Search

Summary Background There is an urgent unmet need for new therapies in amyotrophic lateral sclerosis. In a clinical study with healthy volunteers, levosimendan, a calcium sensitiser, was shown to improve neuromechanical efficiency and contractile function of the human diaphragm. We aimed to evaluate the safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis, with a focus on respiratory function. Methods The REFALS study is a randomised, double-blind, placebo-controlled phase 3 trial at 99 amyotrophic lateral sclerosis specialist centres in 14 countries worldwide. People with amyotrophic lateral sclerosis were eligible for participation if they were at least 18 years of age and had a sitting slow vital capacity (SVC) of 60–90% predicted. Participants were randomly assigned (2:1) by interactive web-response system to receive either levosimendan or placebo. The capsules for oral administration were identical in appearance to maintain blinding of participants and investigators. The primary endpoint was the change from baseline in supine SVC at 12 weeks, assessed as the percentage of predicted normal sitting SVC. The key secondary endpoint was the combined assessment of function and survival (CAFS) up to 48 weeks. Analyses were done in the intention-to-treat population, comprising all participants who were randomly assigned. This trial is registered at ClinicalTrials.gov (NCT03505021) and has been completed. An extension study (REFALS-ES; NCT03948178 ) has also been completed, but will be reported separately. Findings Between June 21, 2018, and June 28, 2019, 871 people were screened for the study, of whom 496 were randomly assigned either levosimendan (n=329) or placebo (n=167). Participants were followed up between June 27, 2018 and June 26, 2020, for a median duration of 50·1 (IQR 37·5–51·1) weeks. The median duration of treatment was 47·9 (IQR 26·4–48·1) weeks. Change from baseline in supine SVC at 12 weeks was –6·73% with levosimendan and –6·99% with placebo, with no significant difference between the treatments (estimated treatment difference 0·26%, 95% CI –2·03 to 2·55, p=0·83). Similarly, at week 48, CAFS did not differ between treatment groups (least squares mean change from baseline 10·69, 95% CI –15·74 to 37·12; nominal p value=0·43). The most frequent adverse events were increased heart rate (106 [33%] of 326 receiving levosimendan vs 12 [7%] of 166 receiving placebo), fall (85 [26%] vs 48 [29%]), headache (93 [29%] vs 36 [22%]), and dyspnoea (59 [18%] vs 32 [19%]). 33 (10%) participants allocated levosimendan and 20 (12%) assigned placebo died during the trial, mainly due to respiratory failure or progression of amyotrophic lateral sclerosis. Interpretation Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation. Funding Orion Corporation.

204 Background: Treatment of men with metastatic castration-resistant prostate cancer (mCRPC) using drugs targeting the AR pathway is hampered by development of resistance including activating AR ligand-binding domain (LBD) point mutations. AR LBD mutations are found in approximately 10-20% of patients (pts) with mCRPC progressing on AR pathway inhibition (ARPi) therapy and may be associated with AR activation by alternative steroid hormones. We utilized the Guardant INFORM real-world database to explore the detection rate and clinical features associated with AR-LBD mutations in men with mCRPC. Methods: This observational study was conducted in a nationally representative clinical-genomic database of 200,000+ advanced cancer pts undergoing comprehensive ctDNA analysis (Guardant360, Redwood City, CA) between 2014 and 2021, with associated clinical information from administrative claims. ctDNA samples of men with mCRPC were assessed for presence or absence of an activating AR-LBD mutation. The incidence of co-occurring genetic alterations was also investigated. Clinical outcomes were studied for matched cohorts comparing pts following first line (1L) or second line (2L) mCRPC therapy with or without AR-LBD mutations. Results: Of 15,705 prostate cancer pts included in the database, 8420 (53.6%) had mCRPC at the time of sample collection. 4122 (49.0%) of these mCRPC pts had prior treatment with an ARPi, of which 854 (21%) had an AR-LBD mutation. AR-LBD mutation prevalence was 15% in mCRPC pts untreated with an ARPi, 23% in those after 1 line, and 24% in those after 2 lines of ARPi treatment. AR L702H and T878A/S showed the greatest increase in prevalence post abiraterone, whereas AR L702H, T878S and F877L had the greatest increase in prevalence post enzalutamide. Prevalence of AR L702H and H875Y doubled (from 8.8% to 17.5%) for pts that received chemotherapy post ARPi, while AR F877L incidence declined by half (3.5% to 1.7%). Compared to pts without AR-LBD mutations, AR-LBD+ mCRPC pts were enriched for co-alterations in APC, CTNNB1, PTEN, BRCA2, and ARID1A. Rates of TP53 and RB1 alterations were comparable in the AR-LBD+ and ARLBD- cohorts. Matched mCRPC pts had similar time-to-treatment-discontinuation (TTD) and time-to-next-treatment (TTNT) between AR-LBD+ and AR-LBD- mCRPC pts in the 1L and 2L settings; however, AR-LBD+ pts exhibited worse overall survival from 1L mCRPC therapy (50.1 vs 60.7 months, log-rank P=0.013). Conclusions: In this large database, the overall detection rate of activating AR-LBD mutations in men with mCRPC undergoing ctDNA analysis was 21%, and increased with prior use of 2nd generation ARPi (abiraterone and enzalutamide). Men with AR-LBD mutations were more likely to harbor other alterations relevant to tumor progression. These findings inform on the ctDNA prevalence and impact of AR-LBD mutations in a real-world dataset of mCRPC.

