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Objective: To identify determinants for the discontinuation of non-ergoline dopamine agonist (DA) treatment in patients with Parkinson's disease (PD) and to identify genetic determinants in genes encoding dopamine receptor (DR)D2 and DRD3 in a exploratory analysis. Methods: Patients included were first-time users of the nonergoline DA ropinirole or pramipexole who had been diagnosed with PD before 2005. Treatment discontinuation was defined as a gap of 180 days or more between two refills of the DA. Non-genetic determinants for discontinuation were studied in the overall population, and genetic determinants [DRD2 141C Ins/Del, DRD2 (CA)n STR, DRD2 TaqIA, DRD3 MscI single nucleotide polymorphism (SNP) and DRD3 MspI SNP] were studied in a subgroup. Cox proportional hazard analysis was used to estimate the hazard ratios (HR) for the discontinuation of non-ergoline DA treatment. Results: The study population comprised 90 patients. Apomorphine use was associated with non-ergoline DA discontinuation, although the apomorphine group consisted only of three patients [HR 6.26; 95% confidence interval (CI) 1.85--21.2]. Daily levodopa dosages between 500 and 1000 mg were positively associated with discontinuation (HR 2.31; 95% CI 1.08--4.93). Included in the exploratory pharmacogenetic analysis were 38 patients. The absence of a 15× DRD2 CA repeat allele was significantly related with a decreased discontinuation of non-ergoline treatment (HR 0.23; 95% CI 0.07--0.81). The DRD3 MspI polymorphism showed a non-significant allele dose effect, suggestive of a causal relationship. Conclusion: This study identified apomorphine use and levodopa dosages between 500 and 1000 mg as nongenetic and the 15× DRD2 CA repeat allele as genetic determinants for the discontinuation of non-ergoline DA treatment in patients with PD. More research is needed to replicate these findings. [ABSTRACT FROM AUTHOR]

BACKGROUND: The high prevalence of drug-related problems (DRPs) in the elderly, occurring as a result of multiple drug use combined with age-related changes in pharmacokinetics and pharmacodynamics, is a well known phenomenon. However, effective intervention strategies are uncommon. OBJECTIVE: A pharmacy-based controlled trial (SMOG [Screening Medicatie Oudere Geneesmiddelgebruiker; Screening Medications in the Older Drug User]) was performed to investigate whether a community pharmacist-led intervention reduces the number of potential DRPs in patients aged >/=65 years using six or more drugs concomitantly. METHODS: This intervention study was conducted from June 2002 until June 2003 in 16 community pharmacies in the Netherlands. Medication assessment was undertaken in elderly patients aged >/=65 years using six or more drugs concomitantly on the date of inclusion. Ten types of potential DRPs were determined and grouped into the following three categories: (i) patient-related potential DRPs: non-compliance; (ii) prescriber-related potential DRPs: expired indication, therapeutic duplication, inappropriate dosage (over- and under-dosage), off-label use, undertreatment, inconvenience of use; and (iii) drug-related potential DRPs: contraindications, drug-drug interactions, drug treatment of adverse drug reactions.A list of recommended changes in medication was compiled by the pharmacist for the patients in the intervention group. Recommendations for medication change were discussed with the general practitioner (GP). Four months after the date of inclusion, the medications of each patient were again reviewed and screened for potential DRPs. The primary outcome corresponded to the change in the number of potential DRPs; the secondary outcome was related to the change in number of used medications between the intervention group and the control group at baseline and 4 months later. RESULTS: A total of 174 patients were analysed: 87 patients in the intervention arm and 87 patients in the usual care arm. After a 4-month period, we observed a significant reduction in the mean number of DRPs per patient (mean difference -16.3%; 95% CI -24.3, -8.3). The mean number of drugs per patient was not significantly reduced (mean difference -4.7%; 95% CI -9.6, 0.2). CONCLUSION: This study showed a positive influence of the community pharmacist in reducing potential DRPs in the elderly. Future interventions should also focus on actual outcomes, including quality of life, morbidity and mortality. [ABSTRACT FROM AUTHOR]

Objective: To compare characteristics and incidence of discontinuation of Parkinson's disease (PD) patients starting ropinirole or pramipexole in clinical practice with data from randomised controlled clinical trials (RCTs). Methods: Included in the retrospective clinical-practice cohort were first-time users of ropinirole or pramipexole diagnosed with PD before 2005. Baseline characteristics and incidence of discontinuation were compared between the clinical-practice cohort and RCTs. Treatment discontinuation was defined as more than 180 days between two refills of ropinirole or pramipexole. The incidence of discontinuation in RCTs was based on the reported rate of discontinuation for any cause. Results: Included were 45 patients who started with ropinirole and 59 patients who started with pramipexole. Treatment was discontinued within 3 years in 51% (ropinirole) and 60% (pramipexole) of the patients. Ten RCTs with ropinirole and 12 with pramipexole were identified. Baseline characteristics did not differ between the clinical-practice cohort and RCTs. RCTs reported discontinuation rates comparable with those at the same timepoint in the clinical practice until 1 year of follow-up. Conclusion: This study shows that the overall incidence of discontinuation of ropinirole and pramipexole between the patients in our clinical-practice cohort and patients in the RCTs was comparable for the short term. However for the long term, discontinuation in practice is possibly higher. [ABSTRACT FROM AUTHOR]

Background: In view of the high rates of off-label and unlicensed prescribing of drugs in children, the US Food and Drug Administration and the European Union have implemented legislative regulations for the pharmaceutical industry to increase the number of drugs with approved pediatric labeling. However, the extent to which the effects of pharmaceutical technologic aspects of pediatric oral drugs (eg, taste, route and frequency of administration, user instructions) on patient-related outcomes (eg, efficacy, tolerability, preference, adherence) can be based on clinical evidence from the available literature is unknown. Objective: This systematic literature review aimed to identify the nature, volume, and quality of comparative studies that have assessed the effects of pharmaceutical technologic aspects of oral pediatric drugs on patient-related outcomes. Methods: The Cochrane, EMBASE, and MEDLINE databases were searched from their start through December 31, 2009. Studies were eligible for inclusion if they were published in English; included search terms for child, study design, medicine, formulation aspects, dosage form, routes of administration, patient acceptance, adherence, side effects and tolerability, and/or efficacy; reported on >/=10 children aged 0 to <18 years; and described the effects of >/=1 of 3 pharmaceutical technologic aspects of an oral pediatric drug (formulation and dosage form; route and frequency of administration; and/or packaging, administration device, and user instruction) on >/=1 of 6 patient-related outcomes (clinical efficacy, side effects and tolerability, patient preference, patient acceptance, administration errors, and/or adherence). Studies were excluded if they concerned a nonallopathic drug (ie, homeopathic remedy, anthroposophic drug, herbal supplement, or food supplement); related to asthma (because modern asthma treatment protocols strongly favor the use of drug inhalation above oral medication); and/or related to analgesics. The characteristics of each of the included publications were assessed with respect to pharmaceutical technologic aspect studied; patient-related outcomes studied; pharmacotherapeutic indication; year of publication; geographic location; number and age of the included subjects; and sponsorship by industry and/or author affiliation with the pharmaceutical industry. The electronic search was supplemented with a manual search of the cited references. Results: Ninety-four publications were identified as eligible for inclusion. These publications reported on 176 assessments of the effects of >/=1 pharmaceutical technologic aspect on >/=1 patient-related outcome. Fiftyfive percent of the studies were conducted in children aged 2 or 3 years, and 69% in children aged 4 or 5 years. Forty-three percent of the publications included >/=100 patients. Fifty-one percent of the studies were conducted in the United States or Canada, and 29% in Europe. Antibacterials for systemic use were the subject of 30% of the included publications. Two of the 94 publications were of appropriate méthodologie quality (Jadad score >/=4). Forty-nine percent of the studies were sponsored by the pharmaceutical industry or were written by >/=1 author affiliated with the industry. Sixty-eight percent of the included studies had Jadad scores of 0 or 1 (poor quality). The proportion of industry-sponsored or industry-authored studies with a Jadad score >/=2 or in >/=100 children was not significantly different from that of non-industry-sponsored or-authored studies. The proportion of industry-sponsored or industry-authored studies conducted in the United States/Canada (48 [51%]) was not significantly different from that of studies conducted elsewhere (46 [49%]). The distribution of technologic aspects assessed in the included studies were formulation and dosage form, 48%; route and frequency of administration, 44%; and packaging, administration device, and user instruction, 8%. Seventy-six assessments included >/=100 patients. Twenty-one of these assessments addressed patient acceptance or patient preference; 17, clinical efficacy; and 14, side effects and tolerability. Conclusions: This systematic review identified 94 articles on oral drugs for use in children and adolescents, which reported on a total 176 assessments of the effects of 3 pharmaceutical technologic aspects (formulation and dosage form; route and frequency of administration; and packaging, administration device, and user instruction) on 6 patient-related outcomes (clinical efficacy, side effects and tolerability, patient preference, patient acceptance, administration errors, and adherence). Only 2 of the 94 publications were of appropriate methodologic quality. These results suggest that published clinical evidence to support pharmaceutical development programs is limited. [ABSTRACT FROM AUTHOR]

