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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.

PURPOSE OF REVIEW: Opioid use is prevalent in the United Kingdom and prior to the COVID-19 pandemic it had been recognized that the safety of opioids was an important issue to be monitored by the UK medicines regulatory agency. With the emergence of COVID-19, this requirement has been even greater. This review was undertaken to determine the impact of the pandemic on safety and surveillance of opioids in the United Kingdom. RECENT FINDINGS: During the COVID-19 pandemic, the surveillance of opioids in the United Kingdom continued, although primary research was often conducted with data prior to the pandemic. Of those studies that were conducted while the pandemic was ongoing, access to opioids (or opioid substitution therapy) and the subsequent effect on patient safety was the main theme. SUMMARY: In the United Kingdom, changes in accessibility to the healthcare system and how healthcare providers operated during the COVID-19 pandemic may have had unintended consequences on use and safety of opioids, due to the shift in focus to preventing COVID-19 from overwhelming the healthcare system. The findings from this review support the need to continue surveillance in the United Kingdom, including the impact of the COVID-19 pandemic on opioid utilization and safety.

PurposeThis study examined how youth would mitigate non-medical use of prescription medication among their peers.Design/methodology/approachThe National Monitoring of Adolescent Prescription Stimulants Study (N-MAPSS) was conducted as an interview comprising 11,048 youth of 10–18 years of age between 2008 and 2011 from entertainment venues of 10 US urban, suburban, and rural areas. Using a mixed-methods approach, participants completed a survey culminating in open-ended questions asking: (1) How should kids your age be informed about prescription drugs and their effects? (2) If you ran the world, how would you stop kids from taking other people’s prescription medicines? (3) Why do people use prescription stimulants without a prescription? Responses from a random sample of 900 children were analyzed using qualitative thematic analyses.FindingsThe random sample of 900 youth (52 percent female, 40 percent white, with a mean age of 15.1 years) believed they should be educated about prescription drugs and their negative effects at schools, at home by parents, through the media, and health professionals. Youth would stop kids from using other people’s prescription drugs through more stringent laws that restricted use, and providing education about negative consequences of use. Peer pressure was the most common reason the youth gave for using other’s pills, though some reported taking them out of curiosity.Originality/valueThe importance of considering youth’s opinions on non-medical use of prescription medications is often overlooked. This evidence, from a peer perspective, could end the illicit use of prescription drugs among today’s youth.

BackgroundPrior to approval in the European Union, a systematic benefit-risk assessment was required to compare buprenorphine implant to sublingual buprenorphine as part of the license application to the European Medicines Agency.ObjectiveThe Benefit-Risk Action Team framework was used to describe the overall benefit-risk of buprenorphine implant in comparison to sublingual buprenorphine.Study selection/methodsA value tree of key benefits and risks related to the implant formulation of buprenorphine was constructed. Risk differences (RD) or reporting ORs (ROR) and corresponding 95% CIs were calculated for each outcome, along with the number needed to treat and number needed to harm. Swing weighting was assigned to outcomes and the weighted net clinical benefit (wNCB) was calculated.FindingsKey benefits assessed: reduced risk of illicit opioid use (RD=0.09, 95% CI 0.01 to 0.17), reduced risk of misuse and diversion (ROR=0.13, 95% CI 0.02 to 0.94), improved compliance and convenience (RD=0.20) and quality of life measures (RD=0.03). Key risks assessed: clinically significant implant breakage (RD=0.01, 95% CI 0.00 to 0.01), migration/missing implant (RD=0.01, 95% CI 0.00 to 0.02), infection at insertion/removal site (RD=0.08, 95% CI 0.03 to 0.12) and implant-related allergic reaction (RD=0.07, 95% CI 0.03 to 0.11). The wNCB for buprenorphine implant was 4.96, which suggests a favourable benefit-risk profile.ConclusionsThe benefit-risk profile of buprenorphine implant is considered favourable in comparison to sublingual buprenorphine, based on this semiquantitative analysis using available data. Further data from real-world use on benefits and risks should be used for ongoing monitoring of the benefit-risk profile of buprenorphine implants in the postmarketing setting.

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.

Non-medical use (NMU) of prescription opioids is of concern due to the opioid epidemic in the United States. Objective: We examined sex differences in the effect of age of first use of prescription...

IntroductionAlthough 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 resultsThe 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.ConclusionIn 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 (

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.

