable safety profile; Drugs and vaccines marketed in Mexico where there is evidence of a risk at national or international level that can potentially exceed the benefit.

“Pharmacovigilance Guide for RMP Development” is the first guide that was published, and also the first one to be on use. For that reason, we have some data that suggest that pharmacovigilance will be the most important information to keep on the market a medicine.

At this moment, there´s three strategies, the first one is the need to design new instruments for evaluation; the second one is the training to the industry and also strengthens human capital within the team.

Results: The submission of RMP increase 60%, most of them are category I 70%, therefore they don´t need any additional activity, the other 20% is category II and the rest is category III.

Conclusion: The implementation of the standar related to Risk Management Plan include the international standars and it´s possible to stablished the best activities posmarketing. The RMP are crucial to provide the best strategy to get information clear, with opotunity that coul be analyse and it´ll be helphul for stakeholders. The results of the implementation of each RMP will help to the analysis and interpretation that helps stakeholder to decide which will be the strategy need to be implemented.

References:

• 1. Diario Oficial de la Federación. Norma Oficial Mexicana NOM-220-SSA1-2016, Instalación y operación de la farmacovigilancia. http://www.dof.gob.mx/nota_detalle.php?codigo=5490830&fecha=19/07/2017

Disclosure of Interest: None declared.

286 ISoP18-1449 Predictors of Serious Adverse Events Following Immunization: 1-Year Pharmacovigilance Study in General Population

286.1 N. Lombardi^*1, G. Crescioli¹, A. Bettiol¹, M. Tuccori², M. Rossi², R. Bonaiuti¹, C. Ravaldi³, M. Levi⁴, A. Mugelli¹, P. Bonanni⁴, A. Vannacci¹

286.1.1 ¹Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Italy; ²Tuscan Regional Centre of Pharmacovigilance, Florence, Italy; ³CiaoLapo Onlus, Prato, ⁴Department of Health Sciences, University of Florence, Florence, Italy

Background/Introduction: An adverse event following immunization (AEFI) is a clinical occurrence which follows vaccination and does not necessarily have a causal relationship with vaccine use. Public health authorities of high-income countries noted an increase in number of vaccine hesitant patients/parents, based on presumed severe side effects.

Objective/Aim: The aims of this study were to describe frequency, preventability and seriousness of AEFI in relation to the number of administered doses, and to identify predictors of AEFI seriousness.

Methods: This is a retrospective study performed on reports of suspected AEFI collected in Tuscany (Italy) between January and December 2017. Patients’ demographics and clinical status, suspected vaccines, AEFIs description were collected. Preventability and causality were assessed using the Schumock and Thornton and the World Health Organization algorithms, respectively. Logistic regression was used to estimate the reporting odds ratios of potential predictors of AEFI seriousness.

Results: We observed 570 AEFIs on a total of 695769 doses administered (0.82/1000 doses). 139 AEFIs were reported as serious, of them 83 led to hospitalization. Reports were mostly related to one vaccine, and a total of 2–5 antigens (n = 364). Among reports with more than one vaccine, only 14 AEFIs presented a potential drug–drug interaction. The most frequently reported AEFI was “general disorders and administration site conditions”. The most frequently reported vaccine was Meningococcus B. Risk of serious AEFI was significantly higher in males (p = 0.036). The total number of administered antigens did not correlate with AEFI seriousness (p = 0.940). Overall, only 46 AEFIs (8.1%) were preventable, and the majority of them (n = 375) were consistently related with the immunization. Considering the number of administered doses, the highest rate of AEFI was observed for Pneumococcus vaccine (5.70/1000 doses).

Conclusion: The rate of AEFIs in Tuscany was considerably low and the majority of them was not serious (75.6%) and not preventable (91.9%). The number of administered antigens did not influence the risk of reporting a serious AEFI, confirming the safety of combination vaccines. Pharmacovigilance represents the best strategy to estimate and characterize the burden of AEFIs in general population, and supports healthcare professionals in addressing patients/parents’ concerns on vaccines recommended in Italian immunization programs.

Disclosure of Interest: None declared.

287 ISoP18-1452 Knowledge and Attitude of Healthcare Providers About Adverse Drug Reactions and Pharmacovigilance in Khartoum State

287.1 M. Elmusbah¹, H. Elkheir^*1

287.1.1 ¹Omdurman Islamic University, University of Science & Technology, Omdurman, Sudan

Background/Introduction: Healthcare professionals play a vital role in the accomplishment of safety surveillance of drugs. Adverse drug reaction (ADR) counseling and reporting provide a proper pharmacovigilance program.

Objective/Aim: To assess knowledge, attitude of health care providers towards adverse drug reactions at Khartoum state.

Methods: A cross-sectional study was done by using a self-administered structured questionnaire. Questionnaires were distributed to 225 healthcare providers (doctors and pharmacists) working at five healthcare facilities at Khartoum state response rate was 88.3%. Total number of health care providers included was 181.

Results: Out of the total respondents, 69.6% had good knowledge about the proper definition of ADR. Professional experience after graduation (as an indipendent variable) was found to be associated with knowledge of ADRs definition by heathcare providers (P-value = 0.042). Only 11.6% of the study subjects were trained on ADR reporting, most of the trained healthcare providers had good knowledge about the minimum reporting requirements. Most of the respondents 60.8% had good knowledge about which type adverse reactions they should report. Majority (96.7%) of healthcare providers were aware about the importance and benefits of ADR reporting. 77 (43%) of the participants stated that there were many factors preventing them from ADRs reporting. Barriers of reporting as stated by them were; lack of time, lack of reporting system and reporting forms, extra work generated by reporting and no need to report recognized adverse drug reactions. Most of the participants (72.4%) had a positive attitude about patient counseling. Age and professional experience after graduation (as indipendent variables) were found to be associated with better patient counseling attitudes (P-value = 0.008, P-value = 0.002) respectively. Only 17.7% of the participants knew about the existence of a pharmacovigilance center in Sudan. Around one-third (36.5%) of the participants were able to properly define pharmacovigilance. Occupation was found to be associated with knowledge about pharmacovigilance and presence of a center in sudan. Pharmacists and specially those with pharmacy specilities had great knowledge about pharmacovigilance and the center in Sudan (P-value = 0.000).

Conclusion: This study identified poor knowledge of health care providers about pharmacovigilance. There was a lack of ADRs reporting training among the healthcare professionals, which could be the main reason for under-reporting. Barriers of reporting as stated by them were; lack of time, lack of reporting system and of reporting forms and an increase in work load.

Disclosure of Interest: None declared.

288 ISoP18-1453 Importance of Background Information of the National Immunization Program for Children in Vaccine Signal Detection

288.1 W. Hilgersom^*1, F. Van Hunsel¹, E. van Puijenbroek^1,2

288.1.1 ¹The Netherlands Pharmacovigilance Centre Lareb, ‘s Hertogenbosch, The Netherlands; ²Pharmacotherapy, -Epidemiology & Economics, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands

Background/Introduction: Annually Pharmacovigilance Center Lareb receives a large number reports of Adverse Events Following Immunisation (AEFIs) after childhood vaccination. Usually, these concern reports of well-known AEFIs. With the current methods for signal detection, being case-by-case analyses and statistical screening of the database, potential signals related to the vaccination scheme of the National Immunization Program (NIP) are less likely to be detected. Detailed information of the NIP, like the number of vaccinees, administered vaccines, batch numbers, per vaccination moment is known. Amendments of the NIP such as changes in the administered vaccine over time are well documented. Current signal detection strategies, may profit from applying this background information.

Objective/Aim: To illustrate the possibility to detect new signals in well-known AEFIs by using by using background information of the NIP.

Methods: Based on a multiannual overview 2011–2017 of reported AEFIs after administration of DTPa-IPV (Diphtheria, acellulair Pertussis, Tetanus, inactivated Poliovirus) booster vaccine at the age of 4, we investigated the added value of using background information (number of vaccinees and changes in administered vaccines) in signal detection.

Results: Reports of AEFIs after administration of DTPa-IPV at the age of 4 years, in the period 2011–2017 were selected and by using the exact number of vaccinees the reporting rate per 10.000 vaccinees were calculated. A graphical overview showed an increase in 2015 and a sharp decrease in 2017. The decrease was outspoken in reports of extensive swelling of the vaccinated limb (ELS).

The decrease in 2017 appeared to be linked to the replacement of Infanrix-IPV^® by Boostrix Polio^® in in the NIP in the spring of 2017. ELS was more frequently reported after administration of the brand Infanrix-IPV^® compared to Boostrix Polio^® (OR 9.1, 95% CI 5.1–16.2). The increase in 2015 may be related to a vaccine change in the primary vaccine series at infant age. Children primed with Infanrix hexa^® reported more frequently an AEFI after administration of Infanrix-IPV^® at the age of 4 compared to children primed with Pediacel^® (OR 2.0; 95% CI 1.9–2.2).

Conclusion: By using background information of the program, two signals were detected related to well-known AEFIs. Using background information of the NIP is of added value in vaccine signal detection.

Disclosure of Interest: None declared.

289 ISoP18-1455 A Novel Approach to Standardizing Data & Detecting Duplicates Across Adverse Event Data Sources Using Machine Learning

289.1 S. Desai^*1, K. Chan², K. Bannout¹, E. Mingle¹, J. Freeman³, U. Parikh², N. Becker²

289.1.1 ¹Global Drug Safety and Risk Management, Celgene Corp, Summit, NJ, United States; ²Informatics, Enigma, New York, NY, United States; ³Global Safety and Risk Management, Celgene Corp., Summit, NJ United States

Background/Introduction: Efficient and reliable PV processes are mandatory for allowing Marketing Authorization Holders to accurately understand and respond to the adverse events associated with their drugs and thus have important implications on the drug’s benefit risk profile. A Pharmacovigilance function within life science organizations faces many challenges due to the variety and quality of incoming adverse event case data. Some of these challenges include:

• 1. Duplication

Finding duplicates among incoming case reports and across disparate sources is a complex and mandatory task.

• 2. Manual and inefficient process

Ensuring optimal processing and computational complexity to detect duplicates to enable speedy access to highly critical data.

• 3. Scalability

As new sources of AE data emerge, existing duplicate detection processes become unsustainable.

Objective/Aim: To address these challenges in AE data and Pharmacovigilance workflows, we sought out to develop a methodology for detecting duplicate records within AE reporting data to account for its scale and heterogeneity with speed and accuracy.

Methods: Data from FDA (2004–Present), WHO Vigibase (1968–Present) was used for

• 1. Case ingestion and standardization

• 2. Case clustering: spark-based locality based hashing and calculation of Jaccard similarities run

• 3. Case deduplication: supervised learning with PV Scientists for labelled data and model tuning

Results: Using supervised learning models from PV scientists, we were able to probabilistically stratify 5.2% of FDA AERS and Vigibase cases into low and high confidence duplicates for further manual curation. 59,000 adverse events reports in FDA AERS data alone were found to be high confidence duplicates. Over 18,000 reports were detected as duplicates in the WHO Vigibase data. The team was able to achieve 70,000 pairwise duplicate checks per minute using this scaled, cloud-computing approach. This novel duplicate detection mechanism processed over 20 million unique adverse events reports in under 24 h.

Conclusion: Accurate signals detection relies on resolved and timely data. The team’s approach here provides a novel and scalable approach to efficiently detect duplicates among large, bulky, and messy datasets. Furthermore, the process reveals key systematic patterns in how duplicates emerge in Adverse Events reporting systems. These patterns could only be revealed through this probabilistic, non-rules based approach to duplicate detection—previous attempts using narrow heuristics of duplicate detection could not reveal. We believe this approach allows PV departments to analyze public and private AE data rapidly and limits duplicates without delaying data release. It also creates a data driven framework that evolves Pharmacovigilance by leveraging emerging sets of tools and methods built for big data.

References:

• 1. Norén GN, Orre R, Bate A. A hit-miss model for duplicate detection in the WHO drug safety database. Proceeding of the eleventh ACM SIGKDD international conference on Knowledge discovery in data mining—KDD 05. 2005

Disclosure of Interest: S. Desai Shareholder of: Celgene Corp, Employee of: Celgene Corp, K. Chan Consultant for: Celgene Corp, K. Bannout Shareholder of: Celgene Corp, Employee of: Celgene Corp, E. Mingle Shareholder of: Celgene Corp, Employee of: Celgene Corp, J. Freeman Shareholder of: Celgene Corp, Employee of: Celgene Corp, U. Parikh Consultant for: Celgene Corp, N. Becker Consultant for: Celgene Corp.

290 ISoP18-1456 A Systematic Step-by-Step Approach to Vaccine Signal Detection

290.1 W. Hilgersom^*1, F. Van Hunsel¹, E. van Puijenbroek^1,2

290.1.1 ¹The Netherlands Pharmacovigilance Centre Lareb, ‘s Hertogenbosch, The Netherlands; ²Pharmacotherapy, -Epidemiology & Economics, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands

Background/Introduction: Pharmacovigilance Centers receives large numbers of reports of Adverse Events Following Immunisation (AEFIs) after childhood vaccination; mostly concerning reports of well-known AEFIs. Usually, methods for signal detection are based on either case by case analysis or disproportionality analysis. Analysing large numbers of reports in routine signal screening, carries the risk that clinical and pharmacological knowledge is not taken into account. This may limit the capability to detect potential signals. Signal detection can be optimised by taking detailed information from the reported AEFIs as well as background information of the National Vaccination Program (NIP), like the numbers of vaccinees, administered vaccines, batch numbers and changes in the NIP over time, into account.

Objective/Aim: To illustrate the use of a step by step approach for vaccine signal detection, in which detailed information from the reported AEFIs and background information of the NIP is taken into account.

Methods: A 6-step approach for vaccine signal detection in frequently reported well-known AEFIs in a vaccination program.

• 1. Collecting information: about background incidence of AEFI, their clinical characteristics, changes in NIP, media attention.

• 2. Selection of dataset: Select reports of the vaccination program of interest, for example The National Immunisation Program Children and defined the period of interest.

• 3. Selection of cases: Define the cases, for example all reports of AEFIs after administration Diphtheria, Tetanus, acellulair Pertussis, Inactivated poliovirus (DTPa-IPV) of 4 year olds in the period of interest.

• 4. Information of exposed: Collect information of the number of vaccinees, per administered vaccine (brand name) per year. When needed, the batch number can be taken into account.

• 5. Define co-variables for stratification: e.g., latency, age, gender, injection site, vaccination moment, vaccine brand name.

• 6. Select analyses method: Description of cases, analysis of reporting patterns/clustering, disproportionality analysis, trend-analyses, batch-analyses, evaluation of cases against the background of changes in the NIP.

Results: By using the described 6-step approach we detected three new signals in well-known AEFIs. Analysis of reports of injection site abscesses at infant age showed clustering of cases of site abscesses around the 3rd or 4th injection moment at the injection site of DTPa-HBV-IPV/Hib. In an overview of AEFIs after administration of DTPa-IPV at the age of 4 an increase was detected in the number of reports in 2015 and a decrease in 2017. The 2015 increase may have been related to a change in priming at infant age. The decrease in 2017 was linked to the replacement of different brands DTPa-IPV vaccines used.

Conclusion: A systematic step-by-step approach and taking detailed information and background information into account is of added value in vaccine signal detection.

Disclosure of Interest: None declared.

291 ISoP18-1460 Factors Associated with Serious Medication Errors in Moroccan Pharmacovigilance Database from 2006 to 2016

291.1 L. Alj¹, A. Khattabi¹, R. Benkirane¹, A. Tebaa², R. Soulaymani Bencheikh^*2

291.1.1 ¹Ecole Nationale de Santé Publique, Rabat, Morocco; ²Centre Anti Poison et de Pharmacovigilance du Maroc, Rabat, Morocco

Background/Introduction: Although serious medication errors “MEs” are relatively rare [1], they have considerable health consequences [2], It is essential to identify factors associated with their occurrence in order to minimize risks.

Objective/Aim: To determine factors associated with serious medication errors associated with adverse drug reactions in Moroccan pharmacovigilance database from 2006 to 2016.

Methods: We conducted a secondary analysis of the database of MEs associated with adverse drug reactions “ADRs” reported to Moroccan Pharmacovigilance Centre from 2006 to 2016. MEs were considered as serious when they lead to serious ADRs according ICH E2A guidelines [3]: the ADR resulted in death, life threatening, hospitalization or prolongation of existing hospitalization, congenital malformation, permanent disability or medically important reaction. Epi info 7 software was used to perform descriptive statistics and bivariate analysis between serious MEs and none serious ones. The statistical significance level was set at p < 0.05.

Results: Among reported MEs associated with ADRs (n = 734), 23.43% (n = 172) were classified as serious. The incidence rate of serious MEs was 5 cases per 1 million inhabitants. The type errors statistically associated with serious MEs were drug prescribing errors (p < 10⁻⁹), inappropriate schedule of drug administration (p = 0003) and incorrect drug administration dosage form (p = 0.03). The Anatomical Therapeutical Chemical “ATC” groups A (p = 0.0000004), G (p = 0.001) and L (p = 0.01) were statistically associated with serious MEs. The system organ classes statistically associated with MEs were: gastrointestinal (p < 10⁻¹⁰), urinary (p = 0.0000001), psychiatric (p = 0.007), respiratory (p = 0.002) disorders, vascular-bleeding and clotting disorder (p = 0.006) as well as metabolic and nutritional disorders (p < 10⁻¹⁰).

Conclusion: In order to minimize risk related to serious MEs, educating programs should be designed for health care professionals about common types and causes of MEs in our context as well as high risk ATC groups identified. Raising awareness of patient about the importance of their engagement in their therapeutic care will help to prevent MEs occurrence. Implementing these actions will contribute to insure patient safety.

References:

• 1. Medication Errors: Technical Series on Safer Primary Care. Geneva: World Health Organization; 2016. Licence: CC BY-NC-SA 3.0 IGO

• 2. Jember A, Hailu M, Messele A, Demeke T and Jember MH et al. Proportion of medication error reporting and associated factors among nurses: a cross sectional study. BMC Nursing 2018;17:9

• 3. International conference on Harmonisation of technical Requirements for registration of pharmaceuticals for human Use. ICH harmonised tripartite guideline. Post-approval safety data management: definitions and standards for expedited reporting. E2D Current Step 4 version dated 12 November 2003. https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2D/Step4/E2D_Guideline.pdf

Disclosure of Interest: None declared.

292 ISoP18-1461 Media-Vigilance Moroccan Experience

292.1 I. Semlali Hassani¹, A. Tebaa^*1, R. Soulaymani Bencheikh¹

292.1.1 ¹Centre Antipoison et de Pharmacovigilance, Rabat, Morocco

Background/Introduction: The media vigilance is a media specialty for continuous information monitoring through different media sources (TV/Radio, newspapers, social networks, etc.). This allows us to be informed on all events related our vigilance field (as an adverse reaction, misuse, medication errors and intoxications…). Also, it permits us to communicate on the risk concerning all products used (health products, consummation products and environmental products).

Objective/Aim: The aim of this paper is to describe the steps used by the Moroccan Poison Control and Pharmacovigilance Center (CAPM) which it applied to the media vigilance.

Methods: We searched concrete examples from prior information related to vigilances published by Moroccan Medias (such as cosmetic-vigilance, herbal-vigilance and others). We screened the collected cases in order to detect signals related health products usage. 

Results: The process of media vigilance is based on integration of tools and techniques classified in six consecutive steps: the information collected through different media sources, the analysis of information collected (validation, quality, causality assessment and preventability), their records in a database, then the signal detection, the alert generation and finally the risk minimization. Among the risk minimization measures, the risk communication is the principal action used by the CAPM to sending credible messages to prevent the risks or reduce the gravity related to the use or to the exposure to certain products (as for example: cream shirley which is used to clear the skin).

Conclusion: The media are an important stakeholder in the vigilance system. The relation between the media and the health system must be rationalized. This allows to communicate permanently and early the risk, so to incite the target population to take actions to avoid this risk. All this can reinforce our vigilances for the population security.

References:

• 1. Chaoui Hanane and all. Vigilances et sécurité sanitaire. Revue Toxicologie Maroc 2014;22:3–4

• 2. Semlali Hassani Ilham and all. La Toxicovigilance au Maroc: de la notification des d’intoxications à la lutte anti-toxique. Revue Toxicologie Maroc 2011;11:9–13

• 3. Rhalem Naîma and all. Usage des plantes et médiavigilance. Revue Toxicologie Maroc 2013;19:15

• 4. Sefiani Houda. Crème “Shirley “: grand danger à petit prix. Revue Toxicologie Maroc 2010;4:15

• 5. Soulaymani Rachida Bencheikh. La revue officielle du Centre Anti Poison du Maroc: Toxicologie Maroc. Revue Toxicologie Maroc 2009;1:2

Disclosure of Interest: None declared.