Abstract: Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment strategy for patients with inborn errors of immunities (IEIs). The objective of this study was to assess the optimal busulfan exposure before allogeneic HCT for patients with an IEI who received an IV busulfan-based conditioning regimen. Patients from 17 international centers were included. The main outcome of interest was event-free survival (EFS). Patients were categorized into 4 IEI subgroups: combined immunodeficiency (CID), severe combined immunodeficiency (SCID), neutrophil disorders, and hemophagocytic lymphohistiocytosis (HLH)-related disorders. Busulfan exposure was calculated by individual centers (area under the curve [AUC]CENTER) and re-estimated using a nonlinear mixed-effects model (NONMEM; exposure defined as AUCNONMEM). Overall, 562 patients were included: 173 (30.8%) with CID, 154 (27.4%) with SCID, 101 (18.0%) with HLH-related disorders, and 134 (23.8%) with neutrophil disorders. The median busulfan AUCNONMEM was 69.0 mg × h/L and correlated poorly with the AUCCENTER (r2 = 0.54). In patients with SCID, HLH-related, and neutrophil disorders with a busulfan AUCNONMEM of 70 to 90 mg × h/L, 2-year EFS was superior to <70 mg × h/L, and >90 mg ×h/L. Full donor chimerism increased with higher busulfan AUCNONMEM, plateauing at 90 mg × h/L. For patients with CID, the optimal AUCNONMEM for donor chimerism was found to be >70 mg × h/L. Improved EFS and higher donor chimerism may be achieved by targeting a cumulative busulfan AUCNONMEM of 80 mg × h/L (range, 70-90). Our study stresses the importance of uniformly using a validated population pharmacokinetic model to estimate AUCNONMEM., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

Importance: Medications are associated with substantial environmental outcomes, yet frequently end up being unused by patients. Waste-minimizing interventions, such as redispensing of quality-approved oral anticancer drugs remaining unused by patients at home, could reduce the environmental footprint of cancer treatment., Objectives: To assess the environmental outcomes of redispensing quality-assured oral anticancer drugs and to explore how redispensing could be environmentally optimized., Design, Setting, and Participants: In this quality improvement study, a cradle-to-grave life cycle assessment was performed in the outpatient pharmacy of 4 Dutch hospitals, based on a prospective multicenter trial comprising 1071 patients with a clinical diagnosis of cancer and an active prescription for an oral anticancer drug stored at room temperature from February 1, 2021, to February 1, 2023, with a follow-up of 12 months per patient., Intervention: Participants received prescribed oral anticancer drugs with additional quality-assurance materials (ie, seal bags and time-temperature indicators), so the pharmacy could redispense quality-assured drugs based on authenticity, appearance, remaining shelf life, and/or adequate storage., Main Outcomes and Measures: The estimated environmental outcomes avoided due to waste reduction (ie, production and transport and incineration of redispensed oral anticancer drugs) corrected for outcomes of process burdens (ie, quality assurance materials), quantified in 3 outcome measures: human health damage (disability-adjusted life-years), ecosystems damage (species × year), and climate change (kg of carbon dioxide equivalent [CO2-eq]) per patient per year., Results: A volunteer sample of 1071 patients (median age, 70 years [IQR, 62-75 years]; 622 men [58.1%]) participated in the intervention. Redispensing oral anticancer drugs was initially associated with an environmental burden, mainly because of the high impact of time-temperature indicators. However, when quality-assurance materials were selectively used for temperature-sensitive oral anticancer drugs (ie, maximum storage temperature of 25 °C), redispensing was environmentally beneficial to human health and ecosystems, providing estimated climate benefits of 1.9 kg (95% CI, 1.4-2.6 kg) of CO2-eq per patient per year., Conclusions and Relevance: In this quality improvement study, redispensing unused oral anticancer drugs was found to be a suitable strategy to reduce waste and improve environmental sustainability of cancer treatment after process optimization. Redispensing unused oral anticancer drugs could contribute to sustainability of cancer treatment through reduced costs and environmental outcomes.

Background: Minimizing medication waste through the redispensing of oral anticancer drugs (OADs) that were unused by patients provides economic and environmental benefits, but this is not yet universally implemented in clinical care., Objectives: To identify barriers and facilitators to the implementation of redispensing unused OADs in clinical care., Methods: A multicentre intervention study following a hybrid effectiveness-implementation type I design was conducted, consisting of semi-structured interviews with key stakeholders involved in the redispensing program: pharmacy employees, prescribing clinicians in oncology and haematology, patients who participated in redispensing and patients who declined trial participation. Questions encompassed experiences and suggestions for future implementation. The Consolidated Framework for Implementation Research (CFIR) guided data collection and categorisation of identified barriers and facilitators through thematic analysis., Results: In total, 35 interviews were conducted, identifying 15 themes encompassing barriers and facilitators, reflecting all CFIR domains. Facilitators encompassed: 1) convenient process requiring an acceptable time-investment; 2) support from project leaders and implementation champions; 3) being well-motivated by personal values and societal impact; 4) feeling ensured of medication quality upon redispensing; 5) endorsement by healthcare providers for patient participation; 6) clear and personal patient communication; 7) good visibility of intervention successes; and 8) implementation well supported through a collaborative network. Barriers encompassed: 1) unclear target population; 2) redispensing legally prohibited; 3) absence of financial compensation for pharmacies; 4) complexity arising from two parallel work processes; 5) widespread communication on adjustments within local teams challenging; 6) patient's low receptiveness due to burden of oncology treatment; and 7) lack of familiarization among pharmacy technicians., Conclusions: Facilitators for implementation of redispensing unused drugs mainly related to people's values, motivation, and societal demand, whereas barriers mainly encompassed practical issues, including knowledge, time, financial resources, and legal conditions. Strategies emphasizing the benefits of redispensing and further streamlining process compatibility could support implementation., Competing Interests: The authors declare that they have no competing interests., (© 2024 The Authors.)