5057 Background: Activating AR mutations ensure a continued AR activation by non-androgen steroid ligands, e.g. progesterone and glucocorticoids. CYP11A1 is the only enzyme that catalyzes the conversion of cholesterol to pregnenolone, from which all steroid hormones (glucocorticoids, mineralocorticoids, and sex steroids) are subsequently derived. ODM-208, an oral, selective inhibitor of CYP11A1, is being evaluated for safety and efficacy as a treatment of mCRPC in the ongoing CYPIDES phase I/II trial in men previously treated with both novel hormonal therapies and taxanes (ClinicalTrials.gov identifier: NCT03436485). Preliminary phase 1 results were previously reported (Fizazi K et al., ASCO GU 2022). Here we confirm that the in-vitro sensitivity of common AR mutations to ODM-208 treatment is mirrored in patient response in CYPIDES phase 1. Methods: ODM-208 was administered at daily doses between 6-150 mg (phase 2 dose: 10 mg) with dexamethasone and fludrocortisone, resulting in maximal suppression in all measured steroids at all doses. AR ligand-binding domain (LBD) mutations (L702H, V716M, W742L, W742C, H875Y, F877L, T878A, T878S, M896T, M896V) were assessed using a BEAMing assay (Sysmex Inostics) from plasma circulating cell-free DNA (cfDNA) collected before the first dose of ODM-208. The activation of wild-type (wt) and LBD mutated AR with various ligands was also studied in vitro using a luciferase reporter assay in AR negative PC3 cells. Results: 17 of 44 patients had at least one AR activating mutation, the most frequent being L702H (n = 11), T878A (n = 10), and H875Y (n = 6). Eleven out of the 16 evaluable patients (68%) with an AR LBD mutation achieved ≥50% reduction in serum PSA compared with 2 out of the 24 evaluable patients (8%) without an AR LBD mutation (P

