Busulfan target exposure attainment in children undergoing allogeneic hematopoietic cell transplantation: a single day versus a multiday therapeutic drug monitoring regimen.

Busulfan exposure has previously been linked to clinical outcomes, hence the need for therapeutic drug monitoring (TDM). Study objective was to evaluate the effect of day 1 TDM-guided dosing (regimen d1) versus days 1 + 2 TDM-guided dosing (regimen d1 + 2) on attaining adequate busulfan exposure. In this observational study, we included all children receiving busulfan-based allogeneic hematopoietic cell transplantation. Primary outcome was the percentage of patients achieving busulfan target attainment in both TDM regimens. Secondary outcomes were the variance in busulfan exposure and day-4 clearance (Clday4) estimates between both TDM regimens and dosing day 1 and 2. In regimen d1, 84.3% (n = 91/108) attained a therapeutic busulfan exposure, while in regimen d1 + 2 a proportion of 90.9% was found (n = 30/33, not-significant). Variance of Clday4 estimate based on busulfan day 2 concentrations was significantly smaller than the variance of Clday4 estimates based on day 1 concentrations (p < 0.001). Therefore, day 1-guided TDM (pharmacometric model-based) of busulfan may be sufficient for attaining optimal target exposure, provided that subsequent TDM is carried out if required. However, performing TDM on subsequent days may be beneficial, as measurements on day 2 seemed to reduce the variance in the estimated clearance as compared to day 1 sampling.

Hospital physicians' and older patients' agreement with individualised STOPP/START-based medication optimisation recommendations in a clinical trial setting.

OBJECTIVE: To evaluate the agreement of hospital physicians and older patients with individualised STOPP/START-based medication optimisation recommendations from a pharmacotherapy team. METHODS: This study was embedded within a large European, multicentre, cluster randomised controlled trial examining the effect of a structured medication review on drug-related hospital admissions in multimorbid (≥ 3 chronic conditions) older people (≥ 70 years) with polypharmacy (≥ 5 chronic medications), called OPERAM. Data from the Dutch intervention arm of this trial were used for this study. Medication review was performed jointly by a physician and pharmacist (i.e. pharmacotherapy team) supported by a Clinical Decision Support System with integrated STOPP/START criteria. Individualised STOPP/START-based medication optimisation recommendations were discussed with patients and attending hospital physicians. RESULTS: 139 patients were included, mean (SD) age 78.3 (5.1) years, 47% male and median (IQR) number of medications at admission 11 (9-14). In total, 371 recommendations were discussed with patients and physicians, overall agreement was 61.6% for STOPP and 60.7% for START recommendations. Highest agreement was found for initiation of osteoporosis agents and discontinuation of proton pump inhibitors (both 74%). Factors associated with higher agreement in multivariate analysis were: female gender (+ 17.1% [3.7; 30.4]), ≥ 1 falls in the past year (+ 15.0% [1.5; 28.5]) and renal impairment i.e. eGFR 30-50 ml/min/1.73 m2; (+ 18.0% [2.0; 34.0]). The main reason for disagreement (40%) was patients' reluctance to discontinue or initiate medication. CONCLUSION: Better patient and physician education regarding the benefit/risk balance of pharmacotherapy, in addition to more precise and up-to-date medical records to avoid irrelevant recommendations, will likely result in higher adherence with future pharmacotherapy optimisation recommendations. CLINICAL TRIAL REGISTRATION: Trial Registration Number NCT02986425.

Nature and frequency of prescription modifications in community pharmacies: A nationwide study in the Netherlands.