Objective: Adverse drug reactions (ADRs) are a significant healthcare concern. They are often documented as free text in electronic health records (EHRs), making them challenging to use in clinical decision support systems (CDSS). The study aimed to develop a text mining algorithm to identify ADRs in free text of Dutch EHRs., Materials and Methods: In Phase I, our previously developed CDSS algorithm was recoded and improved upon with the same relatively large dataset of 35 000 notes (Step A), using R to identify possible ADRs with Medical Dictionary for Regulatory Activities (MedDRA) terms and the related Systematized Nomenclature of Medicine Clinical Terms (SNOMED-CT) (Step B). In Phase II, 6 existing text-mining R-scripts were used to detect and present unique ADRs, and positive predictive value (PPV) and sensitivity were observed., Results: In Phase IA, the recoded algorithm performed better than the previously developed CDSS algorithm, resulting in a PPV of 13% and a sensitivity of 93%. For The sensitivity for serious ADRs was 95%. The algorithm identified 58 additional possible ADRs. In Phase IB, the algorithm achieved a PPV of 10%, a sensitivity of 86%, and an F-measure of 0.18. In Phase II, four R-scripts enhanced the sensitivity and PPV of the algorithm, resulting in a PPV of 70%, a sensitivity of 73%, an F-measure of 0.71, and a 63% sensitivity for serious ADRs., Discussion and Conclusion: The recoded Dutch algorithm effectively identifies ADRs from free-text Dutch EHRs using R-scripts and MedDRA/SNOMED-CT. The study details its limitations, highlighting the algorithm's potential and significant improvements., Competing Interests: The authors have no competing interests to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Aim: Vitamin B 12 deficiency is common in the elderly population. Standard treatment via intramuscular injections, however, has several disadvantages. Safer and more convenient dosage forms such as intranasal are therefore being explored. This study compares the effects of two intranasal vitamin B 12 dosage regimens in elderly vitamin B 12 -deficient patients., Methods: Sixty patients ≥65 years were randomly assigned to either a loading dose (daily administration for 14 days followed by weekly administration) or a no loading dose (administration every 3 days) regimen for 90 days. Each dose contained 1000 μg cobalamin. Total vitamin B 12 , holotranscoblamin (holoTC), methylmalonic acid (MMA) and total homocysteine (tHcy) levels in serum were measured on days 0, 7, 14, 30, 60 and 90., Results: Both dosage regimens resulted in a rapid increase of vitamin B 12 and holoTC concentrations and normalization of initial high, MMA and tHcy concentrations. The loading dose regimen resulted in the fastest and greatest increase to a median vitamin B 12 of 1090 pmol/L (reference 350-650 pmol/L) concentration after 14 days. Following weekly administration, B 12 rapidly decreased to a median concentration of 530 pmol/L after 90 days. The no loading dose regimen resulted in a steady increase to a median vitamin B 12 of 717 pmol/L after 90 days., Conclusions: Intranasal vitamin B 12 administration is an effective and suitable way to replenish and sustain vitamin B 12 levels in elderly patients., (© 2024 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Purpose: In clinical practice, a discrepancy may exist between the prescribed amount of a drug and the commercially available pack sizes in the pharmacy, potentially contributing to drug waste. This study aimed-as an example of this phenomena-to quantify leftover of amoxicillin suspension prescribed to children, due to discrepancies between physician-prescribed and pharmacy-dispensed amounts., Methods: We performed a retrospective cohort study including amoxicillin suspension dispensations for patients aged 0-12 years between 2017 and 2019 utilizing the Dutch PHARMO database. Leftover amount of amoxicillin was estimated by assessing the discrepancy between the prescribed and dispensed amounts. Extrapolated amoxicillin weight and economic spillage estimates for the Netherlands were determined. The impact of two theoretical interventions on leftover amount was assessed: (1) introducing vials with half the volume of the current 100 and 30 mL vials and (2) a combination of the first intervention with a maximum of 10% round-down by the dispensing pharmacy of the prescribed dose., Results: We included 79 512 amoxicillin suspension dispensations for 62 252 patients. The mean leftover amount of amoxicillin suspension per dispensing was 27%. The yearly amount of amoxicillin leftover was 49.8 kg in the study cohort, equivalent to yearly 633 kg and €621 000 when extrapolated to the Netherlands. Employing the first theoretical intervention reduced the mean leftover per dispensing to 20%, reducing the yearly leftover to 31.6 kg amoxicillin in the study cohort, and to 400 kg and €400 000 extrapolated. The second theoretical intervention further reduced leftover to 17%, reducing the yearly leftover to 24.3 kg amoxicillin in the study cohort, and to 300 kg and €300 000 extrapolated., Conclusion: Approximately a quarter of amoxicillin suspension remains as leftover per dispensing. Applying different theoretical intervention shows the potential for a significant reduction of amoxicillin leftover., (© 2024 The Author(s). Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Background and Objective: High variability in tacrolimus pharmacokinetics directly after lung transplantation (LuTx) may increase the risk for acute kidney injury (AKI) and transplant rejection. The primary objective was to compare pharmacokinetic variability in patients receiving tacrolimus orally versus intravenously early after LuTx., Methods: Pharmacokinetic and clinical data from 522 LuTx patients transplanted between 2010 and 2020 in two university hospitals were collected to compare orally administered tacrolimus to intravenous tacrolimus early post-transplantation. Tacrolimus blood concentration variability, measured as intrapatient variability (IPV%) and  percentage of time within the therapeutic range (TTR%), was analyzed within the first 14 days after LuTx. Secondary outcomes were AKI, acute rejection, length of stay in the intensive care unit (ICU), and mortality in the ICU and during hospital admission., Results: We included 224 patients in the oral and 298 in the intravenous group. The mean adjusted IPV% was 10.8% (95% confidence interval [CI] 6.9-14.6; p < 0.001) higher in the oral group (27.2%) than the intravenous group (16.4%). The mean TTR% was 7.3% (95% CI - 11.3 to - 3.4; p < 0.001) lower in the oral group (39.6%) than in the intravenous group (46.9%). The incidence of AKI was 46.0% for oral and 42.6% for intravenous administration (adjusted odds ratio [OR] 1.2; 95% CI 0.8-1.8; p = 0.451). The frequencies of clinically diagnosed acute rejection in the oral and intravenous groups were nonsignificant (24.6% vs 17.8%; OR 1.5 [95% CI 1.0-2.3; p = 0.059]). ICU and hospital mortality rate and ICU length of stay were similar., Conclusions: Administering tacrolimus orally directly after LuTx leads to a higher variability in blood concentrations compared to intravenous administration. There was no difference in the occurrence of AKI or transplant rejection., (© 2024. The Author(s).)

Background: To assess the causal relationship between a medicinal product and a reported event, relevant information needs to be present. Information elements for assessing cases of exposure to medicinal products during pregnancy were predefined and used in a new tool to assess the quality of information. However, the extent in which the presence or absence of these predefined information elements is associated with the overall clinical quality of these cases, as evaluated by pharmacovigilance experts, remains uncertain., Objective: We aimed to validate a novel method to assess the clinical quality of information in real-world pregnancy pharmacovigilance case reports., Methods: The clinical quality of case reports regarding medicinal product exposure and pregnancy-related outcomes was appraised from spontaneous reports, literature, Teratology Information Services (UK and Switzerland), The Dutch Pregnancy Drug Register, the Gilenya pregnancy registry and the Enhanced PV programme of Novartis. Assessment was done by means of the novel standardised tool based on the presence and relevance of information, and by expert judgement. The novel tool was validated compared to the expert assessment as the gold standard expressed as the area under the receiver operating characteristic curves, after which the sensitivity and specificity were calculated using cross-tabulations. Inter-rater variability was determined by means of weighted Cohen's kappa., Results: One hundred and eighty-six case reports were included. The clinical quality score as assessed by the novel method was divided into three categories with cut-off values of 45% (poor to intermediate) and 65% (intermediate to excellent). Sensitivity was 0.93 and 0.96 for poor to intermediate and intermediate to excellent, respectively. Specificity was respectively 0.52 and 0.73. Inter-rater variability was 0.65 (95% confidence interval 0.53-0.78) for the newly developed approach, and 0.40 (95% confidence interval 0.28-0.52) for the gold standard assessment., Conclusions: The tool described in this study using the presence and relevance of elements of information is the first designed, validated and standardised method for the assessment of the quality of information of case reports in pregnancy pharmacovigilance data. This method confers less inter-rater variability compared with a quality assessment by experts of pregnancy-related pharmacovigilance data., (© 2024. The Author(s).)