18 Background: ODM-208 is a novel, oral, non-steroidal and selective inhibitor of CYP11A1, the first and rate-limiting enzyme of steroid biosynthesis. ODM-208 suppresses the production of all steroid hormones and their precursors that may activate the androgen receptor (AR) signalling pathway. This is particularly relevant in patients with AR ligand binding domain (LBD) activating somatic point mutations, a mechanism of resistance to hormone-based therapies in metastatic castration-resistant prostate cancer (mCRPC). We report the first results of the first-in-man phase I CYPIDES trial. Methods: ODM-208 was examined in a dose finding phase 1 trial with a 3+3 design in patients with progressive mCRPC who had previously received ≥1 line of AR signalling inhibitor and ≥1 line of taxane-based chemotherapy. ODM-208 was administered up to 150 mg/day with glucocorticoid (GC) and mineralocorticoid replacement therapy and androgen deprivation therapy (ADT). The phase 1 endpoints included dose-limiting toxicities (DLTs), adverse events, pharmacokinetics, pharmacodynamics, PSA and RECIST response, and exploratory genetic profiling. Results: By Jan 22 2021, 41 patients (median age 70 yrs.) had received ODM-208. The dose finding was completed and included doses ranging from 10 to 150 mg/day. 22 (54%) patients had previously received both abiraterone and enzalutamide, and 23 (56%) patients both docetaxel and cabazitaxel. Although tolerated by most patients, the main safety finding was adrenal insufficiency (AI). Overall, 15/41 (37%) patients experienced Grade 3 AI requiring short-term high-dose GC treatment. ODM-208 plasma exposure was dose proportional. Serum testosterone was undetectable after 4 weeks of start of ODM-208 in almost all patients, as were serum DHEA sulphate, androstenedione, 11β-hydroxyandrostenedione, 11-ketotestosterone and pregnenolone. Overall 12/36 (33%) evaluable patients achieved a PSA decline of ≥50%. In evaluable patients with AR LBD mutation 10/15 (67%) achieved a PSA decline of ≥50%. Clinical improvement in symptoms such as pain was also observed in some men. Conclusions: Administration of ODM-208 to mCRPC men pretreated with abiraterone/enzalutamide and taxanes was highly effective in blocking the production of steroid hormones and showed promising antitumor activity, especially in men with AR mutation-positive cancers. The phase 2 dose expansion part of CYPIDES is ongoing. Clinical trial information: NCT03436485.

Aims Dexmedetomidine (dexdor®) is approved in the European Union (EU) for sedation of adults in the intensive care unit (ICU). The present observational, retrospective study was requested by the European Medicines Agency to investigate dexmedetomidine use in clinical practice, with a particular focus on off-label use, including the paediatric population. Methods Study countries and sites were chosen from those with highest dexmedetomidine use, based on sales. Site selection (blind) was conducted by a multispecialist, independent group. Anonymized data on demographics, treatment indication, dexmedetomidine dosing, concomitant medications and treatment effectiveness were collected retrospectively from records of all dexmedetomidine-treated patients at the site during the enrolment period. Informed consent was waived, to avoid influencing the prescribing of dexmedetomidine. Recruitment was completed within 18 months of first site initiation. Results Data from 2000 patients were collected from 16 hospitals in four EU countries (Finland 750, Poland 505, Germany 470, Austria 275). The median age was 62 years, with more males (70.2%) than females. Dexmedetomidine was primarily used in the adult ICU (86.0%) for ICU sedation (78.6%) and mostly dosed according the product label. The intended sedative effect was obtained in 84.9% of administrations. Paediatric use (5.9% of patients, mostly in Austria and Finland) occurred mainly in the adult or paediatric ICU (75.6%) for sedation (67.2%). Conclusions Overall, most patients were treated with dexmedetomidine according to the product labelling. Use in children was limited but significant and similar in scope to that in adults. Administrations not fully according to the product labelling usually occurred in an ICU environment and reflected extensively investigated clinical uses of dexmedetomidine.

Background This study evaluated the efficacy and safety of levosimendan, a positive inotropic drug with vasodilator effects, given intravenously to patients with acutely decompensated heart failure (ADHF). Methods We performed 2 sequential trials, the first to develop a new measure of efficacy in 100 patients, and the second to use this measure to evaluate levosimendan in an additional 600 patients. Patients admitted with ADHF received placebo or intravenous levosimendan for 24 h in addition to standard treatment. The primary endpoint was a composite that evaluated changes in clinical status during the first 5 days after randomization. Results In the 600-patient trial, more levosimendan than placebo patients (58 vs. 44) were improved at all 3 pre-specified time points (6 h, 24 h, and 5 days), whereas fewer levosimendan patients (58 vs. 82) experienced clinical worsening (p = 0.015 for the difference between the groups). These differences were apparent, despite more frequent intensification of adjunctive therapy in the placebo group (79 vs. 45 patients). Improvements in patient self-assessment and declines in B-type natriuretic peptide levels with levosimendan persisted for 5 days and were associated with reduced length of stay (p = 0.009). Similar findings were present in the 100-patient pilot trial. Levosimendan was associated with more frequent hypotension and cardiac arrhythmias during the infusion period and a numerically higher risk of death across the 2 trials (49 of 350 on a regimen of levosimendan vs. 40 of 350 on a regimen of placebo at 90 days, p = 0.29). Conclusions In patients with ADHF, intravenous levosimendan provided rapid and durable symptomatic relief. As dosed in this trial, levosimendan was associated with an increased risk of adverse cardiovascular events. (Evaluation of Intravenous Levosimendan Efficacy in the Short Term Treatment of Decompensated Chronic Heart Failure; NCT00048425 )

