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Aims: To evaluate the experience with use of sotrovimab following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in high-risk groups.Methods: In a nationwide, population-based cohort study, we identified all individuals treated with sotrovimab (N = 2933) and stratified them by 4 high-risk groups: (A) malignant haematological disease, (B) solid organ transplantation, (C) anti-CD20 therapy ≤1 year and (D) other risks. Cox regression analysis was used to calculate hazard ratios for hospitalization, death and associated prognostic factors.Results: Of 2933 sotrovimab-treated individuals, 83% belonged to high-risk groups (37.6% haematological malignancy, 27.4% solid organ transplantation and 17.5% treatment with anti-CD20 ≤1 year). Only 17.8% had other risks (11.8% were pregnant, 10.7% primary immunodeficiency, 21.2% other malignancy, 4.3% received anti-CD20 >1 year and 52.0% other/unknown causes). Within 90 days of infusion, 30.2% were hospitalized and 5.3% died. The main prognostic factors were the predefined high-risk groups, mainly malignant haematological disease and age ≥65 years. Number of COVID-19 vaccines (≥3) was associated with a decreased risk of hospitalization. The Delta but not the Omicron BA.2 variant was associated with a higher risk of death compared to the BA.1 variant.Conclusion: More than 90% of the patients treated with sotrovimab belonged to the very high-risk groups as described in the Danish guidelines. Sotrovimab-treated individuals remained at a high risk of hospitalization and death which was strongly associated with the underlying immunocompromised state and age. Having received >3 COVID-19 vaccines was association with decreased risk of death and hospitalization. Aims: To evaluate the experience with use of sotrovimab following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in high-risk groups.Methods: In a nationwide, population-based cohort study, we identified all individuals treated with sotrovimab (N = 2933) and stratified them by 4 high-risk groups: (A) malignant haematological disease, (B) solid organ transplantation, (C) anti-CD20 therapy ≤1 year and (D) other risks. Cox regression analysis was used to calculate hazard ratios for hospitalization, death and associated prognostic factors.Results: Of 2933 sotrovimab-treated individuals, 83% belonged to high-risk groups (37.6% haematological malignancy, 27.4% solid organ transplantation and 17.5% treatment with anti-CD20 ≤1 year). Only 17.8% had other risks (11.8% were pregnant, 10.7% primary immunodeficiency, 21.2% other malignancy, 4.3% received anti-CD20 >1 year and 52.0% other/unknown causes). Within 90 days of infusion, 30.2% were hospitalized and 5.3% died. The main prognostic factors were the predefined high-risk groups, mainly malignant haematological disease and age ≥65 years. Number of COVID-19 vaccines (≥3) was associated with a decreased risk of hospitalization. The Delta but not the Omicron BA.2 variant was associated with a higher risk of death compared to the BA.1 variant.Conclusion: More than 90% of the patients treated with sotrovimab belonged to the very high-risk groups as described in the Danish guidelines. Sotrovimab-treated individuals remained at a high risk of hospitalization and death which was strongly associated with the underlying immunocompromised state and age. Having received >3 COVID-19 vaccines was association with decreased risk of death and hospitalization.

Objective: Cardiovascular complications and congenital malformations are known traits in Turner syndrome (TS), which increases mortality. Women with TS have varying phenotype and cardiovascular risks. A biomarker assessing the risk for cardiovascular complications could potentially reduce mortality in high-risk TS and reduce screening in TS participants with low cardiovascular risk.Design, patients, participants and measurements: As part of a study initiated in 2002, 87 TS participants and 64 controls were invited to magnetic resonance imaging of the aorta, anthropometry, and biochemical markers. TS participants were re-examined thrice lastly in 2016. The focus of this paper is the additional measurements of transforming growth factor beta (TGFβ), matrix metalloproteinase (MMP's), tissue inhibitor of matrix metalloproteinase (TIMP), peripheral blood DNA and their associations with TS and the cardiovascular risk and congenital heart disease.Results: TS participants had lower TGFβ1 and TGFβ2 values compared to controls. snp11547635 heterozygosity was not associated with any biomarkers but was associated with increased risk of aortic regurgitation. TIMP4 and TGFβ1 were correlated with the aortic diameter at several measuring positions. During follow-up, the antihypertensive treatment decreased the descending aortic diameter and increased TGFβ1 and TGFβ2 levels in TS.Conclusion: TGFβ and TIMP's are altered in TS and may play a role in the development of coarctation and dilated aorta. snp11547635 heterozygosity was not found to impact biochemical markers. Further studies should investigate these biomarkers to further unravel the pathogenesis of the increased cardiovascular risk in TS participants. Background: The combined effectiveness of remdesivir and dexamethasone in subgroups of hospitalised patients with COVID-19 is poorly investigated. Methods: In this nationwide retrospective cohort study, we included 3826 patients with COVID-19 hospitalised between February 2020 and April 2021. The primary outcomes were use of invasive mechanical ventilation and 30-day mortality, comparing a cohort treated with remdesivir and dexamethasone with a previous cohort treated without remdesivir and dexamethasone. We used inverse probability of treatment weighting logistic regression to assess associations with progression to invasive mechanical ventilation and 30-day mortality between the two cohorts. The analyses were conducted overall and by subgroups based on patient characteristics. Results: Odds ratio for progression to invasive mechanical ventilation and 30-day mortality in individuals treated with remdesivir and dexamethasone compared to treatment with standard of care alone was 0.46 (95% confidence interval, 0.37–0.57) and 0.47 (95% confidence interval, 0.39–0.56), respectively. The reduced risk of mortality was observed in elderly patients, overweight patients and in patients requiring supplemental oxygen at admission, regardless of sex, comorbidities and symptom duration. Conclusions: Patients treated with remdesivir and dexamethasone had significantly improved outcomes compared to patients treated with standard of care alone. These effects were observed in most patient subgroups.