Importance: New strategies targeting waste are required to improve financial and ecologic sustainability of expensive therapies, such as oral anticancer drugs, that frequently remain unused by patients. Redispensing unused oral anticancer drugs seems to be a promising strategy when drug quality is guaranteed., Objectives: To determine the waste reduction and net cost savings attained by redispensing oral anticancer drugs that go unused by patients compared with the standard practice of disposal., Design, Settings, and Participants: The ROAD study was a prospective single-group intervention conducted in the outpatient pharmacies of 4 hospitals in the Netherlands from February 1, 2021, to February 1, 2023, with 12-month follow-up of each patient. Patients with cancer and who had a prescription for an oral anticancer drug that could be stored at room temperature were included. Of 2426 eligible patients, 602 did not consent and 601 did not respond. Data analyses were performed from August 25, 2022, to April 19, 2023., Intervention: Participants received oral anticancer drugs for use at home in special packaging (ie, sealed packaging with time-temperature indicator), to be returned to the pharmacy should these remain unused. The pharmacy ensured quality of returned drugs based on authenticity, appearance, remaining shelf life and adequate storage temperature. Drugs fulfilling quality requirements were redispensed to other patients., Main Outcome and Measure: Total waste reduction and mean net annual cost savings per patient compared with the standard practice of disposal. Optimization of cost savings was explored by introducing variations in the quality assurance procedure and patient population. All analyses used the average exchange rate for 2021 €1 = US $1.18., Results: Of 1223 patients with cancer who consented, 1071 participated (median [IQR] age, 70 [62-75] years; 622 [58.1%] were male). In all, 171 patients (16.0%; 95% CI, 13.8%-18.3%) returned 335 unused oral anticancer drug packages. Of the returned drugs, 228 packages were redispensed, which reduced waste by 68.1% (95% CI, 67.7%-68.5%) compared with the standard practice (disposal). Redispensing unused oral anticancer drugs comprised 2.4% (95% CI, 2.2%-2.5%) of total drug costs, providing mean net annual cost savings of US $680 (95% CI, $524-$837) up to $1591 (95% CI, $1226-$2002) per participant., Conclusions and Relevance: The findings of this multicenter intervention study indicate that redispensing unused oral anticancer drugs is associated with waste reduction and cost savings, which in turn may improve the affordability and sustainability of cancer treatment., Trial Registration: World Health Organization International Clinical Trials Registry Platform Identifier: NL9208.

Background: The availability of ready-to-administer (RTA) syringes for intravenous (IV) drugs facilitates rapid and safe administration in emergency and intensive care situations. Hospital pharmacies can prepare RTA syringes through aseptic batchwise filling. Due to excess production of these RTA syringes for sufficient availability for patient care and their limited (microbiological) shelf-life, waste is unavoidable, which contributes to environmental pollution. RTA prefilled sterilized syringes (PFSSs) have much longer shelf-lives than aseptically prepared RTA syringes and might contribute to reducing drug waste., Aim: This study aimed to evaluate the difference in drug waste between RTA syringes that were prepared through aseptic batchwise filling and RTA PFSSs in the Intensive Care Unit (ICU)., Methods: We measured drug waste of RTA syringes over an 8-year time period from August 2015 to May 2023 in the 32-bed ICU of the University Medical Center Utrecht. We distinguished between RTA syringes prepared through aseptic batchwise filling by our hospital pharmacy ("RTA aseptic syringes", shelf-life of 31 days) and RTA PFSSs (shelf-life of 18 months). An intervention group of three drug products that were replaced by PFSSs was compared to a control group of five drug products that were not replaced by PFSSs during the study period. We then defined four different periods within the total study period, based on quarantine time of the RTA aseptic syringes and time of PFSS introduction: 1) no quarantine, 2) 3-day quarantine, 3) 7-day quarantine and 4) PFSS introduction. Our primary endpoint was the number of RTA syringes that was wasted, expressed as the percentage of the total number of syringes dispensed to the ICU in each of these four periods. We used a Kruskall-Wallis test to test if waste percentages differed between time periods in the control and intervention groups, with a post-hoc Dunn's test for pairwise comparisons. Furthermore, we applied two interrupted time series (ITS) analyses to visualize and test the effect of introducing different quarantine times and the PFSSs on waste percentage., Results: Introduction of PFSSs significantly decreased drug waste of RTA syringes irrespective of drug type in the intervention group, from 31% during the 7-day quarantine period to 5% after introduction of the PFSS (p<0.001). The control group showed no significant decrease in drug waste over the same time periods (from 20% to 16%; p=0.726). We observed a significant difference in the total drug waste of RTA aseptic syringes between time periods, which may be attributed to the implementation of different quality control quarantine procedures. The ITS model of the intervention group showed a direct decrease of 17.7% in waste percentage after the introduction of PFSSs (p=0.083)., Conclusion: Drug waste of RTA syringes for the ICU can be significantly decreased by introducing PFSSs, supporting hospitals to enhance environmental sustainability. Furthermore, the waste percentage of RTA syringes prepared through aseptic batchwise filling is significantly impacted by duration of quarantine time., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Many patients with inflammatory bowel disease (IBD) have transitioned from an infliximab originator to a biosimilar. However, some patients retransition to the originator (i.e. stop biosimilar and reinitiate the originator). Whether this sign of potential unsatisfactory treatment response is specifically related to the infliximab biosimilar or the patient and/or the disease including patients' beliefs on the biosimilar is unclear., Objectives: We aimed to compare the risk of and reasons for infliximab discontinuation between retransitioned patients and those remaining on biosimilar., Design: Non-interventional, multicentre cohort study., Methods: IBD patients who transitioned from infliximab originator to biosimilar between January 2015 and September 2019 in two Dutch hospitals were eligible for this study. Retransitioned patients (retransitioning cohort) were matched with patients remaining on biosimilar (biosimilar remainder cohort). Reasons for discontinuation were categorised as the unwanted response (i.e. loss of effect or adverse events) or remission. Risk of unwanted discontinuation was compared using Cox proportional hazards models., Results: Patients in the retransitioning cohort ( n  = 44) were younger (median age 39.9 versus 44.0 years), more often female (65.9% versus 48.9%) and had shorter dosing intervals (median 48.5 versus 56.0 days) than in the biosimilar remainder cohort ( n  = 127). Infliximab discontinuation due to unwanted response was 22.7% in the retransitioning and 13.4% in the biosimilar remainder cohort, and due to remission was 2.3% and 9.4%, respectively. Retransitioned patients are at increased risk of discontinuing due to unwanted response compared with biosimilar remainder patients (adjusted HR 3.7, 95% CI: 1.0-13.9). Patients who retransitioned due to an increase in objective disease markers had higher discontinuation rates than patients who retransitioned due to symptoms only (66.7% versus 23.7%)., Conclusion: Retransitioned patients are at increased risk of infliximab discontinuation due to unwanted response. Retransitioning appeared related to the patient and/or disease and not the product. Clinicians might switch patients opting for retransitioning to other treatment regimens., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2023.)

Background: Professional associations publish guidance advising gastroenterologists on prescribing biosimilars; however, guidelines differ between countries and change over time. This study aimed to map the presence and content of guidance from European gastroenterology associations on TNFα inhibitor biosimilar use and its development over time., Research Design and Methods: Guidelines on biosimilar prescribing from national gastroenterology associations in the European Economic Area (EEA) partnered with the European Crohn's and Colitis Organization (ECCO) were collected. Treatment guidelines and biosimilar position papers from 2010 to 2022 were included. Data were extracted using a template., Results: 26 of 30 EEA countries have an ECCO-partnered gastroenterology association, of which 14 (53.8%) had national guidelines addressing biosimilars, four (15.4%) followed ECCO's position, and three (11.6%) had treatment guidelines without mentioning biosimilars. From five countries (19.2%) no guidelines were retrieved. Among 18 countries with guidance, 14 (77.8%) associations endorsed initiating biological treatment with biosimilars, and 13 (72.2%) endorsed transitioning from originator to biosimilar. Nine associations published multiple guidelines over time addressing biosimilars; overall, their positions became more encouraging., Conclusions: The majority of gastroenterology associations endorsed biosimilar use. The lack of (up-to-date) guidelines for some associations indicates an area of improvement to support biosimilar use in clinical practice.