ObjectivesWe aimed to review the evidence for a living systematic benefit risk assessment for convalescent plasma use amongst patients with severe COVID-19 disease, based on currently available data.MethodsThe assessment used the Benefit-Risk Action Team (BRAT) framework. Convalescent plasma treatment in severe COVID-19 was compared to standard of care, placebo or other treatments. A literature search was conducted to identify published papers from January 1st, 2019 until July 8th, 2020. A value tree was constructed which included ranked key benefits and risks.ResultsWe screened 396 papers from PubMed and 127 papers from Embase. Four studies were eligible for inclusion as they contained comparative data. Results from a randomised controlled trial revealed a non-statistically significant shortening of time to clinical improvement of 2.15 days (95% CI, −5.28 to 0.99 days) in the intervention group compared with the control group, with a possible signal of increased efficacy amongst a small subset of patients with severe disease (but not life threatening disease), however this study may have been underpowered. Interpretation of findings amongst the three controlled non-randomised studies were limited by small patient numbers, lack of randomisation, and confounding by co-administration of other treatments. Limited data availability at the current time precluded construction of a data summary table and further quantitative analysis.ConclusionsThere was insufficient evidence from controlled studies to complete a data summary table for a systematic benefit-risk assessment of the use of CP for severe COVID-19 disease at the current time, and as such a benefit-risk conclusion could not be made. Whilst uncontrolled case series have suggested positive findings with CP, results from these studies are very difficult to interpret. We provide a framework which can be updated when further data that have an impact on the benefit-risk become available.Article SummaryStrengths and limitations of this studyprovides a living systematic benefit risk assessment based on currently available data for the use of convalescent plasma in patients with severe COVID-19 diseaseestablishes a framework inclusive of ranked key benefits and risks for convalescent plasma in severe COVID-19 disease, into which additional data can be added as this becomes available facilitating re-assessment of the benefit risk profileuses a transparent framework (BRAT framework) which can be applied to other potential treatment options in this disease contextinsufficient data available at the current time from comparative studies to form a benefit risk conclusion

Introduction and Objective: COVID-19 is an ongoing, global public health crisis for which safe and effective treatments need to be identified. The benefit-risk balance for the use of lopinavir-ritonavir in COVID-19 needs to be monitored on an ongoing basis, therefore a systematic benefit-risk assessment was designed and conducted. A key objective of this study was to provide a platform for a dynamic systematic benefit-risk evaluation; although initially this evaluation is likely to contain limited information, it is required because of the urgent unmet public need. Importantly, it allows additional data to be incorporated as they become available, and re-evaluation of the benefit-risk profile.Methods: A systematic benefit-risk assessment was conducted using the Benefit-Risk Action Team (BRAT) framework. The exposure of interest was lopinavir-ritonavir treatment in severe COVID-19 compared to standard of care, placebo or other treatments. A literature search was conducted in PubMed and Embase to identify peer-reviewed papers reporting clinical outcomes. Two clinicians constructed a value tree and ranked key benefits and risks in order of considered clinical importance.Results: We screened 143 papers from PubMed and 264 papers from Embase for lopinavir-ritonavir; seven papers were included in the final benefit-risk assessment. In comparison to standard of care, data for several key benefits and risks were identified for lopinavir-ritonavir. Time to clinical improvement was not significantly different for lopinavir-ritonavir in comparison to standard of care (hazard ratio 1.31, 95% confidence interval 0.95–1.80). From one study, there were fewer cases of acute respiratory distress syndrome with lopinavir-ritonavir compared with standard of care (13% vs 27%). There also appeared to be fewer serious adverse events with lopinavir-ritonavir (20%) vs standard of care (32%). Limited data were available for comparison of lopinavir-ritonavir to other treatments.Conclusions: Based on currently available data, there was no clear benefit for the use of lopinavir-ritonavir compared to standard of care in severe COVID-19. Risk data suggested a possible decrease in serious adverse events. There was a reduction in acute respiratory distress syndrome with lopinavir-ritonavir in one study. Overall, the benefit-risk profile for lopinavir-ritonavir in severe COVID-19 cannot be considered positive until further efficacy and effectiveness data become available.

Background Non-medical use (NMU) of prescription opioids is a public health concern and sex differences in prevalence of NMU have been observed previously. Little is known about how youth are obtaining and using these drugs. While any regular use could be problematic, NMU is particularly concerning. More information is needed on NMU patterns among youth and how these patterns might differ by sex. Methods The National Monitoring of Adolescent Prescription Stimulants Study (N-MAPSS) recruited youth 10–18 years of age from 10 US metropolitan areas from 2008 to 2011 with a final sample of 11,048 youth. The cross-sectional survey included questions on past 30 day use of prescription opioids (10,965 provided responses), with NMU defined as non-oral use and/or use of someone else's opioids. NMU through use of a patient's own prescription orally for a reason other than prescribed could not be identified, though this is usually contained within the standard definition of NMU. Results Among the 10,965 youth, past 30 day prevalence of NMU of prescription opioids was 3.1% (n = 345) with 59.7% (n = 206) using someone else's opioids only, 5.2% (n = 18) having non-oral use only and 35.1% (n = 121) having both. In total, seven sources and three routes of administration were assessed. The most common source among males was someone from school (n = 111, 60.0%), with no highly prevalent second source. Among females, there were two prevalent sources of prescription opioids; a parent (n = 59,41.6%) and someone from school (n = 53,37.3%). For non-oral use, snorting prescription opioids was more frequent among males compared to females (n = 85, 31.8% and n = 44, 17.1%; p Conclusions Based on these findings, to combat the current opioid crisis, implementation of strategies to prevent youth from sharing opioids, especially with friends from school, should be considered and tested.

