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Introduction Cefiderocol is a new siderophore time-dependent antibiotic of last resort. The manufacturer reports a stability of 6 hours for the infusion solution diluted in normal saline (NS) or dextrose 5% in water (D5W) for a concentration between 7.5 and 20 mg/mL. Optimising its effectiveness by continuous infusion is crucial. The aim of this work was to study the physicochemical stability of cefiderocol diluted in NS or D5W in polypropylene syringes for 48 hours at a concentration of 62.5 mg/mL stored at room temperature, protected or not from light. Materials and methods Three preparations for each condition were performed. At each time of the analysis, one sample for each preparation was analysed in triplicate by a validated high performance liquid chromatography method coupled to a photodiode array detector at 260 nm. Particle contamination, absorbance measurement, visual inspection and pH measurement were assessed. The limit of stability was set at 90% of the initial concentration, without physical modification. Results The linearity was validated with an R² of 0.9999. The coefficients of variation for repeatability and intermediate precision were less than 2%. In NS and D5W, cefiderocol retained more than 90% of the initial concentration after 12 hours in syringes, exposed or not to light. Two degradation products (nos 2 and 11, observed during forced degradation) were detected during the stability study. The absorbance at 410 nm increased progressively, regardless of the storage conditions. The particulate contamination test met the specifications of the container. pH values were all between 5.22 and 5.32. No visual changes were detected. Conclusion In polypropylene syringes, cefiderocol 62.5 mg/mL (3 g in 48 mL) diluted in NS or D5W was stable for 12 hours at room temperature. These new data allow the use of cefiderocol in continuous infusion.

Objectives Azacitidine is a pyrimidine nucleoside analogue whose stability is temperature dependent. Numerous publications have studied the stability of this drug with discordant results. The purpose of this work is to study the stability of azacitidine suspensions under different conditions to allow preparation in advance: vials stored at room temperature or between 2 and 8 °C, reconstituted with refrigerated water for injection (WFI) or frozen/thawed WFI, azacitidine suspensions stored at room temperature, 2–8 °C or at −20 °C. The feasibility of a vented ChemoClave® Spike vial was also tested to reconstitute and collect azacitidine to aid the preparation stage. Methods The stability study was performed by HPLC coupled to a photodiode array detector. The method was validated according to ICH Q2(R1). Two syringes were prepared for each analysis condition and two samples were realised for each syringe at each time of the analysis. For a storage at 2–8 °C, analyses were performed for up to 168 h. The stability was studied after 2 h at room temperature. For frozen storage, the stability was studied after 28 days. Results Azacitidine 25 mg/mL suspensions stored between 2 and 8 °C, prepared with refrigerated WFI or frozen/thawed WFI, retained more than 90% of the initial concentration for 96 h and then for 2 h at room temperature. Prepared with frozen/thawed WFI, azacitidine 25 mg/mL suspensions stored at −20 °C for 28 days and then 72 h between 2 and 8 °C after thawing, retained more than 90% of the initial concentration. When using a Spike system compared to using a needle for reconstitution and collection of the suspension, the results obtained by HPLC showed a decrease of 1.47% in the concentration of azacitidine. The comparisons of the volumes withdrawn after reconstitution were similar when using a Spike system or a needle. Conclusions Azacitidine 25 mg/mL suspensions reconstituted with refrigerated WFI were chemically stable for 4 days when stored at 2–8 °C whatever the storage of vials (refrigerator or room temperature), and 2 h at room temperature. A storage of azacitidine 25 mg/mL suspensions in syringes prepared with frozen/thawed WFI at −20 °C has been validated for up to 28 days, leading to the possibility to prepare in advance. A Spike device can be used to reconstitute and collect azacitidine.