Objective: Combining text mining (TM) and clinical decision support (CDS) could improve diagnostic and therapeutic processes in clinical practice. This review summarizes current knowledge of the TM-CDS combination in clinical practice, including their intended purpose, implementation in clinical practice, and barriers to such implementation., Materials and Methods: A search was conducted in PubMed, EMBASE, and Cochrane Library databases to identify full-text English language studies published before January 2022 with TM-CDS combination in clinical practice., Results: Of 714 identified and screened unique publications, 39 were included. The majority of the included studies are related to diagnosis (n = 26) or prognosis (n = 11) and used a method that was developed for a specific clinical domain, document type, or application. Most of the studies selected text containing parts of the electronic health record (EHR), such as reports (41%, n = 16) and free-text narratives (36%, n = 14), and 23 studies utilized a tool that had software "developed for the study". In 15 studies, the software source was openly available. In 79% of studies, the tool was not implemented in clinical practice. Barriers to implement these tools included the complexity of natural language, EHR incompleteness, validation and performance of the tool, lack of input from an expert team, and the adoption rate among professionals., Discussion/conclusions: The available evidence indicates that the TM-CDS combination may improve diagnostic and therapeutic processes, contributing to increased patient safety. However, further research is needed to identify barriers to implementation and the impact of such tools in clinical practice., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Prophylaxis with emicizumab provides effective bleeding protection in persons with hemophilia A (PwHA) but pressures healthcare budgets. The body weight-adjusted dosing at 7-, 14-, or 28-day intervals, according to the label, often mismatches the vial content. Entire-vial dosing resulted in therapeutic concentrations according to pharmacokinetic simulations and was introduced to avoid waste., Objectives: The objective of this study was to evaluate the efficacy of entire-vial dosing of emicizumab by investigating real-world evidence of plasma concentrations, bleeds, and drug waste., Methods: This is a single-center, observational study with PwHA receiving emicizumab in mg/kg doses according to label but dosing interval extrapolated to the nearest vial size. Patient characteristics and bleeds were compared 1 year before starting emicizumab and during emicizumab until January 2022. Concentrations were assessed at weeks 4, 12, and annually. The mean (95% CI) annualized bleed rates were compared by using negative binomial regression. Drug waste between label-based dosing and entire-vial dosing was compared., Results: A total of 112 individuals (94% severe phenotype and 9% positive FVIII inhibitors) were followed for a median of 56 weeks (interquartile range [IQR] 52-68) before and 51 weeks (IQR 29-75) after starting emicizumab. The median emicizumab dose was 5.9 (IQR 5.5-6.2) mg/kg/4 wk with median concentrations of 63 (IQR 51-80) μg/mL. The annualized bleed rate of treated bleeds before emicizumab was 3.6 (95% CI 2.9-4.4) and was 0.8 (95% CI 0.6-1.1) during emicizumab ( P  < .001). Drug waste was reduced by 9%., Conclusion: The entire-vial dosing of emicizumab is an attractive treatment option for PwHA leading to therapeutic plasma concentrations, good bleeding control, and drug waste avoidance., (© 2023 The Author(s).)

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, disabling side effect in non-small cell lung cancer (NSCLC) patients treated with platinum-based therapy. There is increasing evidence for associations between genetic variants and susceptibility to CIPN. The aim of this study was to further explore genetic risk factors for CIPN by investigating previously reported genetic associations. Methods: A multicenter prospective follow-up study (PGxLUNG, NTR NL5373610015) in NSCLC patients (stage II-IV) treated with first-line platinum-based (cisplatin or carboplatin) chemotherapy was conducted. Clinical evaluation of neuropathy (CTCAE v4.03) was performed at baseline and before each cycle (four cycles, every three weeks) of chemotherapy and at three and six months after treatment initiation. The relationship between 34 single nucleotide polymorphisms (SNPs) in 26 genes and any grade (grade ≥ 1) and severe (grade ≥ 2) CIPN was assessed by using univariate and multivariate logistic regression modelling. Results: In total, 320 patients were included of which 26.3% (n = 84) and 8.1% (n = 26) experienced any grade and severe CIPN, respectively. The GG-genotype (rs879207, A > G) of TRPV1, a gene expressed in peripheral sensory neurons, was observed in 11.3% (n = 36) of the patients and associated with an increased risk of severe neuropathy (OR 5.2, 95%CI 2.1−12.8, adjusted p-value 0.012). A quarter (25%, n = 9/36) of the patients with the GG-genotype developed severe neuropathy compared to 6% (n = 17/282) of the patients with the AG- or AA-genotype. Multivariate logistic regression analysis showed statistically significant associations between the GG-genotype (ORadj 4.7, 95%CI 1.8−12.3) and between concomitant use of paclitaxel (ORadj 7.2, 95%CI 2.5−21.1) and severe CIPN. Conclusions: Patients with the GG-genotype (rs879207) of TRPV1 have an almost 5-fold higher risk of developing severe neuropathy when treated with platinum-based therapy. Future studies should aim to validate these findings in an independent cohort and to further investigated the individualization of platinum-based chemotherapy in clinical practice.

Introduction: Multimorbidity and polypharmacy are risk factors for drug-related hospital admissions (DRAs) in the ageing population. DRAs caused by medication errors (MEs) are considered potentially preventable. The STOPP/START criteria were developed to detect potential MEs in older people., Objective: The aim of this study was to assess the detectability of MEs with a STOPP/START-based in-hospital medication review in older people with polypharmacy and multimorbidity prior to a potentially preventable DRA., Methods: Hospitalised older patients (n = 963) with polypharmacy and multimorbidity from the intervention arm of the OPERAM trial received a STOPP/START-based in-hospital medication review by a pharmacotherapy team. Readmissions within 1 year after the in-hospital medication review were adjudicated for drug-relatedness. A retrospective assessment was performed to determine whether MEs identified at the first DRA were detectable during the in-hospital medication review., Results: In total, 84 of 963 OPERAM intervention patients (8.7%) were readmitted with a potentially preventable DRA, of which 72 patients (n = 77 MEs) were eligible for analysis. About half (48%, n = 37/77) of the MEs were not present during the in-hospital medication review and therefore were not detectable at that time. The pharmacotherapy team recommended a change in medication regimen in 50% (n = 20/40) of present MEs, which corresponds to 26% (n = 20/77) of the total identified MEs at readmission. However, these recommendations were not implemented., Conclusion: MEs identified at readmission were not addressed by a prior single in-hospital medication review because either these MEs occurred after the medication review (~50%), or no recommendation was given during the medication review (~25%), or the recommendation was not implemented (~25%). Future research should focus on optimisation of the timing and frequency of medication review and the implementation of proposed medication recommendations., Registration: ClinicalTrials.gov identifier: NCT02986425. December 8, 2016., Funding: European Union HORIZON 2020, Swiss State Secretariat for Education, Research and Innovation (SERI), Swiss National Science Foundation (SNSF)., (© 2022. The Author(s).)

Purpose: Adverse drug reactions (ADRs) account for 10% of acute hospital admissions in older people, often under-recognised by physicians. The Dutch geriatric guideline recommends screening all acutely admitted older patients with polypharmacy with an ADR trigger tool comprising ten triggers and associated drugs frequently causing ADRs. This study investigated the performance of this tool and the recognition by usual care of ADRs detected with the tool., Methods: A cross-sectional study was performed in patients ≥ 70 years with polypharmacy acutely admitted to the geriatric ward of the University Medical Centre Utrecht. Electronic health records (EHRs) were screened for trigger-drug combinations listed in the ADR trigger tool. Two independent appraisers assessed causal probability with the WHO-UMC algorithm and screened EHRs for recognition of ADRs by attending physicians. Performance of the tool was defined as the positive predictive value (PPV) for ADRs with a possible, probable or certain causal relation., Results: In total, 941 trigger-drug combinations were present in 73% (n = 253/345) of the patients. The triggers fall, delirium, renal insufficiency and hyponatraemia covered 86% (n = 810/941) of all trigger-drug combinations. The overall PPV was 41.8% (n = 393/941), but the PPV for individual triggers was highly variable ranging from 0 to 100%. Usual care recognised the majority of ADRs (83.5%), increasing to 97.1% when restricted to possible and certain ADRs., Conclusion: The ADR trigger tool has predictive value; however, its implementation is unlikely to improve the detection of unrecognised ADRs in older patients acutely admitted to our geriatric ward. Future research is needed to investigate the tool's clinical value when applied to older patients acutely admitted to non-geriatric wards., (© 2022. The Author(s).)