BackgroundCOVID-19 is an ongoing, global public health crisis for which safe and effective treatments need to be identified. The benefit-risk balance for use of lopinavir-ritonavir in COVID-19 needs to be monitored on an ongoing basis, therefore a systematic benefit-risk assessment was designed and conducted. A key objective of this study was to provide a platform for a dynamic systematic benefit-risk evaluation; although initially this evaluation is likely to contain limited information, it is required due to the urgent unmet public need. Importantly it allows additional data to be incorporated as it becomes available, and re-evaluation of the benefit-risk profile.MethodsA systematic benefit-risk assessment was conducted using the Benefit-Risk Action team (BRAT) framework. The exposure of interest was lopinavir-ritonavir treatment in COVID-19 compared to standard of care, placebo or other treatments. A literature search was conducted in PubMed and EmBase to identify peer-reviewed papers reporting clinical outcomes. Two clinicians constructed a value tree and ranked key benefits and risks in order of considered clinical importance.ResultsIn comparison to standard of care, data for several key benefits and risks were identified for lopinavir-ritonavir. Time to clinical improvement was not significantly different for lopinavir-ritonavir in comparison to standard of care (HR=1.31, 95% CI:0.95, 1.80). There appeared to be fewer serious adverse events with lopinavir-ritonavir (20%) vs standard of care (32%). In particular, there were fewer cases of acute respiratory distress syndrome with lopinavir-ritonavir compared to standard of care (13% vs 27%). Limited data were available for comparison of lopinavir-ritonavir to other treatments.ConclusionsBased on currently available data, there was no clear benefit for use of lopinavir-ritonavir compared to standard of care in severe COVID-19. Risk data suggested a possible decrease in serious adverse events, including acute respiratory distress syndrome. Overall, the benefit-risk profile for lopinavir-ritonavir in severe COVID-19 cannot be considered positive until further efficacy and effectiveness data become available.

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.

BackgroundThere 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 strengthen the ongoing understanding of the benefit-risk balance for remdesivir in COVID-19 treatment by using a structured method which uses all available data.MethodsThe 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 to 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.ResultsSeveral key benefits and risks for use of remdesivir in COVID-19 compared to 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%) comparted to the placebo group (26%), however more patients in the remdesivir group discontinued treatment as a result of an adverse event compared to those patients receiving placebo (12% vs 5%).ConclusionsPreliminary clinical trial results suggest a favourable benefit-risk profile for remdesivir compared to placebo, however there is limited safety data available at the current time. 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.

ObjectivesGiven the current pandemic, there is an urgent need to identify effective, safe treatments for COVID-19 (coronavirus disease). A systematic benefit-risk assessment was designed and conducted to strengthen the ongoing monitoring of the benefit-risk balance for chloroquine (CQ) and hydroxychloroquine (HCQ) in COVID-19 treatment.MethodsThe overall benefit-risk of the use of chloroquine or hydroxychloroquine as a treatment for COVID-19 compared to standard of care, placebo or other treatments was assessed using the Benefit-Risk Action Team (BRAT) framework. We searched PubMed and Google Scholar to identify literature reporting clinical outcomes in patients taking chloroquine or hydroxychloroquine for COVID-19. A value tree was constructed and key benefits and risks were ranked by two clinicians in order of considered importance.ResultsSeveral potential key benefits and risks were identified for use of hydroxychloroquine or chloroquine in COVID-19 treatment. Currently available results did not show an improvement in mortality risk; Cox proportional hazard ratio (HR) for death between patients who received HCQ alone vs. neither hydroxychloroquine or azithromycin was 1.08 (95% CI 0.63-1.85). A further study compared the incidence of intubation or death (composite outcome) in a time to event analysis between patients who received HCQ vs. those patients who did not (adjusted Cox proportional HR 1.00 (95% CI 0.76-1.32)). Risk of cardiac arrest, abnormal electrocardiogram (ECG) and QT prolongation was greater among patients taking HCQ (with or without azithromycin) compared to standard of care in the same study.ConclusionsOverall, based on the available data there does not appear to be a favourable benefit-risk profile for chloroquine or hydroxychloroquine compared to standard of care in treatment of severe COVID-19. As further data from clinical trials and real world use on these benefits and risks becomes available, this can be incorporated into the framework for an ongoing benefit-risk assessment.

The aim of this analysis is to identify latent subgroups of women based on substance use, exposure to violence, and risky sexual behaviors and quantify discrete stages of behavior change over time. Data comes from 317 women recruited from a Municipal Drug Court System in the Midwest. All participants were interviewed regarding their substance use and sexual behaviors, as well as their exposure to violence at baseline, a 4th-month follow-up, and an 8th-month follow-up. A latent transitional analysis (LTA), a longitudinal extension of a latent class analysis (LCA), was used to quantify discrete stages of behavior change. The results of our analyses revealed 4 distinct behavioral profiles in our sample: 1) women with high probabilities of risky sexual behaviors, exposure to violence, and crack/cocaine use, 2) women with a high probability of exposure to violence, and moderate sexual risk taking, 3) women characterized solely by a high probability of crack/cocaine use, 4) women with low probabilities of all factors. The proportion of women in latent statuses characterized by a high probability of crack/cocaine use did not substantially decrease over time. Women who experienced child sexual abuse, had a greater number of lifetime arrests, were older, and believed they had risky drug using behavior that needed changing at baseline were significantly more likely to be in higher-risk latent statuses. Targeted interventions tailored to crack/cocaine users, as well as a wide-spread need for trauma-informed interventions among females involved in the criminal justice system, are needed.