Objectives Patients hospitalized in intensive care units often require multiple drug infusions. Due to limited intravenous accesses, concomitant administration of drugs in the same infusion line is often necessary. Compatibility studies of Y-site administration are available in the literature, but data of several combinations are lacking. Previous work from d’Huart et al. have performed an observation of the administration of injectable drugs in three adults ICUs and identified a list of Y-site administration without compatibility data. The objective of this study was to test the physical compatibility of the main drugs of this list used in pairs in Y-site infusions in critical care units, in order to provide new compatibility data to the literature, and to secure the administration of intravenous drugs. Methods The physical compatibility in Y-site of nine drugs with other drugs commonly used in intensive care units has been tested. Examinations were performed on 75 mixtures after their preparation, after 1 and 4-h storage. This evaluation included a visual examination with a search for precipitation formation, color change, gas formation, and a subvisual evaluation: absorbance measurements by UV-visible spectrophotometry at 350, 410 and 550 nm, and Light Obscuration Particle Count Test. The pH evaluation was performed at each time of analysis. Results Laboratory tests led to an overall compatibility of 68.0% for all mixtures obtained in this study. Nefopam was found to be quite compatible with other drugs (95.0%). Amiodarone hydrochloride (84.6%), acetylsalicylic acid (80.0%), clonidine hydrochloride (75.0%) and insulin (71.4%) were compatible with other drugs too. Atenolol (42.9%), furosemide (25.0%), heparin sodium (25.0%) showed less compatible results. Pantoprazole sodium (0.0%) was not at all compatible with the other drugs analyzed. Conclusions By the results of these laboratory tests, missing compatibility data are now available, providing additional information to the literature.

Background Cefotaxime sodium is an antibiotic used to treat severe infections such as in intensive care units (ICUs). The recommended dose of cefotaxime sodium can vary from 3 grams (g) to 24 g per day and publications have demonstrated that continuous administration of cefotaxime sodium is the preferred mode of administration. In ICUs, a minimum volume is used for patients requiring fluid restriction, leading to high concentrations of cefotaxime sodium. The objective was to study the stability of cefotaxime sodium solutions at 83.3 mg/mL and 125 mg/mL, diluted in 0.9 % sodium chloride (0.9 % NaCl) or in 5 % glucose (G5 %), stored in polypropylene syringes, after the preparation and after a 6-hour and a 12-hour storage at 20–25 °C. Methods Three syringes for each condition were prepared. At each time of the analysis, three samples for each syringe were prepared and analysed by high performance liquid chromatography (HPLC) coupled to a photodiode array detector. The method was validated according to the International Conference on Harmonisation Q2(R1). Physical stability was evaluated by visual and subvisual inspection (turbidimetry by UV spectrophotometry at 350, 410 and 550 nm as recommended by the European Consensus Conference). pH and osmolality values were measured at each time of the analysis. Results For each solvent, cefotaxime sodium solutions at 83.3 mg/mL and 125 mg/mL retained more than 90 % of the initial concentration after 12 hours. During the stability study, pH values decreased slightly, the intensity of the yellow colour increased and values of absorbance increased progressively for each wavelength and each condition. An additional peak with a relative retention of 3.01 was also observed after the forced degradation gradually increased up to 4.01 % and 3.17 % of the total of surface area of the peaks present on the chromatogram after 12 hours in 0.9 % NaCl and in G5 % respectively. Conclusions In view of the results and despite the fact that solutions retained more than 90 % of the initial concentration after HPLC analysis, we propose to limit the stability of cefotaxime sodium in 0.9 % NaCl and G5 % at 83.3 and 125 mg/mL at 6 hours. These stability data of highly concentrated solutions provide an additional knowledge to assist ICUs in daily practice. This work also demonstrates that highly concentrated cefotaxime sodium solutions are physically unstable after a 6-hour storage and cannot be administered as a daily infusion.

Background The objectives were to perform an observation of the administration of injectable drugs in three ICUs, to identify injectable drugs administered by Y-site infusion or mixed in the same container, to compare with physical compatibility data available in the literature and to test the physical compatibility for missing data. Methods An observational study was realised over two weeks and patients receiving more than one injectable drug in the same line simultaneously were included. Physical compatibilities were assessed in pairs by comparing with three databases. For some missing data, three tests were realised for pairs including an anti-infective drug. Visual and subvisual evaluations were performed after the preparation, 1 and a 4-hour storage. Results A total of 389 combinations between two injectable drugs was observed for Y-site infusions and 31 mixtures in the same container. According to the literature, 21.1 % associations were physically compatible, 1.8 % as physically compatible potentially, 8.0 % as physically incompatible, 6.4 % have divergent data according to the databases and 62.7 % have no data. Two mixtures were documented. 37 pairs were tested and 70.3 % were physically compatible, 8.1 % were physically incompatible after visual evaluation and 21.6 % after subvisual evaluation. Conclusions In the majority of cases, no compatibility data are available in the literature. Laboratory tests give additional information.