Drug-drug interactions (DDIs) frequently trigger adverse drug events or reduced efficacy. Most DDI alerts, however, are overridden because of irrelevance for the specific patient. Basic DDI clinical decision support (CDS) systems offer limited possibilities for decreasing the number of irrelevant DDI alerts without missing relevant ones. Computerized decision tree rules were designed to context-dependently suppress irrelevant DDI alerts. A crossover study was performed to compare the clinical utility of contextualized and basic DDI management in hospitalized patients. First, a basic DDI-CDS system was used in clinical practice while contextualized DDI alerts were collected in the background. Next, this process was reversed. All medication orders (MOs) from hospitalized patients with at least one DDI alert were included. The following outcome measures were used to assess clinical utility: positive predictive value (PPV), negative predictive value (NPV), number of pharmacy interventions (PIs)/1,000 MOs, and the median time spent on DDI management/1,000 MOs. During the basic DDI management phase 1,919 MOs/day were included, triggering 220 DDI alerts/1,000 MOs; showing 57 basic DDI alerts/1,000 MOs to pharmacy staff; PPV was 2.8% with 1.6 PIs/1,000 MOs costing 37.2 minutes/1,000 MOs. No DDIs were missed by the contextualized CDS system (NPV 100%). During the contextualized DDI management phase 1,853 MOs/day were included, triggering 244 basic DDI alerts/1,000 MOs, showing 9.6 contextualized DDIs/1,000 MOs to pharmacy staff; PPV was 41.4% (P < 0.01), with 4.0 PIs/1,000 MOs (P < 0.01) and 13.7 minutes/1,000 MOs. The clinical utility of contextualized DDI management exceeds that of basic DDI management., (© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Redispensing medication unused by patients to other patients could reduce the environmental burden of medication waste. Simultaneously, associated financial loss could be reduced, particularly for expensive medication such as oral anticancer drugs. An important determinant for successful medication redispensing is patient participation., Objective(s): To identify key factors underlying the willingness of patients with cancer to participate in the redispensing of unused oral anticancer drugs., Methods: Semi-structured interviews via telephone or video call were conducted with adult patients diagnosed with cancer from two Dutch hospitals. The interview guide was framed using the COM-B model for behavioural change, to elicit patients' capability, opportunity and motivation to participate in medication redispensing. Questions were related to patients' willingness to accept redispensed medication, reasons thereof, perceived concerns and needs. Inductive thematic analysis was applied., Results: Seventeen patients (aged 38-82 years, 71% female), with nine different types of cancer participated. The majority of participants supported medication redispensing. Four categories of key factors underlying the willingness of patients with cancer to participate in medication redispensing were identified. First, the driver for participation was having positive societal impact, relating to affordability and sustainability of healthcare. Second, having trust in product quality was a requirement, influenced by preconceived beliefs, quality assurance and patients' knowledge of this process. Third, a facilitator for participating in medication redispensing was adequate provision of information. This concerned awareness of medication waste, information about medication redispensing, support from healthcare providers and other patients, and insight into medication dispensing history. Last, a convenient process for returning unused medication to pharmacies would facilitate participation in medication redispensing., Conclusions: The willingness of patients with cancer to participate in medication redispensing relates to a drive for achieving positive societal impact, provided that medication is of high quality, there is adequate information provision and a convenient process., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Emicizumab is a new treatment option for people with hemophilia A. Emicizumab was approved with a body-weight-based dosage regimen, without laboratory monitoring requirements. Guidelines, however, recommend measuring emicizumab concentrations when the presence of antidrug antibodies is suspected. Furthermore, drug monitoring can be useful in clinical decision making, in adherence checking, and for research purposes. Therefore, we developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying emicizumab. We performed a validation study on this LC-MS/MS method quantifying emicizumab in the plasma of people with hemophilia A., Methods: Sample preparation for LC-MS/MS analysis included ammonium sulfate protein precipitation and trypsin digestion. A signature peptide of emicizumab and a matching stable isotope-labeled internal standard were used to quantify emicizumab by LC-MS/MS analysis. Validation was performed in accordance with the "Guideline on Bioanalytical Method Validation" of the European Medicines Agency (EMA). The LC-MS/MS method was cross validated against a modified and calibrated ( r 2 Diagnostics) one-stage clotting assay (OSA)., Conclusions: The LC-MS/MS method demonstrated linearity over a wide range of emicizumab concentrations, far exceeding the concentrations observed in people with hemophilia A. Precision and accuracy were excellent, and all other validation parameters were also within the acceptance EMA criteria. Cross validation showed that the LC-MS/MS method and the OSA-based method can be used interchangeably for drug monitoring of emicizumab without the application of a correction factor., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background: Chemotherapy-induced toxicities frequently occur in non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy. Low skeletal muscle mass (SMM) has been associated with a higher incidence of toxicities for several types of cancers and cytostatics. The aim of this study was to evaluate the association between skeletal muscle measures and chemotherapy-induced toxicity in a large cohort of NSCLC patients., Methods: A multicentre prospective follow-up study (PGxLUNG, NTR number NL5373610015) in NSCLC patients was conducted. Included were patients diagnosed with NSCLC (stage II-IV) treated with first-line platinum-based (cisplatin or carboplatin) chemotherapy of whom pretreatment imaging was available. Skeletal muscle area (SMA) segmentation was performed on abdominal imaging at the level of the third lumbar vertebra (L3). SMA at the level of L3 was corrected for squared height (m 2 ) to yield the lumbar skeletal muscle mass index (LSMI). Skeletal muscle density (SMD) was calculated as the mean Hounsfield Unit (HU) of the segmented SMA. SMM and SMD were categorized as low, intermediate, and high, based on LSMI and mean HU tertiles, respectively. Chemotherapy-induced toxicity was scored using CTCAE v4.03 and categorized into haematological (anaemia, leukocytopenia, neutropenia, and thrombocytopenia), non-haematological (nephrotoxicity, neurotoxicity, and esophagitis), and dose-limiting toxicity (DLT) (treatment switch, delay, de-escalation, discontinuation, or hospitalization). The relationship between SMM, SMD, and toxicities was assessed with logistic regression modelling taking into account potential confounders like gender and body mass index (BMI)., Results: In total, 297 patients (male n = 167, median age 64 years) were included. Haematological toxicity grade 3/4 was experienced in 36.6% (n = 108) of the patients, 24.6% (n = 73) experienced any non-haematological toxicity grade ≥2, and 55.6% (n = 165) any DLT. Multivariate logistic regression analysis showed that low SMM (ORadj 2.41, 95% CI 1.31-4.45, P = 0.005) and age at diagnosis >65 years (ORadj 1.76, 95% CI 1.07-2.90, P = 0.025) were statistically significantly associated with overall haematological toxicity grade 3/4. No statistically significant associations were found between low SMM or low SMD and non-haematological toxicities. Low SMM (ORadj 2.23, 95% CI 1.23-4.04, P = 0.008) and high SMD (ORadj 0.41, 95% CI 0.23-0.74, P = 0.003) were statistically significantly associated with a higher respectively lower risk of DLT., Conclusions: Non-small cell lung cancer patients with pretreatment low SMM are at significant higher risk for haematological toxicities grade 3/4 and DLT. NSCLC patients with high SMD are at significant lower risk for DLT. Further studies should be aimed to investigate whether platinum dosing based on skeletal muscle measurements and/or improvement of pretreatment SMM/SMD could reduce the risk of toxicity without compromising efficacy., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background: Dopamine receptor agonist drugs, which are used, for example, to treat Parkinson's disease (PD), increase the risk for impulse control disorders (ICDs), potentially resulting in devastating psychosocial consequences. It is unknown whether other drugs with dopaminergic properties also increase the risk for ICDs. This study assesses the disproportionality of reporting ICDs between drugs with dopaminergic properties and selected non-dopaminergic drugs., Methods: A case/non-case disproportionality analysis was performed, using data from VigiBase (1968-2020). Reports on ICDs as suspected adverse drug reactions (ADRs) were cases (n=852), and those with ADRs other than ICDs were non-cases (n=281,720). Relative reporting frequencies were expressed as adjusted reporting odds ratios (aRORs). Within the dopamine receptor agonists, the relationship between reporting odds ratios and dopamine receptor occupancy was explored., Results: A high disproportionality was found for reporting ICDs for all dopaminergic drugs (aROR 20.4 [95% CI 17.4-24.1]) compared to non-dopaminergic drugs. In pharmacotherapeutic subgroups, a high disproportionality was found for primary dopaminergic agents used in PD (aROR 52.1 [95% CI 44.1-61.5]), and to a lesser extent for ADHD psychostimulants and antidepressants (aROR 5.8 [95% 4.1-8.3] and aROR 3.9 [95% CI 2.9-5.6], respectively). There was no difference in reporting by consumers and healthcare professionals. The highest disproportionality was found for the dopamine receptor agonists pramipexole and ropinirole., Conclusions: A signal of disproportion in ICD occurrence was found among all investigated drugs with dopaminergic properties, highlighting the importance of counselling and monitoring for ICDs when prescribing dopaminergic drugs., Competing Interests: Declaration of Competing Interest drs. L.E. De Wit has nothing to disclose, dr. I. Wilting has nothing to disclose, dr. P.C. Souverein has nothing to disclose, dr. P. van der Pol has nothing to disclose, prof.dr. A.C.G. Egberts has nothing to disclose, (Copyright © 2022. Published by Elsevier B.V.)

