Supporting Pharmacovigilance Signal Validation and Prioritization with Analyses of Routinely Collected Health Data: Lessons Learned from an EHDEN Network Study.

INTRODUCTION: Individual case reports are the main asset in pharmacovigilance signal management. Signal validation is the first stage after signal detection and aims to determine if there is sufficient evidence to justify further assessment. Throughout signal management, a prioritization of signals is continually made. Routinely collected health data can provide relevant contextual information but are primarily used at a later stage in pharmacoepidemiological studies to assess communicated signals. OBJECTIVE: The aim of this study was to examine the feasibility and utility of analysing routine health data from a multinational distributed network to support signal validation and prioritization and to reflect on key user requirements for these analyses to become an integral part of this process. METHODS: Statistical signal detection was performed in VigiBase, the WHO global database of individual case safety reports, targeting generic manufacturer drugs and 16 prespecified adverse events. During a 5-day study-a-thon, signal validation and prioritization were performed using information from VigiBase, regulatory documents and the scientific literature alongside descriptive analyses of routine health data from 10 partners of the European Health Data and Evidence Network (EHDEN). Databases included in the study were from the UK, Spain, Norway, the Netherlands and Serbia, capturing records from primary care and/or hospitals. RESULTS: Ninety-five statistical signals were subjected to signal validation, of which eight were considered for descriptive analyses in the routine health data. Design, execution and interpretation of results from these analyses took up to a few hours for each signal (of which 15-60 minutes were for execution) and informed decisions for five out of eight signals. The impact of insights from the routine health data varied and included possible alternative explanations, potential public health and clinical impact and feasibility of follow-up pharmacoepidemiological studies. Three signals were selected for signal assessment, two of these decisions were supported by insights from the routine health data. Standardization of analytical code, availability of adverse event phenotypes including bridges between different source vocabularies, and governance around the access and use of routine health data were identified as important aspects for future development. CONCLUSIONS: Analyses of routine health data from a distributed network to support signal validation and prioritization are feasible in the given time limits and can inform decision making. The cost-benefit of integrating these analyses at this stage of signal management requires further research.

Navigating the health system during COVID-19: primary care perspectives on delayed patient care.

AIM: The primary care response to the coronavirus disease 2019 (COVID-19) pandemic has required significant changes to the delivery of healthcare by general practices. This study explores the experiences of New Zealand general practice teams in their perception of delayed patient care during the early stages of the pandemic. METHOD: We qualitatively analysed a subtheme of delayed patient care of the General Practice Pandemic Experience New Zealand study, where general practice team members nationwide were invited to participate in five surveys between May and August 2020. RESULTS: 164 participants initially enrolled in the study, with 78 (48%) completing all surveys. Four delayed-care themes were identified: patient contributors, health system contributors, impacts and opportunities for minimisation. Respondents noted that patients avoided healthcare, downplayed symptoms and feared going out. Non-essential care was put on hold, allied services were reduced and access to secondary care was variable. Certain diseases and screening were commonly impacted. As lockdown lifted a backlog of work resulted. Flexible review periods, outreach care, self-screening, cross-sector collaboration and improved public awareness were strategies for timely healthcare. CONCLUSION: Reducing barriers to patients seeking care and improving integration and relationships across the health system would minimise future pandemic disruption and delayed patient healthcare.

'Here to stay': changes to prescribing medication in general practice during the COVID-19 pandemic in New Zealand.

INTRODUCTION The delivery of health care by primary care general practices rapidly changed in response to the coronavirus disease 2019 (COVID-19) pandemic in early 2020. AIM This study explores the experience of a large group of New Zealand general practice health-care professionals with changes to prescribing medication during the COVID-19 pandemic. METHODS We qualitatively analysed a subtheme on prescribing medication from the General Practice Pandemic Experience New Zealand (GPPENZ) study, where general practice team members nationwide were invited to participate in five surveys over 16 weeks from 8 May 2020. RESULTS Overall, 78 (48%) of 164 participants enrolled in the study completed all surveys. Five themes were identified: changes to prescribing medicines; benefits of electronic prescription; technical challenges; clinical and medication supply challenges; and opportunities for the future. There was a rapid adoption of electronic prescribing as an adjunct to use of telehealth, minimising in-person consultations and paper prescription handling. Many found electronic prescribing an efficient and streamlined processes, whereas others had technical barriers and transmission to pharmacies was unreliable with sometimes incompatible systems. There was initially increased demand for repeat medications, and at the same time, concern that vulnerable patients did not have usual access to medication. The benefits of innovation at a time of crisis were recognised and respondents were optimistic that e-prescribing technical challenges could be resolved. DISCUSSION Improving e-prescribing technology between prescribers and dispensers, initiatives to maintain access to medication, particularly for vulnerable populations, and permanent regulatory changes will help patients continue to access their medications through future pandemic disruption.

