ContexteLe programme d’amélioration continue du travail en équipe (PACTE) a été développé par la HAS, son but est d’améliorer le parcours de soins du patient en se basant sur une résolution des problèmes en équipe. Ce programme a débuté en septembre 2022 pour notre équipe de pharmacie clinique (PC).Une enquête culture sécurité et une séance de « crew resource management » ont été réalisées. Elles ont permis de définir en équipe des actions à prioriser. Celles-ci sont centrées sur le travail en équipe.ObjectifsAméliorer notre culture du « reporting » et du retour d’expérience au sein de notre équipe.MéthodeLa première action était la réalisation d’un exercice de simulation procédurale sur la déclaration d’évènements indésirables (EI). La deuxième consistait en la présentation de 10 cas cliniques. Ces cas sont discutés en équipe afin de définir la réalisation de cette déclaration.Les EI peuvent concerner les services de soins, un autre service de la PUI ou son propre service. Le recueil des déclarations est réalisé sur le logiciel Ennov®.Une fois la déclaration faite, un modérateur l’analyse, redéfinit la gravité, et l’oriente vers la cellule d’analyses des fiches d’événements indésirables (CAFEI) concernée.Ainsi une CAFEI spécifique de pharmacie clinique est créée. Des réunions spécifiques d’analyse d’EI sont alors organisées. Toute l’équipe de PC est conviée (18 pharmaciens et 10 internes).RésultatsLa démonstration de la plateforme de déclaration a été réalisée en mai. Une fiche d’instruction est rédigée.Entre mai et octobre 2023, 12 déclarations ont été recensées. Parmi ces déclarations, 7 étaient destinées aux services de soins, 3 à un autre service de la PUI et 2 concernaient l’équipe de PC.Leurs conséquences étaient mineures (3), peu graves (7) ou importantes (2). Les compétences non techniques le plus souvent responsables d’EI sont le travail en équipe, la communication et la gestion du stress.Tous les EI conduisent à 1 action, parmi celles-ci, 5 sont terminées et 7 sont en cours de mise en place.En juillet et en octobre, 2 CAFEI ont eu lieu. Une synthèse est rédigée reprenant les actions à mettre en place et leur suivi.Discussion/ConclusionLes résultats à 6 mois sont encourageants. La culture du « reporting » s’est améliorée, en effet le nombre d’EI déclaré auparavant était d’environ 5 par an. La réalisation des réunions CAFEI ainsi que la communication de leurs synthèses permet de travailler sur la culture du retour d’expérience en équipe.Plusieurs actions ont été mises en place, de nouvelles déclarations d’EI sur le même sujet nous permettront de discuter de leur pertinence.La prochaine étape est d’analyser l’augmentation des déclarations avec une gravité élevée.La qualité des déclarations (informations transmises, contenu, gravité), devrait s’améliorer. Le nombre de déclarations et d’actions finalisées sera continuellement récolté afin que la démarche soit pérenne.Une nouvelle enquête culture sécurité sera de nouveau à réaliser à 2 an du PACTE.