2576Background: Inhibitors of fibroblast growth factor receptors (FGFR) are being developed for treatment of solid tumours with FGFR genetic alterations. ODM-203 is a small molecule with balanced inhibitory effects on both FGFR 1-4 and VEGFR 1-3 subtypes. We present the results of the first-in-man study. Methods: ODM-203 was evaluated in a 3+3 dose escalation design to identify the maximum tolerated dose (MTD), dosed daily in a 4 week cycle. PK profiles were taken on days 1 and 8, and safety labs, ECG, vital signs and adverse events were recorded on days 1, 4, 8, 15, 22, 29, week (wk) 6 and wk 8. Plasma markers of FGFR and VEGFR inhibition were measured at baseline, day 8 and day 29 and tumour response by RECIST criteria every 8 weeks. Patients continued ODM-203 treatment until disease progression or dose limiting toxicity (DLT). Results: 24 patients (median age 55, range 28-80 years) with advanced solid tumours received ODM-203 in doses between 50-800mg once/day. The longest treatment period so far is 40...

The aim of this study was to characterize the pharmaco-kinetics of long dexmedetomidine (dexmed) infusions and assess the dose linearity of high doses.

Context Long-term sedation with midazolam or propofol in intensive care units (ICUs) has serious adverse effects. Dexmedetomidine, an α(2)-agonist available for ICU sedation, may reduce the duration of mechanical ventilation and enhance patient comfort. Objective To determine the efficacy of dexmedetomidine vs midazolam or propofol (preferred usual care) in maintaining sedation; reducing duration of mechanical ventilation; and improving patients' interaction with nursing care. Design, setting, and patients Two phase 3 multicenter, randomized, double-blind trials carried out from 2007 to 2010. The MIDEX trial compared midazolam with dexmedetomidine in ICUs of 44 centers in 9 European countries; the PRODEX trial compared propofol with dexmedetomidine in 31 centers in 6 European countries and 2 centers in Russia. Included were adult ICU patients receiving mechanical ventilation who needed light to moderate sedation for more than 24 hours (midazolam, n = 251, vs dexmedetomidine, n = 249; propofol, n = 247, vs dexmedetomidine, n = 251). Interventions Sedation with dexmedetomidine, midazolam, or propofol; daily sedation stops; and spontaneous breathing trials. Main outcome measures For each trial, we tested whether dexmedetomidine was noninferior to control with respect to proportion of time at target sedation level (measured by Richmond Agitation-Sedation Scale) and superior to control with respect to duration of mechanical ventilation. Secondary end points were patients' ability to communicate pain (measured using a visual analogue scale [VAS]) and length of ICU stay. Time at target sedation was analyzed in per-protocol population (midazolam, n = 233, vs dexmedetomidine, n = 227; propofol, n = 214, vs dexmedetomidine, n = 223). Results Dexmedetomidine/midazolam ratio in time at target sedation was 1.07 (95% CI, 0.97-1.18) and dexmedetomidine/propofol, 1.00 (95% CI, 0.92-1.08). Median duration of mechanical ventilation appeared shorter with dexmedetomidine (123 hours [IQR, 67-337]) vs midazolam (164 hours [IQR, 92-380]; P = .03) but not with dexmedetomidine (97 hours [IQR, 45-257]) vs propofol (118 hours [IQR, 48-327]; P = .24). Patients' interaction (measured using VAS) was improved with dexmedetomidine (estimated score difference vs midazolam, 19.7 [95% CI, 15.2-24.2]; P Conclusions Among ICU patients receiving prolonged mechanical ventilation, dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation. Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam and improved patients' ability to communicate pain compared with midazolam and propofol. More adverse effects were associated with dexmedetomidine. Trial registration clinicaltrials.gov Identifiers: NCT00481312, NCT00479661.