AIMS: To investigate the nature and frequency of prescription modifications in Dutch community pharmacies. METHODS: In this cross-sectional study, Dutch community pharmacists documented prescription modifications in their pharmacy during 1 predetermined day. Pharmacists from all Dutch community pharmacies were invited to participate. A prescription modification was defined as any modification in a prescription for a medicine or other healthcare product because of an administrative problem, logistic issue or potential drug-related problem (DRP). All documented modifications were assessed to establish the nature and frequency of prescription modifications. RESULTS: Pharmacists in 275 pharmacies completed the study. A modification was performed in 5.5% of all prescriptions. 1.3% of the prescriptions contained an administrative problem, of which insufficient specification of the dosing regimen was most common (63.1%). A modification was performed due to a logistic issue in 2.4% of the prescriptions. The most frequently recorded issues were unavailability of medication (40.9%) and obligatory product substitutions due to reimbursement policies (33.2%). A modification was performed in 1.8% of the prescriptions to solve or prevent potential DRPs. Of these, 69.2% was potentially clinically relevant according to the pharmacist concerned. The most frequently prevented potential DRP was an incorrect strength or dose (31.9%). CONCLUSION: Dutch community pharmacists modified almost 1 in 20 prescriptions per pharmacy. The nature of the modifications reflects current community pharmacy practice, in which pharmacists frequently deal with logistic issues and intervene to solve or prevent for DRPs several times a day. The majority of the DRPs were considered to be potentially clinically relevant.

[Reducing medication waste; a challenge for care providers and society]. / Geneesmiddelverspilling verminderen.

Annually, in the Netherlands, at least 100 million euro is wasted on unused medication. This waste not only has considerable economic implications, but is also associated with an unnecessary burden on the environment and suboptimal care due to nonadherence to therapy. The reasons for medication wastage can be found throughout the entire pharmaceutical supply and use chain, which includes manufacturers, distributors/wholesalers, prescribers, pharmacists and patients, both in the community and hospital setting. A number of strategies are needed to minimize the waste of medication, one of which should be a preventative approach. Involvement of all stakeholders in the supply chain is a prerequisite for a successful outcome. It is important that prescribers are aware of the extent and consequences of wastage, and of the possible ways to reduce it.

Associations between personality traits and adequate home storage of drugs in older patients.

The objective of this study was to investigate the association between personality traits of older patients and adequate home storage of drugs. Forty-four participating Dutch community pharmacists randomly selected each up to four community-dwelling elderly patients (≥65 years) who were using at least one prescription drug. The Big Five Inventory was used to assess the personality traits - 'openness', 'conscientiousness', 'extraversion', 'agreeableness' and 'neuroticism' - of patients. An assessment of adequate home storage of drugs was made using a summed composite score for each patient ranging from zero (adequate storage) to three (inadequate storage) was based on storage criteria representing quality, information and level of storage organization. A 51.2% of the patients stored drugs adequately in accordance with all quality ("Q") and information ("I") criteria. A high level of drug storage organization was found in 70.8% of patients. Forty-three patients (31.4%) stored their drugs adequately based on all storage criteria (composite storage score 0). No associations between personality dimensions and adequate drug storage were found. Having a lower number of drugs was associated with adequate drug home storage (ORadjusted 0.86; 95% CI: 0.77-0.96). In conclusion, this study suggests that personality is not associated with adequate home storage of drugs in older patients.

Quantity and economic value of unused oral anti-cancer and biological disease-modifying anti-rheumatic drugs among outpatient pharmacy patients who discontinue therapy.

BACKGROUND: Patients sometimes discontinue the use of expensive oral anti-cancer drug (OACD) or biological disease-modifying anti-rheumatic drug (bDMARD) therapies early, leading to medication waste if the patient has not used all dispensed medication. OBJECTIVE: To determine the proportion of patients who have unused OACDs or bDMARDs after therapy discontinuation, and the quantity and economic value of these unused medications. Furthermore, patients' reasons for therapy discontinuation and their disposal method for unused medications were determined. METHODS: In a retrospective follow-up study using a Dutch outpatient pharmacy database, patients (≥18 years) who did not refill an OACD or bDMARD prescription, dispensed between November 2015 and February 2016, within two weeks of the prescription end date were contacted by phone and asked about their unused medication and reasons thereof. The economic value was calculated using Dutch medication prices. Data were descriptively analyzed in STATA13. RESULTS: The database included 1173 patients, of whom 159 likely had discontinued therapy and were contacted. Of these, 88 patients were excluded (39 refilled, 47 missing, and 2 other). Of the 71 patients who had discontinued therapy, 39 (54.9%) had unused medications, comprising 22 OACD users (mean age 63.0 (SD ±â€¯15.9) years, 50.0% female) and 17 bDMARD users (mean age 50.7 (SD ±â€¯13.5) years, 47.1% female). A total of 59 packages were unused, with a total value of €60,341. Unused OACD packages and bDMARD packages had median values of €179 (IQR €24-2487) and €992 (IQR €681-1093), respectively. Patients primarily discontinued therapy due to adverse or insufficient effects. CONCLUSIONS: This study illustrates that more than half of patients discontinuing OACD or bDMARD therapies have unused medication. This emphasizes the need for waste-reducing interventions.