Objectives The aim of the study was to identify any unexpected clinical events associated with starting the new CFC-free formulation of Atrovent® MDI in general practice in England. Methods An active surveillance cohort study was conducted with a focus on selected clinical events, including respiratory symptoms, in past users of Atrovent® CFC MDI (‘switchers’) and Atrovent® naïve users. Incidence density rate ratios (with 99% confidence intervals) for events occurring in the first 3 months of exposure (risk period-ID1-3) compared to 3 months prior to starting treatment (reference period-IDR) were calculated. Results The cohort consisted of 13 211 patients (median age 70 years, 50.1% female; 63.5% prior users of Atrovent® CFC MDI (‘switchers’)). Common respiratory events occurred at higher rates after starting treatment than before for switchers, for example lower respiratory tract infection (LRTI) [ID1/IDR = 1.45 (99% CI: 1.17, 1.81)] and worsening asthma [ID1/IDR = 1.58 (99% CI: 1.00, 2.51)]. Of these events only LRTI was significant for Atrovent® naïve patients [ID1/IDR = 1.42 (99% CI: 1.04, 1.95)]. Conclusions The results of this study suggest effect modification of risk as a result of prior Atrovent® CFC MDI use. Overall, Atrovent® CFC-free MDI appeared to be reasonably well tolerated in the immediate postmarketing period and the safety profile appeared similar to that of the CFC formulation.

Objective The current analysis examines whether opioid use is associated with insomnia in a community sample, as the consequences of the growing epidemic of prescription opioid use continue to cause public health concern. Study design A cross-sectional study including 8433 members in a community outreach program, HealthStreet, in Northeast Florida. Methods Community Health Workers (CHWs) assessed health information, including use of opioids (i.e., Vicodin®, Oxycodone, Codeine, Demerol®, Morphine, Percocet®, Darvon®, Hydrocodone) from community members during field outreach. Insomnia was determined based on self-report: “Have you ever been told you had, or have you ever had a problem with insomnia?” Summary descriptive statistics were calculated and logistic regression modeling was used to calculate adjusted odds ratios (ORs) with 95% confidence intervals for insomnia, by opioid use status, after adjustment for demographics and other covariates. Results Among 8433 community members recruited (41% male; 61% Black), 2115 (25%) reported insomnia, and 4200 (50.3%) reported use of opioids. After adjusting for covariates, opioid users were significantly more likely to report insomnia than non-users (adjusted OR, 1.42; 95% CI, 1.25–1.61). Conclusion Insomnia was 42% more likely among those who reported using prescription opioids compared to those who did not. With one half of the sample reporting prescription opioid use, and a fourth reporting insomnia, it is important to further investigate the relationship between the two. Findings provide useful preliminary information from which to conduct further analyses.

Background: Prescription opioid non-medical use (NMU) and its associated consequences have been of concern in the US in recent years.Objective: We examined peer influence and parental guidance, in addition to peer and parental sources of alcohol, on patterns of prescription opioid use, including NMU, among males and females separately. We hypothesized that peer influence and parental guidance would have a differential influence for males and females.Methods: The National Monitoring of Adolescent Prescription Stimulants Study (N-MAPSS) recruited youth 10-18 years from 10 US cities between 2008 and 2011 (n = 11,048). The cross-sectional survey included questions on past 30-day prescription opioid use (10,965 provided responses), with NMU defined as non-oral use and/or use of someone else's opioids. Multinomial logistic regression was conducted, examining medical use only and NMU in the past 30 days.Results: Among the 10,965 youth, 3.1% (n = 345) reported past 30-day NMU. Obtaining alcohol from parents was associated with increased odds of past 30-day NMU among males (OR = 2.49, 95%CI: 1.54,4.03) only. For each additional close friend who used other substances, odds of past 30-day NMU increased among males (OR = 1.23, 95%CI: 1.11,1.37) and females (OR = 1.15, 95%CI: 1.04,1.27). Increased number of close friends was associated with decreased odds of past 30-day NMU among males (OR = 0.87, 95%CI: 0.78,0.97) and females (OR = 0.86, 95%CI: 0.77,0.96).Conclusions: Peer and parental risk factors for prescription opioid NMU were identified among youth, although not all differed by sex. An increased number of close friends was a protective factor against prescription opioid NMU for both males and females.