Introduction Only limited information exists on the pharmacokinetics of prolonged (> 24 hours) and high-dose dexmedetomidine infusions in critically ill patients. The aim of this study was to characterize the pharmacokinetics of long dexmedetomidine infusions and to assess the dose linearity of high doses. Additionally, we wanted to quantify for the first time in humans the concentrations of H-3, a practically inactive metabolite of dexmedetomidine. Methods Thirteen intensive care patients with mean age of 57 years and Simplified Acute Physiology Score (SAPS) II score of 45 were included in the study. Dexmedetomidine infusion was commenced by using a constant infusion rate for the first 12 hours. After the first 12 hours, the infusion rate of dexmedetomidine was titrated between 0.1 and 2.5 μg/kg/h by using predefined dose levels to maintain sedation in the range of 0 to -3 on the Richmond Agitation-Sedation Scale. Dexmedetomidine was continued as long as required to a maximum of 14 days. Plasma dexmedetomidine and H-3 metabolite concentrations were measured, and pharmacokinetic variables were calculated with standard noncompartmental methods. Safety and tolerability were assessed by adverse events, cardiovascular signs, and laboratory tests. Results The following geometric mean values (coefficient of variation) were calculated: length of infusion, 92 hours (117%); dexmedetomidine clearance, 39.7 L/h (41%); elimination half-life, 3.7 hours (38%); and volume of distribution during the elimination phase, 223 L (35%). Altogether, 116 steady-state concentrations were found in 12 subjects. The geometric mean value for clearance at steady state was 53.1 L/h (55%). A statistically significant linear relation (r2 = 0.95; P < 0.001) was found between the areas under the dexmedetomidine plasma concentration-time curves and cumulative doses of dexmedetomidine. The elimination half-life of H-3 was 9.1 hours (37%). The ratio of AUC0-∞ of H-3 metabolite to that of dexmedetomidine was 1.47 (105%), ranging from 0.29 to 4.4. The ratio was not statistically significantly related to the total dose of dexmedetomidine or the duration of the infusion. Conclusions The results suggest linear pharmacokinetics of dexmedetomidine up to the dose of 2.5 μg/kg/h. Despite the high dose and prolonged infusions, safety findings were as expected for dexmedetomidine and the patient population. Trial Registration ClinicalTrials.gov: NCT00747721

Traditionally, intravenous (IV) drugs in decompensated heart failure (HF) have been evaluated based on their hemodynamic effects. Thus, no endpoint to measure symptomatic improvement in decompensated HF has yet been validated. To do so, we adapted the clinical composite (which has been validated in trials of chronic HF) to the evaluation of IV levosimendan in a pilot trial of acute decompensated HF (REVIVE-1). A total of 100 patients who were hospitalized for worsening HF and had dyspnea at rest despite IV diuretics were randomized (double-blind) to receive placebo (PBO) (n = 49) or IV levosimendan (LS) (n = 51), given as a loading dose of 12 μg/kg over 10 min and followed by a continuous infusion (0.1 μg/kg/hour for 50 min and 0.2 μg/kg/hour for 23 hours); patients were then followed closely for an additional 4 days. Patients were classified as improved if they reported their HF to be moderately or markedly improved at specific time points. Patients were classified as worse if they died or received an IV medication for worsening HF during the 5-day study period. Patients were considered unchanged if they were neither improved nor worse. Different models using different definitions for improvement and worsening were prospectively and retrospectively examined. The initial model defined improvement based on the responses at 24 hours and at 5 days and restricted the definition of worsening to the use of IV vasodilators or inotropic agents. Using this model, improvement was observed more frequently with LS than with PBO (49% vs 33%), with no between-group difference in the proportion of patients who were worse (overall P = 0.229). When the definition of worsening was expanded to include the use of IV diuretics for worsening HF and confined to the occurrence of clinical events, LS-treated patients not only were more likely to show improvement (51% vs 33%) but were less likely to exhibit worsening (20% vs 35%) (overall P = 0.043). When the definition of improvement was expanded to include the responses at 6 hours (in addition to 24 hours and 5 days), the separation between the treatment groups increased even further (improvement in 33% vs 14% and worsening in 24% vs 37%) (overall P = 0.029) (LS vs PBO). The greater level of improvement in the clinical composite on levosimendan was supported by significant reductions in median plasma B-type natriuretic peptide concentrations compared with placebo at both 24 hours (-303 pg/ml vs -77.5 pg/ml, P = 0.001) and 5 days (-376 pg/ml vs -99.5 pg/ml, P = 0.027). These findings indicate that a clinical composite approach can be used to develop an endpoint that distinguishes the effects of IV LS in the setting of acute decompensated HF. The new endpoint is now being used prospectively to evaluate the effects of LS in a definitive second study (REVIVE-2).