Inhaled corticosteroid (ICS) in patients with chronic obstructive pulmonary disease (COPD) has been debated for 20 years. In our systematic literature review and meta-analysis, we addressed the following: Should patients with COPD and a blood eosinophil count (EOS) of, respectively, a) < 150 cells/μl, b) 150–300 cells/μl, and c) > 300 cells/μl continue treatment with ICS? Protocol registered in PROSPERO (CRD42020178110) and funded by the Danish Health Authority. We searched Medline, Embase, CINAHL and Cochrane Central on 22nd July 2020 for randomized controlled trials (RCT) of ICS treatment in patients with COPD (≥40 years, no current asthma), which analyzed outcomes by EOS count and where >50% of patients used ICS prior. We used the GRADE method. Meta-analyzes for the outcomes were divided into EOS subgroups and analyzed for differences. We identified 11 RCTs with a total of 29,654 patients. A significant difference (p < 0.00001) between the three subgroups’ reduction of risk of moderate to severe exacerbation was found. Rate ratios for EOS counts: 300 cells/μL was 0.57 (95%CI: 0.49, 0.66). Overall, the certainty of the effect estimates was low to very low due to risk of bias, unexplained heterogeneity, few RCTs, and wide confidence intervals. A clear correlation was demonstrated between effect of continued ICS treatment (number of exacerbations, lung function, and quality of life) and increasing EOS count. Our meta-analyses suggested that treatment with ICS seemed beneficial for everyone except patients with EOS count below 150 cells/μl.

Discontinuation of diabetes medication in the last years of life has been suggested to improve quality of life while deemed safe to implement. However, the extent, patterns, and secular changes in discontinuation of glucose-lowering medication in older people with type 2 diabetes have been scarcely described. We therefore aimed to describe the trends in the use of glucose-lowering medication during the last 10 years of life of older people and explore how key clinical and socioeconomic covariates are associated with these patterns.In this register-based cohort study, all individuals with type 2 diabetes who died aged 80 years or older between Jan 1, 2006, and Dec 31, 2018, were identified through the Danish Diabetes Register and linked to the Danish National Prescription Registry. We followed the population backwards in time from death to date of last medication intake. To estimate the cumulative proportion of people on glucose-lowering medication, a Poisson regression model for the rate of medication as a function of time before death (0 to 10 years before death) and calendar year of death (2006-18) was fitted. Both single-substance and combination glucose-lowering medications were included and categorised as insulins, sulfonylureas, metformin, DPP-4 inhibitors, GLP-1 analogues, SGLT2 inhibitors, acarbose, and thiazolidinediones. Insulin was further subdivided into four groups: fast-acting, intermediate-acting, long-acting, and mixed insulin. To identify which covariates were associated with discontinuation, estimates were adjusted for sex, age at death, diabetes duration at time of death, the total number of diabetes complications at time of death (from no complications to four or more), level of education, immigrant status, and income quartile.52 523 individuals (28 746 [54·7%] females and 23 777 [45·3%] males) were identified, with a mean age at type 2 diabetes diagnosis of 77 years (SD 8), median age at death of 86 years (IQR 83-90), and median diabetes duration at death of 9 years (IQR 5-14). We found a considerable discontinuation of glucose-lowering medication during the last 10 years of life, with the proportion of people on glucose-lowering medication starting at between 89% (95% CI 87-91) in 2006 and 87% (86-88) in 2018 at 10 years before death and decreasing to between 52% (50-54) in 2006 and 38% (37-39) in 2018 at the time of death. Specifically, we found that the proportion of people on sulfonylureas, at any time before death, decreased substantially from 2006 to 2018, whereas the proportion on metformin and DPP-4 inhibitors increased with calendar year of death. Changes were less pronounced for the remaining medications. The overall discontinuation patterns changed with increasing calendar year of death, such that discontinuation rates increased and occurred earlier (further away from time of death) with increasing calendar year. Discontinuations were generally more pronounced during the last year of life. Proportions of people on medication and patterns of discontinuation, as well as the association with covariates, varied with medication class. Covariates most frequently associated with changes in discontinuation rates were sex, age at death, type 2 diabetes duration at death, and number of complications. For example, females were less likely to receive metformin than males at all years before death (rate ratio 0·91 (95% CI 0·89-0·94, p0·0001), and there was a negative association between the proportion of individuals on metformin and increasing age at death (rate ratio per year increase 0·96 [0·96-0·96], p0·0001) and type 2 diabetes duration (0·95 per year increase [0·94-0·95], p0·0001).Our results suggest that increased focus on and implementation of discontinuation of glucose-lowering medication in recent years might have had an effect on discontinuation patterns, particularly during the last year of life.None.

In the elderly population with type 2 diabetes (T2D), decisions about discontinuation of medication is important, as it may lead to improved outcomes and reduced polypharmacy-associated adverse events. However, the extent, patterns and secular changes of discontinuation of cardioprotective medication during the last years of life have been scarcely described. All individuals with T2D that died at age ≥ 80, between 2006-2018 were identified through the Danish Diabetes Register and linked to the Register of Medicinal Products Statistics. The population was followed backward in time, from death to date of last intake of cardioprotective medication. To estimate the cumulative proportion on different medication classes, we fitted a crude Poisson regression model for the rate of medication with time before death. A total of 52,523 persons (55% female) were identified, with a mean (SD) age at T2D diagnosis of 77 (8) years, a median (Q1-Q3) age at death of 86 (83-90) years and a median (Q1-Q3) diabetes duration at death of 9 (5-14) years. From year of death in 2006 to 2018, we found an increased utilization of antihypertensive and lipid-lowering medication, during the last 10 years of life, while the opposite was true for aspirin (ASA) (Figure 1). We also found a simultaneous increase in discontinuation rates during the last years of life, which was particularly pronounced during the last year of life. Disclosure V. Kosjerina: None. B. Carstensen: Stock/Shareholder; Self; Novo Nordisk. M. E. Jorgensen: Research Support; Self; Boehringer Ingelheim International GmbH, Sanofi-Aventis, Stock/Shareholder; Self; Novo Nordisk A/S. B. Brock: None. H. Christensen: None. J. Rungby: None. G. S. Andersen: Stock/Shareholder; Self; Novo Nordisk A/S.