Background and importance Vancomycin is a time dependent antibiotic of the glycopeptide family. The recommended dose of vancomycin is 30–40 mg/kg/day. For an adult, the maximum daily dose can reach 4 g. In clinical practice, vancomycin is mostly administered by continuous infusion. After hospitalisation, administration of concentrated solutions in elastomeric devices would allow a home care service and a better quality of life for the patient. Aim and objectives The objective of this work was to study the stability of vancomycin solutions at 37.5 mg/mL (4.5 g in 120 mL of solvent) diluted in 0.9% sodium chloride (0.9% NaCl) or in dextrose 5% in water (D5W), in elastomeric devices, protected from light, at 37°C for 48 hours. Material and methods Chemical stability was analysed by high performance liquid chromatography coupled to a photodiode array detector and by pH measurements after preparation, after 24 hours and 48 hours of storage. The method was validated according to the International Conference on Harmonisation Q2 (R1). Three elastomeric devices for each condition were prepared. Physical stability was evaluated by a visual and subvisual inspection at each time of analysis (turbidimetry by UV spectrophotometry at three wavelengths: 350, 410 and 550 nm). Results For each solvent, solutions at 37.5 mg/mL retained more than 90% of the initial concentration for 48 hours: for 0.9% NaCl (minimum 96.49%±1.12%; maximum 100.94%±0.51%) and for D5W (minimum 102.75%±1.19%; maximum 104.67%±1.15%). During the study, pH values did not decrease after 48 hours in the two solvents. During the subvisual examination, there was no significant difference between the different analysis times regardless of the solvent used. No colour change was reported during the study. Conclusion and relevance Vancomycin solutions at 37.5 mg/mL in 0.9% NaCl and D5W were stable in elastomeric devices for 48 hours at 37°C, protected from light. Home administration for this concentration is possible. References and/or acknowledgements Conflict of interest No conflict of interest

Background and importance Cloxacillin is an antibiotic indicated in methicillin sensitive Staphylococcus aureus infections. The usual curative dosage ranges from 8 to 12 g/day, divided into 4–6 daily administrations. Continuous infusions are frequently used in the intensive care unit. The administration of concentrated solutions in an electric syringe pump would reduce the water supply and the number of daily intakes. Aim and objectives The objective was to study the stability of cloxacillin solutions at 125 mg/mL diluted in 0.9% sodium chloride (0.9% NaCl) and in dextrose 5% in water (D5W), stored in polypropylene syringes, unprotected from light, at 20–25°C for 48 hours. Material and methods Chemical stability was analysed by high performance liquid chromatography coupled to a photodiode array detector and by pH determination after preparation, and after storage for 6, 24 and 48 hours. The analytical method was validated according to the International Conference on Harmonisation Q2 (R1). Four syringes for each condition were prepared. Physical stability was evaluated by visual and subvisual inspection (turbidimetry by UV spectrophotometry at 350, 410 and 550 nm). Results For each solvent, solutions at 125 mg/mL retained more than 90% of the initial concentration for 24 hours: for 0.9% NaCl (minimum 96.57%±1.69%; maximum 95.96%±1.38%) and for D5W (94.96%±1.38%; 98.08%±0.48%). After 48 hours of storage, the solutions contained 1 pH unit after 48 hours for both solvents. During the subvisual examination, absorbance values at 410 and 550 nm increased after 48 hours. A colour change was observed at 48 hours (from colourless to very slight yellow) in 0.9% NaCl. In D5W, the solutions stained more quickly; a very slight yellow colouration was visible after 6 hours of storage which intensified after 24 and 48 hours. Conclusion and relevance Cloxacillin solutions at 125 mg/mL in 0.9% NaCl and D5W were stable in polypropylene syringes for 24 hours at room temperature. The solutions were unstable after 48 hours of storage. References and/or acknowledgements Conflict of interest No conflict of interest