293 ISoP18-1462 Iatrogenic Adrenal Insufficiency Following Use of Corticosteroids in HIV Infected Patients Receiving Cobicistat-Based Antiretroviral Regimen

293.1 S. D’incau¹, J. Jaafar², R. Ing-Lorenzini^*3, A. Calmy¹

293.1.1 ¹HIV unit, Division of Infectious Diseases; ²Division of Endocrinology, Diabetology, Hypertension and Nutrition; ³Division of Clinical Pharmacology and Toxicology, Hôpitaux Universitaires de Genève, Switzerland, Genève, Switzerland

Background/Introduction: Cobicistat was recently marketed to enhance the activity of antiretroviral medications included in fixed dosed combinations (elvitegravir, darunavir). Cobicistat is a selective inhibitor of cytochromes P4503A(CYP3A), whereas ritonavir, a 1^st generation anti-HIV drug booster, inhibits other CYPs and is also an enzyme inducer. The inhibitory effect of cobicistat on metabolism and transport of other molecules is a source of concern in polymedicated patients. The drug–drug interaction (DDI) between ritonavir and corticosteroids is well described and may result in an iatrogenic Cushing syndrome [1–3]. The involved mechanism being an inhibition of steroids metabolism through CYP3A4/5, the same DDI is expected with cobicistat. Nevertheless, it is poorly documented.

Objective/Aim: To describe the clinical impact of DDI between corticosteroids and cobicistat in a HIV consultation of a large University Hospital in Switzerland (HUG) and to confront it to a literature review.

Methods: We report a case of Cushing syndrome in a patient taking concomitantly cobicistat and steroids in an HIV unit (HUG). Using MEDLINE/Pubmed we searched for similar published cases, in French or English. Key words used were: (cortico)steroid + cobicistat.

Results: Experience in our HIV unit:

The patient developed a Cushing syndrome (moon face, buffalo hump, acne, weight gain) 8 weeks following a single interlaminar injection of triamcinolone performed by a private rheumatologist. These clinical features associated with suppressed cortisolemia [8 nmol/l (N = 166–507)] and ACTH [4.1 ng/l (N = 7.2–63.3)] signed an iatrogenic Cushing syndrome. Triamcinolone suppresses the hypothalamic–pituitary–adrenal (HPA) axis but is undetectable with routine corticosteroids detection tests (chimiluminescence). Outcomes are described in Table 1.

Literature review:

We found only one case report of adrenal insufficiency following injection of triamcinolone in patients taking cobicistat [4]. Another similar case described an interaction between fluticasone nasal drops and cobicistat [5].

Conclusion: Cobicistat administration contributed to the development of profound and persistent adrenal suppression due to the significant inhibition of metabolism of a single interlaminar triamcinolone injection.

There is no pharmacokinetics study assessing the impact of cobicistat on triamcinolone elimination. A case report [3] showed a triamcinolone acetonide half-life prolonged at least 170-fold in presence of ritonavir (2–3 h to 21.3 days). As ritonavir and cobicistat have the same strong inhibitory effect on CYP3A, we could expect similar results. The corticosteroids monograph often fails to mention this potential interaction. Therefore, there is a real need for active pharmacovigilance to document its clinical impact.

Monitoring DDI is a critical aspect of evaluation in HIV infected patients and all professionals involved in the care of such patients should have a heightened sense of awareness for interactions. Active pharmacovigilance is warranted.

References:

• 1. John G, Ollo D, Meyer P, Herold M, Samer CF, Alex, et al. Clinical course and management of iatrogenic Cushing’s syndrome after co-administration of injected-triamcinolone and ritonavir: a systematic review. J Antivir Antiretrovir 2013;5(7):180–4

• 2. Schwarze-Zander C, Klingmüller D, Klümper J, Strassburg CP, Rockstroh JK. Triamcinolone and ritonavir leading to drug-induced Cushing syndrome and adrenal suppression: description of a new case and review of the literature. Infection 2013;41(6):1183–7

• 3. Ramanathan R, Pau AK, Busse KH, Zemskova M, Nieman L, Kwan R, et al. Iatrogenic Cushing syndrome after epidural triamcinolone injections in an HIV type 1-infected patient receiving therapy with ritonavir-lopinavir. Clin Infect Dis 2008;47(12):e97–9

• 4. Wassner C, Maiti S, Kodroff K, Cohen H. Iatrogenic Adrenal Insufficiency Secondary to Combination Therapy with Elvitegravir/Cobicistat/Tenofovir Disoproxil Fumarate/Emtricitabine and Interlaminar Triamcinolone Injection in an AIDS Patient. J Int Assoc Provid AIDS Care 2017;16(6):535–9

• 5. Lewis J, Turtle L, Khoo S, Nsutebu E. A case of iatrogenic adrenal suppression after co-administration of cobicistat and fluticasone nasal drops. Aids 2014;28(17):2636–7

Disclosure of Interest: None declared.

294 ISoP18-1464 Importance of Pharmacovigilance in ihe Pediatric Population

294.1 F. Rodieux^*1, K. Ing-Lorenzini¹, V. Rollason¹

294.1.1 ¹Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Genève, Switzerland

Background/Introduction: Clinical trials are usually conducted in a limited time and on a selected population, most often excluding children. These clinical trials provide a first safety profile of drugs, highlighting only the most common adverse drug reactions (ADR). In addition, due to growth and physiologic maturation, ADRs may be different in children compared to adults and extrapolation of data obtained in adults, including safety data, may be inaccurate in children. These last years, restrictions of use involving only children have occurred (e.g. codeine) as well as market withdrawals (e.g. specific vitamin D preparations).

Objective/Aim: To review the number of pediatric-related ADR reports received in our Regional Pharmacovigilance Center during 1 year.

Methods: We reviewed the number of pediatric-related ADR reports received in our Regional Pharmacovigilance Center during 1 year.

Results: In the Geneva Regional Pharmacovigilance Center from 2013 to 2017, 167 pediatric-related (age 0–17) reports were declared on a total of 2342 reports, i.e., 7.2%. Similarly, in May 2018, there were 1,389,501 pediatric-related reports among a total of 16,977,646 reports, i.e., 8.2% in the WHO global database of Individual Case Safety Reports, VigiBase™.

Conclusion: Pediatric-related notifications may seem low considering that children represent 20–30% of the total population in industrialized countries and up to 50% in some countries of sub-Saharan Africa. This may be partly explained by less drug prescriptions in children but also by the difficulty to detect complaints or signs of ADRs in this population. As in the adults, notifications suffer from an important underreporting due to multiple causes, such as lack of time, misunderstanding of public health importance and ignorance of reporting systems.

Pharmacovigilance, which is based on spontaneous notifications of adverse drug reactions, helps to refine the risk/benefit ratio of drugs prescribed in children and to increase the drugs safe use after market launch. The importance of pharmacovigilance in general and in the pediatric population in particular and the modalities of reporting need to be regularly reminded to health professional.

Disclosure of Interest: None declared.

295 ISoP18-1467 Active Surveillance of Adverse Events Following Immunization (Aefi) Using Both Paper Forms and SMS

295.1 L. Gonella^*1, D. Benetti¹, E. Arzenton¹, L. Magro¹, R. Leone¹, U. Moretti¹

295.1.1 ¹Department of Diagnostics and Public Health, Section of Pharmacology, University of Verona, Verona, Italy

Background/Introduction: The European PV legislation aim to promote patient reporting, using alternative methods compared to paper or web. In Italy large part of the reports related to adverse event following immunization (AEFI) come from vaccination units (VUs). Previous studies show the potential of the short message text service (SMS) in the AEFIs reporting through mobile phones [1–3], widely used in Italy.

Objective/Aim: The aim of this study was to promote AEFI reporting involving parents of children in VUs through both paper form and SMS.

Methods: Two different periods of surveillance were defined. In the first one (Phase 1) a paper form (called vaccination diary) were delivered to all parents of children (< 24 months) vaccinated in the study period (3 months) in selected VUs. Parents returned the forms to the VUs describing potential AEFIs, but it was also possible to report that no adverse event occurred. In the second part (Phase II) all the information about children vaccinated during the study period (1 month) in the selected VUs were collected in a specific web platform. An SMS was sent by the platform to all the parents, asking for the description of potential AEFIs. The SMS received from the parents were recorded in the platform and matched with the information about the vaccination. A NLP software analyzed the received SMS and highlighted in the platform the messages describing serious adverse events.

Results: During the first phase 9502 forms were delivered to parents, 4653 filled forms returned back to the VUs (49%) and 2223 of them described at least one AEFI (23.4%). In the second phase 1362 SMS were sent by the platform, 895 SMS were received (65.7%) and 634 of them described at least one AEFI (46.5%). The parents’ response rates achieved in both phases were significant but with a higher value using SMS due to an easier and faster way of communication compared to paper form (65.7 vs 49%). For the same reason the incidence of reported AEFI using SMS was significantly higher compared to paper (46.5 vs 23.4%) and much higher than the usual spontaneous reporting. The surveillance using SMS was much easier than the procedure with the vaccination diary, with a very low impact on the work of health operators in VUs and with no negative influence on the vaccination hesitancy. Moreover, the software was very efficient in highlighting serious event showing a sensibility of 87.5% and a specificity of 97.6%. Only one “false negative” occurred, this SMS reported “fever 40 °C”.

Conclusion: The results show the potential and the efficiency of an SMS-based reporting system in comparison to other procedure of stimulated reporting.

References:

• 1. Cashman P, Moberley S, Dalton C, Stephenson J, Elvidge E, Butler M, Durrheim DN. Vaxtracker: active on-line surveillance for adverse events following inactivated influenza vaccine in children. Vaccine 2014;32(42):5503–8

• 2. Westphal DW, Williams SA, Leeb A, Effler PV. Continuous active surveillance of adverse events following immunisation using SMS technology. Vaccine 2016;34(29):3350–5

• 3. Regan AK, Blyth CC, Tracey L, Mak DB, Richmond PC, Effler PV. Comparison of text-messaging to voice telephone interviews for active surveillance of adverse events following immunisation. Vaccine 2015;33(31):3689–94

Disclosure of Interest: None declared.

296 ISoP18-1468 Automatic Encoding of ADRS in Italian Spontaneous Reporting System

296.1 E. Arzenton¹, G. Pozzani¹, R. Lora¹, L. Magro^*1, L. Gonella¹, R. Leone¹, U. Moretti¹

296.1.1 ¹Department of Diagnostics and Public Health, Section of Pharmacology, University of Verona, Verona, Italy

Background/Introduction: In almost all web reporting systems the reporter must select the adverse drug reactions (ADRs) among a list of MedDRA terms through a drop-down menu. This approach reduces the work related to encoding but it can influence the reporter’s expressiveness and cause encoding errors. In the Italian web reporting system, the ADR description is a free-text field. MedDRA terms are encoded by a Natural Language Processing (NLP) software and manually validated.

Objective/Aim: The aim of this study was to evaluate the performance of the NLP software in encoding adverse reaction description with MedDRA terms.

Methods: The NLP software has been developed by the University of Verona [1]. The software performance has been evaluated on a sample of 1810 ADRs descriptions randomly selected from the reports inserted in the Italian spontaneous reporting database in 2015. The reports have been grouped in 5 groups according to the length of the ADR description (Group 1, ≤ 50 characters; Group 2, 51–100; Group 3, 101–150; Group 4, 151–200; Group 5, > 201). Three experts reviewed the results of auto encoding and categorized the terms in a standard macro classification. True positives (TP) were terms correctly encoded, false positives (FP) were terms wrongly retrieved or added by the software, whereas false negatives (FN) were terms not identified and not coded by the software. The results for each group were presented also as precision, positive predictive value (TP/TP + FP), and recall or sensitivity (TP/TP + FN).

Results: In the 1810 ADR descriptions 4625 MedDRA terms have been encoded by the software. Table 1 summarizes the results of auto encoding. The number of errors increases as expected according to the length of the text string. Both recall and precision were very high in Group 1 and gradually decreased in Group 5. On the global dataset, the encoding of ADRs was completely correct in 1181 reports (65.2% of the total included reports). False positives were often related to therapeutic indications or concomitant pathologies reported in the description and encoded as ADRs. False negatives included mainly synonyms not present in the Italian translation of MedDRA.

Conclusion: The performance of the encoding software was very good leading to a faster and more accurate encoding of ADRs by the qualified person responsible for ADR report management.

References:

• 1. Zorzi M, Combi C, Pozzani G, Moretti U. Mapping Free Text into MedDRA by Natural Language Processing: A Modular Approach in Designing and Evaluating Software Extensions. In Proceedings of the 8th ACM International Conference on Bioinformatics, Computational Biology, and Health Informatics (BCB) 2017, Boston, MA, USA, August 20–23, 2017, pp 27–35.

Disclosure of Interest: None declared.

297 ISoP18-1471 Prevalence Study of Adverse Effects Associated with the Use of Medicinal Plants at the National Institute of Oncology (Morocco)

297.1 A. Chebat¹, H. Errihani², M. El khattab ³, S. Skalli⁴, A. Tebaâ⁵, R. Soulaymani^*6

297.1.1 ¹Centre Antipoison et de Pharmacovigilance du Maroc, Rabat, Morocco; ²Faculté de Médecine et de Pharmacie; ³Centre d’oncologie et d’hématologie pédiatrique, Faculté de médecine et de pharmacie; ⁴Faculté des Sciences Rabat, Rabat, Morroco; ⁵Centre Antipoison et de Pharmacovigilance; ⁶Centre Antipoison et de Pharmacovigilance, Faculté de Médecine et de Pharmacie, Rabat, Morocco

Background/Introduction: He use of Hebal Medicines in Morocco is wide and without a prescription. Unfortunately, this behavior may contribute to the occurrence of AEs and drug interactions and may delay healing of many patients. Poison control center and Pharmacovigilance of morocco sounds alarm and warns about the increasing usage of herbs.

Objective/Aim: minimizing the risks of poisoning and adverse effects related to the use of medicinal plants in concomitance with anticancer drugs.

Methods:

Thissurvey is based on the use of a 10-item questionnaire used to gather the necessary information about the patient and the MPs used.

Thissurvey is based on the use of a 10-item questionnaire used togather the necessary information about the patient and theMPs used.

• Patient information

• Information on plant

• Dosage and duration of treatment

• Adverse effects resulting from the use of HM

Results:

Our researches on the 1234 patients surveyed showed that 35% use MP. Among them, 98.5% did not disclose the information to their physicians dealing with a sex ratio of 0.6. Of all patients surveyed having used MP, 16% experienced adverse effects more or less serious (68% of women). They cite the tubule-interstitial nephritis, which represents the most common side effect (15.7%) followed by liver damage (12.9%), diarrhea (5.7%), vomiting, constipation and rectal bleeding with a frequency of 4.3% each.

Our researches on the 1,234 patients surveyed showed that35% use MP. Among them, 98.5% did not disclose the informationto their physicians dealing with a sex ratio of 0.6. Of allpatients surveyed having used MP, 16% experienced adverseeffects more or less serious (68% of women). They cite thetubule-interstitial nephritis, which represents the most commonside effect (15.7%) followed by liver damage (12.9%), diarrhea (5.7%), vomiting, constipation and rectal bleeding with a frequencyof 4.3% each.

Conclusion: Although some plants are criminalized such as Nigellasativa L. and Aristolochia longa L. The use of MP by Moroccanpatients is an alternative. These plants can be used before, afteror during medical treatments which contributes to the occurrence of Adverses Effects.

Consequently, some recommendations can be imposed:

• Ensure products are regulated by the national health

• Do not prescribe therapeutic treatments through the media

• Facilitate families access to health care and humane health facilities

References:

• 1. Skalli S, Soulaymani RB. Safety monitoring of herb–drug interactions: a component of pharmacovigilance. Drug Saf 2012;35:785–91

• 2. Stickel F, Patsenker E, Schuppan D. Herbal hepatotoxicity. J Hepatol 2005;43:901–10

• 3. Sur P. Trigonella foenum graecum (fenugreek) seed extract as anantineoplastic agent. Phytother Res 2001;15:257–9

• 4. Vanherweghem JL. Aristolochia sp and chronic interstitial nephropathiesin Indians. Lancet 1997;349:1399

• 5. Vickers KA, Jolly KB, Greenfield SM. Herbal. medicine:women’s views, knowledge and interaction with doctors: a qualitative study. BMC Complement Altern Med 2006;6:40

• 6. White P. Complementary medicine treatment of cancer, a surveyof provision. Complem Ther Med 1998;6:10–3

Disclosure of Interest: None declared.

298 ISoP18-1472 Subclinical Hypothyroidism Associated to Interferon Beta 1A

298.1 F. Ben Salem¹, A. Zaiem¹, I. Hamza¹, M. Bouhlel^*1, S. El Aidli¹, R. Daghfous¹, S. Kastalli¹

298.1.1 ¹National Centre of Pharmacovigilance, Tunis, Tunisia

Background/Introduction: Interferon beta (INFß) is mainly used to treat remittent multiple sclerosis [1]. The most common adverse effects are gastrointestinal, cutaneous, hematological and psychiatric. Since 1985, several clinical cases of hypothyroidism have been reported with interferon [2].

Objective/Aim: To report a case of subclinical hypothyroidism associated to INFß1-a in a patient with autoimmune thyroiditis.

Methods: The case was notified in the natinal centre of pharmacovigilance and analyzed according to the french method of drug imputabilty of Begaud et al.

Results: A 43-year-old woman with a history of Hashimoto’s thyroiditis with positive anti-thyroperoxidase and anti-thyroglobulin native antibodies, has been followed since 2011 for remittent multiple sclerosis. The patient was euthyroid. She started the treatment by Rebif^® (INFß1-a) 1injection ×3 by week since October 2015. The patient developed hypothyroidism which was discovered in thyroid control test on 05/10/2016 (FT4: 8.77 pmol/l, VN 9–20 and TSH-ultrasensitive: 9.12 mIU/l,VN 0.4–4.5). Liver function and blood count were normal. The dose of INFß1-a was decreased to 1injection by week. Two weeks later, thyroid test was within normal limits (FT4: 12.21 pmol/l, TSH-ultrasensitive: 2.59 mIU/l).

Conclusion: The responsibility of INFß1-a was retained because of a compatible delay (1 year) and favorable and spontaneous evolution after decreasing doses.

Patients treated by INFß 1-b can develop thyroid dysfunctions in 2–10% (hypothyroidism and less frequently hyperthyroidism) or exacerbate pre-existing thyroid disorders [3].

The mechanism of hypothyroidism can be related to autoimmune aggression in subjects with a personal or familial predisposition to autoimmune pathologies in particular thyroid diseases, or due to direct drug toxicity (dose dependent). These two mechanisms may be interlinked which is the case of our patient. Thyroid dysfunction mostly occurs in the first year of treatment with INFß and is generally subclinical and reversible [3].

Although not frequent, hypothyroidism is a non-negligible complication of treatment by INFß which imposes the taking into account of the personal or familial history of dysthyroidism or autoimmune diseases and performing a thyroid test. This side effect doesn’t contraindicate the pursuit of treatment. In some cases the decreasing of doses can be necessary.

References:

• 1. F Monzani, N Caraccio, G Meucci, F Lombardo, G Moscato, A Casolaro, et al. Effect of 1-year treatment with interferon-b1b on thyroid function and autoimmunity in patients with multiple sclerosis. Eur J Endocrinol 1999;141:325–31

• 2. Louis SIBERT, Marc PLANET, Jean-Marc KUHN, Marc ANNOOT, Bernard BOILLOT, Philippe GRISE. Hypothyroïdie et immunothérapie par Interféron ou Interleukine pour adénocarcinome rénal métastasé. Prog Urol 1994;4:582–7

• 3. L. Durelli, B. Ferrero, A. Oggero, E. Verdun, A. Ghezzi, E. Montanari, M. et al. Liver and thyroid function and autoimmunity during interferon-1b treatment for MS. Neurology 2001;57:1363–70

Disclosure of Interest: None declared.

299 ISoP18-1474 Measures Taken in Response to the Underreporting of Adverse Drug Reactions in Rabat University Hospital Centers (Chu)

299.1 S. Yanisse^1,2, R. Zoubairi^1,2, A. Tebaa^*2

299.1.1 ¹Faculty of Medicine and Pharmacy Rabat, Rabat, Morocco; ²Antipoison and Pharmacovigilance Center of Morocco, Ministry of Health, Rabat, Morocco

Background/Introduction:

Objective/Aim: The aim of this study is the implementation of a system focused on instilling a culture of pharmacovigilance among the doctors at Rabat’s CHU by raising awareness about the major importance of reporting adverse drug reactions (ADR) to the National Pharmacovigilance Center (NPVC).

Methods: In order to solve the problem of underreporting of ADRs in Rabat’s health facilities, the NPVC took the initiative of offering pharmacy students and residents, through the “11th Francophone Pharmacovigilance Course” in Rabat, a training in pharmacovigilance and then sent them to different CHU in Rabat, in order to regularly contact health professionals within these centers. The responsibilities of these mediators have been clearly defined: to establish a weekly meeting schedule and to select people within the targeted focal points so as to sensitize them to this issue. The ADRs notifications are then proactively collected and focal persons are responsible for listing all suspected ADRs or granting our mediators access to the medical records of patients who have displayed one or more ADRs, in order to collect the necessary information. These meetings aim to enable our mediators and focal persons to have direct and rich information exchanges on all reported cases.

Then a causality study is carried out by the French Method of Imputability, the result of which is then communicated to the health professionals involved in the notification.

In the same way as the above-mentioned initiative, the “National Pharmacovigilance Notification Day 2017” organized annually allows to improve the monitoring of the iatrogenicity of drugs and to encourage health professionals to report any observed ADR.

Results: The NPVC initiative has led to an improvement in the number and quality of ADRs reporting, obtaining devoted notifiers and building a sustainable rapport with them. In total, since the introduction of proactive pharmacovigilance, the notification rate has increased by 25%.