Patient and medication factors associated with preventable medication waste and possibilities for redispensing.

Background Knowledge on factors related to preventable medication waste and waste-reducing interventions, including redispensing unused medications, is needed to maximise effectiveness. Objective To assess patient and medication factors associated with preventable medication waste and possibilities for redispensing unused medications. Setting Dutch community pharmacies. Methods In this cross-sectional study, pharmacy-staff registered patient and medication characteristics of prescription medications returned to 41 Dutch community pharmacies during 1 week in 2014. Medications were classified as preventable waste if the remaining amount could have been prevented and as theoretically eligible for redispensing if the package was unopened, undamaged and ≥ 6 months until the expiry date. Associations were analysed using multivariate logistic regression. Main outcome measures Proportion of medications classified as preventable waste and as eligible for redispensing, including factors associated with these medications. Results Overall, 279 persons returned 759 (low-cost) medications, and 39.3% was classified as preventable waste. These medications were more frequently used by men than women (OR; 1.7[1.2-2.3]) and by older (> 65 years) than younger patients (OR; 1.4[1.0-2.0]). Medications dispensed for longer periods were more often unnecessary wasted (1-3 months OR; 1.8[1.1-3.0], > 3 months 3.2[1.5-6.9]). Of all returned medications, 19.1% was eligible for redispensing. These medications were more frequently used by men than women (OR; 1.9[1.3-2.9]). Medications chronically used were more frequently eligible for redispensing than acute use (OR; 2.1[1.0-4.3]), and used for longer periods (1-3 months OR; 4.6[2.3-8.9], > 3 months 7.8[3.3-18.5]). Conclusions Over one-third of waste due to medications returned to community pharmacies can be prevented. One-fifth of returned medications can be redispensed, but this seems less interesting from an economic viewpoint.

Monitoring of patients treated with lithium for bipolar disorder: an international survey.

BACKGROUND: Adequate monitoring of patients using lithium is needed for optimal dosing and for early identification of patients with (potential) ADEs. The objective was to internationally assess how health care professionals monitor patients treated with lithium for bipolar disorder. METHODS: Using networks of various professional organizations, an anonymous online survey was conducted among health care professionals prescribing lithium. Target lithium serum levels and frequency of monitoring was assessed together with monitoring of physical and laboratory parameters. Reasons to and not to monitor and use of guidelines and institutional protocols, and local monitoring systems were investigated. RESULTS: The survey was completed by 117 health care professionals incorporating responses from twenty-four countries. All prescribers reported to monitor lithium serum levels on a regular basis, with varying target ranges. Almost all (> 97%) monitored thyroid and renal function before start and during maintenance treatment. Reported monitoring of other laboratory and physical parameters was variable. The majority of respondents (74%) used guidelines or institutional protocols for monitoring. In general, the prescriber was responsible for monitoring, had to request every monitoring parameter separately and only a minority of patients was automatically invited. CONCLUSIONS: Lithium serum levels, renal and thyroid function were monitored by (almost) all physicians. However, there was considerable variation in other monitoring parameters. Our results help to understand why prescribers of lithium monitor patients and what their main reasons are not to monitor patients using lithium.

Development of a nomogram for the estimation of long-term adherence to clozapine therapy using neutrophil fluorescence.