ContexteLes inhibiteurs du point de contrôle immunitaire (ICI) ont révolutionné le pronostic des patients atteints de mélanome avancé. Suite aux résultats des essais cliniques, le nivolumab a d’abord été utilisé à la dose de 3mg/kg toutes les deux semaines (Q2W). À partir de 2017, des études pharmacocinétiques ont conduit à utiliser le nivolumab à dose fixe pour le mélanome ; d’abord 240mg/2 semaines (Q2W), puis 480mg/mois (Q4W).ObjectifsL’objectif de cette étude est de comparer la tolérance et l’efficacité en vie réelle de ces deux schémas posologiques.MéthodeUne étude monocentrique, rétrospective, en vie réelle a été menée sur des patients consécutifs. L’étude s’est terminée en février 2023. Les données de patients adultes atteints de mélanome avancé (stade III non résécable et stade IV) ayant reçu une dose de nivolumab de 3mg/kg Q2W (DP) ont été comparées à celles de patients ayant reçu une dose fixe de 480mg Q4W (DF). Le critère de jugement principal était la survenue d’un événement indésirable immunitaire (imEI) de grade≥3 selon la classification CTCAE v5. Parmi les critères secondaires nous avons regardé l’efficacité par analyse de la survie globale à 4ans. Les résultats sont présentés par les hazard ratio (HR) et p-value.RésultatsAu total, 342 patients ont été inclus : respectivement 71 et 271 pour les cohortes DP et DF. L’âge moyen au diagnostic était de 60,5±15ans et le poids moyen de 79,2±17,3kg. Le suivi médian était de 3,4ans [min–max : 1,1–6,3] dans le groupe DP contre 2,0ans [1,1–2,7] dans le groupe DF. Des évènements indésirables ont été observés chez 59,6 % des patients et 24 patients ont présenté un imEI de grade ≥ 3. À 1 an, 4 toxicités de haut grade sont survenues dans le groupe DP (6,1 %) contre 16 dans le groupe DF (6,1 %). Aucune différence significative n’a été observée entre les deux groupes : HR (95 %CI) 0,54 [0,21–1,36], p=0,19. La survie globale à 1 an semble être significativement différente entre les deux groupes : 52,6 vs 88,0 % dans les groupes DP et DF, respectivement (p<0,001).Discussion - ConclusionCette étude n’a pas montré de différence significative entre DP et DF en ce qui concerne la survenue d’imEI. Ce résultat vient confirmer les quelques données déjà publiées (Samlowski et al, Cancer Med. 2023 ; et Likura et al, Health Sci Rep. 2022). De plus, il faut rester prudent sur l’analyse des données de survie, en effet, les cohortes sont suivies sur une période de données différente dans le temps, avec une évolution naturelle de la prise en charge des mélanomes avancés. Des études prospectives sont attendues pour confirmer ces résultats de vie réelle.

Background Despite the use of closed system drug transfer devices (CSTDs), residual contamination by antineoplastic drugs is still retrieved inside isolators.1 Improving the chemical decontamination process has been proposed to reduce this contamination more efficiently. Purpose This study aimed to assess the decontamination efficiency inside isolators of two different decontamination processes associated with a CSTD. Material and methods A comparative and prospective study was performed in a new opening compounding unit. Compounding was performed with a CSTD (BD-Phaseal, Becton-Dickinson). 8 drugs (cyclophosphamide, cytarabine, dacarbazine, fluorouracil, gemcitabine, ifosfamide, irinotecan and methotrexate) were monitored daily for 14 consecutive weeks in 3 locations inside the isolators: gloves, workbench and window. Drugs were alternatively compounded in one or the other isolator on even and odd days. In one isolator (C), the cleaning process was performed daily with a standard biocide solution (Anioxyspray, Anios). In the other (I), a weekly decontamination with an admixture of sodium dodecyl sulfate 10-2 M/isopropanol (70/30) was added.2 Monitoring was performed by a validated LC-MS/MS method. The results are presented as OR of contamination between the two groups and as overall decontamination efficiency (EffQ%) in each group. This latter parameter was computed according to Anastasi, as follows: EffQ=1–(sum of all contaminations after decontamination process (ng)/sum of all contaminations before decontamination process (ng)). The proportion of EffQ >90% was compared using Fisher's exact test. Results The overall contamination rates (CR) after the daily cleaning/decontamination process were significantly different between the two groups: CRC=25.3% versus CRI=10.4% (OR=0.341; p<0.0001). The mean overall EffQ was significantly higher in the intervention group (I: 61.0±41.5% vs C: 42.4±37.3%), but was very variable depending on the drug analysed. Decontamination was more effective for both cyclophosphamide and gemcitabine. The proportion of days with an EffQ >90% was higher in the intervention group (I: 42.9% vs C: 7.1%; p=0.077). Conclusion Combining a decontamination protocol including a tensioactive agent to a CSTD leads to better control of contamination inside isolators. Improving decontamination frequency will be further studied. References and/or acknowledgements Simon, et al. PLOS One2016. Anastasi, et al. Ann Occup Hyg2015. Conflict of interest: Corporate sponsored research or other substantive relationships: The study was funded by Becton-Dickinson laboratories. Data analysis and interpretation and the writing of all scientific communications were performed independently of the funder.

