Utilisation and Safety of Polyethylene Glycol 3350 With Electrolytes in Children Under 2 Years: A Retrospective Cohort.

OBJECTIVES: In the UK, Movicol paediatric plain (polyethylene glycol 3350 with electrolytes [PEG 3350+E], Norgine, UK), is licensed for chronic constipation in children 2 -11 years of age and faecal impaction (FI) from 5 years. This study aimed to investigate usage and characterise the risk profile in children under 2 years of age using PEG 3350+E in the UK. METHODS: Retrospective, single exposure cohort study, with patients identified from Clinical Practice Research Datalink (CPRD) GOLD. Patients first prescribed PEG 3350+E under 2 years of age for the treatment of constipation or FI, between September 2003 and July 2019, were included. RESULTS: There were 13,235 patients with a constipation indication and 40 patients with FI. For the constipation cohort: median age of PEG 3350+E first prescription was 1.2 years [interquartile range (IQR) 0.9, 1.6] and 68.4% had one treatment episode (TE). The mean duration of exposure, in the first TE, was 88.9 days. The most common total daily dose was one sachet (6.9 g).In terms of incident events on treatment, 0.5% of patients had abdominal pain, 3.0% had diarrhoea (may be attributed to treatment) and 4.1% had vomiting. 2.0% had signs/symptoms which could (in extreme cases) be associated with electrolyte disturbance, however, none had abnormal electrolyte values. DISCUSSION: The safety aspect of this study did not identify any signals of concern in the constipation cohort. The number of patients in the FI cohort were too small for robust conclusions. If information were available, then a safety study would ideally assess treatment intake per kilogram, including electrolyte intake, before reaching safety conclusions. Nevertheless, these data contribute to real-world evidence on the use of PEG 3350+E in this population.

The International Working Group on New Developments in Pharmacovigilance: Advancing Methods and Communication in Pharmacovigilance.

PURPOSE: In 2019, the International Working Group (IWG), focusing on New Developments in Pharmacovigilance, was established. This group is coordinated by the Drug Safety Research Unit in the United Kingdom, and the mission of the IWG is to progress pharmacovigilance methodologies and promote the safe and effective use of medicines and vaccines, thereby further protecting patients. Novel therapeutics are continuously being developed to alleviate medical conditions, but with advancing technologies, innovative pharmacovigilance methodologies need to be developed to effectively monitor the use and safety of these products. With reduced timelines proposed for premarketing clinical trials and increased application of real-world evidence supporting regulatory approvals, products may be used in real-world clinical practice in shorter timeframes than before. Therefore, the need for effective methods of monitoring medicines and collecting safety data in real-time is of paramount importance to public health. METHODS: The IWG aims to advance existing methodologies used in the detection, monitoring, and analysis of safety data in pharmacovigilance and to communicate best practice proposals to support decision making in health care. The IWG will identify areas requiring review of current processes or methodologic research and will communicate the output of the IWG through peer-reviewed publications, reports, and presentation of findings at relevant conferences and scientific meetings. FINDINGS: The IWG is currently reviewing two areas in pharmacovigilance; case-level causality assessment and the strengths and limitations of data sources. The IWG is advancing these areas by producing two scoping reviews which will be easily accessible to regulatory agencies, industry, academia, and interested persons or organizations. IMPLICATIONS: The scoping reviews comply with the IWGs mission to progress pharmacovigilance methodologies and promote the safe and effective use of medicines and vaccines. The present article shares details of the objectives of the IWG and provides an overview on the status of IWG activities.

A systematic review of flurbiprofen 8.75 mg dose and risk of adverse events (excluding haemorrhagic) resulting from drug-drug interactions.

Background: Flurbiprofen 8.75 mg lozenges and oromucosal sprays are used for symptomatic relief of sore throat in patients aged 12 years and over. The documented adverse events of flurbiprofen use include those related to its pharmacological actions, namely, increased risk of haemorrhagic events, however other adverse events (such as nephrotoxicity and cardiac failure) have been known to occur. The likelihood of occurrence of adverse events increases when flurbiprofen is used concomitantly with some other medications. Therefore, the objective of this systematic review was to collate the current evidence on adverse events which occur with flurbiprofen 8.75 mg dose (any formulation), in particular as a result of interaction with other medicinal products, with a focus on non-haemorrhagic events. Methods: Systematic searches of the literature were conducted to identify literature on any formulation of flurbiprofen 8.75 mg up to the date of the electronic database search (data lock: 28 April 2020). Publications were screened to identify studies reporting non-haemorrhagic adverse events with flurbiprofen 8.75 mg and/or non-haemorrhagic adverse events in the comparator arm. Data extraction was performed for eligible studies according to pre-defined criteria and summarised in narratives, tables and figures. Risk of bias and certainty of evidence assessments were planned for each included study where results relating to the primary objective of the systematic review were available. Results: Of 1,528 publications identified by systematic literature searches, 26 met the inclusion criteria and were included in this review. None of these 26 studies contained information on non-haemorrhagic adverse events occurring as a result of a drug-drug interaction (interaction with concomitant medication used with flurbiprofen 8.75 mg), as per the primary objective and secondary objectives of the systematic review. Conclusion: Results from this systematic review on the risk of non-haemorrhagic events did not provide evidence for these events occurring as a result of interaction with other medicinal products. Additional appropriately designed studies would be required to confirm whether these findings suggest a true absence of risk or limitations in reporting.