AIMS: Previously, we have reported an association between clozapine use and elevated FL3 neutrophil fluorescence, a flow-cytometric parameter for cell viability. Here, we developed and evaluated a pharmacokinetic-pharmacodynamic model relating FL3-fluorescence to clozapine exposure and derived a nomogram for estimation of long-term adherence. METHODS: Data from 27 patients initiating clozapine were analysed using nonlinear mixed effects modelling. A previously described pharmacokinetic model for clozapine was coupled to a FL3 fluorescence model. For this, an effect compartment with clozapine concentrations as input and a first order decay rate as output was linked with an Emax model to FL3-fluorescence. FL3-fluorescence was simulated for clozapine doses of 50, 150 and 400 mg daily (n = 10 000) to establish the nomogram. Finally, true simulated adherence (% of daily doses taken over 100 days) was compared to nomogram-estimated adherence to evaluate the performance of the nomogram. RESULTS: The half-life of FL3-fluorescence was estimated at 228 h (coefficient of variation 35%). Median absolute prediction errors of the nomogram in case of fully random adherence for 50, 150 and 400 mg ranged from -0.193% to -0.525%. The nomogram performed slightly worse in case of nonrandom adherence (median prediction error up to 5.19%), but was still clinically acceptable. Compliance patterns containing longer drug holidays revealed that the nomogram adequately estimates compliance over approximately the last 3 weeks prior to FL3-measurement. CONCLUSION: Our nomogram could provide information regarding long-term adherence based on prescribed clozapine dose and FL3-fluorescence. Future studies should further explore the clinical value of this biomarker and nomogram.

The Impact of Inadequate Temperature Storage Conditions on Aggregate and Particle Formation in Drugs Containing Tumor Necrosis Factor-Alpha Inhibitors.

PURPOSE: To measure aggregate and particle formation in tumor necrosis factor-alpha (TNF-α) inhibitors etanercept, adalimumab and certolizumab pegol product samples after exposure to freezing temperature conditions similar to storage conditions previously observed in patients' homes. METHODS: TNF-α inhibitors in their original primary and secondary packaging were exposed to 32 freeze-thaw cycles (-10°C for 120min/5°C for 60 min) or continuous low storage temperature (-20°C for 96 h) before thawing at 2-8°C. Non-stressed products were used as controls. The products were analyzed by high pressure size exclusion chromatography (HP-SEC), dynamic light scattering (DLS), nanoparticle tracking analysis (NTA), micro-flow imaging (MFI) and second derivative ultraviolet (UV) spectroscopy. RESULTS: Ten out of twenty-one stressed product samples (47.6%) showed increased particle numbers in the submicron and micron size range when compared to controls. For each product, DLS, MFI and NTA detected an increase in particle level in at least one stressed syringe (both continuous freezing and freeze-thaw), whereas HP-SEC and UV spectroscopy showed no differences between stressed and non-stressed products. CONCLUSION: TNF-α inhibitors are relatively resistant to freezing temperatures similar to storage conditions previously observed in patients' homes. However, almost half of the stressed product samples showed formation of particles in the submicron and micron size range.

Effects of training physicians in electronic prescribing in the outpatient setting on clinical, learning and behavioural outcomes: a cluster randomized trial.

AIMS: Electronic prescribing systems may improve medication safety, but only when used appropriately. The effects of task analysis-based training on clinical, learning and behavioural outcomes were evaluated in the outpatient setting, compared with the usual educational approach. METHODS: This was a multicentre, cluster randomized trial [EDUCATional intervention for IT-mediated MEDication management (MEDUCATE trial)], with physicians as the unit of analysis. It took place in the outpatient clinics of two academic hospitals. Participants comprised specialists and residents (specialty trainees, in the UK) and their patients. Training took the form of a small-group session and an e-learning. The primary outcome was the proportion of medication discrepancies per physician, measured as discrepancies between medications registered by physicians in the electronic prescribing system and those reported by patients. Clinical consequences were estimated by the proportion of patients per physician with at least one missed drug-drug interaction with the potential for causing adverse drug events. A questionnaire assessed physicians' knowledge and skills. RESULTS: Among 124 participating physicians, primary outcome data for 115 (93%) were available. A total of 1094 patients were included. A mean of 48% of registered medications per physician were discrepant with the medications that their patients reported in both groups (P = 0.14). Due to registration omissions, a mean of 4% of patients per physician had one or more missed drug-drug interactions with the potential to cause a clinically relevant adverse drug event in the intervention group, and 7% in controls (P = 0.11). The percentages of correct answers on the knowledge and skills test were higher in the intervention group (57%) compared with controls (51%; P = 0.01). CONCLUSION: The training equipped outpatient physicians with the knowledge and skills for appropriate use of electronic prescribing systems, but had no effect on medication discrepancies.