The number of notifications collected during the “National Pharmacovigilance Notification Day 2017” was 400 ADRs per 1 day. This number reflects the importance of the involvement of the different health system actors in improving the reporting of ADRs.

Conclusion: Increased reporting of ADRs and the good collaboration between health professionals, pharmacists and the NPVC is evidence to the success of the process.

Disclosure of Interest: None declared.

300 ISoP18-1477 Risk Factors Contributing to Insulin Prescription Errors in a Public Tertiary Care Hospital in Sub Saharan Africa

300.1 D. A. Aywak-Aloyo^*1, R. Kinuthia¹, K. Sinei², M. Mulaku², A. Guantai²

300.1.1 ¹Pharmacy, Kenyatta National Hospital, ²Department of Pharmacology and Pharmacognosy, University of Nairobi, Nairobi, Kenya

Background/Introduction: Insulin is ranked among the top 5 “high alert” medications by the Institute of Safe Medication Practices [1]. Medication errors indicate a failure in the treatment process and have the potential to lead to patient harm [2]. Since prescription errors are the most common preventable medication errors, they are an important target for quality improvement [3]. Provision of insulin therapy at the public tertiary hospital from prescribing, dispensing, administration and monitoring is not restricted to only the qualified or competent personnel. This enhances risk of medication errors.

Objective/Aim: To identify risk factors that contributes to insulin prescription errors.

Methods: We performed a qualitative study where a total 14 health workers, comprising of 4 physicians, 7 pharmacists and 3 nurses were interviewed using a structured guide. Healthcare workers were sampled using criterion sampling method which allowed for the recruitment of study participants who were information rich and able to identify system weaknesses in the provision of insulin therapy that can be improved. The interview guide used focused on the hospital’s structure and processes was adapted from the American Society of Health System Pharmacists (ASHP) Recommendations for the Safe Use of Insulin in hospitals.

Results: Nine themes emerged from the key-informant interviews. Risk factors included the lack of standard guidelines, lack of system of monitoring prescription practices, lack of system for handling medication errors, knowledge gap, inadequate supervision, heavy workload, staffing constraints, limited pharmacist participation in clinical areas and cost of therapy.

Conclusion: Medication errors are associated with both human and system factors. Prescription errors are common where there are inadequate safeguards in place. Despite the study limitations of small sampe size,we were able to identify gaps in the patient safety system that when addressed can contribute to preventing and minimizing insulin prescription and medication errors in general.

References:

• 1. Cohen MR. Pharmacists’ role in ensuring safe and effective hospital use of insulin. Am J Health Syst Pharm 2010; 67(16 Supplement 8):S17–21

• 2. Aronson JK. Medication errors: what they are, how they happen, and how to avoid them. QJM. 2009; 102:513–21

• 3. Dean B, Schachter M, Vincent C, Barber N. Causes of prescribing errors in hospital inpatients: a prospective study. Lancet. 2002;359:1373–8

Disclosure of Interest: None declared.

301 ISoP18-1478 Prescribing Issues in the Swiss Hiv Infected Ageing Population

301.1 F. Livio^*1, F. Rrustemi², G. Moffa³, L. Elzi⁴, F. Stader⁵, D. Braun⁶, A. Calmy⁷, A. Hachfeld⁸, M. Cavassini⁹, P. Tarr¹⁰, K. Wissel¹¹, M. Battegay⁵, C. Marzolini^5,12

301.1.1 ¹Service de Pharmacologie clinique, University Hospital Lausanne, Lausanne, Switzerland; ²University of Basel, Basel, Switzerland;³Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, Basel, Switzerland; ⁴Division of Infectious Diseases, Regional Hospital Bellinzona, Bellinzona, Switzerland; ⁵Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Basel, Switzerland; ⁶Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich,Switzerland; ⁷Division of Infectious Diseases, University Hospital Geneva, Geneva, Switzerland; ⁸Department of Infectious Diseases, University Hospital Bern, Bern, Switzerland; ⁹Service of Infectious Diseases, University Hospital Lausanne, Lausanne, Switzerland; ¹⁰University Department of Medicine, Kantonsspital Baselland, University of Basel, Basel, Switzerland; ¹¹Division of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland; ¹²Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom

Background/Introduction: Comorbidities, age-related physiological changes and the care by multiple healthcare providers predispose elderly individuals living with HIV to polypharmacy, drug–drug interactions (DDIs) and inappropriate prescribing. The extent of prescribing issues traditionally observed in geriatric medicine has not been thoroughly evaluated in the ageing HIV population.

Objective/Aim: The main objective of this study was to determine the prevalence of polypharmacy, deleterious DDIs and potentially inappropriate prescribing in elderly participants of the Swiss HIV Cohort Study (SHCS), a nationwide prospective observational study.

Methods: Eligible individuals were > 75 years. Comorbidities and medications at the latest registered SHCS follow-up visit were obtained by reviewing retrospectively the patient medical chart. Socio-demographic, clinical, and laboratory parameters were extracted from the SHCS database. DDIs between HIV and non-HIV medications were screened using www.hiv-druginteractions.org and DDIs between non-HIV drugs from the package insert and published studies. DDIs were not considered if the dosage of the victim drug had been altered to overcome the DDI or if DDIs were of weak clinical relevance. Potentially inappropriate prescribing was screened using the Beers, STOPP/START criteria and published guidelines. Inappropriate prescribing was defined as: (i) drugs administered at incorrect dosage, (ii) drugs prescribed without clinical indication, (iii) prescribing omission, (iv) drugs not recommended in elderly, (v) deleterious DDI between HIV and non-HIV drugs, (vi) deleterious DDI between non HIV-drugs, (vii) drugs administered beyond the recommended treatment duration.

Results: 111 participants (81% were male) with a median age of 78 years were included. The median (IQR) number of non-HIV comorbidities per participant was 7 (5;10). The most prevalent were cardiovascular, metabolic, and musculoskeletal conditions. Polypharmacy (excluding HIV drugs) was highly prevalent (60%). 59% of the participants were treated with an antiretroviral acting as a perpetrator of DDI. 69% of the participants had at least one potentially inappropriate prescribing issue: (i) inappropriate dosage (25%), (ii) inappropriate indication (21%), (iii) prescription omission (19%), (iv) inappropriate drugs in elderly (19%), (v) DDIs HIV/non-HIV drugs (11%); (vi) DDIs non-HIV/non-HIV drugs (2%); and (vii) inappropriate treatment duration (2%). The proportion of participants with more than one inappropriate prescribing was significantly higher in the group of patients with polypharmacy.

Conclusion: Polypharmacy and potentially inappropriate prescribing were highly prevalent in > 75 years old participants of the SHCS. Education on geriatric medicine principles and the periodic review of prescriptions could reduce the risk of adverse drug reaction.

Disclosure of Interest: None declared.

302 ISoP18-1480 Adverse Drug Reactions Leading to Emergency Department Admission in a Tertiary Teaching Hospital

302.1 N. Mohebbi^*1, K. Gholami¹, S. Soufiabadi²

302.1.1 ¹Clinical Pharmacy Department, ²Tehran University of Medical Sciences, Tehran, Iran, Islamic Republic Of

Background/Introduction: Adverse Drug Reactions (ADRs) have caused significant morbidity and mortality. It has also led to increased admission of patients in hospitals, prolong hospitalization period, and raise costs of health system. It is suggested that 3–6% of the hospital admissions are associated with the ADRs.

Objective/Aim: To investigate the frequency of ADRs and to determine the causal relationship between the complication and suspected medication as well as to inspect seriousness, preventability of ADRs and evaluate risk factors.

Methods: This is a cross-sectional observational research performed for 6 months in the Emergency unit of Shariati Hospital. Demographic data of the patients, complete history, especially drug history were recorded at the admission time. If an ADR suspected as the reason of admission, the ADR yellow card were filled. Then, causality, preventability, and outcome of the ADRs were assessed.

Results: From 397 patients in Emergency department admissions 19(4.8%) were ADR related, including 8 female and 11 male patients. Most of ADRs were created by central nervous system (27%) and cardiovascular drugs (17.3%). Eventually 80.7% of ADRs were preventable. Among preventable ADRs, 48.07% was because of Self-medication. Four case of mortality have been detected due to unlicensed medicines.

Conclusion: ADRs can be prevented by appropriate patient education, to make the patients aware about their medications to prevent serious ADRs and improve patient safety.

Disclosure of Interest: None declared.

303 ISoP18-1481 Signal Detection And Risks Communication In Pharmacovigilance For Cardiovascular Clinical Trials

303.1 M. A. Malikova^*1

303.1.1 ¹Surgery, Boston University, Boston Medical Center, Boston, United States

Background/Introduction: In 2016, the ICH revised the E6 guidelines and subsequently issued R2 addendum (1) to further standardize processes in biomedical products development, decrease redundancies; and reflect the current research landscape such as increases in globalization, study complexity, and technological capabilities. The updated ICH GCP E6 R2 is more descriptive than the previous version and describes 26 items of change. These changes consist of new items in definitions; new sections on investigator responsibilities, including oversight; a substantial new sponsor section on quality management, including risk assessment; monitoring plans defined and implemented; introducing Risk-Based Quality Management; serious breaches, and, a new section on computer validation and electronic records. A risk-based approach for signal detection in pharmacovigilance (PV) requires not only strategy but tools to define key risk indicators (KRIs) to measure specific risks. From Recent FDA and EMA guidelines, KRIs and Critical to Quality (CTQ) metrics should focus on safety of research subjects and data integrity (2). The ability to predict potential issues in compliance, reduce risks and improve safety is a valuable asset in PV management. New communication strategies and signal detection practices have to be developed to adapt the revised guidelines as roles and responsibilities between sponsors and clinical research sites in risk-based environment had changed.

Objective/Aim: Identify trends in safety factors as key risk indicators and adverse events occurrence; establish correlation of disease etiology with specific safety concerns. 

Methods: An internal audit of 46 prospective, randomized clinical trials was performed. These studies had similar objectives, eligibility criteria, study design, and outcomes. The rate of serious adverse events (SAEs) was assessed and compared between different studies. SAEs were classified into categories to better understand the correlation between type of the event and etiology.

Results: A comparison of SAEs occurrence showed an average of 2.1 SAEs per patient. The most common SAEs in cardiovascular trials were chronic wound infections. Patients with diabetes had demonstrated slower rate of wound healing and developed several adverse events related to inflammation.

Conclusion: Proactive assessment of potential difficulties in prospective cardiovascular studies can lead to earlier risk mitigation, safety improvement and quality assurance of trials conducted. As understanding of frequency and types of adverse events can provide an expectation for those conducting trials in particular indication and proactively anticipate and mitigate risks and complications. 

References:

• 1. Integrated Addendum to ICH E6(R2): Guideline for Good Clinical Practice. (2015) E6(R2) https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Addendum_Step2.pdf.

• 2. FDA Guidelines for Industry: Oversight of Clinical Investigations—A Risk-Based Approach to Monitoring, August, 2013. www.fda.gov/downloads/Drugs/…/Guidances/UCM269919.pdf.

Disclosure of Interest: None declared.

304 ISoP18-1482 Role of Adverse Drug Reaction in Transfers from Psychiatric Wards to Emergency Unit in Geneva University Hospitals

304.1 V. Hede^*1,2, C. Froment², J.-M. Aubry¹, O. Rutschmann³, J. Desmeules⁴, M. Besson^2,4

304.1.1 ¹Service of Psychiatric Specialties, Departement of Mental health and Psychiatry, ²Psychopharmacology Unit, Clinical Pharmacology and Toxicology Department, ³Emergency Department, ⁴Clinical Pharmacology and Toxicology Departement, Geneva University Hospitals, Geneva, Switzerland

Background/Introduction: Epidemiological studies repeatedly report that adverse drug reactions (ADR) are a major source of hospitalization with a prevalence around 10% [1]. Psychotropic drugs are always listed in the top-ten of drugs leading to ADR requiring hospital admissions. In the psychiatric population the prevalence of ADR is elevated, being estimated between 42 and 87% of the exposed patients [2–5].

Objective/Aim: The aim of the study was to determine the incidence of ADR related transfers of psychiatric patients, from a psychiatric ward (PW) to the emergency unit (EU) of Geneva University hospitals during the year 2016.

Methods: Observational retrospective study using patient’s electronic file. Medical files of all patients who were transferred from PW to EU during 2016 were analyzed. Demographic data, medical history and medication were systematically collected. ADR imputability were independently assessed according to WHO criteria by a psychiatrist and a clinical pharmacologist. Preventability and severity were also quoted. These study was approved by the local ethical committee and according to the retrospective, non interventional design, a patient consent withdrawal was obtained.

Results: Of 526 transfers, 42.6% (224) were related to an ADR; 18% were considered certain, 15% probable and 67% possible. 71% of ADR  were considered preventable. Psychotropic drugs were the first class involved in ADR, mainly antipsychotics (54% of ADR). Cardiac and neurological drugs followed. Off-label or unjustified use was found in 74% of the cases, and drug–drug interactions in 71%. 54% of patient had more than 8 drugs. Mean age of patients was 59 years.  Patients with ADR suffered mostly from dementia (24%), depression (23%) and psychotic disorder (22%). Neurologic consequences represented 65% of all ADR. 30% needed hospitalization for somatic care.

Conclusion: This study underscores that half of the transfers from a psychiatric ward to the emergency unit are related to ADR and that 70% of them are considered preventable. Further analysis will help identifying risk factors as a basis of preventing actions.

References:

• 1. Bouvy JC, De Bruin ML, Koopmanschap MA. Epidemiology of adverse drug reactions in Europe: a review of recent observational studies. Drug Saf 2015;38:437–53

• 2. Ayani N, Sakuma M, Morimoto T, et al. The epidemiology of adverse drug events and medication errors among psychiatric inpatients in Japan: the JADE study. BMC Psychiatry 2016;16:303

• 3. Rotschild JM, Mann K, Keohane CA, et al. Medication safety in a psychiatric hospital. Gen Hosp Psychiatry 2007; 29:156–62

• 4. Thomas M, Boggs AA, DiPaula B, Siddiqi S. Adverse drug reactions in hospital psychiatric patients. Ann Pharmacother 2010;44:819–25

• 5. Lucca JM, Madhan R, Parthasarathi G, Ram D. Identification and management of adverse effects of antipsychotics in a tertiary care teaching hospital. J Res Pharm Pract 2014;3(2):46–50

Disclosure of Interest: None declared.

305 ISoP18-1483 Drug Safety Alert: Time to Action

305.1 C. Anton^*1, T. Ahmad¹, R. Ferner¹, K. Ali², K. Badyal¹

305.1.1 ¹West Midlands Centre for Adverse Drug Reactions, Birmingham, United Kingdom; ²Institute of Experimental Medicine, University of Birmingham, Birmingham, United Kingdom

Background/Introduction: Drug safety alerts (‘alerts’) are issued by the Medicines and Healthcare products Regulatory Agency to inform healthcare professionals of significant adverse drug reactions (ADRs) related to medicines in the United Kingdom. If early warning signs of ADRs are heeded, this can help in reducing the financial burden and improve patient safety. Alerts are cascaded to healthcare professionals in order to change prescribing behaviour or solicit reports of ADRs where necessary.

Objective/Aim: To examine the effect of alerts on prescription rates in primary and secondary care and on ADR reporting rates in the West Midlands, UK.

Methods: We identified drugs in significant alerts in 2012–2017 and selected these for analysis. We obtained prescribing data for primary and secondary care providers in the West Midlands region, UK. Primary care data was obtained from https://openprescribing.net, a publicly available data source for primary care prescribing in the UK. Secondary care prescribing data was obtained from Define (Rx-Info Ltd, Exeter, UK), a data source available to National Health Service (NHS) trusts in the UK. ADR reporting figures for each drug was obtained from interactive Drug Analysis Profiles (https://yellowcard.mhra.gov.uk/iDAP/).

Results: Identified drugs and ADRs were:

Domperidone and cardiac ADRs [1–3] in 2012, 2014 and 2016; metoclopramide and neurological ADRs [4, 5] in 2013 and 2014: and lansoprazole and lupus erythematous [6] in 2012 and 2015. Table 1 shows effects on prescribing rate and ADR reports.

Conclusion: Prescribing of the three drugs fell over time. There were more ADR reports 6 of 7 years in which an alert came out.

Drug safety messages are most effective when there are clear guidelines on the action required, as was the case for domperidone, whose prescribing fell substantially. Lanzoprazole prescribing increased in secondary care despite having warnings of potentially severe (but rare) adverse effects. Perhaps this is because other proton pump inhibitors carry similar warnings, and the alternative H₂-antagonists are less effective.

References:

• 1. The Medicines and Healthcare products Regulatory Agency. Domperidone: small risk of serious ventricular arrhythmia and sudden cardiac A2 death [Internet]. 2012. [Cited 2017 October 05]. Available from: http://www.rcpsych.ac.uk/pdf/Drug%20Safety%20Update%202012.pdf

• 2. The Medicines and Healthcare products Regulatory Agency. Domperidone: risks of cardiac side effects [Internet]. 2014. [Cited 2017 October 05]. Available from: https://www.gov.uk/drug-safety-update/domperidone-risks-of-cardiac-side-effects

• 3. The Medicines and Healthcare products Regulatory Agency. Apomorphine with domperidone: minimising risk of cardiac side effects [Internet]. 2016 [Cited 2017 October 05]. Available from: https://www.gov.uk/drug-safety-update/apomorphine-with-domperidone-minimising-risk-of-cardiac-side-effects

• 4. The Medicines and Healthcare products Regulatory Agency. Metoclopramide: risk of neurological adverse effects [Internet]. 2013. [Cited 2017 October 05]. Available from: https://www.gov.uk/drug-safety-update/metoclopramide-risk-of-neurological-adverse-effects

• 5. The Medicines and Healthcare products Regulatory Agency. Updated indications and posology to minimise risk of (mainly neurological) adverse effects—sent by multiple licence-holders on 12 December 2014 [Internet]. 2014. [Cited 2017 October 05]. Available from: https://www.gov.uk/drug-safety-update/letters-sent-to-healthcare-professionals-since-November-2014

• 6. The Medicines and Healthcare products Regulatory Agency. Proton pump inhibitors: very low risk of subacute cutaneous lupus erythematosus [Internet]. 2015. [Cited 2017 November 15]. Available from: https://www.gov.uk/drug-safety-update/proton-pump-inhibitors-very-low-risk-of-subacute-cutaneous-lupus-erythematosus

Disclosure of Interest: None declared.

306 ISoP18-1486 Angioedema Induced by Atorvastatin

306.1 F. Zgolli¹, O. Charfi¹, I. Aouinti¹, G. Lakhoua¹, H. Zayeni¹, R. Daghfous^*1, S. El Aidli¹, A. Zaiem¹

306.1.1 ¹Tunisian National Centre of Pharmacovigilance, Tunis, Tunisia

Background/Introduction: Statins are 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors, a key enzyme in cholesterol biosynthesis. It is the most widely used class of lipid-lowering drugs and appear to be safe. Statins-induced angioedema is exceptional. Only exceptional cases have been notified so far according to the worldwide literature. 

Objective/Aim: To report a case of atorvastatin-induced angioedema. It was notified in the Tunisian National Centre of Pharmacovigilance in 2018.

Methods: This case was evaluated according to the updated French method of imputability [1].

Results: A 60-year old woman with past medical history of stroke and dyslipidemia was treated with famotidine and the association of dl-Lysine Acetylsalicylate/acetylsalicylic acid and atorvastatin (10 mg daily). She developed, less than 1 h after the first intake of atorvastatin, tongue and lip swelling. Immediately after the second drug intake (the next day), he developed a facial swelling with dyspnea and difficulty swallowing.

She consulted on the emergency room where atorvastatin was stopped and a symptomatic treatment was initiated.

Few months later rosuvastatin, 5 mg daily, was initiated without problems.

Conclusion: The responsibility of atorvastatin in inducing angioedema was evaluated as possible according to the updated French method of imputability because of the suggestive chronology (less than 1 h after dug intake) and the favourable outcome after the medication withdrawal.

The responsibility of other drugs was less suspected because of the favourable outcome despite their pursuit.

Angioedema is rarely reported with statins. A review of the literature reveals only five cases of statin-induced angioedema. These reports described a case of atorvastatin induced angioedema with dermographism and urticaria, atorvastatin-induced angioedema with rash and eosinophilia, pravastatin-induced angioedema, and lovastatin-induced angioedema with urticarial and an ultimate case of atorvastatin-induced angioedema without other hypersensitivity reactions. Time to onset of these reactions varied from 2 days to 9 months [2–5].

The exact mechanism of atorvastatin-induced angioedema remains unknown. This effect may be mediated by bradykinin via the upregulation of bradykinin type 2 receptors [6]. It can also be related to the dose of statins, based on the fact that angioedema did not recur after the introduction of another statin at lower dose.

In conclusion, our case shows that angioedema should be considered in patients who are receiving a statin medication. It also provides evidence supporting challenge to a different type of statin drug as a safe therapeutic alternative to desensitization in case of immediate hypersensitivity reaction.