This study examined risk factors of nonmedical prescription opioid use (NMPOU) among adolescents and how risk factors differ by gender. In the fall of 2017, adolescents attending 6(th) through 12(th) grades across 44 schools in 10 south central Kentucky counties were invited to participate in an anonymous, school-based survey. A total of 11,761 adolescents completed the survey. Logistic regression was conducted to examine the association between NMPOU and constructs of the Theory of Reasoned Action (i.e., attitudes and subjective norms), descriptive norms (i.e., peer use), and parental control of prescription medications in the home. There were 297 (2.7%) adolescents who reported NMPOU in the past 12 months. In the adjusted multivariate logistic regression model, for both males and females, adolescents who perceived that more of their peers engaged in NMPOU were significantly more likely to endorse NMPOU. Whereas, male and female adolescents who perceived their peers disapproved of use were significantly less likely to report NMPOU. Parent disapproval was significantly associated with decreased NMPOU for females only. Moderated regression analyses revealed that gender moderated the relationship between parental disapproval and NMPOU. We found that during adolescence, NMPOU is influenced by peer norms for both genders and parental norms for females. These results indicate that prevention efforts should focus on changing adolescents’ peer and parental norms related to NMPOU.

Using data from a randomized controlled trial of 319 women mainly recruited from a Municipal Drug Court System in St. Louis, MO, this study evaluates substance use, victimization, and HIV/AIDS risk behaviors over time. The results indicated that, for all participants, the likelihood of victimization, using drugs, and meeting the criteria for HIV/AIDS risk decreased by 46% by the eight-month follow-up; however, results did not differ significantly by intervention group. Women who were sexually abused as a child, had 4+ arrests, or believed they had sexual and drug-using behaviors that need changing at baseline were more likely to experience these issues over time.

Introduction Fluenz Tetra is an intranasal quadrivalent live attenuated influenza vaccine (QLAIV) and is recommended as the vaccine of choice for children in the 2014/2015 influenza season vaccination programme in the UK. Objective The primary objective of the study was to estimate the crude incidence rate of adverse events of interest (AEIs) following vaccination with the nasal QLAIV early in the 2014/2015 influenza season in children and adolescents in England. Methods A pilot non-interventional cohort post-authorisation safety study (PASS) was conducted during the 2014/2015 influenza season in England. Vaccinees were recruited via the mass vaccination programme in England. Participant outcomes, validated by a healthcare professional (general practitioner) where appropriate, were captured through questionnaires (surface mail, telephone, e-questionnaire). Data analysis comprised descriptive statistics and calculation of event risks and incidence rates, stratified by age group and selected co-morbidities. Results The final evaluable cohort consisted of 385 participants; the median (interquartile range) age was 4 (3–9) years with a range of 2–17 years, and 53.2 % were female. The most frequently reported AEI was nasal congestion (n = 167; 43.4 %; 312.3 per 1000 patient-weeks [95 % CI 267.3–364.8]). Further frequently reported AEIs were malaise (n = 87; 22.6 %; 123.4 per 1000 patient-weeks [95 % CI 98.9–154.1]) and cough (n = 80; 20.8 %; 118.5 per 1000 patient-weeks [95 % CI 95.1–147.8]). Five hypersensitivity-type reactions were reported, although on follow-up none were true hypersensitivity reactions or required hospitalisation. No serious adverse events (SAEs) were reported, with no hospitalisations or deaths. No significant change in reactogenicity or other apparent safety signals was detected as part of this study. Conclusion The pilot study showed no significant change in reactogenicity or other apparent safety signals from the data collected. Continued enhanced surveillance of seasonal influenza vaccines will ensure their ongoing safety for the prevention of serious illness from seasonal influenza outbreaks. Electronic supplementary material The online version of this article (doi:10.1007/s40264-015-0384-7) contains supplementary material, which is available to authorized users.

BackgroundA post-authorisation safety study was carried out as part of the EU Risk Management Plan to examine the long-term (up to 12 months) use of quetiapine XL as prescribed in general practice in England.AimTo present a description of the drug utilisation characteristics of quetiapine XL.MethodsAn observational, population-based cohort design using the technique of Modified Prescription-Event Monitoring (M-PEM). Patients were identified from dispensed prescriptions issued by general practitioners (GPs) for quetiapine XL between September 2008 and February 2013. Questionnaires were sent to GPs 12 months following the 1st prescription for each individual patient, requesting drug utilisation information. Cohort accrual was extended to recruit additional elderly patients (special population of interest). Summary descriptive statistics were calculated.ResultsThe final M-PEM cohort consisted of 13,276 patients; median age 43 years (IQR: 33, 55) and 59.0% females. Indications for prescribing included bipolar disorder (n = 3820), MDD (n = 2844), schizophrenia (n = 2373) and other (non-licensed) indications (n = 3750). Where specified, 59.3% (7869/13,276) were reported to have used quetiapine IR (immediate release formulation) previously at any time. The median start dose was highest for patients with schizophrenia (300 mg/day [IQR 150, 450]). The final elderly cohort consisted of 3127 patients and 28.5% had indications associated with dementia. The median start dose for elderly patients was highest for patients with schizophrenia or BD (both 100 mg/day [IQR 50, 300]).ConclusionsThe prevalence of off-label prescribing in terms of indication and high doses was common, as was use in special populations such as the very elderly. Whilst off-label use may be unavoidable in certain situations, GPs may need to re-evaluate prescribing in circumstances where there may be safety concerns. This study demonstrates the ongoing importance of observational studies such as M-PEM to gather real-world clinical data to support the post-marketing benefit:risk management of new medications, or existing medications for which license extensions have been approved.