Background and importance Patients hospitalised in intensive care units (ICUs) often require the use of multiple drugs, and the intravenous (IV) route is the most common mode of administration. IV access is usually limited, leading to concomitant administration of different drugs in the same infusion line. A previous work1 identified many administrations via a Y site without compatibility data. A list of missing data was established. Aim and objectives From this list, we decided to evaluate the physical compatibility of two drugs frequently administered (acetylsalicylic acid and atenolol) with other drug used in ICUs by visual tests, subvisual tests and pH measurement. Material and methods Each pair of drugs was mixed in three ratios (drug A/drug B: 9/1; 5/5; 1/9). Visual analysis, such as precipitation formation, colour change, gas formation, subvisual evaluation by UV spectrophotometry at 350, 410 and 550 nm, and pH measurements were performed for each mixture. Results A total of 17 pairs of two drugs were tested: 10 mixtures with acetylsalicylic acid and seven mixtures with atenolol. For the mixtures with acetylsalicylic acid, eight were compatible pairs and two were incompatible pairs: acetylsalicylic acid with canreonate potassium (precipitate formation) and with Nutryelt (colouring in pink). For the mixtures with atenolol, five were compatible pairs and two were incompatible pairs: atenolol with mycophenolate (appearance of haze) and with Nutryelt (colour change). Conclusion and relevance After laboratory tests, new incompatibilities were found which gives additional information to the literature. This study demonstrated that all mixtures were compatible except for acetylsalicylic acid with canreonate potassium and Nutryelt, and atenolol with mycophenolate and Nutryelt. However, many other mixtures should be studied due to missing data. References and/or acknowledgements D’Huart, et al. Pharm Technol Hosp Pharm 2019;4:29–40. Conflict of interest No conflict of interest

Background and importance Ceftolozane/tazobactam is a combination of a new third generation cephalosporin and a β-lactamase inhibitor used to treat infections caused by multidrug resistant Pseudomonas aeruginosa. The usual dose is 3 g/day. To the best of our knowledge, no stability data for ceftolozane/tazobactam at 62.5 mg/mL in polypropylene syringes (PS) for intensive care units or at 25.0/12.5 mg/mL in elastomeric devices (ED) for home administration have been published. Aim and objectives The objective was to study the stability of ceftolozane/tazobactam solutions at 62.5/31.25 mg/mL, diluted in 0.9% sodium chloride (0.9% NaCl) or dextrose 5% in water (D5W), in PS after storage at 20–25°C, not protected from light, and solutions at 25.0/12.5 mg/mL diluted in 0.9% NaCl or D5W in ED after storage at 37°C, during a 48 hour period. Material and methods Three preparations for each condition were prepared. At the time of analysis, one sample for each preparation was analysed by a validated high performance liquid chromatography method coupled to a photodiode array detector at 220 nm. Physical stability was evaluated by visual and subvisual inspection (turbidimetry by UV spectrophotometry at 350, 410 and 550 nm, as recommended by the European Consensus Conference). pH values were measured. Results Linearity was validated with an R² of 0.9999. The coefficients of variation on repeatability and intermediate precision were Conclusion and relevance In ED, ceftolozane/tazobactam was unstable at 37°C in D5W and in 0.9% NaCl. Ceftolozane/tazobactam was stable at 62.5/31.25 mg/mL in PS diluted in 0.9% NaCl or D5W for 48 hours, allowing continuous intravenous infusion. References and/or acknowledgements Conflict of interest No conflict of interest

Background and importance Meropenem is a broad spectrum antibiotic used to treat severe infectious. The maximum dose recommended is 6 g/day. A stability not exceeding 24 hours has been demonstrated by many research teams in different publications. Only two studies were performed at 40 mg/mL in polypropylene syringes with conflicting stability results: 4 hours and 8 hours. Meropenem is a time dependent antibiotic; its continuous administration improves its efficiency. Aim and objectives The objective of this work was to study the stability of meropenem solutions at 41.7 mg/mL (2 g in 48 mL), diluted in 0.9% sodium chloride (0.9% NaCl) or dextrose 5% (D5W), in polypropylene syringes not protected from light, after preparation and after 4 and 8 hours at 20–25°C. Material and methods Three syringes for each condition were prepared. At the time of analysis, one sample from each preparation was analysed by high performance liquid chromatography coupled to a photodiode array detector at 297 nm. The method was validated according to the ICH Q2 (R1). Physical stability was evaluated by visual and subvisual inspection (turbidimetry by UV spectrophotometry at 350, 410 and 550 nm, as recommended by the European Consensus Conference). pH values were measured. Results The method was validated with an r² of 0.9999. The coefficients of variation on repeatability and intermediate precision were Conclusion and relevance In D5W, meropenem was unstable, with chemical and physical instability. Meropenem was stable at 41.7 mg/mL in polypropylene syringes diluted in NaCl 0.9% for 8 hours. This new stability data allows continuous administration. References and/or acknowledgements Curti C, et al. Stability studies of antipyocyanic beta-lactam antibiotics used in continuous infusion. Pharmazie 2019. Carlier M, et al. Stability of generic brands of meropenem reconstituted in isotonic saline. Minerva Anestesiologica 2014. Conflict of interest No conflict of interest

