Antidepressant prescribing patterns and adverse events following introduction of a National Prescribing Indicator to monitor dosulepin usage in Wales.

AIMS: Limiting use of the antidepressant dosulepin has been encouraged due to associated risks of toxicity. In April 2011, the All Wales Medicines Strategy Group introduced a National Prescribing Indicator (NPI) to monitor dosulepin usage. The aim of this study was to investigate antidepressant prescribing patterns, and selected adverse events in patients prescribed dosulepin following introduction of the NPI. METHODS: An e-cohort study was conducted. Adult patients receiving regular dosulepin prescriptions between October 2010 and March 2011 were included. Characteristics of patients who were continued on dosulepin, were switched to an alternative antidepressant or whose dosulepin was discontinued following introduction of the NPI were compared. RESULTS: In total, 4121 patients were included. Of these, 1947 (47%) continued dosulepin, 1487 (36%) were switched and 692 (17%) discontinued. Of the 692 who discontinued, 92% did not receive a prescription for another antidepressant during the follow-up period. Patients whose dosulepin was discontinued were older and were less commonly coprescribed benzodiazepines. During follow-up, recorded incidence of selected adverse events was low across all groups and no significant difference was observed. CONCLUSION: Over half of patients had discontinued dosulepin at the end of the period when the NPI was in place. Further interventions may have been required to have a greater impact on prescribing. This study provides some reassurance that dosulepin discontinuation can be a successful strategy, and that the risk of the adverse events investigated was unlikely to have been greater in those who had dosulepin discontinued than in those in whom dosulepin had been continued.

Improving the spontaneous reporting of suspected adverse drug reactions: An overview of systematic reviews.

AIM: To conduct an overview of systematic reviews examining interventions to stimulate spontaneous reporting of suspected adverse drug reactions (ADRs) by healthcare professionals (HCPs) and/or patients/carers. METHODS: Systematic reviews published since 1 January 2000 were identified and the included publications categorized in relation to the 4Es (education, engineering, economics and enforcement). RESULTS: Almost all studies were aimed at HCPs. Educational initiatives were most often used and, in most studies, were associated with improvements in quantity and/or quality of reports, at least in the short term. Lectures/presentations and regular reminders (eg, verbal or by e-mail) were the educational methods most often identified by systematic reviews. Engineering initiatives were also generally effective, including improving the availability of reporting forms, electronic ADR reporting, modification of reporting procedures/policies or the reporting form and assistance to complete the form. Evidence for the benefit of economic incentives (eg, monetary rewards, lottery tickets, days off work, "giveaways" and educational credits) was often clouded by the potential effects of other concomitant initiatives, and any possible associated improvements often disappeared rapidly after incentives were discontinued. CONCLUSION: Educational and engineering strategies appear to be the interventions most often associated with improvements in reporting rates by HCPs, at least in the short to medium term. However, the evidence for sustained impact is weak. The available data were insufficient to clearly identify the separate impact of economic strategies. Further work is also needed to examine the effects of these strategies on reporting by patients, carers and the public.

Changes in suspected adverse drug reaction reporting via the yellow card scheme in Wales following the introduction of a National Reporting Indicator.

AIMS: This study aimed to assess the impact of a National Reporting Indicator (NRI) on rates of reporting of suspected adverse drug reactions using the Yellow Card scheme following the introduction of the NRI in Wales (UK) in April 2014. METHODS: Yellow Card reporting data for general practitioners and other reporting groups in Wales and England for the financial years 2014-15 (study period 1) and 2015-16 (study period 2) were obtained from the Medicines and Healthcare Products Regulatory Agency and compared with those for 2013-14 (pre-NRI control period). RESULTS: The numbers of Yellow Cards submitted by general practitioners in Wales were 271, 665 and 870 in the control period, study period 1 and study period 2, respectively. This is equivalent to an increase of 145% in study period 1 and 221% in study period 2 compared with the 12-month control period (2013-14). Corresponding increases in England were 17% and 37%, respectively (P < .001 chi-squared test). The numbers of Yellow Cards submitted by other groups in Wales were 906, 795 and 947 in each of the study periods. CONCLUSIONS: Introduction of the NRI corresponded with a significant increase in the number of Yellow Cards submitted by general practitioners in Wales. General practitioner reporting rates continued to increase year on year through to 2018-19 with the NRI still in place. No concomitant change was found in reporting rates by other groups in the health boards in Wales.