One-third of adults in the USA experience chronic pain and use a variety of painkillers, such as nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and opioids. However, some serious adverse events (AEs), such as cardiovascular incidents, overdose, and death, have been found to be related to painkillers. We used 2015 and 2016 AE reports from the US FDA’s Adverse Events Reporting System (FAERS) to conduct exploratory analysis on the demographics of those who reported painkiller-related AEs, examine the AEs most commonly associated with different types of painkillers, and identify potential safety signals. Summary descriptive statistics and proportional reporting ratios (PRRs) were performed. Out of over 2 million reports submitted to FAERS in 2015 and 2016, a total of 64,354 AE reports were associated with painkillers. Reports of opioid-associated AEs were more likely to be from males or younger patients (mean age 47.6 years). The highest numbers of AEs were reported for NSAID and opioid use, and the most commonly found AEs were related to drug ineffectiveness, administration issues, abuse, and overdose. Death was reported in 20.0% of the reports, and serious adverse reactions, including death, were reported in 67.0%; both adverse outcomes were highest among patients using opioids or combinations of painkillers and were associated with PRRs of 2.12 and 1.87, respectively. This study examined the AEs most commonly associated with varying classes of painkillers by mining the FAERS database. Our results and methods are relevant for future secondary analyses of big data and for understanding adverse outcomes related to painkillers.

Deferasirox (EXJADE®, Novartis, UK) is an oral iron-chelating agent primarily used to reduce chronic iron overload in patients receiving blood transfusions for various chronic anaemias and some non-transfusion dependant anaemias. The aim of this study was to examine the utilisation and safety of deferasirox used in general practice in England. A single exposure observational cohort study design was used. Patients were identified from dispensed prescriptions for deferasirox between September 2006 and September 2014. Outcome data were collected via postal questionnaires sent to prescribers ≥ 6 months after first dispensed prescription for an individual patient. Summary descriptive statistics were calculated. The evaluable cohort consisted of 122 patients, of which 41.8% were aged 2–17 years. Frequent reasons for prescribing were sickle cell anaemia (27/103 where specified, 26.2%) and beta thalassaemia (26, 25.2%). The majority of patients (43/51, 84.3%) were prescribed the licensed doses of 10 or 20 mg/kg/day at start. Prior measurements of serum creatinine were only reported for a small proportion this study (18/122, 14.8%). In total, 91 incident events were reported, including two of raised serum creatinine. These results show that deferasirox is largely being prescribed for its licensed indications in general practice in England and events reported were consistent with the known safety profile.

Background - Fentanyl citrate buccal tablets are indicated for the treatment of breakthrough pain (BTP) in cancer, in adults who are receiving maintenance opioid therapy for chronic cancer pain. Objective - One of the objectives of this study was to describe the utilization characteristics of patients prescribed fentanyl buccal and to assess how the product is being used in relation to the terms of license of marketing approval. Methods - An observational post-marketing cohort study was conducted. For the analysis of this study, exposure data were collected from dispensed prescriptions issued by general practitioners (GPs) between March 2009 and June 2011. Outcome data (indication, event, patient demographic and selected clinical characteristics) were collected by sending questionnaires to GPs at least 6 months after the drug was first prescribed. Summary descriptive statistics were calculated. Results - The cohort consisted of 551 patients, of which 54.8% (n = 302 patients) were female. The median age for the cohort was 62 years (interquartile range: 50–72 years), with one patient (0.2%) aged less than 18 years. A primary indication of BTP in cancer was reported for 61.9% (n = 341) patients. Regular opioid therapy was reported upon starting the treatment for 383 patients (69.5% of cohort). In total, 69 patients (12.5%) had one or more contraindications for use. The most frequent initial titration dose was 100 μg/day (n = 247). Conclusions - The final study results show that fentanyl buccal is largely being prescribed according to the terms of the license in general practice in England, but off-licence use and use in the presence of contraindications and warnings have been reported.

The aim of the study was to identify any unexpected clinical events associated with starting the new CFC-free formulation of AtroventAn active surveillance cohort study was conducted with a focus on selected clinical events, including respiratory symptoms, in past users of AtroventThe cohort consisted of 13 211 patients (median age 70 years, 50.1% female; 63.5% prior users of AtroventThe results of this study suggest effect modification of risk as a result of prior Atrovent