Background There are limited data on outcomes of moderate to severe coronavirus disease 2019 (COVID-19) among patients treated with remdesivir and dexamethasone in a real-world setting. We sought to compare the effectiveness of standard of care (SOC) alone versus SOC plus remdesivir and dexamethasone. Methods Two population-based nationwide cohorts of individuals hospitalized with COVID-19 during February through December 2020 were studied. Death within 30 days and need of mechanical ventilation (MV) were compared by inverse probability of treatment weighted (ITPW) logistic regression analysis and shown as odds ratio (OR) with 95% confidence interval (CI). Results The 30-days mortality rate of 1694 individuals treated with remdesivir and dexamethasone in addition to SOC was 12.6% compared to 19.7% for 1053 individuals receiving SOC alone. This corresponded to a weighted OR of 30-day mortality of 0.47 (95% CI: .38–.57) for patients treated with remdesivir and dexamethasone compared to patients receiving SOC alone. Similarly, progression to MV was reduced (OR 0.36; 95% CI: .29–.46). Conclusions Treatment of moderate to severe COVID-19 during June through December that included remdesivir and dexamethasone was associated with reduced 30-day mortality and need of MV compared to treatment in February through May., Treatment of moderate to severe coronavirus disease 2019 (COVID-19) with remdesivir and dexamethasone was associated with a lower risk of mechanical ventilation and a significant better overall 30-day survival as compared to standard care alone.

This study describes the nationwide shift from brand-name adalimumab (originator) to adalimumab biosimilars in Denmark and analyzes what a similar shift in the US would look like.

Purpose A rapidly increasing use of biological drugs has led to substantial costs. Shift to biosimilars enables considerable reduction of these costs without jeopardizing the treatment of patients, but most countries have extensive possibilities of untappedcost-savings. The aim of this study was to describe the Danish quick and near-complete implementation of the two first TNF inhibitor biosimilars (infliximab and etanercept).Methods We shed light on the considerations and experiences made during the implementation, and present key figures from theimplementation.ResultsThe infliximab biosimilar constituted 90.6% of the total amount of infliximab four months following patent expiration of the biooriginator. Similar results were seen for etanercept biosimilar. Substantial cost reductions were experienced in the way that e.g. the infliximab-shift reduced cost by two thirds.Conclusion We believe that a thorough preparation and an organizational setting supporting the implementation is crucial for the successful implementation. This same implementation model will be used for future biosimilars. Purpose A rapidly increasing use of biological drugs has led to substantial costs. Shift to biosimilars enables considerable reduction of these costs without jeopardizing the treatment of patients, butmost countries have extensive possibilities of untapped cost-savings. The aim of this study was to describe the Danish quick and near-complete implementation of the two first TNFinhibitor biosimilars (infliximab and etanercept).Methods We shed light on the considerations and experiences made during the implementation, and present key figures from the implementation.Results The infliximab biosimilar constituted 90.6%of the total amount of infliximab fourmonths following patent expiration of the biooriginator. Similar results were seen for etanercept biosimilar. Substantial cost reductions were experienced in the way that e.g. the infliximab-shift reduced cost by two thirds.Conclusion We believe that a thorough preparation and an organizational setting supporting the implementation is crucial for the successful implementation. This same implementation model will be used for future biosimilars.

Midazolam is a first-line drug for the treatment of status epilepticus, both by buccal and intravenous administration. In children and adolescents with obesity, midazolam pharmacokinetics may be altered, and the current dosing guidelines may therefore be insufficient. The objective of this study was to investigate the pharmacokinetics of midazolam, after intravenous administration, in obese and non-obese adolescents aged 11–18 years. All trial participants received a 1-µg midazolam microdose as an intravenous bolus. 13 blood samples were collected per participant at pre-specified timepoints. Plasma concentration–time data were fitted to pharmacokinetic models using non-linear mixed-effects modeling. Covariates such as weight, age, and body mass index standard deviation score were tested to explain the inter-individual variability associated with the pharmacokinetic parameters. Sixty-seven adolescents were included in the analysis. The pharmacokinetics of midazolam was best described with a two-compartment model. The rate of distribution was faster, and the peripheral volume of distribution was larger in adolescents with a high body mass index standard deviation score compared with adolescents with a lower standard deviation score. Simulations revealed that long-term infusions based on total body weight could lead to high plasma concentrations in adolescents with obesity. Furthermore, simulated plasma concentrations after a fixed buccal dose indicated that adolescents with obesity may be at risk of sub-therapeutic midazolam plasma concentrations. The body mass index standard deviation score was shown to have a significant influence on the peripheral volume of distribution and the inter-compartmental clearance of midazolam. The current dosing guidelines for status epilepticus, where the midazolam dose is adjusted to total body weight or age, may lead to supra- and sub-therapeutic plasma concentrations, respectively, in adolescents with obesity. EudraCT: 2014-004554-34.

AIMS To test the in vivo activity of Cytochrome P450 (CYP) 2E1 in obese children vs. nonobese children, aged 11-18 years. Secondly, whether the activity of CYP2E1 in these patients is associated with NALFD, diabetes or hyperlipidaemia. METHODS Seventy children were divided into groups by body mass index (BMI) standard deviation score (SDS). All children received 250 mg oral chlorzoxazone (CLZ) as probe for CYP2E1 activity. Thirteen blood samples and 20-h urine samples were collected per participant. RESULTS Obese children had an increased oral clearance and distribution of CLZ, indicating increased CYP2E1 activity, similar to obese adults. The mean AUC0-∞ value of CLZ was decreased by 46% in obese children compared to nonobese children. The F was was increased twofold in obese children compared to nonobese children, P

SUMMARYAim To describe the stepwise process towards creating two formulary lists – one for paediatric and one for neonatal patients covering common diseases in hospital settings. Methods This study presents the concept for developing a formulary list. How to: 1) organize the editorial board, 2) procure drug consumption data and database management, including information on labelling status, dosing options, excipients and problematic adverse events, current guidelines, evidence and price, 3) develop the first edition for the formulary list and formulary manual, 4) to establish a paediatric sub-committee within the Regional Drug and Therapeutic Committee to maintain and continually develop the two formularies. Results The total number of drugs was 411 ATC level 5, which covers 1097 unique item numbers prior to the paediatric formulary list, 263 item numbers were included in the final list. In neonates, 201 drugs ATC level 5 were evaluated covering 348 unique item numbers of which 104 item numbers were included in the final neonatal formulary list. Eighty-eight percent of the included drugs in the paediatric formulary were licensed to children (not specified by age group), 2% were unlicensed in Denmark and 7% were extemporaneous preparations. For neonates, the percentage was 48%, 4% and 16%, correspondingly. Conclusion The process is time consuming as studies are lacking and age appropriate dosage forms and concentrations differ amongst countries. Nevertheless, the process should be somewhat similar between countries albeit, different drugs may be selected for the final formulary lists.