Background The use of a post-administration rinsing process for intravenous antineoplastic drugs is very common to help to control occupational exposure to them. In paediatric haemato-oncology, drugs are often compounded in syringes to reduce the volume to be infused. In this case, extension sets with low deadspace volume are used but the required volume to rinse is not clearly specified. Purpose The aims of this study were to propose a simple methodology to assess the rinsing volume of syringe extension sets and to compare several marketed devices. Material and methods A UV spectrophotometry assay using quinine hydrochloride as drug substitute was developed. Quinine concentration ranged from 20 to 200 µg/mL. The assay was validated with the accuracy profile method and tested on 5 different assemblies (device+extension sets) with different deadspace volumes (1.28–2.80 mL) and at two different quinine concentrations (0.3 and 8.0 mg/mL). Rinsing was performed stepwise with water for injection until reaching an undetectable quinine concentration. After fitting the data with a Weibull model, assemblies were compared with an ANOVA performed on ranks (GraphPad, La Jolla, USA). Results The within day and between day precision ranges were 0.39–0.81% and 0.48–0.84%, respectively. The lower limit of quantification was 4.26 µg/mL. The volume required to completely rinse the infusion line was different according to the initial drug concentration and to the device assessed: from 6 to 10 mL for a low quinine concentration and from 7 to 17 mL for a high quinine concentration. Conclusion This study shows that a simple, cheap and easy to use methodology may be used to assess the rinsing volume of syringe extension sets. The rinsing volume is different according to the tested device. References and/or acknowledgements The author thank each supplier who provided free samples for the experiments. No conflict of interest

La prise en charge du mélanome avancé ou métastatique a beaucoup évolué ces dernières années avec notamment la mise sur le marché des thérapies ciblées orales (TCO). Avec ces médicaments, de nouvelles problématiques apparaissent dans la prise en charge des patients dont la gestion des effets indésirables au domicile, l’adhérence au traitement et le risque d’interactions médicamenteuses avec les autres traitements du patient pouvant diminuer l’efficacité ou augmenter la toxicité. Afin de sécuriser la prise en charge des patients, une consultation pharmaceutique a été mise en place. Le but de ce travail est de présenter les premiers résultats du suivi pharmaceutique réalisé. Six patients chez lesquels une TCO a été initiée étaient inclus depuis janvier 2017 dans une étude prospective de faisabilité. La consultation pharmaceutique avait lieu le jour de l’initiation de la TCO après la consultation médicale afin d’informer le patient sur la TCO et de réaliser une conciliation médicamenteuse pour établir la liste exhaustive des traitements pris à domicile. Puis, une analyse des interactions médicamenteuses entre la TCO et les autres traitements était réalisée. Une consultation pharmaceutique de suivi à 1 mois était réalisée. Le nombre d’interactions médicamenteuses, d’interventions pharmaceutiques (IP) et l’adhérence au traitement à l’aide du score de Morisky étaient évalués. Les 6 patientes sont des femmes et la moyenne d’âge est de 56,8 ans (min : 42 ; max : 77). Les TCO concernées sont l’association dabrafénib + tramétinib dans 3 cas et vémurafénib + cobimétinib dans 3 cas. Seules 2 patientes étaient revues à 1 mois, le traitement ayant été arrêté pour iatrogénie pour 4 patientes. Au total, 11 interactions médicamenteuses étaient retrouvées lors de la consultation initiale (moy : 1,8 ; min : 0 ; max : 3) et 5 interactions