References:

• 1. Yannick Arimone, Irène Bidault, Jean-Paul Dutertre,Marie Gérardin, Claire Guy, Françoise Haramburu, Dominique Hillaire-Buys, Carmine Meglio, Catherine Penfornis, Hélène Théophile, Marie-Blanche Valnet-Rabier. Réactualisation de la méthode française d’imputabilité des effets indésirables des médicaments. Therapie.(2011);66:517–25

• 2. Adcock BB, Hornsby LB, Jenkins K. Dermographism: an adverse effect of atorvastatin. J Am Board Fam Pract 2001;14:148–51

• 3. Hampson JP, Smith D, Cowell R, Baker A. Hypotension and eosinophilia with atorvastatin. Pharm World Sci 2005;27:279–80.

• 4. Liebhaber MI, Wright RS, Gelberg HJ, Dyer Z, Kupperman JL. Polymyalgia, hypersensitivity pneumonitis and other reactions in patients receiving HMG-CoA reductase inhibitors: a report often cases. Chest 1999;115:886–9

• 5. Nisly SA, Kara A, Knight TB. Simvastatin: a risk factor for angioedema? J Pharmacy Technol 2013;29:149–52

• 6. Liesmaa I, Kokkonen JO, Kovanen PT, et al. Lovastatin induces the expression of bradykinin type 2 receptors in cultured human coronary artery endothelial cells. J Mol Cell Cardiol 2007;43:593–600.

Disclosure of Interest: None declared.

307 ISoP18-1488 Cetuximab-Induced Acneiform Eruption Resistant to Doxycycline Preventive and Curative Therapy

307.1 T. Badri¹, M. Bouhlel^*2, R. Daghfous ², S. El Aidli ², S. Kastalli², A. Zaiem²

307.1.1 ¹Dermatology Department, Habib Thameur Hospital, Tunis, Tunisia; ²Tunisian National Centre of Pharmacovigilance, Tunis, Tunisia

Background/Introduction: Cetuximab is an epidermal growth factor receptor inhibitor used in metastatic colic adenocarcinoma, among others.

Objective/Aim: To report a case of acneiform eruption in a patient treated with cetuximab.

Methods: A case report.

Results: A 26 year-old male patient was referred to dermatology because of multiple papules and pustules that occurred 2 weeks ago on his chest, upper back, neck and face (Grade II).

The patient had a colic adenocarcinoma with pulmonary and hepatic metastases, and was receiving 5-fluorouracil, folate, oxaliplatin, as well as cetuximab every 2 weeks. The patient was also taking daily doxycycline (100 mg) to prevent cetuximab cutaneous skin effect. He showed after the third cure of chemotherapy multiple follicular papules and pustules, all over his chest, upper back, neck and face. The eruption persisted although patient continued doxycycline. He was advised topical ketokonazole.

Conclusion: Cetuximab-induced acneiform eruption is a folliculitis which occurs in about the half of patients who receive cetuximab and is thought to be due to the inhibition of the effect of epidermal growth factor on the skin. Preventive therapy with tetracyclines as reported in the literature seems to be efficient and their use is recommended. In curative therapy this effect has not been shown. In our patient who was receiving acne-treatment doses of doxycycline as prevention, this effect was not seen. Furthermore, doxycycline did not show any curative effect in our case. Other molecules may be used efficiently, like ciprofloxacin and topical ketoconazole. Some studies recommend the combination of tetracyclines and topical ketoconazole to better target the follicular germs which may be indigenous bacteria or Malassezia species.

Disclosure of Interest: None declared.

308 ISoP18-1489 Cerolizumab Pegol-Induced Palmoplantar Pustulosis

308.1 T. Badri², M. Bouhlel^*1, R. Daghfous ¹, S. El Aidli ¹, S. Kastalli¹, A. Zaiem¹

308.1.1 ¹Tunisian National Centre of Pharmacovigilance, Tunis, Tunisia; ²Dermatology Department, Habib Thameur Hospital, Tunis, Tunisia

Background/Introduction: Cerolizumab pegol is a pegylated tumor necrosis factor-alpha (TNF-α) antagonist approved for the treatment of Crohn’s disease and moderate-to-severe rheumatoid arthritis (RA).

Objective/Aim: To report an exceptional case of palmoplantar psoriasis in a patient with RA associated with cerolizumab.

Methods: Case report.

Results: A 50 year-old female patient was referred to dermatology because of multiple pustules of her palms and soles that occurred 2 weeks ago, as well as some isolated pustules on the legs and abdomen.

The patient was treated in rheumatology for RA and was receiving since 6 months certolizumab pegol (400 mg at weeks 0, 2, and 4, then 400 mg monthly) and methotrexate. Skin biopsy showed epidermal multilocular spongiform pustules which resembled to pustular psoriasis features. Certolizumab pegol was then discontinued and cutaneous lesions healed within days which was consistent with a diagnosis of cerolizumab pegol-induced pustulosis.

Conclusion: The occurrence de novo of psoriasis or pustular psoriasis with tumor necrosis factor-alpha (TNF-α) antagonists is a known side effect although rare. This effect occurs mainly with etanercept, infliximab, and adalimumab. Palmoplantar pustulosis is less commonly reported with such therapies. Cerolizumab pegol-induced plmoplantar pustulosis is even less common with only 3 cases reported since 2012. In one case, a patient who had developed palmoplantar pustulosis with etanercept, had a recurrence when he was put on certolizumab pegol which suggests that de novo psoriasis (and pustulosis) is a class side effect with a paradoxical augmentation in TNF-α level. A more recent publication reported the case of a patient treated with cerolizumab pegol for RA who developed palmoplantar pustulosis which evolved to generalized pustular psoriasis. Although our patient had some isolated pustules outside palms and soles, we considered her condition to be palmoplantar pustulosis.

Disclosure of Interest: None declared.

309 ISoP18-1491 Risk Assessment of Medication Safety in Pharmacotherapeutic Practice

309.1 R. Despott^*1

309.1.1 ¹Ministry for Health, Attard, Malta

Background/Introduction: Medication error continues to represent the single most common preventable cause of patient harm in clinical practice since the landmark studies of the European Expert Group in 2006 [1, 2].

Objective/Aim: The research aims to identify areas of pharmacotherapeutic practice associated with high risk of patient harm and evidence-based strategies for improving standards of medication safety.

Methods: A quality risk management approach is used as a basis for establishing a classification of pharmacotherapeutic failure (Table 1) [3–6]. A risk score is determined according to the frequency and severity of medication errors recorded in the EudraVigilance System between June 2012 and September 2015. Predetermined case variables are also noted. Hypothesis testing is carried out using the Pearson Chi squared test to determine the correlation between the severity and explanatory variables, and the Kruskal–Wallis one way analysis of variance to compare the mean severity rating scores. A Multinomial logistic model for ordinal data is used to establish the relative significance of the predictors.

From 2294 case reports, 1926 (84%) were confirmed cases of medication error and 1300 (57%) were considered preventable. Most cases of pharmacotherapeutic failure were encountered in the prescribing (28%) and the administration (27%) of medicine. Human errors were mainly case based in the prescribing stage (60%), skill based in the dispensing stage (66%) and rule based during administration of drug treatment (75%). The severity of harm showed a strong positive correlation with the pharmacological group, number of drugs and route of administration (p < 0.001), type of error and patient age (p < 0.003).

Conclusion: The research identifies specific processes of pharmacotherapeutic practice which present an increased risk of harm to patients, and points towards the need for better regulation of medication safety standards.

The results support screening of at risk patients to improve the efficiency of quality initiatives in pharmaceutical care, and highlight independent medication review and in-line checks during administration of drugs as the most effective strategies to prevent medication error.

References:

• 1. Report by Expert Group on Safe Medication Practices, Council of Europe; 2006

• 2. European Health Strategy, DG SANCO, European Commission; 2016

• 3. Guidelines on Quality Risk Management, The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use; 2005

• 4. Guideline on Quality Risk Management, World Health Organization; 2010

• 5. Reason J. Human Error: Models and Management. BMJ. 2000;320:768–70

• 6. Aronson JK. Medication errors: definitions and classification. Br J Clin Pharmacol. 2009;67:599–604

Disclosure of Interest: None declared.

310 ISoP18-1492 Adverse Drug Reactions Leading to Ocular Surface Disease Clinic Visits at an Eye Hospital: A Brief Report

310.1 S. Alizadeh^*1, K. Gholami^2,3, M. Jabbarvand⁴, N. Mohebbi³

310.1.1 ¹Eye Research Center, Farabi Eye Hospital, Tehran, Iran, Islamic Republic Of; ²Research Center for Rational Use of Drugs; ³Department of Clinical Pharmacy, Faculty of Pharmacy; ⁴Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran, Islamic Republic Of

Background/Introduction: Drug side effects are responsible for a high mortality rate and impose an economical burden on patients and the health care system. Some of these reactions can lead to patient hospitalization or prolong the patient stay. It is estimated that the incidence of adverse drug reactions (ADRs) is approximately 1.7–25.1% in hospitals [1, 2]. It seems that acute ADRs resulting in eye hospital visits do not have a high prevalence however ophthalmic drugs such as eye drops have also a potential for ocular ADRs [3, 4].

Objective/Aim: The aim of this study was to evaluate ADR resulting in ocular surface disease in clinic visits at tertiary-care eye hospital. The frequency of ocular surface disease clinic visits due to ADRs, the type of ADR, and the suspected drugs were also nvestigateinvestigated.

Methods: In this study all patients admitted to ocular surface disease clinic between 8.00 a.m. and 1.00 p.m. during 15 days were included. The patients’ eye disorders and drug history were evaluated by a pharmacist to detect ADRs. The ophthalmologist performed an eye examination and was then consulted to determine if there was a causal link between the medication and the observed side effects. The national yellow card was completed for each ADR. The data were coded and analyzed afterwards.

Results: Of the 571 patient visits, 20 (3.5%, 95% CI 2.3–7.3%) were drug related. There were 6 males 30% and 14 females 70% (P = 0.063). Corticosteroids were the most commonly drug class that cause ophthalmic ADRs in this study. The majority of the ophthalmic ADRs occurred by oral route of administration of drugs. Posterior subcapsular cataract was the most common ADR, followed by dry eye. Only 1.5% of the ADRs were preventable. Accessing the seriousness, the rate was 9 out of 20 ADRs (4.5%).

Conclusion: Concise monitoring and proper diagnosis of ophthalmic ADRs may reduce ocular complications. It seems that the general population and clinicians should be educated and warned about the hazard of these kinds of ADRs.

References:

• 1. Einarson TR. Drug-related hospital admissions

• 2. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998;279:1200–5

• 3. Miguel A. Adverse Drug Reactions in Ophthalmology-are they a myth?. J Ocul Dis Ther 2013;1:36–40

• 4. Tisdale JE, Miller DA. Drud-Induced Disease. 2ed ed. American Society of Health-System Pharmacists., 2010, Chapter 14, p250

Disclosure of Interest: None declared.

311 ISoP18-1494 Extra Costs Related to Serious Adverse Drug Reactions in Hospitalized Patients, the Example of Long Qt and Agranulocytosis

311.1 K. Ing Lorenzini^*1, N. Vernaz^2,3, F. Girardin^1,2, F. Tirone¹, V. Rollason¹, J. Desmeules¹, C. Samer¹

311.1.1 ¹Clinical Pharmacology and Toxicology, ²Medical Direction; ³Finance Direction, University Hospitals of Geneva, Geneva, Switzerland

Background/Introduction: Adverse Drug Reactions (ADRs) are frequent and associated with significant morbidity, mortality and costs [1]. Based on several studies, the overall costs related to hospital-acquired ADRs approximately ranged between 2000 and 4000 euros [2–4], representing a 19.86% additional increase in the total cost of care and an increase in average length of hospital stay of 8.25% [2].

Objective/Aim: The aim of our study was to estimate the extra costs related to the occurrence of two specific ADRs which could be regarded as surrogate markers for the development of further complications, i.e. drug-induced prolonged QT interval (with risk of Torsades-de-Pointes) and agranulocytosis (with risk of sepsis), in patients hospitalized in a tertiary hospital.

Methods: We performed a retrospective review of the electronic health and administrative records of the patients for whom a specialized consultation by clinical pharmacologists had identified the occurrence of serious ADRs, over a 5-year period (2012–2016). For cases of drug-induced prolonged QT interval/torsade de pointe (TdP) and agranulocytosis, the ADR-related extra costs were specifically analyzed.

Results: A total of 666 cases of serious ADRs were identified from a specialized consultation by clinical pharmacologists, including 17 cases of prolonged QT interval/TdP (mean age 60.6 years), and 6 cases of agranulocytosis (mean age 40.2 years). There was a large heterogeneity and asymmetric ditribution of costs, ranging from 0 to 7465 Euro for long QTs and from 0 to 27,980 Euro for agranulocytosis (including sepsis). Extra costs related to ADRs essentially depend on early detection to contain progression to severe or fatal events, which induce intensive care use and prolonged hospitalization.

Conclusion: To limit costs and consequences of severe events, targeted screening of ADR precursors [5], including pharmacogenetic approaches, need to be better characterized [6]. ECG feature extraction and the use of machine learning technique to project the dynamics of absolute neutrophil count beyond the IT records could be used to reduce the costs and consequences of ADRs.

References:

• 1. Miguel A, Azevedo LF, Araujo M, Pereira AC. Frequency of adverse drug reactions in hospitalized patients: a systematic review and meta-analysis. Pharmacoepidemiol Drug Saf 2012;21:1139–54

• 2. Khan LM. Comparative epidemiology of hospital-acquired adverse drug reactions in adults and children and their impact on cost and hospital stay—a systematic review. Eur J Clin Pharmacol 2013;69:1985–96

• 3. Bordet R, Gautier S, Le Louet H, Dupuis B, Caron J. Analysis of the direct cost of adverse drug reactions in hospitalised patients. Eur J Clin Pharmacol 2001;56:935–41

• 4. Moore N, Lecointre D, Noblet C, Mabille M. Frequency and cost of serious adverse drug reactions in a department of general medicine. Br J Clin Pharmacol 1998;45:301–8

• 5. Poncet A, Gencer B, Blondon M, Gex-Fabry M, Combescure C, Shah D, et al. Electrocardiographic screening for prolonged QT interval to reduce sudden cardiac death in psychiatricpPatients: a cost-effectiveness analysis. PLoS One 2015;10:e0127213

• 6. Girardin FR, Poncet A, Perrier A, Vernaz N, Pletscher M, F. Samer C, et al. Cost-effectiveness of HLA-DQB1/HLA-B pharmacogenetic-guided treatment and blood monitoring in US patients taking clozapine. Pharmacogenomics J 2018 https://doi.org/10.1038/s41397-017-0004-2

Disclosure of Interest: None declared.

312 ISoP18-1495 Overview of Adverse Reactions (Adrs) for Elderly Patients Reported in 2017 in Croatia

312.1 K. Gvozdanovic^*1, D. Kolaric²

312.1.1 ¹Division for the Safe Use of Medicinal Products and Medical Devices, ²The Medicines Authorisation Division, Agency for Medicinal Products and Medical Devices of Croatia, Zagreb, Croatia

Background/Introduction: Elderly patients differ from younger adults in terms of comorbidity, polypharmacy, pharmacokinetics and greater vulnerability to adverse drug reactions (ADRs) [1]. The risk of ADRs in elderly additionally increases if the product information (PI) doesn’t provide helpful information for prescribing in this special population. We wanted to check the PI of the most reported drugs causing ADRs in elderly population in order to assess if observed ADR profile for elderly is adequately reflected in product information.

Objective/Aim: To describe the ADRs for elderly patients reported in Croatia in 2017 and compare it with the PI safety information for drugs causing ADRs for the purpose of detecting gaps in safety information that can explain occurence of preventable ADRs.

Methods: Retrospective analysis of ADRs reported to Croatian Agency for Medicinal Products and Medical Devices (HALMED) from 1st January to 31st December 2017 for patients 65 years and older. The ADRs are exported from VigiLyze [2] and analysed using descriptive statistics. We analysed the profile of medicines suspect of causing the ADR, number of co-reported medicines per patients, seriousness and outcome of reports. We also checked product information at HALMED’s Medicinal Products Database [3] for most commonly reported medicines causing ADRs in elderly to assess if they contain adequate information for supporting appropriate drug administration.

Results: Out of 4252 ADRs reported, 1071(25.19%) refers to ADRs for elderly patients. 334 (31.2%) ADRs were rated serious and 28 (2.6%) had fatal outcome. In 237 (22.1%) cases patient used more than one medicine (maximum was 22 medicines). The most frequently reported medicine was bisoprolole, followed by anticoagulants (wafarin and NOACs) and statins. Nine serious cases were recognized as interactions involving mostly anticoagulants (resulting in haemorrhage) and statins (led to rhabdomyolysis). Most of the ADRs are known and listed in PI.

Conclusion: A quarter of all ADRs reported in 2017. concerns elderly patients. Observed safety profile is consistent with ones described in PI, however, serious preventable ADRs occur. Polypharmacy continues to remain the most important factor for developing ADRs. In this population, benefit risk assessment of each individual and monitoring is needed to reduce known risks of drug use which could be prevented. Individual dosing recommendations should be achieved for this subpopulation.

References:

• 1. Davies EA, O’Mahony MS. Adverse drug reactions in special populations—the elderly. Br J Clin Pharmacol 2015;80:796–807

• 2. Who-umc.org. (2018). UMC | VigiLyze. [online] Available at: https://www.who-umc.org/vigibase/vigilyze/ [Accessed 11 Jun. 2018].

• 3. HALMED’s Medicinal Products Database [online] Available at: http://www.halmed.hr/en/Lijekovi/Baza-lijekova/ [Accessed 11 Jun. 2018]

Disclosure of Interest: None declared.

313 ISoP18-1496 A Mysterious Resistance to Acenocoumarol!

313.1 I. Aouinti¹, O. Charfi¹, I. Hamza¹, S. Ben Hammamia¹, G. Lakhoua¹, R. Daghfous^*1, S. El Aidli¹, A. Zaiem¹

313.1.1 ¹Service de Recueil et Analyse des Effets Indésirables, Centre National de Pharmacovigilance, Tunis, Tunisia

Background/Introduction: Acenocoumarol is an anticoagulant treatment. Its use need to be monitored by prothrombin time (PT) to adjust the posology and achieve the desired efficacy. Some patients are resistant to acenocoumarol. In these persons, PT remains high even with high doses of acenocoumarol.

Objective/Aim: We report herein a case of a suspected resistance to acenoucoumarol in a 67 year old patient.

Methods: This case was notified on October 13, 2017.

Results: A 67-year-old patient with hypertension, diabetes, and coronary disease was treated with captopril, atenolol, atorvastatin, and salicylic acid. In 2014, acenocoumarol treatment was introduced. At biological control, the PT was 100%. The doses of acenocoumarol were raised progressively with iterative controls of PT. PT was always 100% even when acenocoumarol reached the dose of 2 g/day. A resistance to acenocoumarol was suspected. The patient was referred to pharmacovigilance department. During the patient interview, it appears that the patient was confusing acenocoumarol with atenolol. In fact, when his doctor increased the doses of acenocoumarol, the patient increased his intake of atenolol believing that it was acenocoumarol. The patient had never taken acenocoumarol.

Conclusion: A resistance to acenocoumarol was eliminated in this patient since the patient had never taken this drug. We emphasize through this case the importance of patient interview to verify the observance of acenocoumarol before evoking a resistance to acenocoumarol.

Disclosure of Interest: None declared.

314 ISoP18-1497 Risk Perception Of Adverse Drug Reactions By Health Students—Influence Of Undergraduate Education

314.1 I. Carvalho¹, J. Joaquim^1,2, C. Matos^*1,3, T. Pires¹

314.1.1 ¹Pharmacy, Coimbra Health School, Coimbra, Portugal, ²Faculty of Pharmacy, Salamanca, ³Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain

Background/Introduction: Healthcare professionals have a privileged position to collect and process data of possible adverse drug reactions (ADRs). However, under-reporting remains a reality due to uncertainty to recognize a suspected ADRs and poor perception of the risk of ADRs, which may be closely related to the lack of pharmacovigilance training.

Objective/Aim: The objective of this study was to evaluate the level of risk perception of ADRs by students of a higher education School, relating to the Influence of training of healthcare students.

Methods: A descriptive-correlational study was conducted to investigate the risk perception of adverse drug reactions in undergraduate students. A total of 166 students from 8 different courses were surveyed. Data collection was made through a questionnaire during May and June 2016.

Results: Of the students who participated in the study, 45.2% were taking any medication at the moment of data collection, which shows that there is a high percentage of students taking medications. About half of them (n = 78; 47,0%) said they already felt an adverse effect, but none reported the event and 67.5% not knows the National Pharmacovigilance System and how to report an ADR if they suffer it.

Conclusion: It is essential to add pharmacovigilance training to the syllabus of health courses to improve the student’s risk perception about ADRs and the knowledge in drug safety issues. Improving the ADR reporting to the National Pharmacovigilance System (SNF) through training sessions may the pharmacovigilance systems to operate effectively, improving public health.

Disclosure of Interest: None declared.

315 ISoP18-1502 Analysis of Cases of Hepatic Adverse Reactions with Antituberculosis Drugs in Morocco

315.1 I. Smaili¹, R. Soulaymani¹, A. Tebaa^*1

315.1.1 ¹Morroccan National Pharmacovigilance Center, Rabat, Morocco

Background/Introduction: The integration of pharmacovigilance (PV) in the National Antituberculosis Control Program (PNLAT) was carried out in October 2012 thanks to the collaboration of the Anti-Poison Center and Pharmacovigilance of Morocco (CAPM) with the Department of Epidemiology and Disease Control (DELM) and Global Fund support.