Purpose The aim of this study was to identify structure and language elements affecting the quality of responses from Scandinavian drug information centres (DICs). Methods Six different fictitious drug-related queries were sent to each of seven Scandinavian DICs. The centres were blinded for which queries were part of the study. The responses were assessed qualitatively by six clinical pharmacologists (internal experts) and six general practitioners (GPs, external experts). In addition, linguistic aspects of the responses were evaluated by a plain language expert. Results The quality of responses was generally judged as satisfactory to good. Presenting specific advice and conclusions were considered to improve the quality of the responses. However, small nuances in language formulations could affect the individual judgments of the experts, e.g. on whether or not advice was given. Some experts preferred the use of primary sources to the use of secondary and tertiary sources. Both internal and external experts criticised the use of abbreviations, professional terminology and study findings that was left unexplained. The plain language expert emphasised the importance of defining and explaining pharmacological terms to ensure that enquirers understand the response as intended. In addition, more use of active voice and less compressed text structure would be desirable. Conclusions This evaluation of responses to DIC queries may give some indications on how to improve written responses on drug-related queries with respect to language and text structure. Giving specific advice and precise conclusions and avoiding too compressed language and non-standard abbreviations may aid to reach this goal. (c) The Author(s) 2017. This article is published with open access at Springerlink.com. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/)

Background The use of expensive biological drugs in rheumatology is rapidly increasing and has led to substantial increases in drug expenditures. A considerable reduction of drug costs is possible by using biosimilars as soon as they become available and carrying out non-medical shifts to biosimilars (i.e. switching a patient well treated on a biooriginator to the biosimilar). Research on biosimilars has focused on interchangeability and safety outcomes, but little focus has been on nationwide implementation and the direct economic consequences on drug expenses. In Denmark, TNF-inhibitors are solely given in an in-hospital setting and bought through national tenders. The Danish in-hospital organization includes Regional Drug and Therapeutics Committees that ensures regional implementation of treatment guidelines and close collaboration between hospital pharmacies and regional clinical pharmacologists. Furthermore, the implementation of TNF-inhibitor biosimilars was preceded by careful preparations from among others a newly established national biosimilar task force. Objectives The aim of this study was to describe the implementation of the two first TNF-inhibitor biosimilars (infliximab and etanercept) in Danish departments of rheumatology. Methods Monthly data on drug sales to Danish rheumatology departments were used to assess the biosimilar uptake rate and subsequent changes in the drug expenditures during the implementation in Denmark. Results Shifts to biosimilars were begun within a few months following end of biooriginator patent, vertical lines in the figure. Use of the infliximab biosimilar was begun in April 2015, and in August 2015 biosimilar uptake was 92.9% of total infliximab use. Similarly use of etanercept biosimilar was begun in April 2016, and in June 2016 the biosimilar uptake was 91.6% of total etanercept use. In January 2015 the total use in Defined Daily Doses (DDD) were 42.4 thousand DDD’s for infliximab and 37.3 thousand DDD’s for etanercept. The use increased steadily and was in January 2018 138.4 thousand DDD’s for infliximab and 62.1 thousand DDD’s for etanercept (equivalent to increases of 226.6% and 66.8%). The increases in DDD’s were not reflected in total drug costs due to the shift to biosimilars. The total drug cost for infliximab in January 2015 was 6.7 million DKK but was reduced to 5.4 million DKK in January 2018 (-19.4%). A corresponding cost reduction was seen for etanercept (11.3 million DKK in January 2015, 8.1 million DKK in January 2018, -28.7%). Conclusion Danish departments of rheumatology experienced a fast and near-complete switch of infliximab and etanercept biooriginators to biosimilars. At the same time the use of the drugs increased substantially, but due to large price reductions the total drug cost decreased despite the increasing use. We believe that a thorough preparation and an organizational setting supporting the implementation was crucial for the successful implementation. The Danish structure, with its national tendering, probably contributed to the substantial drug discounts obtained. The implementation will be used for future biosimilars in Denmark. Disclosure of Interests None declared

Aims: Registries on in-hospital drug use are sparse, especially those that can be linked to nationwide registries. In this study, we present and validate the Electronic Patient Medication module (EPM)—the electronic administrative database on in-hospital drug use covering the Capital Region of Denmark. Methods: The research database (EPM-research) is an adaptation of the database underlying the electronic administrative database for in-hospital drug use (EPM-clinic). The validation study was comprised of two sub-studies. Sub-study 1: Accordance of registration between EPM-clinic and EPM-research was investigated by analyzing randomly chosen retrospective patient records. Sub-study 2: Workflows and real-life registration practices were investigated through visits to three different (two medical and one emergency) departments. An observer followed a nurse while dispensing and administering drugs. This information was compared with EPM-research. The primary endpoint for both sub-studies was accordance of generic name between registrations. Secondary endpoints were exact brand name, dose, and time of each administration. Accordance (proportions) with 95% confidence intervals (CI) using the Clopper-Pearson method were calculated. The study was approved by the Danish Data Protection Agency (BFH-2016-058-04906) and the Danish Patient Safety Authority (3-3013-1884/1/). Results: In sub-study 1 227 retrospective drug administrations were reviewed. Accordance of generic name was 100.0% (CI 98.4%−100.0%). In sub-study 2 176 drug administrations were observed of which 173 were recorded with identical generic name, resulting in 98.3% (CI 95.1%-99.6%) accordance of data. Conclusions: Our validation of the EPM-research showed very high accordance. With detailed information on in-hospital drug use, the EPM-research may be a useful tool in pharmacoepidemiological research.

The aim of this study is to describe the stepwise process towards creating two formulary lists: one for paediatric and one for neonatal patients covering common diseases in hospital settings.This study presents the concept for developing a formulary list, namely how to: (1) organize the editorial board, (2) procure drug consumption data and database management, including information on labelling status, dosing options, excipients and problematic adverse events, current guidelines, evidence and price, (3) develop the first edition for the formulary list and formulary manual, and (4) to establish a paediatric sub-committee within the Regional Drug and Therapeutic Committee to maintain and continually develop the two formularies.The total number of drugs was 411 ATC level 5, which covers 1097 unique item numbers prior to the paediatric formulary list, of which 263 item numbers were included in the final list. In neonates, 201 drugs ATC level 5 were evaluated, covering 348 unique item numbers, of which 104 item numbers were included in the final neonatal formulary list. Eighty-eight percent of the included drugs in the paediatric formulary were licensed to children (not specified by age group), 2% were unlicensed in Denmark, and 7% were extemporaneous preparations. For neonates, the percentage was 48%, 4% and 16%, correspondingly.The process is time-consuming as studies are lacking and age-appropriate dosage forms and concentrations differ amongst countries. Nevertheless, the process should be somewhat similar between countries, albeit different drugs may be selected for the final formulary lists.