médicamenteuses lors de la consultation à 1 mois. Les médicaments impliqués étaient les antiacides dont l’ésoméprazole dans 6 cas, les corticoïdes dans 3 cas, les antiémétiques dans 2 cas, les anxiolytiques et hypnotiques dans 3 cas et les neuroleptiques dans 1 cas. Une interaction avec l’alimentation entérale étaient relevée. Les IP ont conduit à un arrêt du traitement associé à la TCO dans 2 cas, une modification de posologie dans 2 cas, un suivi clinique dans 2 cas, une optimisation des modalités d’administration dans 1 cas et une réévaluation de la prescription dans les autres cas. L’adhérence au traitement à 1 mois était cotée à 7/8 (adhérence moyenne) et 8/8 (bonne adhérence). Ces premiers résultats montrent un réel risque d’interactions médicamenteuses et de iatrogénie avec les TCO. L’adhérence semble globalement bonne mais ces chiffres doivent être confirmés sur un échantillon plus grand. Une prise en charge pluridisciplinaire avec un temps dédié pour un pharmacien est nécessaire pour optimiser la prise en charge des patients.

Background Closed system drug transfer devices (CSTD) may significantly reduce the contamination of isolators to antineoplastic drugs,1 but persisting contamination remains. To date, no data are available to determine which of the CSTD or the cleaning process is mostly involved in contamination reduction. Purpose To describe the relative contribution of CSTD and the cleaning process in the control of occupational exposure inside isolators. Material and methods A comparative and prospective study was performed over 6 months in a new compounding unit equipped with two new isolators. Spikes and needles were used in one isolator and a CSTD (BD-Phaseal, Becton-Dickinson) was used in the other one. A standard biocide (Surfa'safe, Anios, Lezennes, France) was used daily in both isolators. 10 drugs (cyclophosphamide, cytarabine, dacarbazine, doxorubicin, fluorouracil, ganciclovir, gemcitabine, ifosfamide, irinotecan and methotrexate) were monitored on three locations inside each isolator: gloves, workbench and window. Drugs were alternatively compounded in one or the other isolator between even and odd days. Sampling was performed before and after the daily cleaning on 24 sampling days progressively spaced over 6 months during the study. Monitoring was performed by a validated LC-MS/MS method. Probability of contamination for each drug was analysed using logistic models with repeated measures (PROC GLIMMIX, SAS version 9.4, SAS Institute Inc., Cary, NC, USA). Results Since dacarbazine, doxorubicin, irinotecan and methotrexate were never or very rarely retrieved, our analysis included 6 drugs. For cyclophosphamide, cytarabine, ganciclovir and ifosfamide, the use of a CSTD was significantly associated with a risk reduction of contamination, either independently of other predictors or in interaction with time, leading to a risk reduction from about 70% for cytarabine to 98% for ganciclovir. For all drugs, except cyclophosphamide, the cleaning process alone or in interaction with time and/or localisation was significantly associated with a reduction in contamination by about 30% for gemcitabine to 80% for ifosfamide. Conclusion This study shows that the CSTD plays a major role for most drugs in controlling the occupational exposure inside isolators. Combining a CSTD and an improved decontamination process is required to remove the residual contamination by antineoplastic drugs. References and/or acknowledgements Simon, et al. PLOS One2016. Conflict of interest: Corporate sponsored research or other substantive relationships: The study was funded by Becton-Dickinson laboratories. Data analysis and interpretation, and the writing of all scientific communications, were performed independent of the funder.