The All Wales Medicines Strategy Group: 18 years' experience of a national medicines optimisation committee.

AIMS: To review the medicines optimisation activities of the All Wales Medicines Strategy Group (AWMSG), a committee established in 2002 to advise the Welsh Government on "all matters related to prescribing". Although AWMSG conducts other activities (e.g., health technology appraisal for medicines), we focus here on its role in advising on medicines optimisation. METHODS: Prescribing indicators have been used in Wales to measure change, together with data on volumes and costs of medicines dispensed. A range of improvement strategies have been categorised under the "four Es", namely educational initiatives, economic incentives, "engineering" and "enforcement". RESULTS: AWMSG has helped health professionals in NHS Wales to reduce harm and waste, and to reduce inappropriate local or regional duplication and variation. Specific initiatives include the achievement of major cost savings by supporting increased generic prescribing and an "invest to save" approach related to prescribing of hypnotics and tranquillisers, non-steroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors. AWMSG also successfully commissioned the introduction of a single national in-patient medication chart for Wales in 2004. Ongoing priorities include a focus on reducing prescribing of certain medicines deemed "low value for prescribing" and on optimising the use of biosimilar medicines. CONCLUSIONS: Since 2002, AWMSG has acted as a national medicines optimisation committee in Wales. From the outset, pharmacists and clinical pharmacologists have collaborated closely and shared their complementary expertise to make a much greater contribution to the safe, effective and cost-effective use of medicines than either group could have achieved by working separately.

Public awareness in Wales of the UK Yellow Card scheme for reporting suspected adverse drug reactions.

We used the HealthWise Wales (HWW) platform to explore public knowledge about the UK Yellow Card scheme (YCS), the spontaneous reporting scheme for suspected adverse drug reactions (ADRs) and whether a short information video could improve awareness. Members of the public in Wales (n = 1606) completed a questionnaire about the YCS, watched the information video and then completed a follow-up questionnaire. Almost half (46.5%) of respondents said they had previously experienced an ADR (>90% of the ADRs involving prescribed medicines). Before the video, 18% of respondents knew how to report an ADR via the YCS and of these, 34% were from allied-health professions. Immediately after watching it, 71% participants reported knowing how to report and 82% reported being confident to report. If this awareness were maintained, such an approach could contribute to improved reporting of suspected ADRs by the public.

Estimated Versus Observed Expenditure Associated with Medicines Recommended by the All Wales Medicines Strategy Group.

OBJECTIVES: The All Wales Medicines Strategy Group (AWMSG) appraises the clinical and cost effectiveness of new medicines being considered for National Health Service (NHS) prescribing in Wales (UK). The aim of this study was to compare the estimated expenditure on selected medicines submitted by pharmaceutical companies for appraisal with the observed expenditure on these medicines following recommendation. METHODS: Medicines appraised and recommended for use in NHS Wales by AWMSG between May 2005 and December 2013 were identified for inclusion in the study. Estimates of expenditure were obtained from company submissions to AWMSG. Primary and secondary care dispensing databases were used to obtain observed expenditure. The Wilcoxon matched-pairs signed rank test was used to compare the observed and estimated expenditure in each of the 3 years after introduction of the medicine. RESULTS: Forty-nine medicines appraised and recommended by AWMSG during the period of interest were included in the study. Median estimated and observed expenditure in each of the 3 years post-recommendation were as follows: year 1 £86,400 and £47,300; year 2 £175,500 and £73,200; year 3 £212,100 and £78,900 (p = 0.03, p = 0.006 and p = 0.001, respectively). The expenditure on 42 of the 49 medicines (82%) was overestimated in at least one of the 3 years post-introduction, with 32 (65%) overestimated in all 3 years. CONCLUSION: In their applications for health technology appraisal, pharmaceutical companies tended to overestimate the expenditure of the majority of medicines recommended by AWMSG. These findings have implications for the assessment of predicted expenditure as part of the process of medicines appraisal in Wales.

New Medicines in Wales: The All Wales Medicines Strategy Group (AWMSG) Appraisal Process and Outcomes.