In some hospitals, clinical pharmacists review the medication to find drug-related problems (DRPs) in acutely admitted patients. We aimed to identify the nature of identified DRPs and investigate factors of potential importance for the clinical implementation of pharmacist suggestions. In 100 randomly selected medication review notes, we retrospectively evaluated the clinical implementation and classified 1) timing and communication of the review; 2) DRPs and related suggestions for the physician; and 3) DRPs’ potential clinical relevance to patients as ‘beneficial’, ‘somewhat beneficial’, ‘no relevance’ or ‘other relevance’. Of 327 DRPs (0-13 DRPs/patient), 48% were implemented. The clinical implementation was higher if the medication review note was made prior to (instead of after) the physician's admission, and even higher if the suggestions were communicated verbally (instead of only in writing) to the physicians (44 versus 79%, P

This nationwide study is aimed at describing to what extent the European Paediatric Regulation has met therapeutic needs in children. Data for each drug substance in defined daily doses (DDD) were extracted from the national Danish data base. We evaluated if drug substances were used off-label and whether they had a paediatric investigation plan (PIP). This study did not include drug prescriptions for individual paediatric patients; thus, it was not possible to make use of all off-label categories previously used. Additionally, paediatric standard assortments (SA) were compared to the European survey on paediatric medicinal products. Thirteen percent of the 100 most used drug substances were determined as being used off-label, four of which had a PIP and one had a full waiver. Only one of the three drug substances used off-label most often, accounting for 85 % of such use, had a PIP. Neonates were included in one-third of PIPs and adolescents in 15. Nineteen out of 21 PIPs had a waiver and 14 PIPs were deferred. In line with the European survey, carbapenems, corticosteroids and proton pump inhibitors were frequent found in SAs. PIPs only cover a small proportion of the drugs found to be used off-label in this study. Despite waivers granted, drug substances were used nonetheless. Unmet regulatory needs are still considerable in some therapeutic areas in neonates as well as in children.

Objectives Under reporting of adverse drug events (ADEs) is a global challenge. ADEs contribute to increased morbidity and mortality and many systems have been tried to overcome the lack of reporting. The aim of our study was to introduce an ADE manager (ADEM) at a university hospital in Denmark to increase the number of ADEs reported. Methods An ADEM was introduced in five medical wards at a university hospital in Denmark in the period October 2010–September 2011. The function of the ADEM was to complete the ADE report, whenever a physician required assistance. By using electronic health records, the ADEM was able to collect the necessary information about the ADE and complete a report to the Danish Medicines Agency (DMA), now part of Danish Health and Medicines Authority. Results The clinicians spent 2–3 min reporting the ADE to the ADEM, who spent 30 min completing the report. The study contributed to an increase in reported ADEs from 30 in 2009 to 162 in the 12-month project period at the university hospital. Conclusions An ADEM relieves the clinicians of the administrative burden of reporting ADEs and increases the number of ADEs reported to the DMA.

In Denmark, it is estimated that 3-5% of children are obese. Obesity is associated with pathophysiological alterations that may lead to alterations in the pharmacokinetics of drugs. In adults, obesity was found to influence important drug-metabolising enzyme pathways. The impact of obesity-related alterations on drug metabolism and its consequences for drug dosing remains largely unknown in both children and adults. An altered drug metabolism may contribute significantly to therapeutic failure or toxicity. The aim of this trial is to investigate the in vivo activity of CYP3A4, CYP2E1 and CYP1A2 substrates in obese versus non-obese children.The CYTONOX trial is an open-label explorative pharmacokinetic trial. We intend to include 50 obese and 50 non-obese children. The primary end points are: in vivo clearance of CYP3A4, CYP2E1 and CYP1A2 substrates, which will be defined by using well-tested probes; midazolam, chlorzoxazone and caffeine. Each of the probes will be administered as a single dose. Subsequently, blood and urine samples will be collected at pre-specified times.The aim of the CYTONOX trial is to investigate the in vivo activity of CYP3A4, CYP2E1 and CYP1A2 in obese and non-obese children. The results are expected to be used in the future as a basis for drug dosing recommendations in obese children.The study was funded by the Danish Regions' "Medicinpuljen". The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.EudraCT: 2014-004554-34.

Purpose: The aims of this study were to assess the quality of responses produced by drug information centers (DICs) in Scandinavia, and to study the association between time consumption processing queries and the quality of the responses. Methods: We posed six identical drug-related queries to seven DICs in Scandinavia, and the time consumption required for processing them was estimated. Clinical pharmacologists (internal experts) and general practitioners (external experts) reviewed responses individually. We used mixed model linear regression analyses to study the associations between time consumption on one hand and the summarized quality scores and the overall impression of the responses on the other hand. Findings: Both expert groups generally assessed the quality of the responses as "satisfactory" to "good." A few responses were criticized for being poorly synthesized and less relevant, of which none were quality-assured using co-signatures. For external experts, an increase in time consumption was statistically significantly associated with a decrease in common quality score (change in score, -0.20 per hour of work; 95% CI, -0.33 to -0.06; P = 0.004), and overall impression (change in score, -0.05 per hour of work; 95% CI, -0.08 to -0.01; P = 0.005). No such associations were found for the internal experts assessment. Implications: To our knowledge, this is the first study of the association between time consumption and quality of responses to drug-related queries in DICs. The quality of responses were in general good, but time consumption and quality were only weakly associated in this setting. (C) 2016 The Authors. Published by Elsevier HS Journals, Inc. Funding Agencies|Nord University, Steinkjer, Norway; Norwegian Regional Medicines Information and Pharmacovigilance Centers (RELIS)