Cohort Event Monitoring of Adverse Reactions to COVID-19 Vaccines in Seven European Countries: Pooled Results on First Dose.

INTRODUCTION: COVID-19 vaccines were rapidly authorised, thus requiring intense post-marketing re-evaluation of their benefit-risk profile. A multi-national European collaboration was established with the aim to prospectively monitor safety of the COVID-19 vaccines through web-based survey of vaccinees. METHODS: A prospective cohort event monitoring study was conducted with primary consented data collection in seven European countries. Through the web applications, participants received and completed baseline and up to six follow-up questionnaires on self-reported adverse reactions for at least 6 months following the first dose of COVID-19 vaccine (Netherlands, France, Belgium, UK, Italy) and baseline and up to ten follow-up questionnaires for one year in Germany and Croatia. Rates of adverse reactions have been described by type (solicited, non-solicited; serious/non-serious; and adverse events of special interest) and stratified by vaccine brand. We calculated the frequency of adverse reaction after dose 1 and prior to dose 2 among all vaccinees who completed at least one follow-up questionnaire. RESULTS: Overall, 117,791 participants were included and completed the first questionnaire in addition to the baseline: 88,196 (74.9%) from Germany, 27,588 (23.4%) from Netherlands, 984 (0.8%) from France, 570 (0.5%) from Italy, 326 (0.3%) from Croatia, 89 (0.1%) from the UK and 38 (0.03%) from Belgium. There were 89,377 (75.9%) respondents who had received AstraZeneca vaccines, 14,658 (12.4%) BioNTech/Pfizer, 11,266 (9.6%) Moderna and 2490 (2.1%) Janssen vaccines as a first dose. Median age category was 40-49 years for all vaccines except for Pfizer where median age was 70-79 years. Most vaccinees were female with a female-to-male ratio of 1.34, 1.96 and 2.50 for AstraZeneca, Moderna and Janssen, respectively. BioNtech/Pfizer had slightly more men with a ratio of 0.82. Fatigue and headache were the most commonly reported solicited systemic adverse reactions and injection-site pain was the most common solicited local reaction. The rates of adverse events of special interest (AESIs) were 0.1-0.2% across all vaccine brands. CONCLUSION: This large-scale prospective study of COVID-19 vaccine recipients showed, for all the studied vaccines, a high frequency of systemic reactions, related to the immunogenic response, and local reactions at the injection site, while serious reactions or AESIs were uncommon, consistent with those reported on product labels. This study demonstrated the feasibility of setting up and conducting cohort event monitoring across multiple European countries to collect safety data on novel vaccines that are rolled out at scale in populations which may not have been included in pivotal trials.

Influenza H1N1 (swine flu) vaccination: a safety surveillance feasibility study using self-reporting of serious adverse events and pregnancy outcomes.

AIMS: During the global H1N1 influenza A (swine flu) pandemic 2009-2010, swine flu vaccines were expeditiously licensed and a mass vaccination programme for high risk groups, including pregnant women, was introduced in the UK. This pilot active safety surveillance study was performed to establish the feasibility of rapidly monitoring the new swine flu vaccines in large patient numbers receiving or offered the vaccination under normal conditions of use within a short time frame. METHODS: A cohort design with safety data capture through modern technologies was carried out in Scotland, UK during the winter swine flu vaccination programme 2009-2010 in individuals receiving or offered the swine flu vaccination. The main outcome measures were self-reported serious adverse events (SAEs) and pregnancy outcomes. RESULTS: The cohort comprised 4066 people; 3754 vaccinated and 312 offered the vaccination but not vaccinated. There were 939 self-reported events (838 different events), 53 judged to fit SAE criteria by the investigators, with nine judged as possibly, probably or definitely vaccine related. None of the seven deaths (six in vaccinees) were judged as vaccine related. One hundred and twenty-eight women reported 130 pregnancies during the study with 117 pregnant at study start. There were reports of four miscarriages in three women and six possible congenital abnormalities in live births. CONCLUSIONS: Overall, no significant safety issues were identified. The methodology and use of modern technologies to collect safety data from large numbers of patients was successful and could be used again in similar safety studies.