Remdesivir in the COVID-19 Pandemic: An Analysis of Spontaneous Reports in VigiBase During 2020.

INTRODUCTION: The safety profile of remdesivir, conditionally approved for COVID-19, was limited at its 2020 introduction. Adverse drug reactions (ADRs) for medicines are collected in VigiBase, the WHO Global Database of Individual Case Safety Reports (ICSRs). OBJECTIVE: This study aimed to provide a descriptive analysis of COVID-19 ICSR data focusing on remdesivir, including a disproportionality analysis (DA) of ADRs. METHODS: A dedicated algorithm enabled retrieval of all COVID-19 treatment-specific ICSRs. A severity algorithm based on co-reported medicines and symptoms enabled selection of tocilizumab with its well established safety profile as comparator for remdesivir. Descriptive statistics were used for general ICSR demographics for all COVID-19-specific medicines, remdesivir and tocilizumab individually and furthermore to present treatment patterns of medicines co-reported with remdesivir. A COVID-19 indication-focused DA was deployed to minimize confounding from underlying polysymptomatic disease. RESULTS: 14,574 COVID-19-related ICSRs were entered into VigiBase during 2020. Remdesivir was the most common medicine reported. Of 4944 remdesivir ICSRs, where tocilizumab was not co-reported, 93% described remdesivir as the sole suspect medicine. Sixty percent of ICSRs concerned males, median age was 63 years and the majority originated from the Americas (72%). In 1089 (21%) of remdesivir ICSRs, data indicated severe/critical disease. Co-reported medicines peaked during the first 3 days of remdesivir treatment. The DA for the established tocilizumab and the new remdesivir were mainly in line with the safety profiles for both medicines but suggested new safety concerns. The most reported ADRs for remdesivir represented liver dysfunction, kidney injury, death and bradycardia. CONCLUSION: Global COVID-19-related ADR reporting proved useful in providing information on ADRs as well as on treatment patterns in this patient group. Indication-focused disproportionality analysis, together with the use of a comparator with a known safety profile, proved effective in identifying known safety information and suggested new safety concerns for remdesivir.

Empty waiting rooms: the New Zealand general practice experience with telehealth during the COVID-19 pandemic.

AIM: The primary care response to the coronavirus disease 2019 (COVID-19) pandemic in early 2020 required significant changes to the delivery of healthcare by general practices. This study explores the experiences of New Zealand general practice teams in their use of telehealth during the early stages of the COVID-19 pandemic in New Zealand. METHOD: We qualitatively analysed a subtheme on telehealth of the General Practice Pandemic Experience New Zealand (GPPENZ) study, where general practice team members across the country were invited to participate in five surveys between 8 May 2020 to 27 August 2020. RESULTS: 164 participants enrolled in the study during survey one, with 78 (48%) completing all surveys. Five telehealth themes were identified: benefits, limitations, paying for consults, changes over time and plans for future use. Benefits included rapid triage, convenience and efficiency, and limitations included financial and technical barriers for practices and patients and concerns about clinical risk. Respondents rapidly returned to in-person consultations and wanted clarification of conditions suited to telehealth, better infrastructure and funding. CONCLUSION: To equitably sustain telehealth use, the following are required: adequate funding, training, processes communicated to patients, improved patient access to technology and technological literacy, virtual physical examination methods and integration with existing primary health care services.

Diclofenac and the Risk of Rhabdomyolysis: Analysis of Publications and the WHO Global Pharmacovigilance Database.