The Danish Society of Clinical Pharmacology was founded in 1976, and mainly thanks to the persistent efforts of the society, clinical pharmacology became an independent medical speciality in Denmark in 1996. Since then, clinical pharmacology has gone from strength to strength. In the Danish healthcare system, clinical pharmacology has established itself as an indispensible part of the efforts to promote the rational, safe and economic use of drugs. Clinical pharmacologists are active in drug committees both in hospitals and in the primary sector. All clinical pharmacology centres offer a local medicines information service. Some centres have established an adverse drug effect manager function. Only one centre offers a therapeutic drug monitoring service. Clinical pharmacologists are responsible for the toxicological advice at the Danish Poison Information Centre at Bispebjerg University Hospital in the Capital Region. The Department of Clinical Pharmacology at Aarhus University Hospital works closely together with forensic toxicologists and pathologists, covering issues regarding illicit substances, forensic pharmacology, post-mortem toxicology, expert testimony and research. Therapeutic geriatric and psychiatric teach-inns for specialist and junior doctors are among the newest initiatives organized by clinical pharmacologists. Clinical pharmacologists work also in the Danish Medicines Agency and in the Danish pharmaceutical industry, and the latter has in particular a great growth potential for creating new jobs and career opportunities for clinical pharmacologists. As of July 2016, the Danish Society of Clinical Pharmacology has 175 members, and 70 of these are specialists in clinical pharmacology corresponding to approximately 2.5 specialists per 1000 doctors (Denmark has in total 28,000 doctors) or approximately 12 specialists per one million inhabitants.

BACKGROUND: High blood pressure (BP) is one of the most important risk factors for stroke, and antihypertensive therapy significantly reduces the risk of cardiovascular morbidity and mortality. However, achieving a regulated BP in hypertensive patients is still a challenge. OBJECTIVE: To evaluate the impact of an intervention targeting GPs' management of hypertension. METHODS: A cluster randomized trial comprising 124 practices and 2646 patients with hypertension. In the Capital Region of Denmark, the participating GPs were randomized to an intensive or to a moderately intensive intervention group or to a control group and in Region Zealand and Region of Southern Denmark, practices were randomized into a moderately intensive intervention and to a control group. The main outcome measures were change in proportion of patients with high BP and change in systolic BP (SBP) and diastolic BP (DBP) from the first to the second registration. RESULTS: The proportion of patients with high BP in 2007 was reduced in 2009 by ∼9% points. The mean SBP was reduced significantly from 2007 to 2009 by 3.61 mmHg [95% confidence interval (CI): -4.26 to -2.96], and the DBP was reduced significantly by 1.99 mmHg (95% CI: -2.37 to -1.61). There was no additional impact in either of the intervention groups. CONCLUSION: There was no impact of the moderate intervention and no additional impact of the intensive intervention on BP.

Obesity can affect the pharmacokinetics of most drugs, which may result in under‐ or overdosing if traditional pediatric dosing strategies are used. To investigate currently applied dosage strategies in children with overweight or obesity (overweight/obesity), in a clinical treatment facility. In particular, whether dosing guidelines were available and metrics of body size applied. A retrospective cohort study of 200 patients admitted to the Danish Children′s Obesity Clinic. Data were collected from 2007 to 2015. Overweight/obese children 3‐18 years were included if they had at least one drug prescription. Overall there were 658 prescriptions, primarily analgesics, psychotropics, asthma medications, and antibiotics. Except for one prescription, guidelines for dosage of overweight/obese children were not available in the clinic. In one prescription of gentamicin, the dose was adjusted by a metric body size. Otherwise dose was predominately prescribed either by total body weight or as fixed dose by age, in accordance with the recommendations of normal weight children. In drugs with a narrow therapeutic interval, we found large interindividual variations in dosing regimens, that is, for gentamicin, paracetamol, and prednisolone. Reduction of dose to the maximum recommended adult dose was common practice, when the dose calculated by total body weight (ie, mg/kg) exceeded this maximum. This study highlights the shortage of dosing guidelines in overweight/obese children. We found a large interindividual variability in dosage regimens, even in drugs with narrow therapeutic intervals. The clinicians rely on “best practice”, as evidence‐based dosage regimens are missing for many drugs prescribed during childhood.

The amount of activated charcoal needed to treat drug overdoses has arbitrarily been set at a charcoal-drug ratio of 10:1. Recent in vitro studies have shown a larger adsorptive capacity for activated charcoal when used in a model of paracetamol overdose. In the present study, we investigated whether this reserve capacity exists in vivo. This is clinically relevant in cases of large overdoses or if the full standard dose of 50 g activated charcoal cannot be administered. We performed a randomized, cross-over study (n = 16). One hour after a standard breakfast, 50 mg/kg paracetamol was administered, followed 1 hr later by an activated charcoal-Water slurry containing 50 (control), 25 or 5 g activated charcoal. The areas under the serum concentration-time curve (AUC) for paracetamol were used to estimate the efficacy of each activated charcoal dose. The AUC of the 25-g dose was found to be of similar size compared to the control, although statistics were weak. The AUC of the 5-g dose was 59% larger than the AUC of the 50-g dose (p = 0.0003). The terminal elimination half-life (t(1/2)) of paracetamol was 1.6 (CI 1.4-2.0) and 1.9 (CI 1.5-2.4) hr for 50 and 25 g, respectively (NS), and 2.5 (CI 1.8-3.0) hr for the 5-g dose (p = 0.003). The decrease in t(1/2) of paracetamol for the two larger activated charcoal doses indicates a possible effect of activated charcoal on paracetamol clearance and warrants further investigation. The large adsorptive reserve capacity of activated charcoal in vitro could not be reproduced for the smallest dose of activated charcoal. An activated charcoal-drug ratio of 10:1 is therefore still recommendable.

The prevalence of obesity in children is increasing rapidly worldwide. Obese children have a higher use of medicinal products than their normal-weight peers. Several general physiological alterations associated with obesity have been described. However, the impact of these alterations on drug metabolism and its consequences for drug dosing in children remains largely unknown. Pharmacokinetic studies are of utmost importance in order to avoid undertreatment, adverse effects or even toxicity.