BACKGROUND: The All Wales Medicines Strategy Group (AWMSG) develops prescribing advice and is responsible for appraising new medicines for use in Wales. In this article, we examine the medicines appraisal process in Wales, its timeliness and its impact on medicines availability in Wales, and compare its processes and recommendations with the two other UK health technology appraisal bodies [the National Institute for Health and Care Excellence (NICE) and the Scottish Medicines Consortium (SMC)]. METHODS: We reviewed the medicines appraisals conducted by AWMSG between October 2010 and September 2015. The duration of the process and the recommendations made by AWMSG were compared with those of NICE and SMC. Only publicly available data were considered in this review. RESULTS: AWMSG conducted 171 single technology appraisals for 137 medicines during the study period (34 were for medicines previously appraised by AWMSG but these were for new indications). Of these, 152 appraisals were supported for use in NHS Wales (33 with restrictions) and 19 were not supported. Recommendations broadly concurred with SMC and NICE for the majority of appraisals. Compared with NICE recommendations, the median time advantage gained in Wales for those medicines that received a positive AWMSG recommendation and which were subsequently superseded by NICE advice was 10.6 months (range 3.5-48.3 months; n = 17). CONCLUSION: This review highlights the work carried out by AWMSG over a 5-year period, and provides evidence to support the effectiveness of the appraisal process in terms of patients in Wales gaining earlier access to medicines and efficiency through reduced duplication with NICE.

Impact of the phased abolition of co-payments on the utilisation of selected prescription medicines in Wales.

We have taken advantage of a natural experiment to measure the impact of the phased abolition of prescription co-payments in Wales. We investigated 3 study periods covering the phased abolition: from £6 to £4, £4 to £3, and £3 to £0. A difference-in-difference modelling was adopted and applied to monthly UK general practice level dispensing data on 14 selected medicines which had the highest percentage of items dispensed subject to a co-payment prior to abolition. Dispensing from a comparator region (North East of England) with similar health and socio-economic characteristics to Wales, and where prescription co-payments continued during the study periods, was used to isolate any non-price effects on dispensing in Wales. Results show a small increase in dispensing of 14 selected medicines versus the comparator. Compared with NE England, monthly average Welsh dispensing was increased by 11.93 items (7.67%; 95% CI [7.2%, 8.1%]), 6.37 items (3.38%; 95% CI [2.9%, 3.7%]) and 9.18 items (4.54%; 95% CI [4.2%, 4.9%]) per practice per 1,000 population during the periods when co-payment was reduced. Price elasticities of the selected medicines utilisation were -0.23, -0.13, and -0.04 in 3 analyses, suggesting the abolition of co-payment had small effect on Welsh dispensing.

An evaluation of rational prescribing in hospital outpatient practice in Sierra Leone and assessment of affordability of a prescription as an outcome.

INTRODUCTION: Medicines are the most frequently used intervention in healthcare. Rational and cost-effective prescribing is especially important in countries where access to effective medicines may be challenged by affordability issues. This study describes the prescribing patterns of doctors in government hospitals in Freetown, Sierra Leone, considering the scope for rationalising prescribing and reducing cost to the patient. METHODS: A descriptive, retrospective, cross-sectional study was conducted at four hospitals, using selected World Health Organisation (WHO) indicators applied to 600 prescriptions, after systematic random sampling. The data was analysed using SPSS.16 and the Index of Rational Drug Prescrib-ing (IRDP) calculated. The Spearman's rank coefficient was used to examine possible associations between the number of medicines prescribed as generics and from the National Essential Medicines List (NEML) and cost of the prescription respectively. Affordability was determined from the average number of days of work required to purchase a prescription, based on the minimum wage of the lowest paid government worker in Sierra Leone. RESULTS: The mean number of medicines per prescription from the four hospitals was 4.37(range 4.18-4.56) with 57% prescribed generically and 64% from the NEML. An antibiotic and injection were found on 72% and 26% of prescriptions respectively. The overall IRDP was 2.65/5. The aver-age cost per prescription was Le. 29,376.30 ($6.78), equivalent to 43 days of work of the lowest paid government worker. CONCLUSION: In this study, opportunities were identified for significant rationalisation and improvement in cost-effective prescribing.

Benzodiazepines, Z-drugs and the risk of hip fracture: A systematic review and meta-analysis.