Background Closed-system transfer devices (CSTD) are promoted in all recommendations to reduce the occupational exposure to antineoplastic drugs during the compounding process. Numerous in vitro studies have shown that using the PhaSeal system may limit chemical contamination. Purpose To compare the chemical contamination inside isolators between a standard (S) and a PhaSeal (P) compounding process in routine practice. Material and methods A 6-month prospective study started at the opening of a new compounding unit (checked as not contaminated). Two isolators with 2 workstations were used, one to compound with standard devices (needles and spikes) and the other one using the PhaSeal devices. Drugs were alternatively compounded in each isolator (90 preparations/day). Sampling was performed by wiping three surfaces (gloves, window (inner surface), worktop), before and after a cleaning process. Exposure to ten antineoplastic drugs (cyclophosphamide, ifosfamide, dacarbazine, 5-FU, methotrexate, gemcitabine, cytarabine, irinotecan, doxorubicin and ganciclovir) was evaluated on wipes by LCMSMS analysis. Contamination rates (% of samples revealing contamination) were compared using a Chi2 test and the drug amounts by a Mann-Whitney test. Significance was defined as p < 0.05. Results 655 samples were analysed (P: n = 327, S: n = 328). The amounts of drugs compounded in each isolator were not significantly different, excepted for methotrexate. The overall contamination rate before cleaning was significantly lower in the PhaSeal isolator (P: 12.6% vs. S: 25.4%; <0.0001). Both isolators were mainly contaminated before cleaning by gemcitabine (P: 295.9 vs. S: 224.7 ng; p < 0.67) and cyclophosphamide (P: 139.7 vs. S: 575.8 ng; p < 0.03). Only traces of methotrexate were retrieved one time in each isolator. Conclusion This study demonstrates that using a CSTD significantly reduces the overall contamination without cancellation. This intermediate analysis will be implemented by an analysis of the drug amounts handled and the occurrence of incidents. Reference Sessink PJ, Trahan J, Coyne JW. Reduction in surface contamination with antineoplastic drugs in 22 hospital pharmacies in the US following implementation of a closed-system drug transfer device. Hosp Pharm 2013;48(3):204–12 Conflict of interest

Background For several years, many infusion systems have been marketed for the administration of antineoplastic drugs (AD). Purpose To compare the ability of these devices to deliver the expected volume of antineoplastic drug in solution. Material and methods Seven infusion devices were assessed (see table 1) by simulated infusions with a radiotracer (99mTcO4−) as drug substitute. The same activity (370 MBq) was diluted in 250 mL 0.9% NaCl bags. The evolution of the drug concentration at the egress of the infusion system was recorded continuously with a sodium iodine crystal detector. The area-under-curve of drug concentration according to time of both administration (AUCadm) and rinsing (AUCrin) steps were calculated using the linear trapezoidal rule after correcting for radioactivity decay. The rinsing volumes (Vrin), volumes required to get no more radioactivity, were measured in a graduated test tube. The values were compared using a Kruskall-Wallis test (p < 0.05). Results Despite the differences in dead-space volume, AUCadm were not significantly different (see table 1). The rinsing volumes were significantly different between the tested devices, ranging between 46.8 ± 5.7 mL and 92.2 ± 8.9 mL. Conclusion The rinsing conditions required to administer the same dose are really different between devices. The impact of good handling practice of these devices has to be assessed on the pharmacokinetic parameters. Reference Kontny NE, Boos J, Würthwein G, et al. Minimization of the preanalytical error in pharmacokinetic analyses and therapeutic drug monitoring: focus on IV drug administration. Ther Drug Monit 2012;34:460–6 No conflict of interest.