BACKGROUND: Diclofenac, a nonsteroidal anti-inflammatory drug, is not a documented cause of rhabdomyolysis in the Summaries of Product Characteristics held by major regulators. There are, however, eight published single case reports that associate rhabdomyolysis with diclofenac. OBJECTIVE: Triggered by a serious local case report, this study was conducted to evaluate the evidence for a causal association between diclofenac and rhabdomyolysis. PATIENTS AND METHODS: A descriptive analysis of rhabdomyolysis associated with diclofenac was conducted by mining data from the WHO Global Database of Individual Case Safety Reports, VigiBase, and published case reports. RESULTS: 70 eligible cases were retrieved from VigiBase. The median age was 56.5 years (range 1-90). Where reported precisely (26 reports), the median time to onset of rhabdomyolysis following administration of diclofenac was 3 days. In 20 cases, diclofenac was reported as a sole suspect and was solely administered in 14 of these. In 30 cases, rhabdomyolysis abated following withdrawal of diclofenac. Seven of these cases fulfilled the WHO-UMC case-causality assessment criteria for 'probable'. Diclofenac was probably an indirect cause in another five reports where rhabdomyolysis ensued from injection-site necrosis. There were eight fatalities and intramuscular administration was over-represented in this group. In 27 patients taking lipid-lowering agents, the incidence of acute kidney injury with rhabdomyolysis was 62.9% compared with 37.1% for the whole cohort. Off-label use of diclofenac for minor or undiagnosed conditions was reported. CONCLUSION: Currently available data suggests a causal link between diclofenac and rhabdomyolysis either directly or indirectly.

The safety of cardioselective ß1-blockers in asthma: literature review and search of global pharmacovigilance safety reports.

INTRODUCTION: Beta-blockers are key in the management of cardiovascular diseases but blocking airway ß2-receptors can cause severe and sometimes fatal bronchoconstriction in people with asthma. Although cardioselective ß1-blockers may be safer than non-selective ß-blockers, they remain relatively contraindicated and under-prescribed. We review the evidence of the risk associated with cardioselective ß1-blocker use in asthma. METHODS: We searched "asthma" AND "beta-blocker" in PubMed and EmbaseOvid from start to May 2020. The World Health Organization (WHO) global database of individual case safety reports (VigiBase) was searched for reports of fatal asthma or bronchospasm and listed cardioselective ß1-blocker use (accessed February 2020). Reports were examined for evidence of pre-existing asthma. RESULTS: PubMed and EmbaseOvid searches identified 304 and 327 publications, respectively. No published reports of severe or fatal asthma associated with cardioselective ß1-blockers were found. Three large observational studies reported no increase in asthma exacerbations with cardioselective ß1-blocker treatment. The VigiBase search identified five reports of fatalities in patients with pre-existing asthma and reporting asthma or bronchospasm during cardioselective ß1-blocker use. Four of these deaths were unrelated to cardioselective ß1-blocker use. The circumstances of the fifth death were unclear. CONCLUSIONS: There were no published reports of cardioselective ß1-blockers causing asthma death. Observational data suggest that cardioselective ß1-blocker use is not associated with increased asthma exacerbations. We found only one report of an asthma death potentially caused by cardioselective ß1-blockers in a patient with asthma in a search of VigiBase. The reluctance to use cardioselective ß1-blockers in people with asthma is not supported by this evidence.

E-Learning in Pharmacovigilance: An Evaluation of Microlearning-Based Modules Developed by Uppsala Monitoring Centre.

INTRODUCTION: An increasing global need for pharmacovigilance training cannot be met with classroom courses alone. Several e-learning modules have been developed by Uppsala Monitoring Centre (UMC). With distance learners and technological challenges such as poor internet bandwidth to be considered, UMC opted for the microlearning approach based on small learning units connected to specific learning objectives. The aim of this study was to evaluate how this e-learning course was received. METHODS: The course was evaluated through usage data and the results of two user surveys, one for modules 1-4, signal detection and causality assessment, and the other for module 5, statistical reasoning and algorithms in pharmacovigilance. The evaluation model used was based on the Unified Theory of Acceptance and Use of Technology (UTAUT). A questionnaire was developed, divided into demographic profile, performance expectancy, effort expectancy, educational compatibility and behavioural intention. The two surveys were disseminated to 2067 learners for modules 1-4 and 1685 learners for module 5. RESULTS: Learners from 137 countries participated, predominantly from industry (36.6%), national pharmacovigilance centres (22.6%) and academia (16.3%). The overall satisfaction level was very high for all modules, with over 90% of the learners rating it as either 'excellent' or 'good'. The majority were satisfied with the learning platform, the course content and the lesson duration. Most learners thought they would be able to apply the knowledge in practice. Almost 100% of the learners would recommend the modules to others and would also study future modules. Suggested improvements were an interactive forum, more practical examples in the lessons and practical exercises. CONCLUSION: This e-learning course in pharmacovigilance based on microlearning was well received with a global coverage among relevant professional disciplines.