Assessing Case Fatality on Cases of Thrombosis with Concurrent Thrombocytopenia Following COVID-19 Vaccine AstraZeneca (Vaxzevria) in the United Kingdom: A Review of Spontaneously Reported Data.

INTRODUCTION: Thrombotic thrombocytopenia syndrome (TTS) events were reported very rarely following the coronavirus disease 2019 (COVID-19) vaccine AstraZeneca (Vaxzevria). Clinical and demographic characteristics of the affected people, including the outcomes of TTS events, need to be examined using available information to better understand aspects of this association. OBJECTIVE: To analyse clinical and demographic information of TTS events, including calculating the case fatality of reported cases of TTS by age and sex, using spontaneously reported data from the UK's Yellow Card spontaneous reporting system of suspected adverse drug reactions. METHODS: TTS events reported to the Yellow Card scheme were extracted at weekly time points between 12 May 2021 and 25 May 2022. Cumulative numbers of TTS cases and deaths were recorded for each weekly interval, overall and stratified by age, sex, and vaccine dose. RESULTS: To 25 May 2022, 443 cases (81 fatal, 18.28%) had been reported in the UK. Events more frequently occurred following the first vaccine dose. No trends were observed for case fatality overall, or by age or sex. CONCLUSION: In the UK, case fatality of TTS events reported to the Medicines and Health products Regulatory Agency (MHRA) following Vaxzevria has been approximately 17-18% since May 2021. There were no statistical differences in fatality based on age or sex. Most reports followed the first vaccine dose; none have been reported following a third dose to date, although Vaxzervia was not recommended for a third dose of COVID-19 vaccine in the UK. TTS remains very rare, and benefits of vaccination outweigh the risks.

Reports of myocarditis and pericarditis following mRNA COVID-19 vaccination: a systematic review of spontaneously reported data from the UK, Europe and the USA and of the scientific literature.

OBJECTIVES: To combine spontaneously reported data from multiple countries to estimate reporting rate, and better understand risk factors for myocarditis and pericarditis following COVID-19 messenger RNA (mRNA) vaccines. DESIGN: Systematic review of spontaneously reported data from UK, USA and European Union/European Economic Area (EU/EEA) and of the scientific literature. DATA SOURCES: UK Yellow Card scheme, Vaccine Adverse Event Reporting System (VAERS), EudraVigilance were searched from date of vaccine launch to 14 March 2022-16 March 2022. PubMed/MEDLINE and Embase were searched to 15 March 2022. ELIGIBILITY CRITERIA: We included publicly available spontaneous reporting data for 'Myocarditis' and 'Pericarditis' from UK, USA and EU/EEA following COVID-19 mRNA vaccines. Pharmacoepidemiological observational studies investigating myocarditis/pericarditis following mRNA COVID-19 vaccines were included (no restrictions on language or date). Critical Appraisal Skills Programme tools assessed study quality. DATA EXTRACTION AND SYNTHESIS: Two researchers extracted data. Events of myocarditis and pericarditis were presented for each data source, stratified by vaccine, age, sex and dose (where available). Reporting rates were calculated for myocarditis and pericarditis for each population. For published pharmacoepidemiological studies, design, participant characteristics, and study results were tabulated. RESULTS: Overall, 18 204 myocarditis and pericarditis events were submitted to the UK, USA and EU/EEA regulators during the study period. Males represented 62.24% (n=11 331) of myocarditis and pericarditis reports. In the UK and USA, most reports concerned vaccinees aged <40 years (59.7% and 47.3% of reported events, respectively); trends in age were less clear for EU/EEA. Reports were more frequent following a second dose (47.1% of reports, where data available). Reporting rates were consistent between the data sources. Thirty-two pharmacoepidemiological studies were included; results were consistent with our spontaneous report analyses. CONCLUSIONS: Younger vaccinees more frequently report myocarditis and pericarditis following mRNA COVID-19 vaccines than older vaccinees. Results from published literature supported the results of our analyses.

Systematic review of spontaneous reports of myocarditis and pericarditis in transplant recipients and immunocompromised patients following COVID-19 mRNA vaccination.