Purpose There is little research-based documentation on the services provided by drug information centres (DICs). The aim of this multi-centre study was to explore for the first time the factors associated with time consumption when answering drug-related queries at eight different but comparable DICs. Methods During an 8-week period, staff members at eight Scandinavian DICs recorded the number of minutes during which they responded to queries. Mixed model linear regression analyses were used to explore the factors associated with time consumption when answering queries. Results The mean time consumption per query was 178 min (range 4-2540 min). The mean time consumed per query increased by 28 (95 % confidence interval (CI) 23 to 33, p Purpose: There is little research-based documentation on the services provided by drug information centres (DICs). The aim of this multi-centre study was to explore for the first time the factors associated with time consumption when answering drug-related queries at eight different but comparable DICs.Methods: During an 8-week period, staff members at eight Scandinavian DICs recorded the number of minutes during which they responded to queries. Mixed model linear regression analyses were used to explore the factors associated with time consumption when answering queries.Results: The mean time consumption per query was 178 min (range 4-2540 min). The mean time consumed per query increased by 28 (95 % confidence interval (CI) 23 to 33, p∈Conclusions: This study demonstrates the large variation in time consumed answering queries posed to Scandinavian DICs. The results highlight the need for highly competent staff members and easy access to drug information sources. Further studies are required to explore the association between time consumption and response quality.

Background. An activated charcoal–yogurt mixture was evaluated in vivo to determine the effect on the gastrointestinal absorption of paracetamol, as compared to activated-charcoal–water slurry. The...

Objective Our objective was to study the effect of recombinant human growth hormone (rhGH) on hepatic cytochrome P450 (CYP) activity in 30 healthy elderly men. Methods The study was carried out as a randomized, double-blind, placebo-controlled parallel-group study. rhGH or placebo was administered for a period of 12 weeks. CYP activity was measured before, after 12 weeks of rhGH and placebo administration, and at 4 weeks after termination of rhGH and placebo administration with use of the biomarker reactions of CYP1A2 (caffeine), CYP2C19 (mephenytoin), CYP2D6 (sparteine), CYP3A4 (endogenous cortisol metabolism), and antipyrine clearance as common markers of CYP activity. Results The metabolic ratio of caffeine increased significantly in the group that received growth hormone compared with placebo (median difference, 4.55; 95% confidence interval (CI), 1.64 to 8.60; versus −0.90; 95% CI, −5.70 to 1.36), indicating an induction of CYP1A2. Moreover, the S/R ratio of mephenytoin showed a small but significant increase (median difference, 0.02; 95% CI, 0 to 0.31; versus 0; 95% CI, −0.01 to 0.06), indicating an inhibition of CYP2C19. There were no significant changes of the metabolic ratios of cortisol and sparteine or the antipyrine clearance compared with placebo. Conclusions These results indicate that growth hormone induces CYP1A2 and, to a lesser extent, inhibits CYP2C19 in elderly men, but it exerts no effects on CYP2D6 and CYP3A4. Although the induction of CYP1A2 may be of some clinical relevance, the small inhibition of CYP2C19 is probably unimportant. Clinical Pharmacology & Therapeutics (2002) 71, 162–168; doi: 10.1067/mcp.2002.121373

Dizziness is a well-known side effect of a wide range of drugs. However, the side effects reported in the summary of product characteristics are not exclusively based on placebo-controlled trials. Based on a systematic review of the literature including randomised placebo-controlled clinical trials, antihypertensive combination drugs, methylphenidate, high doses of tramadol and serotonin-norepinephrine reuptake inhibitors were associated with an increased risk of dizziness. Antihypertensive monotherapy and selective serotonin reuptake inhibitors were generally not associated with an increased risk of dizziness when compared with placebo.

Isradipine is a calcium channel-blocking agent of the dihydropyridine type, used in the treatment of hypertension. A terminal half-life of 8-9 hr has been reported, in several pharmacokinetic studies after oral administration of isradipine. In a yet unpublished study a much shorter half-life was observed, and the present trial was therefore conducted in order to estimate the half-life after intravenous administration of isradipine. The bioavailability was estimated as well. In a randomised cross-over design ten healthy young volunteers were given either isradipine orally or an intravenous infusion. The two study periods were separated by at least 3 days. Blood samples for measurement of isradipine concentration were collected for 10-12 hr after administration and half-life and bioavailability were estimated. Mean terminal half-life after intravenous administration was calculated to be 2.8 hr, and the bioavailability to be 0.28. None of the 10 subjects suffered from side effects. In the present intravenous study the half-life of isradipine seems to be of much shorter than demonstrated in previous oral studies.

rac-Isradipine is a dihydropyridine type calcium antagonist. Its calcium entry blocking effect is due primarily to the (+)-(S)-enantiomer. This study describes a sensitive enantioselective method for the determination of isradipine in human serum. Following alkaline extraction into hexane, the enantiomers of isradipine are separated quantitatively by high-performance liquid chromatography on a Chiralcel OJ column at 39 degrees C. The collected fractions were evaporated and assayed using capillary gas chromatography on a HP 50+ column with nitrogen selective detection. Using 2.0 ml of serum, 0.7 nmol/1 (0.26 ng/ml) of each enantiomer could be determined with acceptable precision. The method has successfully been used to measure (+)-(S)- and (-)-(R)-isradipine concentrations in samples from volunteers after intravenous and oral administration of isradipine.

Background. The gastrointestinal tract is highly responsive to the trophic effect of growth hormone (GH). GH stimulates the healing of colonic anastomoses either directly or through insulin-like growth factor I (IGF-I) since specific GH receptor as well as IGF-I receptor have been demonstrated in colon. Aim. To determine whether exogeneous treatment with IGF-I could stimulate the healing of left colonic anastomoses in rats. Methods. After colonic anastomotic operations adult rats were randomised to treatment with either IGF-I (500 μg per day) or vehicle (controls). Anastomotic breaking strength and collagen deposition were determined at day 3 after surgery. Results. IGF-I treatment increased the anastomotic collagen content by 23% compared with controls. This resulted in a lower extensibility of the anastomosis (P

This study was conducted to determine age and sex stratified normal values for 24-h ambulatory blood pressure. A sample of 352 healthy subjects (all white) were randomly selected from the community register and stratified by sex and age groups in decades from 20 to 79 years of age. Persons with a history of hypertension, cerebral apoplexy, diabetes, myocardial or renal disease, and who were taking blood pressure-influencing medication were excluded. Ambulatory blood pressure was recorded over 24 h, with measurements taken every 15 min from 07:00 to 22:59, and every 30 min from 23:00 to 06:59. Systolic blood pressure increased only slightly with age and was significantly higher in men than in women. The diastolic blood pressure increased only slightly with age in both sexes until the 50 to 59 years age group and declined thereafter. The diastolic blood pressure was not different for the two sexes. Both systolic and diastolic blood pressure were approximately 15% lower during the night regardless of age or sex. Ambulatory blood pressure during the daytime was on an average of 5 mm Hg lower than office blood pressure, but the mean difference between the two measurements increased with age. The variability of the difference also increased with age. In conclusion: Normal values for ambulatory blood pressure are presented in a randomly selected age- and gender-stratified population. Differences between office blood pressure and ambulatory blood pressure increased with age suggesting that the previously observed higher blood pressure seen in the elderly partly might be explained by a greater impact of white coat hypertension in older people.