The Association between Metformin Therapy and Lactic Acidosis.

INTRODUCTION AND OBJECTIVES: There is increasing evidence to suggest that therapeutic doses of metformin are unlikely to cause lactic acidosis. The aims of this research were (1) to formally evaluate the association between metformin therapy and lactic acidosis in published case reports using two causality scoring systems, (2) to determine the frequency of pre-existing independent risk factors in published metformin-associated lactic acidosis cases, (3) to investigate the association between risk factors and mortality in metformin-associated lactic acidosis cases, and (4) to explore the relationship between prescribed metformin doses, elevated metformin plasma concentrations and the development of lactic acidosis in cases with chronic renal impairment. METHODS: A systematic review was conducted to identify metformin-associated lactic acidosis cases. Causality was assessed using the World Health Organisation-Uppsala Monitoring Centre system and the Naranjo adverse drug reaction probability scale. Compliance to dosing guidelines was investigated for cases with chronic renal impairment as well as the association between steady-state plasma metformin concentrations prior to admission. RESULTS: We identified 559 metformin-associated lactic acidosis cases. Almost all cases reviewed (97%) presented with independent risk factors for lactic acidosis. The prescribed metformin dose exceeded published guidelines in 60% of cases in patients with impaired kidney function. Metformin steady-state plasma concentrations prior to admission were predicted to be below the proposed upper limit of the therapeutic range of 5 mg/L. CONCLUSIONS: Almost all cases of metformin-associated lactic acidosis reviewed presented with independent risk factors for lactic acidosis, supporting the suggestion that metformin plays a contributory role. The prescribed metformin dose, on average, exceeded the dosing recommendations by 1000 mg/day in patients with varying degrees of renal impairment but the predicted pre-admission plasma concentrations did not exceed the therapeutic range.

Suspected Hepatotoxicity With a Supercritical Carbon Dioxide Extract of Artemisia annua in Grapeseed Oil Used in New Zealand.

A case series of hepatotoxicity associated with an extract of Artemisia annua L. was identified through the New Zealand spontaneous adverse drug reaction reporting system. A. annua extract, produced using a supercritical carbon dioxide extraction method and formulated with grapeseed oil, has been marketed in New Zealand as a natural product for joint health. As of 31 January 2019, the New Zealand Pharmacovigilance Centre had received 29 reports of hepatic adverse reactions occurring in patients taking A. annua extract in grapeseed oil. The case reports were assessed for patient and adverse reaction characteristics, patterns of A. annua extract use and causality (based on the WHO-UMC system for standardized case causality assessment). Patients were aged 47 to 93 years (median 67). Time to onset of hepatotoxicity from starting A. annua extract was 7 days to approximately 12 months in the 23 reports with this information. Nineteen of these reports indicated onset within 12 weeks. A. annua extract was the sole suspect medicine in 27 reports. A few patients had possible predisposing conditions. Twenty-seven patients were reported to have recovered or improved on stopping A. annua extract. Nine patients required hospital admission. The pattern of hepatic injury varied. Jaundice, often with pruritus and dark urine, was experienced by 16 patients. There was considerable consistency across case reports from various reporters. We assessed the case reports as a series using the Bradford Hill guidelines for causal inference and concluded that there was a safety signal of a causal association between the A. annua extract and hepatotoxicity sufficient to be communicated and investigated further.

Case Series Analysis of New Zealand Reports of Rapid Intense Potentiation of Warfarin by Roxithromycin.