BACKGROUND: Hip fractures in the older person lead to an increased risk of mortality, poorer quality of life and increased morbidity. Benzodiazepine (BNZ) use is associated with increased hip fracture rate, consequently Z-drugs are fast becoming the physician's hypnotic prescription of choice yet data on their use is limited. We compared the risk of hip fracture associated with Z-drugs and BNZ medications, respectively, and examined if this risk varied with longer-term use. METHODS AND FINDINGS: We carried out a systematic review of the literature and meta-analysis. MEDLINE and SCOPUS were searched to identify studies involving BNZ or Z-drugs and the risk of hip fracture up to May 2015. Each included study was quality-assessed. A pooled relative risk of hip fracture was calculated using the generic inverse variance method, with a random effects model, with the length of hypnotic usage as a subgroup. Both BNZ, and Z-drug use respectively, were significantly associated with an increased risk of hip fracture (RR = 1.52, 95% CI 1.37-1.68; and RR = 1.90, 95% CI 1.68-2.13). Short-term use of BNZ and Z-drugs respectively, was also associated with the greatest risk of hip fracture (RR = 2.40, 95% CI 1.88-3.05 and RR = 2.39, 95% CI 1.74-3.29). CONCLUSIONS: There is strong evidence that both BNZ and Z-drugs are associated with an increased risk of hip fracture in the older person, and there is little difference between their respective risks. Patients newly prescribed these medicines are at the greatest risk of hip fracture. Clinicians and policy makers need to consider the increased risk of fallings and hip fracture particularly amongst new users of these medications.

Safe prescribing: a titanic challenge.

The challenge to achieve safe prescribing merits the adjective 'titanic'. The organisational and human errors leading to poor prescribing (e.g. underprescribing, overprescribing, misprescribing or medication errors) have parallels in the organisational and human errors that led to the loss of the Titanic 100 years ago this year. Prescribing can be adversely affected by communication failures, critical conditions, complacency, corner cutting, callowness and a lack of courage of conviction, all of which were also factors leading to the Titanic tragedy. These issues need to be addressed by a commitment to excellence, the final component of the 'Seven C's'. Optimal prescribing is dependent upon close communication and collaborative working between highly trained health professionals, whose role is to ensure maximum clinical effectiveness, whilst also protecting their patients from avoidable harm. Since humans are prone to error, and the environments in which they work are imperfect, it is not surprising that medication errors are common, occurring more often during the prescribing stage than during dispensing or administration. A commitment to excellence in prescribing includes a continued focus on lifelong learning (including interprofessional learning) in pharmacology and therapeutics. This should be accompanied by improvements in the clinical working environment of prescribers, and the encouragement of a strong safety culture (including reporting of adverse incidents as well as suspected adverse drug reactions whenever appropriate). Finally, members of the clinical team must be prepared to challenge each other, when necessary, to ensure that prescribing combines the highest likelihood of benefit with the lowest potential for harm.

Developing and delivering clinical pharmacology in the UK National Health Service.

Clinical pharmacologists are active in the delivery of general and specialist medical services across the UK. They also make major contributions, both locally and nationally, to medicines management and appraisal in the National Health Service. Most are also heavily involved in the organization and delivery of teaching and training of a range of healthcare professionals, both undergraduates and postgraduates. In the past, these contributions may not have been fully recognized, perhaps in part because the discipline is small. However, the British Pharmacological Society, particularly through its Clinical Section, is committed to initiatives to ensure that all clinical pharmacologists (whatever their background, training or subsequent working environment) can work together to improve patient care, nationally and internationally. Effective engagement with universities, the National Health Service and pharmaceutical companies will be vital if these initiatives are to have sustained benefits and improve health outcomes for patients.

Flumazenil use in benzodiazepine overdose in the UK: a retrospective survey of NPIS data.

OBJECTIVE: Benzodiazepine (BZD) overdose (OD) continues to cause significant morbidity and mortality in the UK. Flumazenil is an effective antidote but there is a risk of seizures, particularly in those who have co-ingested tricyclic antidepressants. A study was undertaken to examine the frequency of use, safety and efficacy of flumazenil in the management of BZD OD in the UK. METHODS: A 2-year retrospective cohort study was performed of all enquiries to the UK National Poisons Information Service involving BZD OD. RESULTS: Flumazenil was administered to 80 patients in 4504 BZD-related enquiries, 68 of whom did not have ventilatory failure or had recognised contraindications to flumazenil. Factors associated with flumazenil use were increased age, severe poisoning and ventilatory failure. Co-ingestion of tricyclic antidepressants and chronic obstructive pulmonary disease did not influence flumazenil administration. Seizure frequency in patients not treated with flumazenil was 0.3%. The frequency of prior seizure in flumazenil-treated patients was 30 times higher (8.8%). Seven patients who had seizures prior to flumazenil therapy had no recurrence of their seizures. Ventilation or consciousness improved in 70% of flumazenil-treated patients. Flumazenil administration was followed by one instance each of agitation and brief seizure. CONCLUSIONS: Flumazenil is used infrequently in the management of BZD OD in the UK. It was effective and associated with a low incidence of seizure. These results compare favourably with the results of published randomised controlled trials and cohort studies, although previous studies have not reported the use of flumazenil in such a high-risk population. This study should inform the continuing review of national guidance on flumazenil therapy.