OBJECTIVES: To determine whether spontaneous reporting rates of myocarditis and pericarditis differed in immunocompromised patients compared with the whole population overall, and in terms of demographics, vaccine dose and time-to-onset. DESIGN: Systematic review of spontaneously reported data from the European Union/European Economic Area (EU/EEA), the USA and the UK. DATA SOURCES: EudraVigilance (EU/EEA), Vaccine Adverse Event Reporting System (VAERS; USA) and the Medicines and Healthcare products Regulatory Agency (UK) spontaneous reporting databases were searched from date of vaccine launch to 1 December 2021. ELIGIBILITY CRITERIA: Publicly available spontaneous reporting data for 'myocarditis' and 'pericarditis' from EU/EEA and USA following COVID-19 messenger RNA vaccines. Reports with comorbidities or concurrent medication indicative of transplantation, HIV infection or cancer ('immunocompromised' population) were compared with each overall database population. DATA EXTRACTION AND SYNTHESIS: Two researchers extracted data. Spontaneously reported events of myocarditis and pericarditis were presented for immunocompromised populations for each data source, stratified by age, sex, dose and time-to-onset (where available). Seriousness of each event was determined according to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guideline E2A definition. Proportional reporting ratio (PRR) was calculated. RESULTS: There were 178 reports of myocarditis and pericarditis among immunocompromised individuals overall. Seriousness was comparable between the immunocompromised and overall populations in both databases. No trends in age or sex were observed among immunocompromised individuals. Most reports followed a second vaccine dose and occurred within 14 days. The frequency of reporting was similar to the wider population (PRR=1.36 (95% CI=0.89 to 1.82) for VAERS population). CONCLUSIONS: Myocarditis and pericarditis following COVID-19 vaccination are very rare, and benefits of COVID-19 vaccination continue to outweigh any perceived risks. Reporting rates of myocarditis and pericarditis were similar in immunocompromised individuals, however defining characteristics differed compared with the whole population; therefore, continued monitoring of adverse events following vaccination remains vital to understand differences between population subgroups.

Postmarketing studies: can they provide a safety net for COVID-19 vaccines in the UK?

In the current era of the COVID-19 pandemic, the world has never been more interested in the process of vaccine development. While researchers across the globe race to find an effective yet safe vaccine to protect populations from the newly emergent SARS-CoV-2 virus, more than one-third of the world has been subjected to either full or partial lockdown measures. With communities having felt the burden of prolonged isolation, finding a safe and efficacious vaccine will yield direct beneficial effects on protecting against COVID-19 morbidity and mortality and help relieve the psychological and economic load on communities living with COVID-19. There is hope that with the extraordinary efforts of scientists a vaccine will become available. However, given the global public health crisis, development of a COVID-19 vaccine will need to be fast tracked through the usual prelicensing development stages and introduced with limited clinical trial data compared with those vaccines that are developed conventionally over more than a decade. In this scenario, surveillance of the vaccine in the real world becomes even more paramount. This responsibility falls to observational researchers who can provide an essential safety net by continuing to monitor the effectiveness and safety of a COVID-19 vaccine after licensing. Postauthorisation observational studies for safety and effectiveness are complementary to prelaunch clinical trials and not a replacement. In this paper, we highlight the importance of postmarketing studies for future newly licensed COVID-19 vaccines and the key epidemiological considerations.

Rare Variation in Drug Metabolism and Long QT Genes and the Genetic Susceptibility to Acquired Long QT Syndrome.

BACKGROUND: Acquired long QT syndrome (aLQTS) is a serious unpredictable adverse drug reaction. Pharmacogenomic markers may predict risk. METHODS: Among 153 aLQTS patients (mean age 58 years [range, 14-88], 98.7% White, 85.6% symptomatic), computational methods identified proteins interacting most significantly with 216 QT-prolonging drugs. All cases underwent sequencing of 31 candidate genes arising from this analysis or associating with congenital LQTS. Variants were filtered using a minor allele frequency <1% and classified for susceptibility for aLQTS. Gene-burden analyses were then performed comparing the primary cohort to control exomes (n=452) and an independent replication aLQTS exome sequencing cohort. RESULTS: In 25.5% of cases, at least one rare variant was identified: 22.2% of cases carried a rare variant in a gene associated with congenital LQTS, and in 4% of cases that variant was known to be pathogenic or likely pathogenic for congenital LQTS; 7.8% cases carried a cytochrome-P450 (CYP) gene variant. Of 12 identified CYP variants, 11 (92%) were in an enzyme known to metabolize at least one culprit drug to which the subject had been exposed. Drug-drug interactions that affected culprit drug metabolism were found in 19% of cases. More than one congenital LQTS variant, CYP gene variant, or drug interaction was present in 7.8% of cases. Gene-burden analyses of the primary cohort compared to control exomes (n=452), and an independent replication aLQTS exome sequencing cohort (n=67) and drug-tolerant controls (n=148) demonstrated an increased burden of rare (minor allele frequency<0.01) variants in CYP genes but not LQTS genes. CONCLUSIONS: Rare susceptibility variants in CYP genes are emerging as potentially important pharmacogenomic risk markers for aLQTS and could form part of personalized medicine approaches in the future.