Non-medical use (NMU) of prescription opioids in youth is of concern since they may continue this pattern into adulthood and become addicted or divert medications to others. Research into risk factors for NMU can help target interventions to prevent non-medical use of opioids in youth.The National Monitoring of Adolescent Prescription Stimulants Study (N-MAPSS) was conducted from 2008 to 2011. Participants 10-18years of age were recruited from entertainment venues in urban, rural and suburban areas of 10 US cities. Participants completed a survey including questions on their use of prescription opioids. NMU was defined as a non-labeled route of administration or using someone else's prescription. Information on age, gender, alcohol, marijuana and tobacco use was also collected. Summary descriptive, chi-square statistics and logistic regression were conducted using SAS 9.4.Of the 10,965 youth who provided information about past 30day prescription opioid use, prevalence of reported opioid use was 4.8% with 3.2% reported as NMU (n=345) and 1.6% as medical use (MU) only (n=180). More males than females (55.7% vs. 44.4%) reported opioid NMU (p0.0001). Logistic regression revealed that among males (comparing NMU to MU only), current smokers were 4.4 times more likely to report opioid NMU than non-smokers (95% CI: 1.8, 10.7). Among females (comparing NMU to MU only), current smokers and alcohol users were more likely to report opioid NMU than those who had never smoked or used alcohol (OR=3.2, 95% CI: 1.4, 7.0 and OR=4.1, 95% CI: 1.7, 10.4, respectively).These results suggest that further research on gender differences in opioid NMU is needed; interventions for opioid NMU may need to be gender specific to obtain the best results.

Background: Intrinsa® is a transdermal testosterone patch that is indicated for use in hypoactive sexual desire disorder (HSDD) in women who have undergone bilateral oophorectomy and hysterectomy (surgically-induced menopause) receiving concomitant oestrogen therapy. Objective: To describe the utilization characteristics of the patients prescribed testosterone patch (Intrinsa®) based on an interim analysis of an ongoing Prescription-Event Monitoring study in England, and to assess, where possible, if the product is being used within the licensed therapeutic indication. Methods: In this interim analysis, patients were identified from dispensed prescriptions that had been issued by general practitioners (GPs) for Intrinsa® from March 2007. ‘Green form’ questionnaires were sent to GPs 6 months following the date of the first prescription for Intrinsa® for each individual patient, requesting information including age, sex, start and stop dates of treatment (if stopped), prescribing indication and reasons for stopping. Additional questions were asked regarding the patient’s menopausal status and use of concomitant oestrogen therapy. Results: The interim cohort consisted of 756 patients. The majority of patients were reported to be female (746 [98.7%]) with a median (interquartile range) age of 50 years (44–55 years). The most commonly reported indication was the licensed indication of HSDD in 580 patients (76.7%). Just under one-half of the patients (n=364 [48.1%]) were reported to have been hysterectomized and bilaterally oophorectomized (surgically-induced menopause) prior to starting Intrinsa®; 127 patients (16.8%) were naturally menopausal. For 222 patients (29.4%) the GP specified that the patient was not using concomitant oestrogen therapy. Overall, only 219 patients (29.0%) in the cohort were being prescribed Intrinsa® according to the manufacturer’s recommendations. Conclusions: This study has highlighted that some clinicians are prescribing this product outside the recommended terms of the licence, with less than 30% of patients receiving Intrinsa® according to prescribing guidelines. All events experienced by these patients will be analysed to detect any possible adverse events from using Intrinsa® outside of the licensed therapeutic indication. The findings support the ongoing postmarketing risk management of the product.

Introduction Off-label use is where a medicinal product is used for a medical purpose not in accordance with the authorised product information. Intrinsa® is a transdermal testosterone patch, which is indicated for use in hypoactive sexual desire disorder in bilaterally oophorectomised and hysterectomised women receiving concomitant estrogen therapy. Objectives To describe the utilization characteristics of patients prescribed testosterone patch (Intrinsa®) and to assess, where possible, if the product is being used according to the authorised product information. Study design Patients identified from dispensed prescriptions issued by general practitioners for Intrinsa® between March 2007 and August 2010. Postal questionnaires were sent to general practitioners six months following the date of the first prescription for Intrinsa® for each patient, requesting information including patient demographics and drug utilization. Main outcome measures Menopausal status and use of concomitant estrogen therapy. Results The final cohort consisted of 3073 patients; the majority were females (3017, 98.2%). The most commonly reported indication was hypoactive sexual desire disorder in 2324 female patients (77.0%). Only 43.5% female patients ( n = 1313) were reported to have been hysterectomised and bilaterally oophorectomised. For 1029 (34.1%) female patients there was no evidence that the patient was using concomitant estrogen therapy. Overall, only 643 patients (20.9%) in the cohort were being prescribed Intrinsa® according to the manufacturer’s recommendations. Conclusions Evidence obtained solely from clinical trials might not be generalisable where off-label prescribing occurs in real-life, so evidence from post-marketing observational studies is important to provide complimentary data on a product’s safety and effectiveness.