Managing the challenge of chemically reactive metabolites in drug development.

The normal metabolism of drugs can generate metabolites that have intrinsic chemical reactivity towards cellular molecules, and therefore have the potential to alter biological function and initiate serious adverse drug reactions. Here, we present an assessment of the current approaches used for the evaluation of chemically reactive metabolites. We also describe how these approaches are being used within the pharmaceutical industry to assess and minimize the potential of drug candidates to cause toxicity. At early stages of drug discovery, iteration between medicinal chemistry and drug metabolism can eliminate perceived reactive metabolite-mediated chemical liabilities without compromising pharmacological activity or the need for extensive safety evaluation beyond standard practices. In the future, reactive metabolite evaluation may also be useful during clinical development for improving clinical risk assessment and risk management. Currently, there remains a huge gap in our understanding of the basic mechanisms that underlie chemical stress-mediated adverse reactions in humans. This review summarizes our views on this complex topic, and includes insights into practices considered by the pharmaceutical industry.

Abolition of prescription charges in Wales: the impact on medicines use in those who used to pay.

OBJECTIVES: patient co-payments for prescription medicines in Wales were abolished in April 2007 and there has been much speculation on the possible effects. We analysed patient-reported use of medicines before and after abolition of the prescription charge, noting changes in the number of items prescribed, number of non-prescription medicines purchased and participants not collecting all prescribed items (primary non-adherence). METHODS: a sample of community pharmacists across Wales (n = 249) issued questionnaires to customers at the point of dispensing who were not exempt from the prescription charge. A second questionnaire was delivered by post to those who returned the first questionnaire (n = 1027) and expressed a willingness to participate further. Paired t-tests were applied to responses from those completing both questionnaires (n = 593). Further analyses were carried out according to gender, age and reported levels of household income. KEY FINDINGS: there was a statistically significant (P = 0.03) rise in the number of items prescribed, and a statistically significant fall (P = 0.02) in the number of non-prescription medicines purchased. Primary non-adherence was also found to fall between pre- and post-abolition periods. Those most affected in terms of increase in number of prescribed items prescribed were the older age group (45-59 years), and those with household income of between £15600 and £36400. The most affected in the fall in number of medicines purchased were males, those in the lower age group (25-34 years) and those with a higher household income (>£36400). CONCLUSIONS: although the rise in number of items prescribed and fall in number of medicines purchased was generally anticipated, there appeared to be little or no effect for those on the lowest incomes.

Abolition of prescription copayments in Wales: an observational study on dispensing rates.

OBJECTIVE: To assess effects of abolition of prescription copayments in Wales on rates of dispensing. METHODS: General practice-level monthly dispensing data were compared before/after abolition between Wales and North East (NE) England where the charge was retained. Data for 14 medicines that had most items dispensed subject to charge before abolition were similarly compared with NE England. For those with over-the-counter substitutes, wholesale sales to pharmacies were examined. A survey examined local initiatives, which might differentially affect dispensing between the two areas. RESULTS: Total dispensing rates (items/1000 patients) increased significantly in both areas but significantly less so in Wales (difference = -19.7, P = 0.024, 95% confidence interval [CI] = -36.7 to -2.6). For the 14 selected medicines, combined dispensing rates increased significantly in both areas but significantly more in Wales (difference = 27.51, P < 0.0001, 95% CI = 23.66-31.35). There was much variation for individual drugs, but categories tended to show this same trend except for antibiotics, where rates increased in Wales but decreased in NE England. The survey revealed few local initiatives that could explain these differences. Sales of over-the-counter substitutes did not explain the changes in dispensing. CONCLUSIONS: The Welsh policy was associated with a modest increase in dispensing rates relative to NE England for the 14 medicines with the highest number of items dispensed subject to charge before abolition. Although factors besides the copayment may have influenced these observations, the smaller relative increase in total dispensing rates in Wales suggests that the overall impact of abolition was minimal.