Metformin (MET) is the first-line agent in treatment of type 2 diabetes. However, MET has been associated with lactic acidosis (MALA), a potential but rare complication which has influenced treatment strategies in decades. Recently, guidelines have been changed in regards of age and heart failure and the contradiction of chronic renal impairment has been debated. This article identifies potential risk groups and situations that would benefit from a temporary interruption in the MET treatment.

Background. Most hypertensive patients are managed in primary care in Denmark, but previous studies have shown that only 21–43% of hypertensive patients achieve optimal blood pressure (BP) control. Antihypertensive drug treatment, risk factors and cardiovascular disease (CVD) are some of the important factors to consider when optimizing the individual treatment strategy in hypertensive patients. Objective. To examine treatment of BP according to Danish guidelines (BP < 140/90 mmHg generally and Methods. A cross-sectional study comprising 184 practices and 5413 hypertensive patients was carried out in Denmark. The general practitioners filled in information on each patient’s risk factors, CVD and antihypertensive drug treatment. Patients filled in a questionnaire on risk factors. The outcome measures were optimal BP control according to Danish guidelines and antihypertensive drug treatment. Results. Mean patient age was 65.9 years [95% confidence interval (CI): 65.6–66.1]. Optimal BP control was achieved in 29.1% (95% CI: 27.9–30.3) of the study population. Among 842 diabetics with or without CVD, optimal BP control was achieved in 10.9% (95% CI: 8.8–10.3), while 38.7% (35.5–41.9) of patients with CVD achieved optimal BP control. The majority of all patients were treated with 1 (32.5%, 95% CI: 32.5 (31.3–33.8)) or two antihypertensive drugs (39.0%, 95% CI: 38.2–40.8). In hypertensive diabetics, 17.7% were not treated with an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker. Conclusion. In general practice, the proportion of hypertensive patients achieving optimal BP control is inadequate. The majority of hypertensive patients are treated with only one or two antihypertensive drugs.

A relatively simple, sensitive and precise gas chromatographic method for the determination of isradipine, a calcium antagonist of the dihydropyridine type, and its main metabolite in serum is described. Using a one-step extraction procedure, a wide-bore column and a nitrogen—phosphorus detector, a limit of quantitation of 0.5 and 2.0 n M for isradipine and the metabolite was found. No interferences from several drugs were observed. The method was successfully used in a pharmacokinetic study in hypertensive women during pregnancy.

The amount of activated charcoal needed to treat drug overdoses has arbitrarily been set at a charcoal-drug ratio of 10:1. Recent in vitro studies have shown a larger adsorptive capacity for activated charcoal when used in a model of paracetamol overdose. In the present study, we investigated whether this reserve capacity exists in vivo. This is clinically relevant in cases of large overdoses or if the full standard dose of 50 g activated charcoal cannot be administered. We performed a randomized, cross-over study (n = 16). One hour after a standard breakfast, 50 mg/kg paracetamol was administered, followed 1 hr later by an activated charcoal-Water slurry containing 50 (control), 25 or 5 g activated charcoal. The areas under the serum concentration-time curve (AUC) for paracetamol were used to estimate the efficacy of each activated charcoal dose. The AUC of the 25-g dose was found to be of similar size compared to the control, although statistics were weak. The AUC of the 5-g dose was 59% larger than the AUC of the 50-g dose (p = 0.0003). The terminal elimination half-life (t(1/2)) of paracetamol was 1.6 (CI 1.4-2.0) and 1.9 (CI 1.5-2.4) hr for 50 and 25 g, respectively (NS), and 2.5 (CI 1.8-3.0) hr for the 5-g dose (p = 0.003). The decrease in t(1/2) of paracetamol for the two larger activated charcoal doses indicates a possible effect of activated charcoal on paracetamol clearance and warrants further investigation. The large adsorptive reserve capacity of activated charcoal in vitro could not be reproduced for the smallest dose of activated charcoal. An activated charcoal-drug ratio of 10:1 is therefore still recommendable.

Prescribing involves careful considerations of outcome, duration of treatment and follow-up, and such considerations should be communicated to everyone involved in the medication process. Hospital admission and discharge involve a high risk of medication errors caused by unclear division of responsibilities, lack of communication, frequent exchanges between synonymous and analogous drugs, polypharmacy, compliance issues and insufficient education and training of staff. There is an obvious need for a joint internet-based online prescription system covering all physicians.

A person with a digital signature can access his or her own personal electronic medicinal profile (PEM) which can also be accessed by the person's prescribing doctors. The PEM provides an overview and contains an overview of the prescription medicine sold to the patient over the previous two years.Randomly-selected geriatric ambulatory patients were included. Accordance between physicians' medication records and the PEM was calculated. Moreover, the prescribing ambulatory doctor and the patient's general practitioner were asked if the PEM could contribute with non-recognized information about patients' prescription medicine.We found a 13-20% discrepancy between physicians' medication records and PEMs, involving 50-60% of the patients. In most cases, access to the PEM significantly corrected the discrepancies. Discrepancies were neither correlated to gender, age nor to the amount of prescription medicine. Discrepancies were judged to be serious or influential.The PEM provides insight into unrecognized information about patients' prescription medicine and access to the PEM bridges the gap between primary and secondary health care. Easier access to the digital signature, inclusion of over-the-counter drugs, and improved protection against misuse would further improve the PEM and ensure access to updated drug information.

Non-adherence or incomplete adherence to drug prescriptions is common. In long-term therapy for chronic disease, it has been estimated that only half of all drug doses are taken as prescribed. In this article we discuss poor adherence in terms of prevalence, clinical significance, treatment opportunities and ethical aspects.