Comparison of antibiotic dosing recommendations for neonatal sepsis from established reference sources.

Background Incorrect dosing is the most frequent prescribing error in neonatology, with antibiotics being the most frequently prescribed medicines. Computer physician order entry and clinical decision support systems can create consistency contributing to a reduction of medication errors. Although evidence-based dosing recommendations should be included in such systems, the evidence is not always available and subsequently, dosing recommendations mentioned in guidelines and textbooks are often based on expert opinion. Objective To compare dosage recommendations for antibiotics in neonates with sepsis provided by eight commonly used and well-established international reference sources. Setting An expert team from our Dutch tertiary care neonatal intensive care unit selected eight well-established international reference sources. Method Daily doses of the seven most frequently used antibiotics in the treatment of neonatal sepsis, classified by categories for birth weight and gestational age, were identified from eight well-respected reference sources in neonatology/pediatric infectious diseases. Main outcome measure Standardized average daily dosage. Results A substantial variation in dosage recommendations of antibiotics for neonatal sepsis between the reference sources was shown. Dosage recommendations of ampicillin, ceftazidime, meropenem and vancomycin varied more than recommendations for benzylpenicillin, cefotaxime and gentamicin. One reference source showed a larger variation in dosage recommendations in comparison to the average recommended daily dosage, compared to the other reference sources. Conclusion Antibiotic dosage recommendations for neonates with sepsis can be derived from important reference sources and guidelines. Further exploration to overcome variation in dosage recommendations is necessary to obtain standardized dosage regimens.

[Instructions for monitoring clinical parameters in the Summary of Product Characteristics (SmPC) for psychotropic drugs: overview and applicability for clinical practice]. / Instructies voor monitoren van klinische parameters in de registratieteksten van psychofarmaca: overzicht en toepasbaarheid voor de klinische praktijk1.

BACKGROUND: The Summary of Product Characteristics (Smpc) for psychotropic drugs includes instructions for clinical and biomarker monitoring intended to optimise effectiveness and minimise harm.
AIM: To evaluate which monitoring instructions are given in the Smpc and to assess the applicability in clinical practice.
METHOD: The reasons and requirements for monitoring in Smpcs for psychotropic drugs were assessed and somatic parameters were distinguished from non-somatic parameters, thereby the applicability was assessed.
RESULTS: An average of 3.3 instructions per drug label was found. Monitoring was primarily for safety reasons (78%). Requirement was predominantly mandatory (71%). Somatic parameters were most often mentioned (80%). Only 34% of the instructions were determined applicable.
CONCLUSION: Monitoring instructions for psychotropic drugs are aimed at improving safe use. However, most instructions on monitoring do not provide sufficient information to be applicable in clinical practice.

Anti-epileptic drug changes and quality of life in the community.

OBJECTIVE: Changes in anti-epileptic drug (AED) regimens may indicate unsatisfactory treatment results such as insufficient seizure control or adverse effects. This inference underlies epilepsy management and research, yet current studies often do not account for AED changes. We assessed AED change patterns and their association with quality of life (QoL), as main outcome measure, in a community-based setting. METHODS: We assessed a cohort of 248 people with epilepsy identified from community pharmacy records from whom we retrieved AED dispensing history. We assessed all changes in AED use during the 2 years prior to the index date and current QoL using the validated Dutch QOLIE-31 questionnaire. RESULTS: Thirty-one per cent had at least one AED change during the study period, either in drug type or dose. People who changed showed significantly lower QoL (QOLIE score 73 vs 79), especially those who intensified their treatment. Each additional change was associated with a further reduction of 4.9 points in QoL score. CONCLUSIONS: AED changes are common practice, even in people with long-standing epilepsy. Frequent changes, as objective measure of epilepsy severity, are associated with a progressively lower QoL. Changes, even in dose, should be monitored in daily clinical practice and used as a red flag that may require adjustments in epilepsy management. This may include earlier referral to a specialized centre for a more thorough evaluation or counselling. AED changes can also be used as an outcome marker in epilepsy research as a proxy of QoL for better translation of drug-efficacy results to general practice.