This integration allowed:

• To elucidate the epidemiological profile of the adverse effects (AEs) of antituberculosis drugs (AT);

• to know rare EIs;

• generate signals;

• and manage these AEs by implementing risk minimization actions.

The integration of pharmacovigilance (PV) in the National Antituberculosis Control Program (PNLAT) was carried out in October 2012 thanks to the collaboration of the Anti-Poison Center and Pharmacovigilance of Morocco (CAPM) with the Department of Epidemiology and Disease Control (DELM) and Global Fund support.This integration allowed:

• To elucidate the epidemiological profile of the adverse effects (AEs) of antituberculosis drugs (AT);

• To know rare EIs; -generate signals;

• And manage these AEs by implementing risk minimization actions.

Objective/Aim: To analyze the cases of hepatic adverse effects with antituberculous drugs in Morocco.

Methods: We used the Vigiflow national database, Vigilyze and Excel software.

Results: Of the 2271 cases of reports of adverse reactions with antituberculosis drugs, there were 886 cases of hepatic adverse reactions, 39% of all anti-tuberculosis adverse reactions.

• Since 2011, there has been an annual average of 105 cases of hepatic adverse reactions.

• The most affected age group was between 18 and 44 years old with 50% of all cases, followed by the age group between 45 and 64 years old with 28% of total cases, with a predominance of females (56.7%).

• The most incriminated antituberculosis drugs in the occurrence of hepatic adverse reactions  are the combined forms including ERIP K4 (67%).

• During the period 2011–2017 and on all cases of hepatic adverse reactions, there were 397 serious cases which represents 45% of total hepatic adverse reactions with an annual average of 44 serious cases.

• Taking into account the severity criteria, and among the 397 cases of severe hepatic adverse reactions, 341 cases required hospitalization or prolongation of hospitalization which represents 85% of cases; life-threatening was involved in 28 cases and there were 23 deaths.

Conclusion: Hepatotoxicity due to antituberculosis drugsis very common in Morocco;

• Among the reported cases of hepatobiliary adverse reactions, the proportion of cases considered serious is significant;

• The most incriminated antituberculosis drugs are especially those used in combination including ERIP K4;

• In some Asian and African countries, including Morocco, hepatic disease with antituberculosis constitutes a signal of pharmacovigilance that deserves to be evaluated in order to implement the necessary risk minimization actions.

References:

• Vigiflow Moroccan Database

• Vigibase

• Vigilyze

Disclosure of Interest: None declared.

316 ISoP18-1504 Toxic Epidermal Necrolysis Related to Lamotrigine: About a Case

316.1 Z. Lachhab¹, N. Nchinech¹, A. Tebaa^*2, S. Siyah³, R. soualymani², Y. Bousliman¹

316.1.1 ¹Pharmacy Pole, Military Training Hospital Mohamed V, Rabat, Morocco; ²Moroccan Center of Pharmacovigilance, Rabat, Morocco; ³Burns Service, Military Training Hospital Mohamed V, Rabat, Morocco

Background/Introduction: Lamotrigine is a new generation antiepileptic drug that is increasingly used not only in generalized or partial epilepsy, but also in its new indication for the prevention of depressive episodes during bipolar I disorder.The risk of a cutaneous reaction is good known, estimated at about 10%. This risk appears higher in children. These are usually benign and transient maculopapular exanthemal reactions, but the risk of serious toxidermia such as Lyell’s syndrome exists.

Objective/Aim: the objective is to share a case of pharmacovigilance in order to better know the risks related to the use of medicines in pediatric population.

Methods: We report a case of severe toxic epidermal necrolysis (NET) toxidermia in a young girl following administration of lamotrigine.

Results: The young R, 12 years old known as epileptic since 2010, treated by Dépakine at a dosage of 200 mg/day. Notion of treatment changing with initiation of synaxe^® (lamotrigine) at a dosage of 25 mg/day. After 11 days of the beginning of treatment, there was installation of cutaneous lesions marked by detachments and bullous lesions in the forearms, hands, feet, trunk, face, back and ears. When she was admitted to the pediatric ward, the patient was conscious, normal, eupnetic and apyretic. Management was based on the elimination of any medication, putting on emollients, biological assessment: c-reactive protein, blood count, Ionogram, monitoring of T°, cardiac frequency and respiratory rate, the realization of a chest X-ray and the transfer to the service of burns. When she was admitted to the burn department, the patient was hemodynamically and respiratory stable, and local examination showed extensive diffuse skin lesions on 85% of the body surface area. The ophthalmological examination did not reveal any abnormality. The patient was isolated to reduce the risk of cross-contamination; local care consists of the use of antiseptic topicals, balneotherapy and care with Biafine^® and Mebo^®. The evolution was favorable and the patient left the service at D15. The team made a notification at the Moroccan center of pharmacovigilance.

Conclusion: Lyell’s syndrome or Toxic epidermal necrolysis (NET) is an acute and very serious dermatological condition that involves the skin and mucous membranes and can cause detachment of the epidermis on more than 30% of the body surface. NET is induced in about 80% of cases by drugs “drug allergy”.

Lamotigine has proved its value in several indications; however its use is limited by the risk of potentially life-threatening dermatological reactions, mainly the estimated NET at 10%. Risk factors for this reaction include excessively high initial dosages, dose escalation, valproate combination, a history of allergy with other antiepileptic drugs, female sex, and age less than 13 years. In this observation, we would like to emphasize that lamotrigine can cause potentially life-threatening skin reactions such as NET in the adolescent age group and that good and timely management will improve the prognosis of patients.

In conclusion, it is essential to recall the importance of reporting such adverse effects to the pharmacovigilance center in order to be able to continuously assess the benefit–risk ratio of drugs and review their conditions of use.

Disclosure of Interest: None declared.

317 ISoP18-1505 The New Pharmacovigilance Guidance in India-Diluted Wine Iin a Borrowed Bottle

317.1 A. Ramkumar^*1

317.1.1 ¹Arkus Research Pvt Ltd, Ahmedabad, India

Background/Introduction: Until recently the Pharmacovigilance program of India or PvPI has focused its efforts with great success in setting up and maintaining about 149 Adverse Drug Monitoring centres across the country in various medical colleges and hospitals. From virtually no reports in 2010 to contributing close to 150,000 ICSRS to the WHO Vigibase in 2015, PVPI also has dedicated programs running for adverse event monitoring due to HIV, Tuberculosis treatment and for AE post immunisation. It was recently included as a WHO Collaborating centre for vaccine safety.

Objective/Aim: Effective Jan 2018, a new Pharmaco-vigilance guidance for MAHs of pharmaceutical products has been published by the Central Drug Control Standard Organisation and the Indian Pharmacopia commission. It sets down similar norms and expectations for PV as that of EMA and all MAH regardless of their size or scope of operations are required to set up systems in place to ensure compliance. There is very little in this guidance that seeks to address the unique challenges in its implementation and enforcement, in terms of cost, resource or quality constraints.

Methods: The Indian pharmaceutical industry while large both in terms of volume (3rd) value (10th) is based on a model of manufacturing and selling generic products in both the international as well as the domestic market.

The manufacturing facilities are inadequately regulated (or regulations inadequately enforced) by the local regulatory agency which deals with about 20,000 pharmaceutical companies registered in the country with the majority of them small or medium enterprises.

Results: India as a country is restricted by severe resource constraints (skilled expertise and funding) of an evolving regulatory agency, plagued by the more urgent and pressing concerns of manufacturing and quality issues of the products it manufactures and flooded with counterfeits also faces the challenges of a large diverse population, 22% of which lives under the poverty line with a purchase power parity of about 1.25 USD but on the other is also dubiously known as the diabetic capital of the world with an estimated 66.8 million diabetics in 2015.

The new PV guidance in its present borrowed format is unlikely to yield any significant benefit in terms of safer use of medicines but runs a higher risk of diluting the innovative efforts and focus of PvPI which have succeeded spectacularly in harnessing and integrating with the WHO vigilance program and its technology, set up its unique ecosystem in the form of fully functional ADR monitoring centres, and also initiated globally recognised successful and focused vigilance programs (Bedaquiline Vigilance for Tuberculosis and the AEFI). 

Conclusion: A clear rethink the risk benefit assessment of implementation of this guidance is an urgent requirement.

References:

• 1. Vivekanandan K, et al. Pharmacovigilance Programme of India: Recent developments and future perspectives. Indian J Pharmacol 2016;48:624–38

  Joshi JR. Diabetes care in India, Ann Glob Health 2015; 81:830–38

• 2. Pharmaceutical and Medical Products Practice,India Pharma 2020,Propelling access and acceptance, realising true potential- Mckinsey report

Disclosure of Interest: None declared.

318 ISoP18-1506 Desensitization-Reintroduction Test with Anti-tuberculosis Drugs

318.1 F. Ben Salem¹, A. Zaiem¹, I. Aouinti¹, M. Bouhlel^*1, S. El Aidli¹, R. Daghfous¹, S. Kastalli¹

318.1.1 ¹National Centre of Pharmacovigilance, Tunis, Tunisia

Background/Introduction: The tuberculosis is a serious problem of public health in developing countries and in patients affected by AIDS. The treatment of tuberculosis involves combinations of anti-tuberculosis drugs (ATD) including isoniazid, rifampicin, ethambutol and pyrazinamide. ATD may have side effects including early or delayed reactions leading to treatment withdrawal. Many ways of reintroducing the ATD are proposed, with recently the desensitization–reintroduction test.

Objective/Aim: To analyze cases of delayed side effects induced by ATD, in which desensitization–reintroduction test were performed.

Methods: It was a retrospective study realized between 2012 and 2017. Selected patients were those who have initially presented delayed adverse reactions to ATD, and have then benefited from desensitization–reintroduction test. After complete regression of the side event, the decision of reintroduction of ATD was made depending on the seriousness of the first reaction and according to the tolerability and the results of biologic investigations. ATD were introduced in a sequential and progressive way. The least suspected drug was introduced first, with low and progressive doses. The dose was increased in case of tolerability every 3 days, until reaching the target dose. 

Results: We collected 5 cases: 3 women and 2 men. Ages ranged from 24 to 56 years. Among these 5 patients, 3 presented cases of exanthematous skin rash and 2 had cases of DRESS syndrome. Desensitization–reintroduction test was successful in the 3 cases of exanthema. It failed in the 2 cases of DRESS syndrome.

Conclusion: The benefit of desensitization–reintroduction test seems promising. We suggest working on a larger population.

Disclosure of Interest: None declared.

319 ISoP18-1507 Pharmacovigilance System in Arabic Countries: A Systematic Review of 22 Arab Countries

319.1 T. Alshammari^*1,2, N. Mendi³, Y. Alsowaida⁴

319.1.1 ¹College of Pharmacy, University of Hail, Hail, Saudi Arabia; ²Saudi Food and Drug Authority, Riyadh, Saudi Arabia;³Boehringer Ingelheim, Dubai, United Arab Emirates; ⁴College of Pharmacy, University of Illinois at Chicago, Chicago, United States

Background/Introduction: Pharmacovigilance concept and activities have been growing over the last two decades in Arabic countries. However, there is a different level of maturity among all these countries. Nevertheless, pharmacovigilance in the Arabic countries is still considered underdeveloped compared to the developed countries. World Health Organization (WHO) has established a program for international drug monitoring and a center at Uppsala city, Sweden has been responsible as technical and operational on the safety of medications and processing ICSR for this program.

Objective/Aim: To assess the current situation of pharmacovigilance legislation, activities, practice and other pharmacovigilance related activities among all 22 Arabic countries.

Methods: A systematic review of all types of studies (cohort, case–control studies, and reviews) describing the pharmacovigilance activities, practices, legislation, guidance and other related activities was conducted using the following databases and search engines: MEDLINE, Cochrane Database of Systematic Reviews, Pubmed, ProQuest, ScienceDirect, and Google Scholar. Besides, direct communication with the national pharmacovigilance activities using data collection form was performed to get as much information as we can. Two of the researcher team has independently performed the searches, and a specific abstraction was used to extract the data.

Results: Among the 22 countries, most of the countries have started some sort of pharmacovigilance activities except, Mauritania, Somalia, Djibouti and Comoro Islands. The maturity of the system varies among the Arabic nations, Saudi Arabia, Egypt, and Morocco are considered to have a mature pharmacovigilance system. Saudi Arabia is the recent country to be a member of World Health Organization-Uppsala monitoring center (WHO-UMC). Morocco is the first country that got the full membership with WHO-UMC among the Arabic countries at 1992, followed by Tunisia and Sultanate of Oman on 1993 and 1995, respectively. Countries such as Jordan, UAE, and Oman have the pharmacovigilance system; however, there is some lack of having full activities to be conducted in these countries. Furthermore, some countries are still in early phases to have their system completed such as Kuwait, Bahrain, Lebanon, Palestine, Yemen, Sudan and Qatar. In 2018, among the 22 countries belonging to the Arab League, 40% were official members, and 20% were associate members of the WHO. Half of the Arab countries are not yet members. Furthermore, the representation of Arab countries in VigiBase amounts to only 0.6% of all individual case reports keeping in mind that there are 16.000.000 individual case safety reports (ICSRs) in Vigibase^® in 2017. Despite that there is an Arab guideline for pharmacovigilance, few countries are following this guideline. All the details of these countries will be presented at the conference.

Conclusion: There is a slight development in the pharmacovigilance concept and practice among Arabic countries. However, there is a need for the authorities in these countries to put more efforts, human resources and funds to apply the pharmacovigilance activities because it is the gate to guarantee the patient safety.

Disclosure of Interest: None declared.

320 ISoP18-1509 Lyell Syndrome with Carbamazépine and Amoxicilline: Clinical Case

320.1 M. Mabrouki¹, S. Yanisse¹, I. Bennani¹, R. Soulaymani², A. Tebaa^*2

320.1.1 ¹Mohammed V University, Faculty of Medicine and Pharmacy, Rabat, Morocco; ²Pharmacovigilance, Poison and Pharmacovigilance Center, Rabat, Morocco

Background/Introduction: Increased use of drugs in children may be the cause of multiple reactions. The reactions described in this patient include cheilitis, conjunctivitis, and skin reactions typical of generalized erythematous lesions, following the intake of Carbamazepine, rapidly extensive after taking an antibiotic. This case has been reported to the National Center of Pharmacovigilance in Morocco, and is presented in this communication.

Objective/Aim: The aim of this work is to determine the evaluation of the causality between Lyell’s syndrome and the administration of Carbamazepine and Amoxicillin.

Methods: It is a 12-year-old child, treated for neuralgia by Carbamazepine, after 20 days of taking he developed a start of Lyell syndrome, after consultation the doctor thought of an infection by prescribing an antibiotic the condition of The child became aggravated, and was hospitalized for extensive bullous dermatosis treated with Aspirin and Methylprednisolone. The drugs were discontinued and all etiological causes were eliminated, a skin biopsy was performed confirming Lyell’s syndrome. The relationship between Lyell syndrome and Carbamazepine–Amoxicillin was suspected and evaluated using the French method of accountability.

Results: Anti-seizure drugs (antiepileptic drugs), which stabilize the nerve cell membrane, often with Carbamazepine (Tegretol^®), which makes it possible to eliminate painful seizures or reduce their frequency and intensity. The imputability score was I4B4 with the French method. In our patient, we were tempted to retain Carbamazepine and Amoxicillin as responsible for Lyell’s syndrome. This is a well-known effect already described in the literature. However, the cases notified at the level of the national pharmacovigilance center concerning Lyell’s syndrome are 5 cases with Carbamazepine and 3 cases with Amoxicillin.

According to the literature, the occurrence of Lyell syndrome related to Carbamazepine and Amoxicillin is a possible collateral effect, although rarely reported. Lyell syndrome is a skin reaction most commonly caused by an allergy to a drug. Poisoning is based on hospitalization of the patient in an emergency in a specialized setting (intensive care for severely burned patients.) Although this reaction is often fatal, disabling sequelae are frequent among survivors.

Conclusion: This work helped determine the causality between Lyell’s syndrome and the administration of carbamazepine and amoxicillin. a precaution of use must be indicated during the prescription of this association.

Disclosure of Interest: None declared.

321 ISoP18-1510 Development of Inhibitors in Hemophils A: About Four Case

321.1 Z. Lachhab¹, I. Louhab¹, A. Tebaa^*2, R. Soulaymani², M. Aitcadi¹

321.1.1 ¹Pharmacy, Ibn Sina Hospital; ²Moroccan Center of Pharmacovigilance, Rabat, Morocco

Background/Introduction: Hemophilia A is an X-linked hereditary hemorrhagic disease, and its treatment uses pre-infused factor VIII concentrates to prevent bleeding episodes.

The development of factor VIII inhibitors is currently considered to be one of the most serious complications of hemophilia A substitutive therapy. By compromising to varying degrees the effectiveness of the anti-hemophilic fractions, these inhibitors considerably hinder the therapeutic management of these patients.

Objective/Aim: The objective is to highlight this problem, which involves the vital prognosis of hemophiliac patients.

Methods: We report four cases of inhibitor development in hemophilia A patients hospitalized in Ibn Sina University Hospital.

Results: Out of a total of 36 hemophiliac A patients hospitalized in our facility between January and June 2018, four patients developed inhibitors against factor VIII, which represents a rate of 11%.

The average age of patients is 22.5 years, screening of inhibitors was positive in the four patients with a 99% inhibition rate in three patients and 57% in the fourth.

Since the anti-inhibitory coagulant complex FEIBA * is not included in the drug formulary of our hospital, a protocol based on Rituximab has been proposed as a therapeutic alternative. This protocol is based on the weekly administration of Rituximab at the dose of 375 mg/m ³ for 1 month, followed by the monthly administration of the same dose for 6 monthsUnfortunately, about 30% of people with severe hemophilia A can develop antibodies (inhibitors) to factor VIII, because the factors are not recognized by the immune system.

Conclusion: The treatment of hemophilia with inhibitors is a real challenge. The different current strategies are based on three solutions: restore the coagulation process other than by administering factor VIII, deceive the immune system, or, more radical solution, try to eliminate inhibitors.

Several published studies have shown a high response rate following administration of Rituximab in patients with hemophilia B with inhibitor. However, the absence of randomized controlled trials evaluating rituximab in these patients implies that this drug is not recommended as first-line therapy and its use is reserved for cases where there are no therapeutical alternatives.

Disclosure of Interest: None declared.

322 ISoP18-1512 Implementation of Medication Errors Reporting Tools in Two Teaching Hospitals in Kinshasa

322.1 Y. Lula^*1, R. Tshibuabua², P.-M. Ntamabyaliro¹, A. Engo¹, D. Nzolo¹, T. Lutete¹

322.1.1 ¹Pharmacology, University of Kinshasa/National Pharmacovigilance Centre, The Democratic Republic of the Congo; ²University of Kinshasa, Kinshasa, The Democratic Republic of the Congo

Background/Introduction: Since implementation of pharmacovigilance (PV) system in Democratic Republic of Congo (DRC) in 2009, clinicians are reluctant to report medication errors (MEs) because of blame, punishment from their institution or legal consequences [1]. To make clinicians confident to report MEs, national PV centre has design a specific and anonymous form.

Objective/Aim: To evaluate the feasibility of MEs reporting implementation and to assess the profile of reported MEs.

Methods: This was an observational, prospective study conducted in the Kinshasa university hospital and one teaching hospital over a 6-month period. Healthcare professionals were invited to report MEs anonymously. MEs reporting forms were collated by a designed focal point, and then forwarded to national PV centre. MEs were coded using MedDRA (version 21.0), preferred term (PT) was the hierarchy of interest.

Results: Of 200 forms distributed, 118 (59%) were completed and given to focal points. After completeness and coherence check, only 100 reports with MEs were kept for analysis. Sixty-four percents of MEs resulted in adverse events (AE), of which 31 were judged as serious. Skin eruption (9%) was the main reported AE, five cases of death and two cases of cardiac arrest occurred. Majority of MEs consisted of administration error (65%) mostly through intravenous route (nearly half of cases) and prescription error (31%). The mostly frequently reported PT were the following: drug prescribing error (21%), incorrect dose administered (17%), incorrect drug administered rate (13%), incorrect route of drug administered (10%) and drug dose omission (95).

Conclusion: MEs recording and reporting are feasible; awareness meetings in different hospitals are needed to stimulate healthcare professionals and reassure them about the fear of legal proceedings. Assessing the profile of MEs could help to trigger preventive or minimizing actions.

References:

• 1. Lula NY, Pandi BD, Sarah HN, Ntamabyaliro PN, Engo BA, Mpiempie NT, et al. Perception of medication errors in healthcare professionnals in Kinshasa. Drug Saf 2012;35:953

Disclosure of Interest: None declared.