Intravenous busulfan is widely used as part of myeloablative conditioning regimens in children and young adults undergoing allogeneic hematopoietic cell transplantation (HCT). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious clinical problem observed with busulfan-based conditioning HCT. The development of VOD/SOS may be associated with busulfan exposure. Getting more insight into the association between busulfan exposure and the development of VOD/SOS enables further optimization of dosing and treatment strategies. The objective of this study was to assess the association between the magnitude of busulfan exposure and the occurrence of VOD/SOS in children and young adults undergoing myeloablative conditioning with a busulfan-containing regimen before allogeneic HCT. In this observational study we included all patients who underwent allogeneic HCT with intravenous busulfan as part of the conditioning regimen at 15 pediatric transplantation centers between 2000 and 2015. The endpoint was the development of VOD/SOS. The magnitude of busulfan exposure was estimated using nonlinear mixed effect modeling and expressed as the maximal concentration (Cmax; day 1 and day 1 to 4 Cmax), cumulative area under the curve (AUC; day 1, highest 1-day AUC in 4 days, and 4-day cumulative AUC), cumulative time above a concentration of 300 µg/L, and clearance on day 1. A total of 88 out of 697 patients (12.6%) developed VOD/SOS. The number of alkylators in the conditioning regimen was a strong effect modifier; therefore we stratified the regression analysis for the number of alkylators. For patients receiving only busulfan as one alkylator (36.3%, n = 253), cumulative busulfan exposure (>78 mg × h/L) was associated with increased VOD/SOS risk (12.6% versus 4.7%; odds ratio [OR] = 2.95, 95% confidence interval [CI] 1.13 to 7.66). For individuals receiving busulfan with one or two additional alkylators (63.7%, n = 444), cumulative busulfan exposure (≤78 and >78 mg × h/L) did not further increase the risk of VOD/SOS (15.4% versus 15.2%; OR = 1.03, 95% CI 0.61 to 1.75). The effect of the magnitude of busulfan exposure on VOD/SOS risk in children and young adults undergoing HCT is dependent on the number of alkylators. In patients receiving busulfan as the only alkylator, higher cumulative busulfan exposure increased the risk of VOD/SOS, whereas in those receiving multiple alkylators, the magnitude of busulfan exposure did not further increase this risk., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

What Is Known and Objective: Paediatric intensive care patients are at high risk for prescription errors due to the more complex process of medication prescribing. Clinical decision support systems (CDSS) have shown good results in effectively reducing prescription errors. A specific dosing CDSS was developed that can check and suggest normal dose, dose limits and administration frequencies. This study aimed to assess the effect of this CDSS on protocol deviation (as measure of prescription error) types and frequency in a paediatric intensive care unit (PICU)., Methods: A retrospective observational study was conducted evaluating 9342 prescriptions in a 4-month period before and after the implementation of a CDSS in the PICU of the University Medical Center Utrecht. Medication forms were reviewed to identify protocol deviations (and therefore possible prescription errors). The incidence and nature of deviations from evidence-based protocols that were unintended and needed to be adjusted, were determined., Results and Discussion: In the period before the dosing CDSS, we identified 45 protocol deviations in 5034 prescriptions (0.89%), 28 of which could not be justified (0.56%) and 11 needed to be adjusted (0.22%). In the period after the implementation of the CDSS, there were 21 protocol deviations in 4308 prescriptions (0.49%) of which ten without a valid reason (0.23%) of which two were adjusted (0.05%)., What Is New and Conclusion: The specific dosing CDSS was able to significantly reduce unintentional prescription dose deviations and the number of prescriptions that needed to be adjusted, in an existing low incidence situation., (© 2021 The Authors. Journal of Clinical Pharmacy and Therapeutics published by John Wiley & Sons Ltd.)

Objective: The aim of the study was to assess monitoring of adverse drug reaction (ADR)-related parameters in children, youth, and young adults treated with second-generation antipsychotic drugs (SGAs) prescribed by general practitioners (GPs). Methods: This retrospective follow-up study included children, youth, and young adults aged 0 - 24 years, who had an initial prescription of an SGA recorded in the Clinical Practice Research Datalink between 2000 and 2017, and who were prescribed an SGA more than once for a duration of at least 6 months. It included an assessment of which ADR-related physical parameters (weight, height, body-mass index, waist circumference, pulse, blood pressure, and heart examination) and laboratory parameters (glucose, HbA1c, lipids, and prolactin) were monitored in children, youth, and young adults at least once every 6-month period, stratified by sex, age categories, and calendar years. Results: In total, 7006 patients were included and the mean duration of follow-up was 1.6 years. Monitoring frequencies of all parameters were below 25%. Blood pressure and weight were monitored in 23.6% and 23.4%, respectively, of all children, youth, and young adults during the first half year; waist circumference was monitored in 0.2%. Females were monitored more often than males, some differences between age categories were observed, and monitoring frequencies increased after 2000, but did not exceed 35% in any year. Conclusion: Monitoring frequencies of ADR-related parameters in children, youth, and young adults treated with SGAs prescribed by a GP were low. Monitoring in primary care should be improved to enable a better evaluation of the benefit-risk balance during antipsychotic drug therapy.