The Association Between Potentially Inappropriate Prescribing and Medication-Related Hospital Admissions in Older Patients: A Nested Case Control Study.

INTRODUCTION: Medication-related problems can cause serious adverse drug events (ADEs) that may lead to hospitalization of the patient. There are multiple screening methods to detect and reduce potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs). Whether this will result in less medication-related hospitalizations is unknown. The study objective was to assess the risk of preventable medication-related hospital admissions associated with potentially inappropriate prescribing, using the Beers 2012 and the Screening Tool of Older Person's Prescriptions and the Screening Tool to Alert doctors to Right Treatment (STOPP & START) 2008 criteria. DESIGN, SETTING AND PARTICIPANTS: A nested case-control study was conducted with a subset of Dutch participants from the Hospital Admissions Related to Medication (HARM) study. Cases were defined as patients aged ≥65 years with a potentially preventable medication-related hospital admission. For each case, one control was selected, matched for age and sex. The primary determinant was the presence of one or more PIMs according to the Beers 2012 and STOPP 2008 criteria. The secondary determinant was the presence of one or more PIMs and PPOs according to the STOPP & START 2008 criteria. The strength of the association between inappropriate prescribing and medication-related hospital admission was evaluated with multivariate logistic regression and expressed as odds ratios (ORs) with 95 % confidence intervals (CIs). RESULTS: The prevalence of Beers 2012 criteria PIMs in the total cohort was 44.4 %. The prevalence of STOPP & START 2008 criteria PIMs and PPOs were, respectively, 34.1 and 57.7 %. STOPP 2008 criteria PIMs were associated with preventable medication-related hospital admissions [OR adjusted for number of drugs and comorbidities (ORadj) 2.30, 95 % CI 1.30-4.07], whereas there was no association with Beers 2012 criteria PIMs (ORadj 1.49, 95 % CI 0.90-2.47). STOPP PIMs and START PPOs together were also associated with preventable medication-related hospital admissions (ORadj 3.47, 95 % CI 1.70-7.09). CONCLUSION: Our study shows that patients with potentially inappropriate prescribing detected with the STOPP & START 2008 criteria are at risk of preventable medication-related hospital admissions. The STOPP & START 2008 criteria can be used to identify older people at risk of medication-related problems.

Drug-induced progressive multifocal leukoencephalopathy: Lessons learned from contrasting natalizumab and rituximab.

Progressive multifocal leukoencephalopathy (PML) has been identified as a serious adverse drug reaction (ADR) of several immunomodulatory biologicals. In this study, we contrasted the reporting patterns of PML for two biologicals for which the risk was identified at different points in their lifecycle: natalizumab (before reapproval) and rituximab (nine years postapproval). We found that, apart from the differences in clinical characteristics (age, gender, indication, time to event, fatality), which reflect the diversity in context of use, PML reports for natalizumab were more complete and were received sooner after occurrence. This study serves as an important reminder that spontaneous reports should only be used with great caution to quantify and compare safety profiles across products over time. The observed variability in reporting patterns and heterogeneity of PML cases presents challenges to such comparisons. Lumping uncharacterized PML reports together without taking these differences into account may result in biased comparisons and flawed conclusions about differential safety.

The relation between risk-taking behavior and alcohol use in young adults is different for men and women.

OBJECTIVE: The present study examined the relationship of risk-taking behavior and alcohol use and the role of sex herein, while adjusting for age, depression, anxiety, stress and lifestyle. METHODS: Participants were 6002 university students. They were classified as either abstinent, drinker but non-binge drinker, or binge drinker based on self-reported alcohol consumption. Risk-taking and risk assessment were evaluated with the RT-18 and depression, anxiety and stress with the DASS-21. RESULTS: The odds of being a binge versus non-binge drinker increased with risk-taking as well as risk assessment for both men and women. The odds being a non-binge drinker versus abstinent were increased by risk-taking for women only. For binge drinking versus abstinence, risk-taking had a significant increasing effect for both sexes, but risk assessment was only significant in women. CONCLUSION: These results may assist with alcohol use prevention techniques because risk-taking behavior exerts, even when corrected for age, lifestyle, depression, anxiety, and stress levels, a solid, sex-specific independent effect on alcohol use.