Paediatric post-marketing pharmacovigilance: comparison of the adverse event profile of vigabatrin prescribed to children and adults.

PURPOSE: Post-marketing pharmacovigilance is a cornerstone of monitoring and evaluating the safety of medicines in children and adults. However the methods may require modification to detect paediatric signals. The aim of this study was to compare the adverse event (AE) profile of children and adults taking vigabatrin, using modified signal detection methods (SDMs). METHODS: Data from the vigabatrin prescription-event monitoring study an observational cohort study (cohort 10,177 patients), stratified into one paediatric (0-17 years) and one adult (≥ 18 years) age group were examined using summary statistics for adverse drug reactions (ADRs), reasons for stopping and deaths. Incidence densities of AEs in children and adults in the first month of treatment were compared to months two to six to examine whether the AE rate was different in these two periods. AE rates in children were compared to those in adults (proportional reporting rates; PRRs and incidence rate ratios), to compare the AE profile between these age groups. RESULTS: Abnormal behaviour (PRR 5.3) and hyperactivity (PRR 4.5) were more frequently reported in children; confusion (PRR 25.0) and psychosis (PRR 12.5) more frequently in adults. In children 11.8% of ADRs were reported to the regulatory authority compared to 27.3% in adults. A higher proportion of children stopped treatment due to lack of effectiveness (57.7% vs. 47.5%). No deaths were attributed to vigabatrin. CONCLUSION: This study demonstrated that modified SDMs can be used to detect differences in the AE profiles between children and adults taking a medicinal product, and also to identify drug safety signals.

The Role of the Contextual Cohort to Resolve Some Challenges and Limitations of Comparisons in Pharmacoepidemiology.

In pharmacoepidemiology, comparison studies can provide a useful estimate of the level of increased or decreased risk of specific events with a medication (through a measure of effect). A key focus of pharmacoepidemiological studies is the safety and effectiveness of medicines in their real-world use, and adequate comparisons of effect estimates are critical. However, consideration of guidelines, pharmacoeconomic assessments, and policies for reimbursement have made comparisons in pharmacoepidemiological studies far more difficult to conduct in recent years. Where certain subject characteristics influence the probability of being exposed to a treatment, this can introduce issues of selection bias and confounding. Methodologies are available to minimise selection bias (through case-only and randomised study designs) and deal with confounding (such as regression modelling or propensity score matching methods), however these each have their own limitations. Where prescribing guidelines are present, conducting comparisons in pharmacoepidemiology produces many challenges and not all of these can be easily overcome. Patient channelling can be more frequent with adherence to clinical guidelines compared with when prescribing decisions by doctors are based predominantly on their clinical judgement. Use of a contextual cohort could be considered as an option to characterise the adoption of new medications into clinical practice and describe the prevalence of clinical characteristics and risk factors in the two cohorts, rather than compare event rates and produce an estimate of effect.

A Systematic Review of Flurbiprofen 8.75 mg Dose and Risk of Haemorrhagic Events.

Oral non-steroidal anti-inflammatory drugs (NSAIDs) are known to be associated with an increased risk of bleeding. The NSAID, flurbiprofen, in the form of 8.75 mg lozenge or oromucosal spray is indicated for the symptomatic relief of sore throat. Despite the low dose as compared to alternative flurbiprofen preparations, concerns have been raised regarding its safety in terms of haemorrhagic events. This systematic review was conducted to identify existing evidence on the risk of haemorrhagic events with flurbiprofen 8.75 mg dose (any formulation), particularly where this may be due to potential interactions with other medicinal products. The systematic review examined studies reporting haemorrhagic events in patients receiving flurbiprofen 8.75 mg dose. Six individual electronic databases were searched up to 28th April 2020. Records were initially screened for relevance followed by further review of potentially eligible studies. Data extraction was performed for eligible studies and risk of bias in studies was assessed. The search strategy identified 1093 individual records. Of these, 1038 records were excluded after initial review; the majority of these records related to flurbiprofen in alternative formulations with alternative doses (e.g., eye drops, skin patches, oral tablets) thus were not considered relevant for further review. The 55 remaining records related to flurbiprofen 8.75 mg dose (any formulation) or flurbiprofen lozenge/oromucosal spray where the dose was not specified. After further review, 52 of these records were not considered eligible. Thus, only three records were included in this systematic review. The three studies reported a total of five haemorrhagic events in patients taking flurbiprofen 8.75 mg lozenge; the corresponding risk in each of the studies was 8.33, 1.98 and 1.96%. Where possible, comparison of flurbiprofen 8.75 mg lozenge to placebo produced risk ratios of 0.96 (95% CI 0.07, 13.25) and 2.00 (95% CI 0.10, 118.0). This systematic review found limited evidence on the risk of haemorrhagic events with flurbiprofen when used at a dose of 8.75 mg. Counts were low across all studies and results comparing flurbiprofen and placebo treatment arms were non-significant. However, scarcity of studies and low certainty of evidence for the outcome of haemorrhagic events limits the conclusions of this systematic review.