Levocetirizine was launched onto the UK market in September 2001. It is indicated for symptomatic treatment of allergic rhinitis (AR), including persistent AR and chronic idiopathic urticaria.The aim of the study was to monitor the safety of levocetirizine prescribed in the primary care setting in England, in the immediate postmarketing period.Exposure data were derived from dispensed prescriptions written by primary care physicians (general practitioners [GPs]) for levocetirizine (November 2001-November 2002): patient demographic, indication, pattern of use and outcome (event) data from enhanced prescription-event monitoring (PEM) questionnaires (with additional questions to gather further relevant information) returned by GPs. Incidence density observation rates (IDobs) [number of first reports/1000 patient-months] between months 1 and 2 (IDobs(m1/m2)) were compared for the whole cohort and by groups defined by indication and pattern of use.The cohort comprised 12 367 patients (median age 37 years [interquartile range 22-55]; 58% female). The most frequent indication was AR (67%; n = 8275). After 2 months, 35.7% (n = 2414) of patients were still taking levocetirizine. 'Condition improved' was the most common event and reason for stopping treatment. Headache/migraine was uncommon but associated with starting treatment (IDobs(m1/m2) 2.4 [95% CI 1.1, 6.0]), as was drowsiness/sedation (IDobs(m1/m2) 11.5 [95% CI 4.2, 43.9]). Cardiovascular events occurred rarely or very rarely, as did most central and peripheral nervous system events. No serious adverse drug reactions (ADRs) were reported. Events related to effectiveness were more frequent in month 1 than month 2 for all patient subgroups.This postmarketing surveillance study shows that levocetirizine is well tolerated when used in general practice in England. No previously unrecognized ADRs were detected. This study highlights how modifications to PEM, such as additional questions, are contributing to the evaluation of drug utilization factors in relation to risks.

Strontium ranelate is indicated for the treatment of postmenopausal osteoporosis. An association between strontium ranelate and venous thromboembolism (VTE) was identified in an analysis of phase III clinical trials.To estimate the incidence of VTE in patients within the strontium ranelate (Protelos(R)) Prescription-Event Monitoring (PEM) study cohort during the first 12 months after starting treatment.Patients in this analysis were identified from dispensed prescriptions that had been issued by general practitioners (GPs) in England for strontium ranelate between October 2004 and January 2008. For each individual patient, a Green Form questionnaire was sent to their GP 12 months after the date of the first prescription issued for strontium ranelate, requesting information about the patient including start and stop dates of treatment (if stopped), age, sex, indication, any history of VTE events, reasons for stopping and whether the patient had any events since starting the drug. VTE was defined as reports of deep vein thrombosis (DVT) or pulmonary embolism (PE). The crude incidence of VTE was calculated for events that occurred during the first 12 months after starting treatment (plus 30 days after stopping), with 95% Poisson exact CIs for the whole cohort, and subsets defined by age and past history of VTE.The final analysis cohort consisted of 10 782 patients. Where specified, mean age was 73.3 years (SD 11.45) [n = 10 696]; 9833 (91.3%) were female and 934 (8.7%) were male. Where the history of VTE was specified, 233 patients (2.6%) had a history of VTE prior to starting. In the first 12-month period, there were 48 incident reports of VTE (DVT or PE) during treatment (or within 30 days of stopping) in the cohort, with 7696.89 years of exposure, giving a crude incidence rate of VTE of 6.24 cases (95% CI 4.60, 8.27) per 1000 patient-years exposed.This analysis has provided an estimate of the incidence of VTE in patients treated with strontium ranelate in the general practice setting. The rate is similar to estimates in populations of similar age and corresponds to the incidence found in patients from phase III clinical studies and observational cohort studies of strontium ranelate on this topic. The crude annual incidence rate of VTE in the PEM cohort is higher than the background annual incidence rate found in the UK population, but is similar to estimates in populations of similar age and populations receiving treatment for postmenopausal osteoporosis. Also, we acknowledge the potential for underestimating the incidence in this population. Nevertheless, this analysis contributes to the ongoing postmarketing safety assessment of this product.

Background Problematic prescription drug use is reflected by or associated with drug-seeking aberrant behaviours. Research gaps include lack of post-marketing evidence and instruments. As part of the pharmacovigilance requirements, a risk management plan was developed for fentanyl buccal tablets (FEBT) by the manufacturer, with an additional pharmacovigilance activity requested by the regulatory authority, to investigate the risks of misuse, abuse, criminal use, off-label use and accidental exposure to FEBT after the product became commercially available. A Modified Prescription-Event Monitoring (M-PEM), observational, post-authorisation safety surveillance (PASS) study was conducted, with an overall aim to examine the use of FEBT in relation to their safety as prescribed in primary care in England. One of the exploratory objectives included estimating the prevalence of aberrant behaviours during FEBT treatment. Objective To determine the feasibility of estimating the prevalence of risk factors associated with dependence on starting treatment and aberrant behaviours in patients during treatment with a prototypical abuse liable substance (fentanyl), as based on the application of an existing index (the Chabal criteria). Methods Data were collected as part of the M-PEM PASS study; exposure and outcome data (including risk factors for dependence and aberrant behaviours based on behavioural not clinical manifestations) were derived from questionnaires sent to primary care physicians in England during April 2008 to June 2011. For the exploratory objective of interest, descriptive statistics and simple (non-weighted) risk scores were constructed on aggregate counts (score ≥3 considered ‘high-risk’). Supplementary analyses explored the relationship between the two indices and the characteristics of patients with aberrant behaviours and those without (crude odds ratios plus 95 % confidence interval (CI) were calculated). Results In a cohort of 551 patients, the prevalence of at least one pre-existing risk factor for dependence was 26 % (n = 145), whilst the frequency of aberrant behaviours observed during treatment was 8 % (n = 46). Patients with aberrant behaviours had several different characteristics to patients without. The two indices were associated (χ2 df (20) = 58.72, p