MEDUCATE trial: effectiveness of an intensive EDUCATional intervention for IT-mediated MEDication management in the outpatient clinic - study protocol for a cluster randomized controlled trial.

BACKGROUND: Using information technology for medication management is an opportunity to help physicians to improve the quality of their documentation and communication and ultimately to improve patient care and patient safety. Physician education is necessary to take full advantage of information technology systems. In this trial, we seek to determine the effectiveness of an intensive educational intervention compared with the standard approach in improving information technology-mediated medication management and in reducing potential adverse drug events in the outpatient clinic. METHODS/DESIGN: We are conducting a multicenter, cluster randomized controlled trial. The participants are specialists and residents working in the outpatient clinic of internal medicine, cardiology, pulmonology, geriatrics, gastroenterology and rheumatology. The intensive educational intervention is composed of a small-group session and e-learning. The primary outcome is discrepancies between registered medication (by physicians) and actually used medication (by patients). The key secondary outcomes are potential adverse events caused by missed drug-drug interactions. The primary and key secondary endpoints are being assessed shortly after the educational intervention is completed. Sample size will be calculated to ensure sufficient power. A sample size of 40 physicians per group and 20 patients per physician will ensure a power of >90 %, which means we will need a total of 80 physicians and 1,600 patients. DISCUSSION: We performed an exploratory trial wherein we tested the recruitment process, e-learning, time schedule, and methods for data collection, data management and data analysis. Accordingly, we refined the processes and content: the recruitment strategy was intensified, extra measures were taken to facilitate smooth conductance of the e-learning and parts were made optional. First versions of the procedures for data collection were determined. Data entry and analysis was further standardized by using the G-standard database in the telephone questionnaire. TRIAL REGISTRATION: ISRCTN registry: ISRCTN50890124 . Registered 10 June 2013.

Task analysis of information technology-mediated medication management in outpatient care.

AIMS: Educating physicians in the procedural as well as cognitive skills of information technology (IT)-mediated medication management could be one of the missing links for the improvement of patient safety. We aimed to compose a framework of tasks that need to be addressed to optimize medication management in outpatient care. METHODS: Formal task analysis: decomposition of a complex task into a set of subtasks. First, we obtained a general description of the medication management process from exploratory interviews. Secondly, we interviewed experts in-depth to further define tasks and subtasks. SETTING: Outpatient care in different fields of medicine in six teaching and academic medical centres in the Netherlands and the United States. PARTICIPANTS: 20 experts. Tasks were divided up into procedural, cognitive and macrocognitive tasks and categorized into the three components of dynamic decision making. RESULTS: The medication management process consists of three components: (i) reviewing the medication situation; (ii) composing a treatment plan; and (iii) accomplishing and communicating a treatment and surveillance plan. Subtasks include multiple cognitive tasks such as composing a list of current medications and evaluating the reliability of sources, and procedural tasks such as documenting current medication. The identified macrocognitive tasks were: planning, integration of IT in workflow, managing uncertainties and responsibilities, and problem detection. CONCLUSIONS: All identified procedural, cognitive and macrocognitive skills should be included when designing education for IT-mediated medication management. The resulting framework supports the design of educational interventions to improve IT-mediated medication management in outpatient care.

Risk management plans as a tool for proactive pharmacovigilance: a cohort study of newly approved drugs in Europe.

Risk Management Plans (RMPs) have become a cornerstone in the pharmacovigilance of new drugs in Europe. The RMP was introduced in 2005 to support a proactive approach in gaining knowledge on safety concerns through early planning of pharmacovigilance activities. However, the rate at which uncertainties in the safety profile are resolved through this proactive approach is unknown. We therefore examined the evolution of safety concerns in the RMP after initial approval for a selected cohort of 48 drugs, to provide insight into the knowledge gain over time. We found that 20.7% of the uncertainties existing at approval had been resolved 5 years after approval. Because new uncertainties were included in the RMP at a similar rate, the overall number of uncertainties remained approximately equal. The relatively modest accrual of knowledge, as demonstrated in this study through resolution of uncertainties, suggests that opportunities for optimization exist while ensuring feasible and risk-proportionate pharmacovigilance planning.