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.

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.

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.

Pharmacokinetic and pharmacodynamic study of morphine and morphine 6-glucuronide after oral and intravenous administration of morphine in children with cancer.

The aim of this study was to characterize the pharmacokinetics and pharmacodynamics of morphine and morphine 6-glucuronide (M6G) in children with cancer. Serum concentrations of morphine and M6G in children who received single oral or short term continuous intravenous morphine were determined by HPLC and ELISA assays, respectively. The serum C(max) of morphine and M6G after i.v. morphine administration was 560.5 and 309.0 nM and the T(max) was 61 and 65 min, respectively. The elimination half-life was 140.0 and 328.7 min, respectively. After oral administration of morphine, the serum C(max) of morphine and M6G was 408.34 and 256.3 nM and the T(max) was 40.0 and 60 min, respectively. The half-life was 131.0 and 325.8 min, respectively. The side effects were: drowsiness (100%), nausea and/or vomiting (57%), pruritus (28%) and urinary retention (14%). There were no reports of respiratory complications. This study showed that pharmacokinetics factors of morphine and M6G in children were significantly different from adults. Therefore the required dose for children should be different from that of adults and should be based on studies performed on children rather than on studies on adults. Some adverse effects, particularly nausea and pruritus, may be commoner than is usually thought, while others, particularly respiratory problems did not occur.

The European Herbal Medicines Directive: could it have saved the lives of Romeo and Juliet?

Herbal medicines have a long tradition of therapeutic use. However, they may occasionally cause dose-related (type A) or idiosyncratic (type B) toxicity and herb-drug interactions are also possible. Toxicity can arise as a result of misidentification or adulteration of the preparation. Legislation (the Directive on traditional herbal medicinal products 2004/24/EC) was enacted on 30 April 2004 to improve public health protection and promote the free movement of traditional medicinal products in the EU. It requires each Member State to set up a simplified registration scheme for manufactured traditional herbal medicines that are suitable for use without medical supervision. Evidence of 30 years of traditional use, at least 15 years of which should normally be within the EU, is required to permit minor claims, replacing the requirement to demonstrate efficacy. Safety is based on evidence in the published literature, although the regulator can also ask for more data if there are safety concerns. The pharmacovigilance requirements and quality standards are the same as for licensed medicines. Patient information is similar to that for any over-the-counter medicine, with an additional requirement for a statement on labels and in advertisements that the indication is based on traditional use. A European positive list of herbal substances will set out the indication, strength, dosing recommendations, route of administration and other information on safe use. Where a product complies with the list, the applicant will not need to demonstrate either the traditional use or the safety of the product. The list will be compiled by the recently established Committee on Herbal Medicinal Products at the European Medicines Agency. EU Member States were required to comply with the Directive by 30 October 2005. Traditional herbal medicinal products already on the market when the Directive became law need not comply with its provisions for 7 years after its coming into force. The public need to be aware that 'natural' does not necessarily mean 'safe' in all circumstances. They should be fully informed about all medicines they take. Consideration also needs to be given to effective regulation of herbal medicines practitioners, so that they are identifiable in law, are governed by professional codes of practice and have agreed standards of training and competency. There are many references to herbal medicines in Shakespeare's tragedy, Romeo and Juliet, which was written around 1595. A herbal medicine (distilled liquor) was almost certainly used to put Juliet into a deep sleep. A poison, possibly of herbal origin, was used by Romeo to take his own life when he thought his beloved Juliet was dead, rather than sleeping. While European herbal medicines regulation seeks to protect the public health by ensuring the necessary guarantees of quality, safety and efficacy, it was poor communication that appears to have triggered the chain of events leading to the death of Romeo and Juliet. Good communication between regulators, practitioners, patients and the public is necessary so that those who choose to take herbal medicines can do so with acceptable safety.

Morphine in children with cancer: impact of age, chemotherapy and other factors on protein binding.

The aim of this study was to contrast protein binding of morphine and morphine-6 glucuronide in cord blood and children with adults and examine impact of chemotherapy and other factors. Morphine binding was measured in spiked samples from 18 adults and 18 neonates (cord blood), and compared with six children with cancer receiving morphine. The influence of the following was examined: Human serum albumin (HSA), alpha-1 acid glycoprotein (AAG), non-esterified fatty acids (NEFA); palmitic acid and oleic acid, pH, vincristine, methotrexate, 6-mercaptopurine and M6G. binding correlated with concentrations of albumin and alpha1 acid glycoprotein. In vitro, binding was not altered by vincristine, 6-mercaptopurine, methotrexate or M6G. Compared with HSA alone, AAG increased binding, palmitic acid reduced it and oleic acid had no effect. Binding was unaffected by pH in samples from patients. Morphine binding was influenced by concentrations of albumin, AAG and morphine itself, but not by age.

A distance-learning programme in pharmacovigilance linked to educational credits is associated with improved reporting of suspected adverse drug reactions via the UK yellow card scheme.

AIMS: The effect of a distance-learning package linked to educational credits on the rate and quality of spontaneous adverse drug reaction (ADR) reporting by general practitioners (GPs) and pharmacists in Wales was investigated. METHODS: In April 2000, 477 GPs and 261 pharmacists enrolled in the 12 month programme. RESULTS: The number and quality of yellow card reports improved compared with those of a control region in England (Northern Region). CONCLUSIONS: We conclude that an educational initiative in drug safety linked to incentives may be associated with a significant but perhaps short-lived improvement in the rate and quality of ADR reporting.

Pulmonary function, body composition, and protein catabolism in adults with cystic fibrosis.

Increased survival in cystic fibrosis (CF) is associated with bone thinning and fat-free mass (FFM) loss. We hypothesized that the severity of lung disease would be associated with increased protein catabolism and systemic inflammatory status in clinically stable patients. Forty adults with CF and 22 age-matched healthy subjects were studied. Body composition was determined by dual-energy X-ray absorptiometry. Urinary pseudouridine (PSU), a marker of protein breakdown, and cross-linked N-telopeptides of type I collagen (NTx), a marker of bone connective tissue breakdown, serum tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and their soluble receptors were measured. A 3-d food intake diary revealed 21 patients had a low energy intake. Excretion of PSU (p = 0.019) and NTx (p < 0.01) was increased in patients and was inversely related to FEV(1); PSU (r = - 0.53, p = 0.001) and NTx (r = - 0.43, p < 0.01). Increased excretion of PSU and NTx (p < 0.05 for both) was also related to a low FFM. All inflammatory mediators were greater in patients and were related to PSU and NTx. Clinically stable adults were catabolic with both cellular and connective tissue protein breakdown, which was related to lung disease severity, systemic inflammation, and body composition.

Carbamazepine kinetics in cardiac patients before and during amiodarone

Carbamazepina e amiodarona podem frequentemente ser usadas em conjunto, especialmente em países em que as cardiomiopatias säo comuns. Neste estudo doses de carbamazepina (400 mg) foram administradas a pacientes com doenças cardíacas antes e depois de um mês de terapia com amiodarona, 400 mg ao dia. O perfil cinético da carbamazepina, sua fraçäo livre e o nível sérico da amiodarona, foram avaliados nas duas ocasiöes. Näo foram observadas diferenças estatísticamente significantes na cinética da carbamazepina ou mesmo em sua fraçäo livre, antes e depois da introduçäo da amiodarona. A concentraçäo da amiodarona após um mês de terapia foi baixa. Conclui-se que a possível interaçäo no metabolismo hepático näo foi demonstrada devido as baixas concentraçöes de amiodarona, que provavelmente tenham sido suficientes para inibir o metabolismo da carbamazepina