Real-world efficacy of deep TMS for obsessive-compulsive disorder: Post-marketing data collected from twenty-two clinical sites.

BACKGROUND: Deep transcranial magnetic stimulation (dTMS) with the H7-coil was FDA cleared for obsessive-compulsive disorder (OCD) in August 2018 based on multicenter sham-controlled studies. Here we look at the efficacy of dTMS for OCD in real world practices. METHODS: All dTMS clinics were asked to supply their data on treatment details and outcome measures. The primary outcome measure was response, defined by at least a 30% reduction in the Yale Brown Obsessive Compulsive Scale (YBOCS) score from baseline to endpoint. Secondary outcome measures included first response, defined as the first time the YBOCS score has met response criteria, and at least one-month sustained response. Analyses included response rate at the endpoint (after 29 dTMS sessions), number of sessions and days required to reach first response and sustained response. RESULTS: Twenty-two clinical sites with H7-coils provided data on details of treatment and outcome (YBOCS) measures from a total of 219 patients. One-hundred-sixty-seven patients who had at least one post-baseline YBOCS measure were included in the main analyses. Overall first and sustained response rates were 72.6% and 52.4%, respectively. The response rate was 57.9% in patients who had YBOCS scores after 29 dTMS sessions. First response was achieved in average after 18.5 sessions (SD = 9.4) or 31.6 days (SD = 25.2). Onset of sustained one-month response was achieved in average after 20 sessions (SD = 9.8) or 32.1 days (SD = 20.5). Average YBOCS scores demonstrated continuous reduction with increasing numbers of dTMS sessions. CONCLUSIONS: In real-world clinical practice, the majority of OCD patients benefitted from dTMS, and the onset of improvement usually occurs within 20 sessions. Extending the treatment course beyond 29 sessions results in continued reduction of OCD symptoms, raising the prospect of value for extended treatment protocols in non-responders.

Safety profile of oxcarbazepine: results from a prescription-event monitoring study.

PURPOSE: To monitor safety of oxcarbazepine, prescribed in primary care in England, using prescription-event monitoring (PEM). METHODS: Postmarketing surveillance using observational cohort technique of PEM. Exposure data were obtained from dispensed British National Health Service prescriptions issued by general practitioners (GPs) March 2000-July 2003. Demographic, drug utilization, and clinical event data were collected from questionnaires posted to GPs at least 6 months after first prescription date for each patient. Incidence densities (IDs) (number of first reports per 1,000 patient-months of treatment) were calculated and differences for events reported in month 1 (ID(1)) and months 2-6 (ID(2-6)) (99% confidence intervals) were examined for changes in event rates. Follow-up and causality assessment of medically significant events were undertaken. RESULTS: The cohort comprised 2,243 patients [mean age 40.4 years; range 2-99 years; standard deviation (SD) 18.8; 46.3% (n = 1,038) male]. Most frequently reported primary indications were epilepsy, convulsion (n = 1,111; 49.5%, n = 209; 9.3%, respectively). GPs recorded 932 reasons for stopping medication in 698 (31.1%) patients; most frequent clinical reason "drowsiness/sedation" (n = 57; 2.5% of cohort). Clinical events (excluding indication) associated with starting treatment (lower 99% CI > 0) included: "drowsiness/sedation" (ID(1)-ID(2-6) = 14.2), "nausea/vomiting" (ID(1)-ID(2-6) = 13.0), and dizziness (ID(1)-ID(2-6) = 11.6). Events followed up and assessed as probably related to oxcarbazepine use included rash (7 of 11) and hyponatremia (15 of 38). DISCUSSION: There were no serious adverse drug reactions reported during this study. Results of the study should be taken in context with other epidemiologic studies.

The UK BIO-TRAC Study: A Cross-Sectional Study of Product and Batch Traceability for Biologics in Clinical Practice and Electronic Adverse Drug Reaction Reporting in the UK.