INTRODUCTION: We undertook an analysis of all the reports to the New Zealand Centre for Adverse Reactions Monitoring of a roxithromycin/warfarin interaction after two recent reports described intense rapid warfarin potentiation. The interaction was first published in 1995. Cytochrome P450 3A4 inhibition has been the proposed mechanism but has limited biologic plausibility. There are suggestions that the clinical significance of the interaction may be increased by severe illness, polypharmacy, renal dysfunction, older age and increased warfarin sensitivity. METHODS: To investigate the potentiating effect of warfarin on roxithromycin in this New Zealand case series, the reports were reviewed to identify patients at risk, compare the reporting pattern with published Australian data and evaluate the appropriateness of current prescribing advice. RESULTS: Thirty patient reports were identified. The age range was 23-88 years, mean 66.8, median 73.0 (standard deviation 17.7) and the international normalised ratios after roxithromycin commencement ranged from 3.6 to 16.7 (mean 7.6, median 7.6, standard deviation 3.6). For eight patients with measurements on day 3, international normalised ratios were 4.3-16.7 (mean 10.4, median 8.8, standard deviation 4.4). Four patients had serious haemorrhage. Indications for roxithromycin were a range of respiratory tract infections. Anticoagulation was stable for most patients prior to acute infection. Serious infection occurred in 54.5% (12 of 22 patients with information). Polypharmacy (five or more medicines daily) was used by 36.7% of patients long term, increasing acutely to 83.3%, including additional potentially interacting medicines. Warfarin daily dose (1.5-13.0 mg, mean 4.4, median 4.0, standard deviation 2.2) was moderate to low. Pre-roxithromycin international normalised ratio values ranged from 1.4 to 3.7, mean and median 2.5, standard deviation 0.5. A high proportion of interactions were observed between warfarin and roxithromycin compared with other macrolides and compared with cytochrome P450 3A4-related macrolide interactions. The pattern was similar to published Australian data. CONCLUSION: In this case series, the high prevalence of acute polypharmacy, including potentially interacting medicines, and serious infection suggests that they may have contributed to warfarin potentiation and increased the clinical significance of a roxithromycin/warfarin interaction.

Impact of New Genomic Technologies on Understanding Adverse Drug Reactions.

It is well established that variations in genes can alter the pharmacokinetic and pharmacodynamic profile of a drug and immunological responses to it. Early advances in pharmacogenetics were made with traditional genetic techniques such as functional cloning of genes using knowledge gained from purified proteins, and candidate gene analysis. Over the past decade, techniques for analysing the human genome have accelerated greatly as knowledge and technological capabilities have grown. These techniques were initially focussed on understanding genetic factors of disease, but increasingly they are helping to clarify the genetic basis of variable drug responses and adverse drug reactions (ADRs). We examine genetic methods that have been applied to the understanding of ADRs, review the current state of knowledge of genetic factors that influence ADR development, and discuss how the application of genome-wide association studies and next-generation sequencing approaches is supporting and extending existing knowledge of pharmacogenetic processes leading to ADRs. Such approaches have identified single genes that are major contributing genetic risk factors for an ADR, (such as flucloxacillin and drug-induced liver disease), making pre-treatment testing a possibility. They have contributed to the identification of multiple genetic determinants of a single ADR, some involving both pharmacologic and immunological processes (such as phenytoin and severe cutaneous adverse reactions). They have indicated that rare genetic variants, often not previously reported, are likely to have more influence on the phenotype than common variants that have been traditionally tested for. The problem of genotype/phenotype discordance affecting the interpretation of pharmacogenetic screening and the future of genome-based testing applied to ADRs are also discussed.

Visual search for emotional expressions: Effect of stimulus set on anger and happiness superiority.

Prior reports of preferential detection of emotional expressions in visual search have yielded inconsistent results, even for face stimuli that avoid obvious expression-related perceptual confounds. The current study investigated inconsistent reports of anger and happiness superiority effects using face stimuli drawn from the same database. Experiment 1 excluded procedural differences as a potential factor, replicating a happiness superiority effect in a procedure that previously yielded an anger superiority effect. Experiments 2a and 2b confirmed that image colour or poser gender did not account for prior inconsistent findings. Experiments 3a and 3b identified stimulus set as the critical variable, revealing happiness or anger superiority effects for two partially overlapping sets of face stimuli. The current results highlight the critical role of stimulus selection for the observation of happiness or anger superiority effects in visual search even for face stimuli that avoid obvious expression related perceptual confounds and are drawn from a single database.