Background: The Screening Tool of Older Persons' Prescriptions (STOPP)/Screening Tool to Alert to Right Treatment (START) instrument is used to evaluate the appropriateness of medication in older people. STOPP/START criteria have been converted into software algorithms and implemented in a clinical decision support system (CDSS) to facilitate their use in clinical practice., Objective: Our objective was to determine the frequency of CDSS-generated STOPP/START signals and their subsequent acceptance by a pharmacotherapy team in a hospital setting., Design and Methods: Hospitalised older patients with polypharmacy and multimorbidity allocated to the intervention arm of the OPERAM (OPtimising thERapy to prevent Avoidable hospital admissions in the Multimorbid elderly) trial underwent a CDSS-assisted structured medication review in four European hospitals. We evaluated the frequency of CDSS-generated STOPP/START signals and the subsequent acceptance of these signals by a trained pharmacotherapy team consisting of a physician and pharmacist after evaluation of clinical applicability to the individual patient, prior to discussing pharmacotherapy optimisation recommendations with the patient and attending physicians. Multivariate linear regression analysis was used to investigate potential patient-related (e.g. age, number of co-morbidities and medications) and setting-related (e.g. ward type, country of inclusion) determinants for acceptance of STOPP and START signals., Results: In 819/826 (99%) of the patients, at least one STOPP/START signal was generated using a set of 110 algorithms based on STOPP/START v2 criteria. Overall, 39% of the 5080 signals were accepted by the pharmacotherapy team. There was a high variability in the frequency and the subsequent acceptance of the individual STOPP/START criteria. The acceptance ranged from 2.5 to 75.8% for the top ten most frequently generated STOPP and START signals. The signal to stop a drug without a clinical indication was most frequently generated (28%), with more than half of the signals accepted (54%). No difference in mean acceptance of STOPP versus START signals was found. In multivariate analysis, most patient-related determinants did not predict acceptance, although the acceptance of START signals increased in patients with one or more hospital admissions (+ 7.9; 95% confidence interval [CI] 1.6-14.1) or one or more falls in the previous year (+ 7.1; 95% CI 0.7-13.4). A higher number of co-morbidities was associated with lower acceptance of STOPP (- 11.8%; 95% CI - 19.2 to - 4.5) and START (- 11.0%; 95% CI - 19.4 to - 2.6) signals for patients with more than nine and between seven and nine co-morbidities, respectively. For setting-related determinants, the acceptance differed significantly between the participating trial sites. Compared with Switzerland, the acceptance was higher in Ireland (STOPP: + 26.8%; 95% CI 16.8-36.7; START: + 31.1%; 95% CI 18.2-44.0) and in the Netherlands (STOPP: + 14.7%; 95% CI 7.8-21.7). Admission to a surgical ward was positively associated with acceptance of STOPP signals (+ 10.3%; 95% CI 3.8-16.8)., Conclusion: The involvement of an expert team in translating population-based CDSS signals to individual patients is essential, as more than half of the signals for potential overuse, underuse, and misuse were not deemed clinically appropriate in a hospital setting. Patient-related potential determinants were poor predictors of acceptance. Future research investigating factors that affect patients' and physicians' agreement with medication changes recommended by expert teams may provide further insight for implementation in clinical practice., Registration: ClinicalTrials.gov Identifier: NCT02986425., (© 2021. The Author(s).)

Background: Anticholinergic acting drugs have been associated with delirium in older patients., Objective: To examine the association between the anticholinergic burden (ACB) and the duration and severity of delirium in older hip-surgery patients with or without haloperidol prophylaxis., Methods: Older patients with a postoperative delirium following hip surgery from a randomized controlled trial investigating the effects of haloperidol prophylaxis on delirium incidence were included in this study. The ACB was quantified using two different tools, the Anticholinergic Drug Scale and an Expert Panel. Using linear regression, the association between the ACB and delirium was analyzed., Results: Overall delirium duration and severity were not significantly associated with the ACB. Also, no statistically significant differences were found in delirium duration or severity between the placebo and haloperidol treatment groups for the ACB groups. The protective effect of haloperidol on delirium duration and severity however tended to be present in patients with no or a low ACB but not or to a lesser extent in patients with an intermediate to high ACB., Conclusions: The ACB was not significantly associated with delirium duration or severity. Haloperidol prophylaxis tended to shorten delirium duration and decrease delirium severity in patients with no or a low ACB. To further explore the influence of anticholinergic acting drugs on delirium duration and severity and the effect of concomitant haloperidol use, additional research with a higher haloperidol dose, a larger study population, and ACB quantification taking drug exposure into account is warranted., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

This study aims to evaluate genetic risk factors for cisplatin-induced nephrotoxicity by investigating not previously studied genetic risk variants and further examining previously reported genetic associations. A genome-wide study (GWAS) was conducted in genetically estimated Europeans in a discovery cohort of cisplatin-treated adults from Toronto, Canada, followed by a candidate gene approach in a validation cohort from the Netherlands. In addition, previously reported genetic associations were further examined in both the discovery and validation cohorts. The outcome, nephrotoxicity, was assessed in two ways: (i) decreased estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) and (ii) increased serum creatinine according to the Common Terminology Criteria for Adverse Events v4.03 for acute kidney injury (AKI-CTCAE). Four different Illumina arrays were used for genotyping. Standard quality control was applied for pre- and post-genotype imputation data. In the discovery cohort ( n = 608), five single-nucleotide polymorphisms (SNPs) reached genome-wide significance. The A allele in rs4388268 (minor allele frequency = 0.23), an intronic variant of the BACH2 gene, was consistently associated with increased risk of cisplatin-induced nephrotoxicity in both definitions, meeting genome-wide significance (β = -8.4, 95% CI -11.4--5.4, p = 3.9 × 10 -8 ) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3-6.7, p = 7.4 × 10 -7 ) by AKI-CTCAE. In the validation cohort of 149 patients, this variant was identified with the same direction of effect (eGFR: β = -1.5, 95% CI -5.3-2.4, AKI-CTCAE: OR = 1.7, 95% CI 0.8-3.5). Findings of our previously published candidate gene study could not be confirmed after correction for multiple testing. Genetic predisposition of BACH2 (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies.

Background: Patients in clinical practice are transitioned from originator etanercept (OR-ETA) to biosimilar etanercept (BS-ETA), but some subsequently retransition. Insights into the incidence of and reasons for retransitioning and the characteristics of these patients could help clinicians successfully introduce biosimilars., Objective: Our objective was to assess the incidence of and reasons for retransitioning from BS-ETA to OR-ETA in patients with a rheumatic disease (RD) and to explore the determinants thereof., Methods: This cohort study included all patients with RD who had transitioned from OR-ETA to BS-ETA in a large hospital in the Netherlands in 2016. The incidence of retransitioning to OR-ETA and the 1-year persistence with BS-ETA were assessed using the Kaplan-Meier estimator. Reasons for retransitioning were classified as related to (1) efficacy, (2) adverse events, (3) the administration device, and (4) other. Determinants for retransitioning, including baseline and treatment characteristics, were assessed in a nested case-control study using conditional logistic regression., Results: We included 342 patients (median age 57.8 years; 53.5% females). At 1 year after transitioning, 9.4% of patients had retransitioned to OR-ETA and 69.7% were persistent with BS-ETA. At the end of follow-up (median 4.4 years), 47 patients (13.7%) had retransitioned to OR-ETA. The median time until retransitioning was 0.55 years (interquartile range 0.2-1.3). Most patients (n = 34 [72.3%]) retransitioned because of a (perceived) loss of effect, followed by adverse events (23.4%). In total 3.8% of patients switched to another biological treatment or a Janus kinase inhibitor; 17.1% of patients discontinued BS-ETA without retransitioning or switching within the first year. Univariate determinants for retransitioning included initiating corticosteroids or intensifying immunomodulator treatment (odds ratio [OR] 2.37; 95% confidence interval [CI] 1.03-5.45) and the number of visits to the rheumatology department (OR 2.06; 95% CI 1.55-2.74). In the multivariate analysis, only the number of visits to the rheumatology department remained significantly associated with retransitioning (OR 2.19; 95% CI 1.60-3.01)., Conclusion: When introducing a biosimilar in clinical care, clinicians should anticipate that one in seven patients will retransition to the originator. A (perceived) loss of effect was the most frequently reported reason for retransitioning. Patients who visited the rheumatology department more frequently had an increased risk of retransitioning, which is likely to be related to patients reporting a loss of effect and to adverse events resulting in more visits to the rheumatology department., (© 2021. The Author(s).)