323 ISoP18-1517 Surveillance of Anti-tuberculosis Drugs in Thailand

323.1 P. Sriphiromya^*1, W. Suwankesawong¹

323.1.1 ¹Ministry of Public Health, Mueang Nonthaburi, Thailand

Background/Introduction: Tuberculosis (TB) is a public health problem and TB patients must receive combination drug more than two regimens in long term use. There were an estimated of 10.4 million new TB cases and 480,000 multi-drug resistant TB (MDR-TB) cases worldwide each year. World Health Organization issued guidance that people with TB resistant to rifampicin, with or without resistance to other drugs, should be treated with a MDR-TB treatment regimen. In Thailand, TB new cases have been detected which high ranked among high-burden countries and MDR-TB cases resistant to at least isoniazid and rifampicin of approximately 1.7%. Anti-tuberculosis drug group is one of most reported serious adverse drug reactions (ADRs). It is thus important to review the TB surveillance system and the ADRs’aspects in Thailand where the TB epidemic is rather increased and less drugs to cure MDR-TB but such new resistant cases are most expanding.

Objective/Aim: This study is aimed to review in surveillance methods of TB and MDR-TB. The ADRs were evaluated.

Methods: The interview survey was done to responsible people; currently involved in TB and MDR-TB surveillance. Anti-tuberculosis ADRs’characteristics (year 1996–2015) were reviewed. Descriptive analysis is used.

Results: TB surveillance in Thailand has been responsible by various institutions. The ADRs surveillance is under the ministry but some parts of its new MDR-TB are done by the Center of Control Disease. Other TB projects are operated by non-government organizations. 1309 ADRs were reported. Hepatitis (68.10%) and jaundice (20.30%) were most ADRs; of which 66.60% serious and 1.40% death.

Conclusion: The initial implement of MDR-TB surveillance should be the effective way to reduce TB burden. The rational drug use policy can minimize MDR-TB. Intensive serious-ADRs surveillance can trigger unknown events and reduce TB patients’ death.

Disclosure of Interest: None declared.

324 Abstract Authors Index for ISoP 2018

A.alghafar, Walaa ISoP18-1394

A.alrhman, Dalia ISoP18-1394

Abatemarco, Danielle ISoP18-1192, ISoP18-1197, ISoP18-1199, ISoP18-1198

Abbas, Ammar ISoP18-1232, ISoP18-1394

Abda, naima ISoP18-1291

Abdelghadir, Alraiyan ISoP18-1232

Abenhaim, Lucien ISoP18-1294

Abiodun, Abiola Sadikat ISoP18-1279

Abiri, Onome ISoP18-1343

Abou Taam, Malak ISoP18-1144

Adadi, Najlae ISoP18-1189

Adeyeye, Mojisola Christiana ISoP18-1279

Ahmad, Muhammad ISoP18-1258

Ahmad, Tohfa ISoP18-1483

Ahmad, Tohfa J ISoP18-1419

AIT MOUSSA, LATIFA ISoP18-1292

Aït Moussa, Latifa ISoP18-1372, ISoP18-1324

Aitcadi, Mina ISoP18-1510

Ajaja, Mohamed Rida ISoP18-1216

Akakpo, Samantha O-032

Akazawa, Manabu ISoP18-1176

Akici, Ahmet ISoP18-1266

Akici, Narin ISoP18-1266

Aklillu, Eleni O-004

Akparibo, Robert ISoP18-1140

Aksoy, Mesil ISoP18-1266

Al Metwazi, Mansour ISoP18-1208

Alakeel, Abdulaziz ISoP18-1092

alami, zayneb ISoP18-1291

ALATORRE, ROCIO ISoP18-1442

Alaya, Nabiha ISoP18-1328, ISoP18-1162, ISoP18-1375, ISoP18-1402, ISoP18-1406

Albashir, Maysaa ISoP18-1394

Al-Braik, F. A. ISoP18-1211

AL-Charakh, Ahmed ISoP18-1094

Al-Dossari, Dalal ISoP18-1024

Alem, Mohamed ISoP18-1291

Alenazi, Khalidah ISoP18-1511

AlGhannam, Wed ISoP18-1125

Alharbi, Fawaz ISoP18-1169, ISoP18-1172

Ali, Khawaja ISoP18-1483

Ali, Takreem ISoP18-1232

ALIAT, ZINEB ISoP18-1231, ISoP18-1439

Alizadeh, Safa ISoP18-1492

Alj, Loubna ISoP18-1460, ISoP18-1437

AlJasser, Nasser ISoP18-1125

Allen, Elizabeth ISoP18-1267

Almofada, Malak ISoP18-1092

Alqahtani, Nasser ISoP18-1511

Alruqayb, Wadia ISoP18-1385

Alshahrani, Ali ISoP18-1092, ISoP18-1125

Alshahrani, Fahad ISoP18-1416

Alshammari, Thamir ISoP18-1507, ISoP18-1511

Alsharif, Alaa ISoP18-1208

Alshatri Almotiry, Amal ISoP18-1125

Alsowaida, Yazeed ISoP18-1507

Alves, Carlos ISoP18-1308, ISoP18-1326

Alwafi, Hassan ISoP18-1208

Al-Zaagi, Ibrahim ISoP18-1024

Amadi, Emmanuel ISoP18-1279

Amaning Danquah, Cynthia ISoP18-1362

Amdouni, Narjess ISoP18-1222

Amitai, Alina O-014

Anderson, Claire ISoP18-1129

Anderson, Steven A. ISoP18-1173

Anton, Christopher ISoP18-1483, ISoP18-1415

Aoki, Yasunori ISoP18-1110, ISoP18-1102

Aouint, Imen ISoP18-1402

Aouinti, Imen ISoP18-1414, ISoP18-1421, ISoP18-1496, ISoP18-1309, ISoP18-1220, ISoP18-1328, ISoP18-1340, ISoP18-1375, ISoP18-1396, ISoP18-1352, ISoP18-1423, ISoP18-1392, ISoP18-1393, ISoP18-1408, ISoP18-1411

Aouinti, Imene ISoP18-1486, ISoP18-1506, ISoP18-1350

Aragão, Angela ISoP18-1297, ISoP18-1299

Aral Karakulak, Emine Defne ISoP18-1138

Arcoraci, Vincenzo ISoP18-1163

Aronson, Jeffrey ISoP18-1129,O-015

Arora, Narendra Kumar ISoP18-1206

Arzenton, Elena ISoP18-1268, ISoP18-1468, ISoP18-1467

Asati, Dinesh ISoP18-1051

ASGARI, Nili ISoP18-1187

Assuncao, Bruno ISoP18-1192, ISoP18-1197, ISoP18-1199, ISoP18-1198

Attjioui, Houda ISoP18-1221, ISoP18-1231, ISoP18-1359, ISoP18-1439

Attjoui, Houda ISoP18-1434

Atzenhoffer, Marina ISoP18-1274

AUBERT, Léa ISoP18-1097

Aubry, Jean-Michel ISoP18-1482

Audouard-Marzin, Youna ISoP18-1188

Auffret, Marine ISoP18-1274

Axente, Bianca ISoP18-1263

Aywak-Aloyo, Dorothy Atieno ISoP18-1477

AZZOUZ, Brahim ISoP18-1097

Babatunde, Zainab ISoP18-1419

Baccouche, Khadija ISoP18-1241, ISoP18-1242

Badri, Talel ISoP18-1488, ISoP18-1489

Badyal, Karamjit ISoP18-1483, ISoP18-1415

Bagheri, Haleh ISoP18-1286, ISoP18-1316, ISoP18-1331

Bahri, Priya O-010,O-014

Bakhriansyah, Mohammad ISoP18-1171

Balakrishnan, Madhava Ram ISoP18-1206

Balcescu, Teodora ISoP18-1087

Bamidis, Panagiotis ISoP18-1409

Bangalee, Varsha ISoP18-1500

Banholzer, Sarah ISoP18-1228

Bannout, Khaled ISoP18-1131, ISoP18-1153, ISoP18-1455

Bao, Jing O-021

Bao, Shenghua ISoP18-1198

Baqar, Jaffer ISoP18-1258

Barbieri, Maria Antonietta ISoP18-1166, ISoP18-1163

Bari, Ghislaine ISoP18-1399

Barışkaner, Hülagu ISoP18-1138

Barnes, Jo ISoP18-1135

Barnes, Joanne ISoP18-1345

BARTOLOMEI, Fabrice ISoP18-1035

Batel-Marques, Francisco ISoP18-1308, ISoP18-1326

Battegay, Manuel ISoP18-1478

Bazo-Alvarez, Juan Carlos ISoP18-1175

Beauchamp, Sheryl ISoP18-1192, ISoP18-1197

Bechar, Hafsa ISoP18-1217

Becker, Nick ISoP18-1455

Bégaud, Bernard ISoP18-1294

Belajouza, Colandane ISoP18-1243

Belasfar, Nadia ISoP18-1290

Bell, Simon ISoP18-1208

Bellet, Florelle ISoP18-1274

Ben Hammamia, Syrine ISoP18-1413, ISoP18-1414, ISoP18-1421, ISoP18-1417, ISoP18-1496, ISoP18-1220, ISoP18-1340, ISoP18-1348, ISoP18-1162, ISoP18-1352, ISoP18-1423, ISoP18-1378, ISoP18-1387, ISoP18-1392, ISoP18-1393, ISoP18-1405, ISoP18-1406, ISoP18-1408, ISoP18-1411

Ben Saida, Imen ISoP18-1237

Ben Salem, Chaker ISoP18-1181, ISoP18-1233, ISoP18-1234, ISoP18-1236, ISoP18-1239, ISoP18-1241, ISoP18-1242, ISoP18-1243, ISoP18-1244, ISoP18-1277, ISoP18-1283, ISoP18-1287, ISoP18-1290, ISoP18-1182, ISoP18-1237

Ben Salem, Fatma ISoP18-1472, ISoP18-1506

Ben Salem, Mouna ISoP18-1357

BEN SASSI, Mouna ISoP18-1145, ISoP18-1130

Ben Sayed, Nesrine ISoP18-1287

Ben Tekaya, Souha ISoP18-1130

Ben Youssef, Yosra ISoP18-1287

Benabdallah, Ghita O-001, ISoP18-1437

Béné, Johana ISoP18-1380

Benetti, Davide ISoP18-1467

Benevent, Justine ISoP18-1078, ISoP18-1118

BENHADDOU, HAJAR ISoP18-1292

Benkebil, Mehdi ISoP18-1144

Benkirane, Raja ISoP18-1460, ISoP18-1372

Bennani, ismail ISoP18-1509, ISoP18-1146, ISoP18-1215, ISoP18-1221, ISoP18-1231, ISoP18-1359, ISoP18-1364

BENNIS, SOUKAINA ISoP18-1292

Benomar, Ali ISoP18-1216

Bereznicki, Bonnie ISoP18-1040

Bereznicki, Luke ISoP18-1040

Bergvall, Tomas ISoP18-1158

Berlanda-Scorza, Francesco O-030

Bertazzoli, Mario ISoP18-1021

Bertoli, Raffaela ISoP18-1261

Besson, Marie ISoP18-1482

Bettiol, Alessandra ISoP18-1449

Bhat, Niranjan O-030

Bianchin, Matteo ISoP18-1325

Bielen, Cvijeta ISoP18-1177

Biswas, Himal ISoP18-1151, ISoP18-1224

Biswas, Pipasha ISoP18-1151, ISoP18-1224

Blandizzi, Corrado ISoP18-1341, ISoP18-1313

Blin, Olivier ISoP18-1426

Bloem, Lourens ISoP18-1174

Boer, Jeltje ISoP18-1117

Bonaiuti, Roberto ISoP18-1449

Bonanni, Paolo ISoP18-1449

Borsi, Valentina ISoP18-1293

Bosco-Lévy, Pauline ISoP18-1380

bouallala, adnane ISoP18-1291

Bouatia, Mustapha ISoP18-1216, ISoP18-1215, ISoP18-1221, ISoP18-1231, ISoP18-1292, ISoP18-1359

Bouguila, Jihene ISoP18-1239

Bouhlel, Mehdi ISoP18-1488, ISoP18-1489, ISoP18-1472, ISoP18-1506,O-013, ISoP18-1222, ISoP18-1420

Bouklouze, Abdelaziz ISoP18-1216

Boulle, Andrew ISoP18-1317

Boulvain, Michel ISoP18-1126

Boumaïza, Sabrina ISoP18-1126

Bourneau-Martin, Delphine ISoP18-1170

Bousliman, Yasser ISoP18-1504

BOUTAYEB, SABER ISoP18-1439

Bovet, Luc ISoP18-1323

Božina, Nada ISoP18-1315

Brahem, Afra ISoP18-1277

Brahim, Afra ISoP18-1234, ISoP18-1283, ISoP18-1287, ISoP18-1290

Brauer, Ruth ISoP18-1082, ISoP18-1084

Braun, Dominique ISoP18-1478

Braund, Rhiannon ISoP18-1254

Bräutigam, Katrin ISoP18-1066

Briet, Marie ISoP18-1170

Briquet, Caroline ISoP18-1152

Brooks, Dennis ISoP18-1057

Brown, Cristina ISoP18-1098

Bucsa, Camelia ISoP18-1207, ISoP18-1264, ISoP18-1275, ISoP18-1263

Bulik, Noemi ISoP18-1264, ISoP18-1275, ISoP18-1263

Bulik, Noemi Beatrix ISoP18-1207

Burri, Christian O-032, ISoP18-1202

Butuca#, Anca ISoP18-1327

Byomire Ndagije, Helen ISoP18-1365, ISoP18-1367

Caduff, Pia O-007

Caduff- Janosa, Pia ISoP18-1103

Caduff-Janosa, Pia O-003

Calapai, Fabrizio ISoP18-1333

Calapai, Gioacchino ISoP18-1333

Calmy, Alexandra ISoP18-1462, ISoP18-1478

Canak, Eren ISoP18-1155

Cao, Joyce ISoP18-1133

Capuano, Annalisa ISoP18-1448

Cardia, Luigi ISoP18-1333

Carlhant-Kowalski, Dominique ISoP18-1188

Carnovale, Carla ISoP18-1080

Caro-Rojas, Angela O-019,O-012

Carpenter, James ISoP18-1175

Carvalho, Iris ISoP18-1497

Castillon, Genaro ISoP18-1132,O-036

Cauvin, Jean-Michel ISoP18-1188

Cavassini, Matthias ISoP18-1478

Cavazza, Mario ISoP18-1325

Cazacu, Irina ISoP18-1207, ISoP18-1389, ISoP18-1263

Ceschi, Alessandro ISoP18-1261

CHABARDES, Stéphan ISoP18-1035

Chakraborty, DR Dwaipayan Sarathi

Chalmers, Leanne ISoP18-1040

Chan, Kelvin ISoP18-1455

Chandler, Rebecca ISoP18-1110,O-003,O-027

Chao, Pi-Hui ISoP18-1025, ISoP18-1134

Charfi, Ons ISoP18-1413, ISoP18-1414, ISoP18-1421, ISoP18-1417, ISoP18-1486, ISoP18-1496, ISoP18-1219, ISoP18-1309, ISoP18-1220, ISoP18-1318, ISoP18-1328, ISoP18-1347, ISoP18-1348, ISoP18-1396, ISoP18-1402, ISoP18-1387, ISoP18-1392, ISoP18-1405

Charfi, Rim ISoP18-1130

CHARFI, Rym ISoP18-1145, ISoP18-1357

Chaudhary, Deepa ISoP18-1051

Chebane, Leila ISoP18-1119, ISoP18-1316, ISoP18-1331

Chebat, Abderrahim ISoP18-1471

Cheikh, Amine ISoP18-1216, ISoP18-1215, ISoP18-1221, ISoP18-1231, ISoP18-1359

Chen, Wen-Wen ISoP18-1025, ISoP18-1134

Cherrah, Yahia ISoP18-1216, ISoP18-1302

Chien, Mei-Yi ISoP18-1025

Chimimba, Frider O-029

Choy, Michael ISoP18-1065

Chulu, Chrissy O-029

Chung, Sooyoun ISoP18-1124

Cicala, Giuseppe ISoP18-1166, ISoP18-1163

Cicirello, Salvatore ISoP18-1192, ISoP18-1197, ISoP18-1199

Cilmi Arslan, Belce ISoP18-1320

Clementi, Emilio ISoP18-1080

Cobelens, Frank O-005

Cole, Abimbola ISoP18-1436

Colucci, Valentina ISoP18-1166

Comfort, Shaun O-038

Cong, Jia Lin ISoP18-1303

Convertino, Irma ISoP18-1341, ISoP18-1313

Cooper, Richard ISoP18-1140

Cornforth, Emma ISoP18-1191

Cornu, Pieter ISoP18-1172

Corona, Tiberio ISoP18-1341, ISoP18-1313

Coskuncay, Elif ISoP18-1320

Cosmi, Benildec ISoP18-1325

Cottin, Judith ISoP18-1167

Cottin, Yves ISoP18-1294

Coukan, Flavien ISoP18-1061, ISoP18-1141, ISoP18-1142

Cox, Anthony ISoP18-1385, ISoP18-1416

Cox, Anthony R ISoP18-1419

Crescioli, Giada ISoP18-1449

Curtain, Colin ISoP18-1040

Cutroneo, Paola Maria ISoP18-1166, ISoP18-1193, ISoP18-1163

D´Alessio, Luciana ISoP18-1098

Daghfous, Riadh ISoP18-1413, ISoP18-1414, ISoP18-1421, ISoP18-1417, ISoP18-1486, ISoP18-1488, ISoP18-1489, ISoP18-1496, ISoP18-1472, ISoP18-1506, ISoP18-1145,O-013, ISoP18-1309, ISoP18-1318, ISoP18-1328, ISoP18-1340, ISoP18-1347, ISoP18-1350, ISoP18-1357, ISoP18-1162, ISoP18-1375, ISoP18-1396, ISoP18-1402, ISoP18-1130, ISoP18-1222, ISoP18-1352, ISoP18-1420, ISoP18-1423, ISoP18-1378, ISoP18-1387, ISoP18-1392, ISoP18-1393, ISoP18-1405, ISoP18-1406, ISoP18-1408, ISoP18-1411

Dagistanli, Seyfullah ISoP18-1155

Dal Pan, Gerald ISoP18-1068, ISoP18-1226, ISoP18-1300

D’Anna, Rosario ISoP18-1333

Dante, Giulia ISoP18-1333

Danysz, Karolina ISoP18-1192, ISoP18-1197, ISoP18-1199, ISoP18-1198

Daoudi, Issam ISoP18-1204, ISoP18-1434

Darderes, Guadalupe ISoP18-1098

Dashdondov, Khongorzul ISoP18-1214

Davies, Mary-Ann ISoP18-1317

Davies, Miranda ISoP18-1063, ISoP18-1077, ISoP18-1141, ISoP18-1142, ISoP18-1143

de Boer, Anthonius ISoP18-1169, ISoP18-1171

de Canecaude, Claire ISoP18-1286

De Carlo, Ilenia ISoP18-1341

de Groot, Mark ISoP18-1172

DE GUILLEBON, Eléonore O-016

De Jong, Wim H. ISoP18-1321

De Meestere, Dieter ISoP18-1314

De Ponti, Fabrizio ISoP18-1325, ISoP18-1270

de Vries, Sieta ISoP18-1104

Default, Anne ISoP18-1426

Del Lungo, Martina ISoP18-1293

Delcher, Chris ISoP18-1068, ISoP18-1226

Delepine, Stéphane ISoP18-1170

Delumeau, Jean-Christophe O-036,O-037

Deng, Jianxiong ISoP18-1038

Denig, Petra ISoP18-1104

Dentith, Jacky ISoP18-1057

Desai, Sameen ISoP18-1192, ISoP18-1197, ISoP18-1361, ISoP18-1199, ISoP18-1455

Desmeules, Jules ISoP18-1482, ISoP18-1494, ISoP18-1126, ISoP18-1096, ISoP18-1323, ISoP18-1356

Despott, Richard ISoP18-1491

Devlieger, Hugo ISoP18-1173

Dhanda, Sandeep ISoP18-1061, ISoP18-1062, ISoP18-1063, ISoP18-1212

Didier, Nzolo ISoP18-1381

D’incau, Stéphanie ISoP18-1462

DJERADA, Zoubir ISoP18-1097

Dodoo, Alex ISoP18-1362

Dokas, Ioannis ISoP18-1298

Dominicus, Hanneke ISoP18-1161

Dondera, Roxana ISoP18-1389

Dormidor, Arthur ISoP18-1479

Doua, Joachim ISoP18-1161

Drablier, Guillaume ISoP18-1170

Drago, Flavia ISoP18-1166

DRAGON-DUREY, Marie-Agnès O-016

Draoui, Mustapha ISoP18-1215, ISoP18-1221, ISoP18-1359

Dumortier, Jérôme ISoP18-1167

Dunstan, Hannah ISoP18-1022

Duparc, Stephan O-032

Dupont, Alain ISoP18-1172

Duran, Hilda ISoP18-1442

Durieu, Geneviève ISoP18-1167

Durrieu, Genevieve ISoP18-1118, ISoP18-1119

Durrieu, Geneviève ISoP18-1286

Dzabala, Nettie O-029

Edwards, Brian ISoP18-1021,O-020, ISoP18-1298,O-014,O-011

Egan, Brian ISoP18-1361

Egberts, Toine ISoP18-1269

Egorova, Elena ISoP18-1479, ISoP18-1484

Egunsola, Oluwaseun ISoP18-1024

Ekhart, Corine ISoP18-1104

El Aidli, Sihem ISoP18-1413, ISoP18-1414, ISoP18-1421, ISoP18-1417, ISoP18-1486, ISoP18-1488, ISoP18-1489, ISoP18-1496, ISoP18-1472, ISoP18-1506,O-013, ISoP18-1309, ISoP18-1220, ISoP18-1318, ISoP18-1328, ISoP18-1342, ISoP18-1340, ISoP18-1347, ISoP18-1350, ISoP18-1348, ISoP18-1162, ISoP18-1375, ISoP18-1396, ISoP18-1402, ISoP18-1222, ISoP18-1352, ISoP18-1420, ISoP18-1423, ISoP18-1378, ISoP18-1387, ISoP18-1392, ISoP18-1393, ISoP18-1405, ISoP18-1406, ISoP18-1408, ISoP18-1411