Varenicline and abnormal sleep related events.

STUDY OBJECTIVES: To assess adverse drug reaction reports of "abnormal sleep related events" associated with varenicline, a partial agonist to the α4ß2 subtype of nicotinic acetylcholine receptors on neurones, indicated for smoking cessation. DESIGN: Twenty-seven reports of "abnormal sleep related events" often associated with abnormal dreams, nightmares, or somnambulism, which are known to be associated with varenicline use, were identified in the World Health Organisation (WHO) Global Individual Case Safety Reports Database. Original anonymous reports were obtained from the four national pharmacovigilance centers that submitted these reports and assessed for reaction description and causality. MEASUREMENTS AND RESULTS: These 27 reports include 10 of aggressive activity occurring during sleep and seven of other sleep related harmful or potentially harmful activities, such as apparently deliberate self-harm, moving a child or a car, or lighting a stove or a cigarette. Assessment of these 17 reports of aggression or other actual or potential harm showed that nine patients recovered or were recovering on varenicline withdrawal and there were no consistent alternative explanations. Thirteen patients experienced single events, and two had multiple events. Frequency was not stated for the remaining two patients. CONCLUSIONS: The descriptions of the reports of aggression during sleep with violent dreaming are similar to those of rapid eye movement sleep behavior disorder and also nonrapid eye movement (NREM) sleep parasomnias in some adults. Patients who experience somnambulism or dreams of a violent nature while taking varenicline should be advised to consult their health providers. Consideration should be given to clarifying the term sleep disorders in varenicline product information and including sleep related harmful and potentially harmful events.

The effect of face inversion on the detection of emotional faces in visual search.

Past literature has indicated that face inversion either attenuates emotion detection advantages in visual search, implying that detection of emotional expressions requires holistic face processing, or has no effect, implying that expression detection is feature based. Across six experiments that utilised different task designs, ranging from simple (single poser, single set size) to complex (multiple posers, multiple set sizes), and stimuli drawn from different databases, significant emotion detection advantages were found for both upright and inverted faces. Consistent with past research, the nature of the expression detection advantage, anger superiority (Experiments 1, 2 and 6) or happiness superiority (Experiments 3, 4 and 5), differed across stimulus sets. However both patterns were evident for upright and inverted faces. These results indicate that face inversion does not interfere with visual search for emotional expressions, and suggest that expression detection in visual search may rely on feature-based mechanisms.

Renal replacement therapy associated with lithium nephrotoxicity in New Zealand.

AIM: To document the numbers and characteristics of New Zealand patients commencing renal replacement therapy because of end-stage kidney disease attributed to lithium treatment, and to calculate incidence rates. METHOD: Data on such patients were provided by the Australia and New Zealand Dialysis and Transplant Registry from the start of the Registry in 1977 until 2013. Numbers of patients prescribed lithium in the community were provided by the Ministry of Health for 2009-2013; earlier years had fewer than 96% of prescriptions for lithium linked to individuals by their unique National Health Index number. Time trends were analysed by linear, logistic and Poisson regression. Incidence rates were also calculated for five-year periods. RESULTS: Thirty-five new patients were located with 'lithium toxicity' as their primary renal disease, starting the year after 'lithium toxicity' was included in the standard list (1995). A broader search for lithium within 'other' causes and 'other' comorbidities did not yield further patients. The mean age at the start of renal replacement therapy was 61.1 years (SD 9.2). Twenty-five patients were female. For 1996 onwards, new patient numbers increased on average by 8% per year (95% CI 1 to 15%) and incidence rates increased by 7% per year (95% CI 0 to 14%), an approximate doubling per decade. Form 2007-2011, the average annual incidence per million population was 0.74 (95% CI 0.43 to 1.21) for New Zealand, similar to that reported elsewhere: 0.78 (95% CI 0.67 to 0.90) for Australia and 0.91 (95% CI 0.50 to 1.52) for southern Sweden. Prescription rates across the three countries were also similar. In New Zealand between 2009 and 2013, over 7,500 patients were prescribed lithium each year. CONCLUSION: Dosing and monitoring of patients prescribed lithium should follow guidelines, not only to avoid future psychiatric episodes and acute toxicity but also because such adherence may reduce uncommon but serious outcomes of long-term treatment such as end-stage kidney disease.