Background and Objectives Although the pharmacokinetics of dexmedetomidine in healthy volunteers have been studied, there are limited data about the pharmacokinetics of long-term administration of dexmedetomidine in critically ill patients. Methods This population pharmacokinetic analysis was performed to quantify the pharmacokinetics of dexmedetomidine in critically ill patients following infusions up to 14 days in duration. The data consisted of three phase III studies (527 patients with sparse blood sampling, for a total of 2,144 samples). Covariates were included in a full random-effects covariate model and the most important covariate relationships were tested separately. The linearity of dexmedetomidine clearance was evaluated by observing steady-state plasma concentrations acquired at various infusion rates. Results The data were adequately described with a one-compartment model. The clearance of dexmedetomidine was 39 (95 % CI 37–41) L/h and volume of distribution 104 (95 % CI 93–115) L. Both clearance and volume of distribution were highly variable between patients (coefficients of variation of 62 and 57 %, respectively), which highlights the importance of dose titration by response. Covariate analysis showed a strong correlation between body weight and clearance of dexmedetomidine. The clearance of dexmedetomidine was constant in the dose range 0.2–1.4 μg/kg/h. Conclusions The pharmacokinetics of dexmedetomidine are dose-proportional in prolonged infusions when dosing rates of 0.2–1.4 μg/kg/h, recommended by the Dexdor® summary of product characteristics, are used.

Background Dexmedetomidine can be used for sedation of mechanically ventilated patients and has minor respiratory effects. The aim of this study was to compare the incidence of patient-ventilator dyssynchronies during sedation with dexmedetomidine or propofol. Methods We conducted a multicentre, prospective, open-label, randomised clinical trial, comparing dexmedetomidine with standard propofol sedation at three intensive care units of university hospitals in Italy. Twenty difficult-to-wean patients for whom the first weaning trial had failed and who were on pressure support ventilation were randomised to receive sedation with either dexmedetomidine or propofol at a similar level of sedation (Richmond Agitation-Sedation Scale [RASS] score +1 to −2). The asynchrony index (AI) was calculated using tracings of airflow, airway pressure and electrical activity of the diaphragm sampled at 0, 0.5, 1, 2, 6, 12, 18 and 24 h. Results The mean AI was lower with dexmedetomidine than with propofol from 2 h onwards, although the two groups significantly differed only at 12 h (2.68 % vs 9.10 %, p

Aims Dexmedetomidine (dexdor®) is approved in the European Union (EU) for sedation of adults in the intensive care unit (ICU). The present observational, retrospective study was requested by the European Medicines Agency to investigate dexmedetomidine use in clinical practice, with a particular focus on off‐label use, including the paediatric population. Methods Study countries and sites were chosen from those with highest dexmedetomidine use, based on sales. Site selection (blind) was conducted by a multispecialist, independent group. Anonymized data on demographics, treatment indication, dexmedetomidine dosing, concomitant medications and treatment effectiveness were collected retrospectively from records of all dexmedetomidine‐treated patients at the site during the enrolment period. Informed consent was waived, to avoid influencing the prescribing of dexmedetomidine. Recruitment was completed within 18 months of first site initiation. Results Data from 2000 patients were collected from 16 hospitals in four EU countries (Finland 750, Poland 505, Germany 470, Austria 275). The median age was 62 years, with more males (70.2%) than females. Dexmedetomidine was primarily used in the adult ICU (86.0%) for ICU sedation (78.6%) and mostly dosed according the product label. The intended sedative effect was obtained in 84.9% of administrations. Paediatric use (5.9% of patients, mostly in Austria and Finland) occurred mainly in the adult or paediatric ICU (75.6%) for sedation (67.2%). Conclusions Overall, most patients were treated with dexmedetomidine according to the product labelling. Use in children was limited but significant and similar in scope to that in adults. Administrations not fully according to the product labelling usually occurred in an ICU environment and reflected extensively investigated clinical uses of dexmedetomidine.