El Aridi, Layal ISoP18-1188

El Asil, Zineb ISoP18-1215, ISoP18-1221

El Biali, Myriam ISoP18-1096

El Harrak, Meryem ISoP18-1048

El JEBARI, hanene ISoP18-1145, ISoP18-1357, ISoP18-1130

El khattab, Mohammed ISoP18-1471

El ouadghiri, Brahim ISoP18-1047

El Rherbi, afaf ISoP18-1189, ISoP18-1324

Elad, Aviva O-014

Elaissaoui, Yousra

Elkheir, Habab ISoP18-1310, ISoP18-1452, ISoP18-1394

Ellenius, Johan ISoP18-1158, ISoP18-1178,O-007

Elmusbah, Muna ISoP18-1452

Elsidig, Mohamed ISoP18-1310

Elzi, Luigia ISoP18-1478

Engo, Aline ISoP18-1512,O-031

Errihani, Hassan ISoP18-1471, ISoP18-1439

Evans, Alison ISoP18-1077, ISoP18-1141, ISoP18-1142

Exposito, Manon ISoP18-1085

FABRE, Elizabeth O-016

Facchinetti, Fabio ISoP18-1333

Fang, Gang ISoP18-1208

Faouzi, El Abbes ISoP18-1216

Farcas, Andreea ISoP18-1074, ISoP18-1086, ISoP18-1087, ISoP18-1207, ISoP18-1275, ISoP18-1263

Fathallah, Neila ISoP18-1181, ISoP18-1233, ISoP18-1234, ISoP18-1236, ISoP18-1239, ISoP18-1241, ISoP18-1242, ISoP18-1243, ISoP18-1244, ISoP18-1277, ISoP18-1283, ISoP18-1287, ISoP18-1290, ISoP18-1182, ISoP18-1237

FAZAA, ikram ISoP18-1145

Feher, Gabriella ISoP18-1264

FELIU, Catherine ISoP18-1097

Ferard, Claire ISoP18-1144

Fermont, Rina Irene O-014

Ferner, Robin ISoP18-1483

Ferner, Robin E ISoP18-1415, ISoP18-1419

Ferrajolo, Carmen ISoP18-1448

Ferrara, Yuri Vincenzo ISoP18-1293

Ferraro, Sara ISoP18-1341, ISoP18-1313

Flores, Jorge O-030

Fonte, Ana ISoP18-1308

Forcesi, Emanuele ISoP18-1270

Fornaratto, Nicole ISoP18-1192

Fornarotto, Nicole ISoP18-1197

Fouda, Mohammed ISoP18-1092

Foufi, Vasiliki ISoP18-1356

Franchini, Michela ISoP18-1341

Freeman, John ISoP18-1361, ISoP18-1455

Freni, Francesco ISoP18-1163

Frippiat, Frédéric ISoP18-1152

Frise, Sarah O-036

Froment, Carole ISoP18-1482

Furlan, Giovanni ISoP18-1021

Gagliano, Antonella ISoP18-1166

GAIES, Emna ISoP18-1145, ISoP18-1357, ISoP18-1130

Galić, Iva ISoP18-1377

Galiulo, Maria Teresa ISoP18-1313

Galiwango, Edward ISoP18-1367

Galletti, Francesco ISoP18-1163

Gallo, Juan Carlos ISoP18-1098

Galvan-Cantu, Marcela ISoP18-1210

Ganso, Matthias ISoP18-1185

Gardarsdottir, Helga O-002, ISoP18-1269

Gardner, Adrian O-035

Garza Ocañas, Lourdes ISoP18-1210

Gattepaille, Lucie O-033, ISoP18-1158, ISoP18-1102

Gaudet-Blavignac, Christophe ISoP18-1356

GAVARD, Marylaure ISoP18-1035

Geiling, Katharina ISoP18-1349

Gentili, Marta ISoP18-1080

Germanò, Eva ISoP18-1166

Gerrett, David O-034

Gesztesi, Zsuzsanna ISoP18-1132

Getov, Ilko ISoP18-1056

Getova, Violeta ISoP18-1056, ISoP18-1227

Ghaeli, Padideh ISoP18-1493

Ghariani, Najat ISoP18-1242, ISoP18-1237

Gholami, Kheirollah ISoP18-1480, ISoP18-1493, ISoP18-1492

Giezen, Thijs ISoP18-1269

Girardin, François ISoP18-1494

Giuovannetti, Linda ISoP18-1293

giwa, ayuba O-023

Gligor, Felicia ISoP18-1327

Gonella, Laura ISoP18-1467, ISoP18-1468

Gouraud, Aurore ISoP18-1167, ISoP18-1380

Gouverneur, Amandine ISoP18-1380, ISoP18-1312

Grandvuillemin, Aurélie ISoP18-1170

Greenall, Amanda ISoP18-1022

Greer, Gary ISoP18-1129

Grimaldi-Bensouda, Lamiae ISoP18-1294

Grimes, Emiri ISoP18-1386

Grosgurin, Olivier ISoP18-1096

Grundmark, Birgitta ISoP18-1178

Guantai, Anastacia ISoP18-1477

Guantai, Anastasia N. O-008

Guerra Mendoza, Yolanda O-029

Guillard Maure, Christine ISoP18-1173

Gulati, Rishi ISoP18-1361

Gundert-Remy, Ursula ISoP18-1066

Gunnlaugsson, Sigurjón Viðar ISoP18-1307

Guo, Yu-ming ISoP18-1045

Gvozdanovic, Katarina ISoP18-1495

Gvozdanović, Katarina ISoP18-1315

Haaksman, Michelle ISoP18-1101

Hachfeld, Anna ISoP18-1478

Hachfi, Wissem ISoP18-1290

Hagemann, Ulrich O-010

Haj Khalifa, Mohamed ISoP18-1283

Hajjar, Issam

Hall Ramirez, Victoria O-018, ISoP18-1262

Halleux, Christine O-026

Hammond, Edward ISoP18-1057

Hamza, Imen ISoP18-1496, ISoP18-1328, ISoP18-1162, ISoP18-1396

Hamza, Imene ISoP18-1472, ISoP18-1408

Happe, Andre ISoP18-1188

Harings-Kaim, Annette ISoP18-1354

Harinstein, Lisa ISoP18-1300

Härmark, Linda ISoP18-1103, ISoP18-1117

Harrison-Woolrych, Mira ISoP18-1191

Hartigan-Go, Kenneth Yu ISoP18-1276

Hasan, M Y. ISoP18-1211

Haschke, Manuel ISoP18-1349, ISoP18-1228

Hassan, Sarah ISoP18-1394

Haydar, Samir ISoP18-1277

Hazell, Lorna ISoP18-1057, ISoP18-1160

Hede, Vincent ISoP18-1482

Hedfors Vidlin, Sara ISoP18-1158, ISoP18-1102

Hegerius, Anna O-007

Hek, Karin ISoP18-1128

Herdeiro, Maria Teresa ISoP18-1430, ISoP18-1412

Heredia, Romina ISoP18-1120

Hermens, Walter ISoP18-1282

Herrero Martinez, Esteban ISoP18-1064

Hilgersom, Wil ISoP18-1456, ISoP18-1453

Hitz, Paolo ISoP18-1261

Hmouda, Houssem ISoP18-1181, ISoP18-1233, ISoP18-1244, ISoP18-1182

Ho, Phoebe ISoP18-1065

Hoebert, Joëlle ISoP18-1321

Hoegberg, Alexandra ISoP18-1165

Hoekman, Jarno ISoP18-1174

Holemans, Xavier ISoP18-1152

HUANG, Ju Kai O-022, ISoP18-1303

Huang, Wei-I ISoP18-1134

Hugman, Bruce Peter John ISoP18-1154

Huruba, Madalina ISoP18-1074, ISoP18-1086

Ibrahim, Ali ISoP18-1279

Ientile, Valentina ISoP18-1193, ISoP18-1448

Ilic, Katarina O-010

Ilomaki, Jenni ISoP18-1208

Ilombe, Gillon Kaounga ISoP18-1076

Ing Lorenzini, Kuntheavy ISoP18-1494, ISoP18-1323, ISoP18-1356

Ing Lorenzini, Kuntheavy Roseline ISoP18-1126

Ing-Lorenzini, Kuntheavy ISoP18-1464

Ing-Lorenzini, Roseline ISoP18-1462

Isah, Ambrose O-005

Isgrò, Valentina ISoP18-1193

Ishikawa, Tomofumi ISoP18-1176

Ishikuro, Mami ISoP18-1176

İsli, Fatma ISoP18-1266

Iurian, Sonia ISoP18-1264

Jaafar, Jaafar ISoP18-1462

Jabbarvand, Mahmoud ISoP18-1492

Jaber, Jaber ISoP18-1032

Jacob, Nisha ISoP18-1317

Jacobs, Frédérique ISoP18-1152

Jacquot, Julien ISoP18-1286

Jain, Sourabh ISoP18-1051

Jakait, Beatrice O-035

Jani, Yogini O-034

Jantzem, Hélène ISoP18-1188

Janusorn, Prathan ISoP18-1368

JARRION, Quentin ISoP18-1097

Javot, Lucie ISoP18-1274

JEBABLI, Nadia ISoP18-1145, ISoP18-1357, ISoP18-1130

Jeenapongsa, Rattima ISoP18-1183

Jessurun, N.T. ISoP18-1282

Jhaj, Ratinder ISoP18-1051

Joaquim, João ISoP18-1497, ISoP18-1284

Johnson, Joy ISoP18-1343

Johnson, Wiltshire ISoP18-1343

Juncan#, Anca ISoP18-1327

Jusot, Viviane O-029

Kaabi, Widd ISoP18-1347, ISoP18-1350, ISoP18-1162, ISoP18-1375

Kaabia, Ons ISoP18-1277

Kaegi, Alina ISoP18-1386

Kajungu, Dan ISoP18-1365, ISoP18-1367

Kalamaro, Vardit O-014

Kalk, Emma ISoP18-1317

Kalra, Dipti ISoP18-1300

Kandzija, Neva ISoP18-1377

Kang, Mingyu ISoP18-1214

Kant, Agnes O-002, ISoP18-1280

Karki, Renu ISoP18-1252

Karomi, Mariana ISoP18-1174

Karwa, Rakhi O-035

Kasatlli, Sarah ISoP18-1402

Kassai, Behrouz ISoP18-1274

Kassaï-koupaï, Behrouz ISoP18-1167

Kastalli, Sarrah ISoP18-1413, ISoP18-1414, ISoP18-1421, ISoP18-1417, ISoP18-1488, ISoP18-1489, ISoP18-1472, ISoP18-1506, ISoP18-1219, ISoP18-1309, ISoP18-1220, ISoP18-1318, ISoP18-1342, ISoP18-1340, ISoP18-1347, ISoP18-1350, ISoP18-1348, ISoP18-1162, ISoP18-1222, ISoP18-1352, ISoP18-1420, ISoP18-1423, ISoP18-1378, ISoP18-1387, ISoP18-1392, ISoP18-1393, ISoP18-1405, ISoP18-1406, ISoP18-1408, ISoP18-1411

Kaur, Moninder ISoP18-1334

Kaur, Sarabjeet ISoP18-1379

Khan, Henna ISoP18-1379

Khan, Riaz ISoP18-1323

Khattabi, Asmae ISoP18-1460, ISoP18-1246

Kheloufi, Farid ISoP18-1426

Kholod, Anzhelika ISoP18-1169

Khosrow-khavar, Farzin ISoP18-1078

Kim, Mi-Hye ISoP18-1214

Kim, Moonjung ISoP18-1124

Kim, Sunkyung ISoP18-1124

Kim, Yong-Ki ISoP18-1214

Kinuthia, Rosaline ISoP18-1477

Kirchmayer, Ursula ISoP18-1341

Kirmizi, N. Ipek ISoP18-1266

Klaassen, Meike ISoP18-1321

Klarica, Marijan ISoP18-1315

Klein, Kevin ISoP18-1160

Klungel, Olaf ISoP18-1169, ISoP18-1171, ISoP18-1172, ISoP18-1174

Köberle, Ursula ISoP18-1066

Koka, Nono Ngombe ISoP18-1076

Kolaric, Darija ISoP18-1495

Kondi, Awoussi ISoP18-1427

Kongkaew, Chuenjid ISoP18-1183,O-017, ISoP18-1368

Kortepeter, Cindy ISoP18-1068, ISoP18-1226, ISoP18-1300

Kothari, Charmy ISoP18-1123

Kouvelas, Dimitrios ISoP18-1409

Kovari, Helen ISoP18-1386

Krähenbühl, Stephan ISoP18-1354

Krasheninnikov, Anatoly ISoP18-1479, ISoP18-1484

Krnić, Darko ISoP18-1315

Kuemmerle, Andrea O-032, ISoP18-1202

Kuriyama, Shinichi ISoP18-1176

Laarabi, fatima zahra ISoP18-1189

Lachhab, zineb ISoP18-1046, ISoP18-1504, ISoP18-1510

Ladhari, Chayma ISoP18-1236, ISoP18-1239, ISoP18-1241, ISoP18-1242, ISoP18-1396, ISoP18-1402

Lagarce, Laurence ISoP18-1170

Lai, Maria Grazia ISoP18-1293

Lakhoua, Ghozlane ISoP18-1309

Lakhoua, Ghozlane ISoP18-1413, ISoP18-1417, ISoP18-1486, ISoP18-1496, ISoP18-1220, ISoP18-1318, ISoP18-1328, ISoP18-1342, ISoP18-1340, ISoP18-1347, ISoP18-1350, ISoP18-1375, ISoP18-1396, ISoP18-1402, ISoP18-1378, ISoP18-1393, ISoP18-1406

Lamprianou, Smaragda ISoP18-1173

Lamsaouri, Jamal ISoP18-1046, ISoP18-1047, ISoP18-1048

Lamzouri, Afaf ISoP18-1189

Lane, Samantha ISoP18-1150, ISoP18-1149

Langlade, Claire ISoP18-1380

LARA, OCTAVIO ISoP18-1442

Larif, Sofene ISoP18-1239, ISoP18-1241, ISoP18-1242, ISoP18-1243, ISoP18-1244, ISoP18-1237

Larif, Sofien ISoP18-1181, ISoP18-1277, ISoP18-1283, ISoP18-1287, ISoP18-1290

Larif, Sofiene ISoP18-1233, ISoP18-1234, ISoP18-1236, ISoP18-1182

Larson, Heidi ISoP18-1276

Lassoued, Latifa ISoP18-1283

LE BELLER, Christine ISoP18-1187,O-016

Le Guillou, Clara ISoP18-1188

Le Louët, Hervé O-036

Lebanova, Hristina ISoP18-1056

Lebanova, Hristina Viktorova ISoP18-1227

Lee, Sang-Mu ISoP18-1214

Lenhart, Sebastian Peter ISoP18-1185

Lenoir, Camille ISoP18-1126, ISoP18-1096

Lenti, Maria Carmela ISoP18-1333

Leone, Roberto ISoP18-1268, ISoP18-1468, ISoP18-1467

Leufkens, Bert ISoP18-1269

Leufkens, Hubert ISoP18-1174

Leuppi-Taegtmeyer, Anne ISoP18-1354

Levi, Miriam ISoP18-1449

Li, Haona ISoP18-1038

Li, Ying ISoP18-1153

LILLO-LE LOUET, Agnès ISoP18-1187,O-016

Lillo-Le Louët, Agnès ISoP18-1170

Lima, Fátima ISoP18-1430, ISoP18-1412

Litaiem, Noureddine ISoP18-1405

Litman, Ronald O-014

Litwa, Matthias ISoP18-1066

Livio, Francoise ISoP18-1478

Livneh, Ayalah O-014

Liwono, Jerry O-032

Lombardi, Niccolò ISoP18-1449

Lora, Riccardo ISoP18-1468

Louhab, Imane ISoP18-1510

Loureiro, Manuel ISoP18-1284

Loureiro, Marcia ISoP18-1308

Lovis, Christian ISoP18-1356

Lula, Yves ISoP18-1512,O-031

Lutete, Tona ISoP18-1512

Luthy, Christophe ISoP18-1096

Lyahyai, jaber ISoP18-1189

Lynn, Elizabeth ISoP18-1150, ISoP18-1149

Mabrouki, Meryem ISoP18-1509

Magnaud, Jérémie ISoP18-1085

Magro, Lara ISoP18-1268, ISoP18-1468, ISoP18-1467

Mahaux, Olivia ISoP18-1156

Maina, Mercy O-035

Maison, Patrick ISoP18-1144

Makila, Félicité Bool-Miting ISoP18-1076

Makila, Felicité Boolmiting ISoP18-1256

Makram, Sanaa ISoP18-1047, ISoP18-1048

MALAMUT, Georgia O-016

Malikova, Marina Alexandrovna ISoP18-1404, ISoP18-1481

Mampunza, Samuel ISoP18-1388

Mampunza Ma Miezi, Samuel ISoP18-1363

Mampuya, Warner Mbuila ISoP18-1256

Man, Kenneth ISoP18-1065

Mangtani, Punam ISoP18-1173

Mannucci, Carmen ISoP18-1333

Mano, Nariyasu ISoP18-1176

Mansaray, Sheku ISoP18-1343

Mantel-Teeuwisse, Aukje ISoP18-1174

Margan Koletić, Željana ISoP18-1315

Marques, João ISoP18-1284

Marriott, John ISoP18-1416

Martin, Florence ISoP18-1022

Marušić, Srećko ISoP18-1315

Marzolini, Catia ISoP18-1202, ISoP18-1478

Masmoudi, Kamel ISoP18-1426

Matarangolo, Elena ISoP18-1193

Matos, Cristiano ISoP18-1497, ISoP18-1250, ISoP18-1284

Matveev, Aleksandr ISoP18-1479, ISoP18-1484

Matveeva, Natalia ISoP18-1484

Maurier, Anaïs ISoP18-1170

Mazhar, Faizan ISoP18-1080

Mazzarella, Alessandra ISoP18-1270

Mboma, Mapipi Odette ISoP18-1076

Mboma, Odette Mapipi ISoP18-1256

Mease, Mary ISoP18-1257

MEDDAH, BOUCHRA ISoP18-1439

Mefetah, Hafid ISoP18-1215, ISoP18-1221, ISoP18-1231, ISoP18-1359

Mehrabifar, Atefeh ISoP18-1493

Mehta, Ushma ISoP18-1317

Meijboom, Ron ISoP18-1171

Meldau, Eva-Lisa ISoP18-1102

Menang, Olga O-029,O-030

Mendes, Diogo ISoP18-1308, ISoP18-1326

Mendi, Neslihan ISoP18-1507

Mesia, Gauthier Kahunu ISoP18-1256

Mesia, Kahunu Gauthier ISoP18-1076

Metoki, Hirohito ISoP18-1176

Micallef, Joëlle ISoP18-1426

MIGNEN, Paul O-016

Miljkovic, Milena ISoP18-1177

Mingle, Edward ISoP18-1192, ISoP18-1361, ISoP18-1197, ISoP18-1199, ISoP18-1455

Minnema, Lotte ISoP18-1269

Miremont, Ghada ISoP18-1312

Miremont-Salamé, Ghada ISoP18-1380, ISoP18-1399

Mirošević Skvrce, Nikica ISoP18-1315, ISoP18-1377

Mitashi, Mulopo Patrick ISoP18-1076

Miyakoda, Keiko ISoP18-1176

Mocciaro, Eleonora ISoP18-1163

Mockute, Ruta ISoP18-1192, ISoP18-1197, ISoP18-1199, ISoP18-1198

Moffa, Giusi ISoP18-1478

Mogosan, Cristina ISoP18-1074, ISoP18-1086, ISoP18-1087, ISoP18-1264, ISoP18-1389, ISoP18-1263

Mohamed, Sara ISoP18-1394

Mohamed alhabib, Einas ISoP18-1394

Mohebbi, Niayesh ISoP18-1493, ISoP18-1492, ISoP18-1480

Mokni, Sana ISoP18-1242, ISoP18-1243, ISoP18-1237

Mol, Peter ISoP18-1104

Molimard, Mathieu ISoP18-1312

Molto-Puigmarti, Carolina ISoP18-1321

Mongkhon, Pajaree ISoP18-1183, ISoP18-1368

Montastruc, Francois ISoP18-1078, ISoP18-1118, ISoP18-1119

Montastruc, François ISoP18-1426

Montastruc, Jean Louis ISoP18-1286

Montastruc, Jean-Louis ISoP18-1078, ISoP18-1118, ISoP18-1119, ISoP18-1316, ISoP18-1331, ISoP18-1426