INTRODUCTION: Due to the complexity of biologics and the inherent challenges for manufacturing, it is important to know the specific brand name and batch number of suspected biologics in adverse drug reaction (ADR) reports. OBJECTIVE: The aim of this study was to assess the extent to which biologics are traceable by brand name and batch number in UK hospital practice and in ADRs reported by patients and healthcare professionals. METHODS: We performed an online hospital pharmacist survey to capture information on how specific product details are recorded during the processes of prescribing, dispensing and administration of biologics in routine UK hospital practice. We also assessed the proportion of ADR reports specifying brand name and batch number from electronic ADR reports submitted to the UK national spontaneous reporting database, the Yellow Card Scheme, between 1 January 2009 and 30 September 2017. RESULTS: Brand name recording in routine hospital processes ranged from 79 to 91%, whereas batch numbers were less routinely recorded, ranging from 38 to 58%. Paper-based recording of product details was more commonly used for recording information. A total of 6108 electronic ADR reports were submitted to the Yellow Card Scheme for recombinant biologics, of which 38% and 15%, respectively, had an identifiable brand name and batch numbers. Whereas batch number traceability in electronic ADR reports improved slightly after the implementation of the European Union pharmacovigilance legislation in 2012, no improvement of brand name traceability was observed. CONCLUSION: Brand name and batch number traceability for biologics in UK ADR reports are generally low. Shortcomings in the systematic recording of product details in UK clinical practice may contribute to the limited traceability.

Observational assessment of safety in seroquel (OASIS): a specialist cohort event monitoring (SCEM) study in England.

BACKGROUND: This study was designed to monitor the short-term (up to 12 weeks) use and safety of quetiapine (Seroquel) extended release (XL) and quetiapine immediate release (IR) prescribed to patients with a clinical diagnosis of schizophrenia, and/or manic episodes associated with bipolar disorder by psychiatrists under normal conditions of use. METHODS: A Specialist Cohort Event Monitoring (SCEM) study was conducted in England February 2010-April 2013. This observational cohort study recruited patients prescribed quetiapine XL within the secondary care setting by psychiatrists. A reference cohort of quetiapine IR users was also recruited. Baseline and 12 week observational data were collected from psychiatrists who abstracted information from medical records onto bespoke questionnaires. Data were collected on demographics, indication, past medical history, prescribing information and events of interest. Summary descriptive statistics were calculated. RESULTS: The final cohort consisted of 869 eligible patients; 646 XL users and 223 IR users. The majority of XL and IR users were female (56.2% and 55.6%, respectively), with a median age of 40 (interquartile range [IQR]: 29, 49) and 39 (IQR: 28, 50) years, respectively. The most frequent indication for treatment was Manic episodes associated with Bipolar Affective disorder (53.4% XL and 49.8% IR). Median index dose was 200 mg/day (IQR: 100, 300) for XL users and 50 mg/day (IQR: 50, 100) for IR users, while median final maintenance dose was 400mg/day (IQR: 250, 600) and 300 mg/day (IQR: 100, 400), respectively. The most frequently reported event of interest in both cohorts was sedation (n = 151, 23.9% XL cohort and n = 49, 23.0% IR cohort). CONCLUSION: Utilisation of quetiapine XL appeared to be in line with prescribing guidelines in terms of dose, and commonly reported events of interest were in concordance with the known safety profile. Overall, this SCEM study provided important information on the safety and utilisation of quetiapine XL in the secondary care setting in England.

Incidence of major and clinically relevant non-major bleeding in patients prescribed rivaroxaban for stroke prevention in non-valvular atrial fibrillation in secondary care: Results from the Rivaroxaban Observational Safety Evaluation (ROSE) study.

INTRODUCTION: Although the direct oral anticoagulant rivaroxaban is recommended for stroke prevention in patients with non-valvular atrial fibrillation based on Phase III clinical trials, there is still a need for additional safety data from everyday clinical practice. The ROSE study was initiated to collect further information on the safety and utilisation of rivaroxaban in a broader range of patient groups in routine clinical practice. METHODS AND RESULTS: The ROSE study was conducted in hospitals in England and Wales. Consenting adults with non-valvular atrial fibrillation newly started on rivaroxaban were eligible and followed up for 12 weeks. Data was derived through secondary use of medical records. The primary outcome was major bleeding within gastrointestinal, urogenital and intracranial sites. A total of 4846 patients were enrolled in the study September 2013 to January 2016, 965 of which were treated with rivaroxaban for non-valvular atrial fibrillation. The median age in the rivaroxaban non-valvular atrial fibrillation cohort was 76 years, 53.6% were male. The median HAS-BLED score was 2 and the median CHA2DS2-VASc score was 4. The risk of major bleeding within each of the primary sites of gastrointestinal, urogenital and intracranial during the 12 week observation period was low (0.2%; n = 2). The risk of major bleeding in all sites was 1.0% (n = 10) at a rate of 5.5 events per 100 patient years. CONCLUSION: In terms of the primary outcome risk of major bleeding within gastrointestinal, urogenital and intracranial sites during the 12 week observation period, the risk estimates in the non-valvular atrial fibrillation rivaroxaban user population were low (<1%), and consistent with risk estimated from clinical trial data and in routine clinical practice.