Background Intraspinal administration errors are identified in the list of ‘never events’ of the French Health Authority (ANSM). New devices with different connectors incompatible with standard Luer-lock connectors (Univia syringe, Becton-Dickinson) could be used to make the spinal administration of cytotoxic drugs safer. Purpose To perform a feasibility study regarding to the minimum capacity (2 mL). Materials and methods A comparative study between Univia (U, 2 ml) and Tuberculin (T, BD) syringes was performed. Volumes of water (0.6mL, 0.48mL, 0.15mL, 0.1mL) simulating usual volumes of cytotoxics were measured by an operator and weighed on a precision scale (n = 30). For each volume, accuracy (%) and precision (CV%) were determined. A difference of 10% from the nominal volume was the chosen threshold. Results For U, the accuracy was 0.2%, 6.5%, 11.2% and 21.8% for 0.6, 0.48, 0.15 and 0.1 mL, respectively. It was 1.2%, 2.0%, 6.1% and 6.1% for T. For U, the precision was 2.4%, 2.3%, 5.9% and 6.2% for 0.6, 0.48, 0.15 and 0.1 mL, respectively whereas it was 1%, 1.0%, 7.3% and 8% for T. Accordingly, the volumes of 0.6 and 0.48 mL may be prepared with U. For both, 0.15 and 0.1 mL, a transfer step with a tuberculin syringe increases both accuracy (3.9%) and precision (3.9%). Conclusions This study suggests the possibility of using U to compound cytotoxic drugs for intraspinal injection. It remains to evaluate the practical constraints related to the administration. No conflict of interest.

INTRODUCTION:For 1 year, our unit has been equipped with portable H₂O₂ Dräger detectors contributing to protect the staff from a possible exposure to this odourless and toxic gas. This work shows the current available data about H₂O₂ toxicity, describes the organization of the implementation and the analysis of the values measured over 12 months. MATERIAL AND METHODS:Data about H₂O₂ toxicity have been obtained through a literature review. The measured values are presented in instantaneous value and occupational exposure limit (OEL) over 8 h. RESULTS:Over six technicians, the average percentage, of detected values superior to zero reached 1.06% in August. The detected maximum instantaneous value reached 2.2 ppm in May. These isolated exposures have little incidence when related to the 8-h exposure with an occupational exposure limit (OEL) of 0.072 ppm over 12 months. DISCUSSION AND CONCLUSION:The implementation of this tool has allowed to highlight a technical problem of the sterilization airlock that could be resolved. This measuring device of H₂O₂ concentration in the air in real time allows to secure everyday working conditions and to alert the staff of a possible technical failure. However, literature data regarding chronic toxicity are limited and restrict the analysis of the measured values.

Background When pharmacy staff is not available, nurses used to prepare diluted busulfan solution from commercial vials just before administration because of its low stability. Doing this without protection may cause occupational exposure to this cytotoxic drug. Purpose To devise a new protocol and perform a preliminary evaluation. Materials and Methods Literature and technical studies were performed to choose the best devices. Nurses and physicians performed a clinical evaluation using a 5-item satisfaction form. Results Medical devices containing polycarbonate must be avoided because of the interaction with N,N-dimethylacetamide used as an excipient. The new protocol consists of an individual kit with the commercial solution packed in a syringe, an infusion bag with the exact volume of diluent and a closed system transfer device (CSTD). Nurses just have to dilute the solution into the bag under a laminar air-flow hood using the CSTD. Although 2-part syringe methods were found in the literature, 3-part syringes with limited contact between the elastomeric tip and busulfan solution (reference 62.8426, Codan) were chosen because leaks were observed with the 2-part syringes during the technical study. PhaSeal devices: Injector to close the syringes and a Connector-Luer for infusion bags were selected as CSTDs. All these devices are polycarbonate free. 7 new kits were prepared for a period of 8 days without contact. The results of the evaluation show that nurses and physicians (n = 14) were overall dissatisfied by the previous protocol (neither good nor bad: 35.7%, bad: 21.4% and very bad: 35.7%) while the majority preferred the new one (very satisfied: 28.6%, satisfied: 42.9%, neither good nor bad 7.14%, no response: 21.4%). Overall nurses and physicians answered that new modalities limit the risk of dose errors (93%) and occupational exposure (86%). Conclusions Implementing this procedure has improved handling practise with good satisfaction. No conflict of interest.