MOREL, Aurore ISoP18-1097

Moretti, Ugo ISoP18-1268, ISoP18-1448, ISoP18-1467, ISoP18-1468, ISoP18-1270

Morgovan#, Claudiu ISoP18-1327

Moride, Yola ISoP18-1132,O-036

Morin, Agathe ISoP18-1426

Morris, Tim ISoP18-1175

Mousa, Mona ISoP18-1394

Mpiempie, Ngamasata Maleluka Therese ISoP18-1076

Mpiempie, Therese Ngamasata Maleluka ISoP18-1256

Mtiraoui, Ahlem ISoP18-1236

Mucalo, Iva ISoP18-1315, ISoP18-1377

Mudnić, Ivana ISoP18-1315

Mugelli, Alessandro ISoP18-1293, ISoP18-1449

Mulaku, Mercy ISoP18-1477

Müller, Laura ISoP18-1261

Munoz, Monica O-038, ISoP18-1068, ISoP18-1226, ISoP18-1300

Muntean, Andrei ISoP18-1327

Muresan, Ioan ISoP18-1264, ISoP18-1275

Muresan, Sandra ISoP18-1264, ISoP18-1275

Mvete Luemba, Bibiche ISoP18-1363

Myer, Landon ISoP18-1317

N. Oluka, Margaret O-008

Nagumo, Walter-Rodney ISoP18-1140

Nakhli, Jaafar ISoP18-1236

Nambasa, Victoria ISoP18-1365, ISoP18-1367

Nascimento, Luis Miguel ISoP18-1297, ISoP18-1299

Naser, Abdallah ISoP18-1084, ISoP18-1208

Naseva, Emilia ISoP18-1056

Navarra, Michele ISoP18-1333

Nchinech, Naoual ISoP18-1046, ISoP18-1047, ISoP18-1048, ISoP18-1504

Nejjari, Rachid

Ngetich, Celia O-035

Nguyen, Hoang-Anh ISoP18-1316, ISoP18-1331

Nguyen, Khac-Dung ISoP18-1316, ISoP18-1331

Nicholls, Dasha ISoP18-1082, ISoP18-1084

Niedrig, David ISoP18-1386

Niggemeier, Verena ISoP18-1386

Nishigori, Hidekazu ISoP18-1176

Norén, G. Niklas ISoP18-1110, ISoP18-1102

Norén, Niklas O-027

Nosiri, Helga ISoP18-1279

NSEKA ZI NSEKA, ARNOLD ISoP18-1400

Nsengi Ntamabyaliro, Pierre ISoP18-1363, ISoP18-1400

Nsibu, Ndosimao Celestin ISoP18-1076

Nsimba, Gancia ISoP18-1381

Ntamabyaliro, Nsengi O-031, ISoP18-1388

Ntamabyaliro, Pierre ISoP18-1381

Ntamabyaliro, Pierre-Michel ISoP18-1512

Nyambayo, Priscilla ISoP18-1206

Nzolo, Didier ISoP18-1512, ISoP18-1388

Nzolo Bomene, Didier ISoP18-1363,O-031

Obara, Taku ISoP18-1176

Obsorne, Vicki ISoP18-1062

Ogar, Comfort Kunak ISoP18-1279

Ohene Buabeng, Kwame ISoP18-1362

Ohkubo, Takayoshi ISoP18-1176

Okalebo, Faith Apolot O-008

okoro, emmanuel O-023

Oniga, Ovidiu ISoP18-1207, ISoP18-1275

Oosthuizen, Frasia ISoP18-1500

Osman, Amro ISoP18-1310

Osman, Rehab ISoP18-1394

OUDARD, Stéphane O-016

Ouni, Bouraoui ISoP18-1181, ISoP18-1233, ISoP18-1234, ISoP18-1236, ISoP18-1239, ISoP18-1241, ISoP18-1242, ISoP18-1243, ISoP18-1244, ISoP18-1277, ISoP18-1283, ISoP18-1287, ISoP18-1290, ISoP18-1182, ISoP18-1237

oyejola, benjamin O-023

Pacadi, Carmen ISoP18-1377

Pace, Cheryl ISoP18-1267

Pageot, Cecile ISoP18-1399

Papale, Rosamaría ISoP18-1120

Papazian, Maria Gabriela ISoP18-1120

Papazisis, Georgios ISoP18-1409

Parameswaran Nair, Nibu ISoP18-1040

Pariente, Antoine ISoP18-1380, ISoP18-1399

Parikh, Urvish ISoP18-1455

Park, Jiyoon ISoP18-1124

Parrilli, Maria ISoP18-1293, ISoP18-1341, ISoP18-1313

Parthasarathi, Gurumurthy ISoP18-1351

Patel, Harshil ISoP18-1353

Paudyal, Vibhu ISoP18-1385

Pecori, Alessandro ISoP18-1341, ISoP18-1313

Pellegrino, Nicola ISoP18-1193

Pelzer, Levi ISoP18-1321

Peppers, Laura ISoP18-1436

Pérault-Pochat, Marie-Christine ISoP18-1380

Perera, Sujan ISoP18-1198

Pérez-Garza, Adriana ISoP18-1210

Pérez-Rodríguez, Edelmiro ISoP18-1210

Perez-Vilar, Silvia ISoP18-1173

Perone, Marcello ISoP18-1333

Peters, Laura O-002

Petersen, Irene ISoP18-1175

Peterson, Gregory ISoP18-1040

Pieroni, Stefania ISoP18-1341

Pierre, Sabrina ISoP18-1167, ISoP18-1274

Piffaretti, Vasco ISoP18-1261

Piguet, Valérie ISoP18-1323

Pinel, Sylvine ISoP18-1274

Pires, Timoteo ISoP18-1497

Pitts, Peter O-014

Pitzer, Martina ISoP18-1066

Pizzoglio, Véronique ISoP18-1167

Plácido, Ana Isabel ISoP18-1430, ISoP18-1412

Poluzzi, Elisabetta ISoP18-1325, ISoP18-1270

POUCHOT, Jacques O-016

Pozzani, Gabriele ISoP18-1468

Prause, Lea ISoP18-1066

Prpic, Sanja ISoP18-1315

Radice, Sonia ISoP18-1080

Raetz Bravo, Alexandra ISoP18-1354

Ramakrishnan, Cartic ISoP18-1198

Ramkumar, Anupama ISoP18-1505

Ramlawi, Majd ISoP18-1323

Raschi, Emanuel ISoP18-1325, ISoP18-1270

Rashed, Asia ISoP18-1307

Ravaldi, Claudia ISoP18-1449

Ravi, M D ISoP18-1351

Raza, Mahwish ISoP18-1258

Regaieg, Haifa ISoP18-1287

REGIS, Pierre-Marie ISoP18-1035

Reid, Isobel ISoP18-1320

Ren, Xuequn ISoP18-1038

Renoux, Christel ISoP18-1078

Reumerman, Michael O-009

Ribeiro, Maria Isabel Barreiro ISoP18-1297, ISoP18-1299

Richardson, Jonathan L. ISoP18-1022

Richir, Milan O-009

Riera, Margarita ISoP18-1173

Rodieux, Frederique ISoP18-1464

Rodríguez-Almendariz, Mayra ISoP18-1210

Roldan, Emilio ISoP18-1098

Rolfes, Lean ISoP18-1195

Rolfes, Leàn ISoP18-1128, ISoP18-1101

Rollason, Victoria ISoP18-1494, ISoP18-1126, ISoP18-1096, ISoP18-1356, ISoP18-1464

Roque, Fátima ISoP18-1297, ISoP18-1299, ISoP18-1430, ISoP18-1412

Rossi, Francesco ISoP18-1448

Rossi, Marco ISoP18-1341, ISoP18-1449

Rousseau, Vanessa ISoP18-1118, ISoP18-1119

Rousset, Marine ISoP18-1312

Routray, Ramani ISoP18-1198

Rowlands, Sam ISoP18-1191

Roy, Debabrata ISoP18-1063, ISoP18-1069, ISoP18-1212

Rrustemi, Flamur ISoP18-1478

Ruggiero, Rosanna ISoP18-1448

Russmann, Stefan ISoP18-1386

Russo, Carmelita ISoP18-1166

Rütsche, Adrian ISoP18-1349

Rutschmann, Olivier ISoP18-1482

Saad, RA. ISoP18-1211

Sabokbar, Afsie ISoP18-1129

Sadasivam, Balakrishnan ISoP18-1051

Saevels, Jan ISoP18-1314

Said, André ISoP18-1185

Saii, A ISoP18-1181, ISoP18-1233, ISoP18-1182

SALOUAGE, Issam ISoP18-1145, ISoP18-1357, ISoP18-1130

Salvadori, Stefano ISoP18-1341, ISoP18-1313

Samal, Vivek ISoP18-1156

Sambakunsi, Cecilia O-029

Samer, Caroline ISoP18-1494, ISoP18-1356

Sandberg, Lovisa ISoP18-1110, ISoP18-1102

Santamaria, Angelo ISoP18-1333

Santarpia, Mariacarmela ISoP18-1193

Santoro, Vincenza ISoP18-1166

Sartori, Daniele ISoP18-1178

Savage, Ruth O-007

Savage, Ruth ISoP18-1135

Schiaffino, Santiago ISoP18-1120

Scholfield, C. Norman ISoP18-1368

Scholz, Irene ISoP18-1349, ISoP18-1228

Schulz, Martin ISoP18-1185

Sebastian, Juny ISoP18-1351

Sefiani, abdelaziz ISoP18-1189

Sefiani, Houda ISoP18-1311

Semlali Hassani, Ilham ISoP18-1461

Senouci, Karima ISoP18-1324

Serra, Andreas ISoP18-1386

Serragui, Samira ISoP18-1046, ISoP18-1302

Serrano, Ellie ISoP18-1294

Sevdalis, Nick O-014

Shah, Manan ISoP18-1123

Shakir, Saad ISoP18-1061, ISoP18-1062, ISoP18-1063, ISoP18-1069, ISoP18-1150, ISoP18-1149, ISoP18-1077, ISoP18-1057, ISoP18-1160, ISoP18-1212, ISoP18-1141, ISoP18-1142, ISoP18-1143

Sharda, Puja ISoP18-1415

Sharma, Latika ISoP18-1334

Sharma, Varun O-030

Shen, Katherine ISoP18-1131, ISoP18-1153

Shongwe, Nomsa ISoP18-1500

Siafis, Spyridon ISoP18-1409

Silva, Carla ISoP18-1284

Simic, Mima ISoP18-1082, ISoP18-1084

Simic-Koumoutsaris, Marija ISoP18-1177

Simon, Anne ISoP18-1202

Simon, Corinne ISoP18-1167

Sinei, Kipruto ISoP18-1477

sirinan, sunicha ISoP18-1373

Siyah, samir ISoP18-1504

Skalli, Souad ISoP18-1053, ISoP18-1471, ISoP18-1345

Slade, Jan ISoP18-1062

Slattery, Jim ISoP18-1149

Slavcovici, Adriana ISoP18-1207

Slim, Raoudha ISoP18-1181, ISoP18-1233, ISoP18-1234, ISoP18-1236, ISoP18-1239, ISoP18-1241, ISoP18-1242, ISoP18-1243, ISoP18-1244, ISoP18-1277, ISoP18-1283, ISoP18-1287, ISoP18-1290, ISoP18-1182, ISoP18-1237

Slogrove, Amy ISoP18-1317

Smaili, Iassine ISoP18-1502

Socquet, Muriel O-030

Sommet, Agnes ISoP18-1119

Sommet, Agnès ISoP18-1118

Sottosanti, Laura ISoP18-1163, ISoP18-1448

soualymani, rachida ISoP18-1504

Soufinia, Sepideh ISoP18-1480

Souilem, Ines ISoP18-1318, ISoP18-1340, ISoP18-1348, ISoP18-1352, ISoP18-1423, ISoP18-1378, ISoP18-1387, ISoP18-1392, ISoP18-1393, ISoP18-1405, ISoP18-1406, ISoP18-1411

Soulaymani, Rachida ISoP18-1047, ISoP18-1048, O-001, ISoP18-1502, ISoP18-1471, ISoP18-1509, ISoP18-1510, ISoP18-1146, ISoP18-1217, ISoP18-1291, ISoP18-1204, ISoP18-1302, ISoP18-1311, ISoP18-1364, ISoP18-1372, ISoP18-1437, ISoP18-1439, ISoP18-1324

Soulaymani Bencheikh, Rachida ISoP18-1046, ISoP18-1053, ISoP18-1460, ISoP18-1189, ISoP18-1292, ISoP18-1461

Soulaymani-Bencheikh, Rachida ISoP18-1246

Soussi Tanani, Driss ISoP18-1302

Souverein, Patrick ISoP18-1171, ISoP18-1269

Spachos, Dimitrios ISoP18-1409

Spangler, Scott ISoP18-1131

Spechbach, Hervé ISoP18-1323

Spina, Edoardo ISoP18-1166, ISoP18-1193, ISoP18-1163

Spinewine, Anne ISoP18-1152

Sreerattanachotchai, Methavee O-017

Stader, Felix ISoP18-1478

Stam Moraga, Margot ISoP18-1401

Stammschulte, Thomas ISoP18-1066

Star, Kristina O-003

Staynova, Radiana ISoP18-1227

Stegmann, Jens-Ulrich O-029

Stephens, Sally ISoP18-1022

Stergachis, Andy O-032

Stolk, Pieter ISoP18-1160

Stroe, Roxana ISoP18-1389

Stuurman, Anke L. ISoP18-1173

Sudnongbua, Supaporn O-017

Sugawara, Junichi ISoP18-1176

Suktragool, Thitiwut ISoP18-1373

Taavola, Henric ISoP18-1110, ISoP18-1102,O-003

Tadlaoui, Yasmina ISoP18-1047, ISoP18-1048

Talibi, Ismail ISoP18-1246

Tambwe, Emmanuel Sumaili ISoP18-1256

Tanasombat, Tanasin ISoP18-1183

Tarr, Philip ISoP18-1478

Tashtoush, Mohammad M. ISoP18-1211

Tata, Carmela ISoP18-1166

Tatley, Michael ISoP18-1254, ISoP18-1135

Tebaa, Amina ISoP18-1046, ISoP18-1047, ISoP18-1048, ISoP18-1460, ISoP18-1474, ISoP18-1502, ISoP18-1504, ISoP18-1509, ISoP18-1510, ISoP18-1146, ISoP18-1217, ISoP18-1231, ISoP18-1189, ISoP18-1292, ISoP18-1291, ISoP18-1204, ISoP18-1246, ISoP18-1364, ISoP18-1372, ISoP18-1439, ISoP18-1434, ISoP18-1324, ISoP18-1461

Tebaâ, Amina ISoP18-1471

Tej, Amal ISoP18-1239

Tetarenko, Niki ISoP18-1192, ISoP18-1197, ISoP18-1199, ISoP18-1198

Thiankhanithikun, Kannika ISoP18-1373

Thirot, Hélène ISoP18-1152

Thomas, Simon H. L. ISoP18-1022

Tichelaar, Jelle O-009

Tirone, Fabiana ISoP18-1494, ISoP18-1356

Tomić, Siniša ISoP18-1315

Tomlin, Stephen ISoP18-1307

Tona, Gaston ISoP18-1381, ISoP18-1400,O-031

Tona, Lutete Gaston ISoP18-1076

Tona Lutete, Gaston ISoP18-1363

Torres-Garza, Julia Daniela ISoP18-1210

Touzé, Emmanuel ISoP18-1294

TRABELSI, Sameh ISoP18-1145, ISoP18-1357, ISoP18-1130

Trantza, Sofia ISoP18-1298

TRENQUE, Thierry ISoP18-1097

Trifirò, Gianluca ISoP18-1193

Trifiro’, Gianluca ISoP18-1448

Tshibuabua, Rosette ISoP18-1512

Tuccori, Marco ISoP18-1341, ISoP18-1313, ISoP18-1449, ISoP18-1270

Tulkens, Paul ISoP18-1152

Turchetti, Giuseppe ISoP18-1313

Urakpo, Adebunmi ISoP18-1177

Utepova, Dinara ISoP18-1137

van Agtmael, Michiel O-009

van Balveren, Leontine ISoP18-1272

Van Bambeke, Françoise ISoP18-1152

Van Broeck, Dorien ISoP18-1314

van Dijk, Liset ISoP18-1128

van Eekeren, Rike O-009,O-006

Van Gorp, Anne-Marie ISoP18-1195, ISoP18-1196

van Hunsel, Florence O-002, ISoP18-1250, ISoP18-1345, ISoP18-1456, ISoP18-1453, ISoP18-1272

Van Leeuwen, Bert ISoP18-1021

van Lint, Jette ISoP18-1282

van Puijenbroek, Eugene ISoP18-1128, ISoP18-1104,O-028, ISoP18-1456, ISoP18-1453

van Puijenbroek, Eugène ISoP18-1272

Vanadia, Francesca ISoP18-1166

Vannacci, Alfredo ISoP18-1293, ISoP18-1341, ISoP18-1333, ISoP18-1449

Vanobberghen, Fiona ISoP18-1202

Verheij, Robert ISoP18-1128

Vernaz, Nathalie ISoP18-1494

Verstraeten, Thomas ISoP18-1173, ISoP18-1161

Veyries, Marie-Laure ISoP18-1144

Vial, Thierry ISoP18-1274

Vladimir-Knežević, Sanda ISoP18-1315

Vonica, Loredana ISoP18-1327

Vorstenbosch, Saskia O-025, ISoP18-1195, ISoP18-1196

Wainstein, Laura ISoP18-1323

Wallis, Wayne ISoP18-1131, ISoP18-1153

Wambura, Catherine ISoP18-1410

Wang, Fei ISoP18-1153

Wang, Jia-Bo ISoP18-1045

Wang, Zixuan ISoP18-1065

Wannang, Noel ISoP18-1343

Watson, Sarah ISoP18-1103

Weber-Schoendorfer, Corinna O-024

Webley, Sherael ISoP18-1298

Wei, Jenny ISoP18-1068, ISoP18-1226

Wei, Li ISoP18-1208

WEISS, Laurence O-016

Weits, Gerda ISoP18-1250, ISoP18-1280

Weyler, Joost ISoP18-1172

Wicki, Andreas ISoP18-1354

Widdowson, Mark ISoP18-1192, ISoP18-1197, ISoP18-1199, ISoP18-1198

Winterstein, Almut ISoP18-1068, ISoP18-1226

Wise, Lesley ISoP18-1061, ISoP18-1062, ISoP18-1063, ISoP18-1069, ISoP18-1077, ISoP18-1212, ISoP18-1141, ISoP18-1142, ISoP18-1143

Wissel, Kerstin ISoP18-1478

Wong, Ian ISoP18-1065, ISoP18-1082, ISoP18-1084, ISoP18-1208

Woo, Sung-Il ISoP18-1214

Woo, Yeonju ISoP18-1124

Wu, Eileen ISoP18-1300

Xia, Jielai ISoP18-1038

Xiao, Cao ISoP18-1153

Xiao, Hong ISoP18-1068, ISoP18-1226

Xiao, Xiao-he ISoP18-1045

YACHI, LAMYAE ISoP18-1292

Yaegashi, Nobuo ISoP18-1176

Yakhchi Beykloo, Maedeh ISoP18-1082, ISoP18-1084

Yaman, Meryem ISoP18-1155

YANG, Xiao Hui O-022, ISoP18-1303

Yanisse, Siham ISoP18-1509

Yanisse, Siham ISoP18-1474, ISoP18-1204, ISoP18-1434

Yasan, Fulya ISoP18-1320

Yates, Laura M. ISoP18-1022

Yeboah Mensah, Abraham ISoP18-1362

Yerima, Mouhoudine ISoP18-1427

Yesbatyrova, Lazzat ISoP18-1137

Yilmaz, Murat ISoP18-1386

Youdarene, Rym ISoP18-1144

Younus, Manal Mohammed ISoP18-1094

Yousef, Tsneem ISoP18-1232

Yousif, Tsneem ISoP18-1394

Yu, Peiming ISoP18-1038

Zaiem, Ahmed ISoP18-1413, ISoP18-1414, ISoP18-1421, ISoP18-1417, ISoP18-1486, ISoP18-1488, ISoP18-1489, ISoP18-1496, ISoP18-1472, ISoP18-1506, ISoP18-1309, ISoP18-1220, ISoP18-1318, ISoP18-1328, ISoP18-1342, ISoP18-1348, ISoP18-1375, ISoP18-1396, ISoP18-1402, ISoP18-1222, ISoP18-1352, ISoP18-1420, ISoP18-1423, ISoP18-1378, ISoP18-1387, ISoP18-1392, ISoP18-1393, ISoP18-1405, ISoP18-1406, ISoP18-1408, ISoP18-1411

Zayeni, Hamida ISoP18-1486, ISoP18-1348, ISoP18-1396, ISoP18-1402

Zehani, Hamida ISoP18-1387

Zekarias, Alem O-003

Zgolli, Fatma ISoP18-1486, ISoP18-1347, ISoP18-1350, ISoP18-1162, ISoP18-1357, ISoP18-1375, ISoP18-1396, ISoP18-1402

Zhaldybayeva, Saule ISoP18-1137

ZHANG, Li O-022, ISoP18-1303

Zhu, Feng ISoP18-1038

Zhussupova, Gulzira ISoP18-1137

Zimmermanns, Barbara ISoP18-1354

Zoubairi, rihane ISoP18-1474, ISoP18-1434

Zuber, Patrick ISoP18-1173

Zweers, Petra ISoP18-1321