Evaluation of the incidence of bleeding in patients prescribed rivaroxaban for the treatment and prevention of deep vein thrombosis and pulmonary embolism in UK secondary care: an observational cohort study.

OBJECTIVES: To evaluate the short-term (12 weeks) safety and utilisation of rivaroxaban prescribed to new-user adult patients for the treatment of deep vein thrombosis and pulmonary embolism and for the prevention of recurrent deep vein thrombosis and pulmonary embolism in a secondary care setting in England and Wales. DESIGN: An observational cohort study using the technique of Specialist Cohort Event Monitoring. SETTING: The Rivaroxaban Observational Safety Evaluation study was conducted across 87 participating National Health Service secondary care trusts in England and Wales. PARTICIPANTS: 1532 patients treated with rivaroxaban for the prevention and treatment of deep vein thrombosis/pulmonary embolism from September 2013 to January 2016. INTERVENTIONS: Non-interventional postauthorisation safety study of rivaroxaban. PRIMARY AND SECONDARY OUTCOME MEASURES: (1) Risk of major bleeding in gastrointestinal, intracranial, and urogenital sites and (2) risk of all major and clinically relevant non-major bleeds. RESULTS: Of a total of 4846 patients enrolled in the study from September 2013 to January 2016, 1532 were treated with rivaroxaban for the prevention and treatment of deep vein thrombosis/pulmonary embolism. The median age of the deep vein thrombosis/pulmonary embolism cohort was 63 years, and 54.6% were men. The risk of major bleeding within the gastrointestinal, urogenital and intracranial primary sites was 0.7% (n=11), 0.3% (n=5) and 0.1% (n=1), respectively. The risk of major bleeding in all sites was 1.5% (n=23) at a rate of 8.3 events per 100 patient-years. CONCLUSIONS: In terms of the primary outcome risk of major bleeding in gastrointestinal, intracranial and urogenital sites, the risk estimates in the population using rivaroxaban for deep vein thrombosis/pulmonary embolism were low (<1%) and consistent with the risk estimated from clinical trial data and in routine clinical practice. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov Registry (NCT01871194); ENCePP Registry (EUPAS3979).

Remdesivir in Treatment of COVID-19: A Systematic Benefit-Risk Assessment.

INTRODUCTION: There is a need to identify effective, safe treatments for COVID-19 (coronavirus disease) rapidly, given the current, ongoing pandemic. A systematic benefit-risk assessment was designed and conducted to examine the benefit-risk profile of remdesivir in COVID-19 patients compared with standard of care, placebo or other treatments. A key objective of this study was to provide a platform for a dynamic systematic benefit-risk evaluation, which starts with inevitably limited information (to meet the urgent unmet public health need worldwide), then update the benefit-risk evaluation as more data become available. METHODS: The Benefit-Risk Action Team (BRAT) framework was used to assess the overall benefit-risk of the use of remdesivir as a treatment for COVID-19 compared with standard of care, placebo or other treatments. We searched PubMed, Google Scholar and government agency websites to identify literature reporting clinical outcomes in patients taking remdesivir for COVID-19. A value tree was constructed and key benefits and risks were ranked by two clinicians in order of considered importance. RESULTS: Using the BRAT method, several key benefits and risks for use of remdesivir in COVID-19 compared with placebo have been identified. In one trial, the benefit of time to clinical improvement was not statistically significant (21 vs 23 days, HR 1.23, 95% CI 0.87-1.75), although the study was underpowered. In another trial, a shorter time to recovery in patients treated with remdesivir was observed (11 vs 15 days), with non-significant reduced mortality risk (8% vs 12%). Risk data were only available from one trial. This trial reported fewer serious adverse events in patients taking remdesivir (18%) compared with the placebo group (26%); however, more patients in the remdesivir group discontinued treatment as a result of an adverse event compared with those patients receiving placebo (12% vs 5%). CONCLUSIONS: Preliminary clinical trial results suggest that there may be a favourable benefit-risk profile for remdesivir compared with placebo in severe COVID-19 infection and further data on benefits would strengthen this evaluation. There is limited safety data for remdesivir, which should be obtained in further studies. The current framework summarises the key anticipated benefits and risks for which further data are needed. Ongoing clinical trial data can be incorporated into the framework when available to provide an updated benefit-risk assessment.