Background and importance Cefepime is a fourth generation cephalosporin used to treat severe infectious. For β-lactam antibiotics, publications have demonstrated that continuous administration is the preferred mode of administration. To the best of our knowledge, no stability data for cefepime solutions at 110 mg/mL in polypropylene syringes or at 50 mg/mL in elastomeric devices have been published. Aim and objectives The objectives of the study were to assess the stability of cefepime solutions (1) at 110 mg/mL, in 0.9% sodium chloride (0.9% NaCl) or 5% dextrose (D5W), in polypropylene syringes at 20–25°C and (2) at 50 mg/mL, in 0.9% NaCl, in elastomeric devices at 37°C, after preparation and after storage for 6, 24 and 48 hours. Material and methods Three preparations for each condition were made. For each analysis, one sample was taken from each preparation and analysed by high performance liquid chromatography. The method was validated according to the International Conference on Harmonisation Q2 (R1). Physical stability was evaluated by visual and subvisual inspection with a nephelometer. pH values were measured. Results In syringes, for each solvent, cefepime solutions at 110 mg/mL retained more than 90% of the initial concentration after 24 hours. No visual modification and no turbidity were observed. After 48 hours, the solutions retained around 83% of the initial concentration and pH values increased with the addition of 1 pH unit compared with the initial value. In elastomeric devices, cefepime solution in 0.9% NaCl at 50 mg/mL retained more than 90% of the initial concentration over a period of 6 hours. After 24 and 48 hours, the solutions retained around 83% and 59% of the initial value, respectively. After 6 hours, visual colour modifications were observed. Under this condition, the initial pH value was 4.81 and 6.18 after 24 hours. Conclusion and relevance The stability of cefepime in 0.9% NaCl and D5W at 110 mg/mL was demonstrated for 24 hours in syringes at 20–25°C. These stability data provide additional knowledge when performing continuous infusion of cefepime in syringe. In elastomeric devices, cefepime solution at 50 mg/mL in 0.9% NaCl stored at 37°C was unstable. These preparations are not recommended. In view of these results, the stability of cefepime in D5W in elastomeric devices was not studied. References and/or acknowledgements No conflict of interest.

Objectives Concomitant administration of two incompatible drugs in the same infusion line can lead to a precipitation which could have clinical consequences for patients. The objective of this work was to study the physical compatibility of injectable posaconazole with other drugs commonly used in an adult hematology care unit. Methods The most widely used injectable drugs co-administered with posaconazole have been listed with a total of 19 drugs. For some drugs, different conditions have been tested. A total of 24 solutions were produced (not including the posaconazole). In the absence of compatibility data, the physical compatibility was tested for each pair including one of the 24 solutions and posaconazole. For each pair studied, three different ratios were prepared (9:1, 1:1, 1:9). Visual evaluations were performed after the mixture, after one and 4 h. Results Seventy two mixtures have been realised: 55.56% of pairs (n=40/72) resulted in a precipitation, against 44.44% (n=32/72) with no visual modification after a 4-h storage. On the 19 drugs tested, only filgrastim and tacrolimus showed no visual change with posaconazole during a 4-h storage. Conclusions In majority of cases, posaconazole was not compatible with drugs having alkaline pH, commonly used in a hematology unit.

Background Many publications described sodium thiosulfate used to prevent the renal toxicity induced by cisplatin hyperthermic intraperitoneal chemotherapy. After around 60 or 90 minutes of hyperthermic chemotherapy, cisplatin was drained and then, sodium thiosulfate was infused by intravenous route. Sodium thiosulfate is used in two steps: a first step, at 9 g/m2 in 250 mL of 0.9 % sodium chloride over 10 minutes followed by a second step, at 12 g/m2 in 1000 mL of 0.9 % sodium chloride over 6 hours. The purpose of this work was to study the stability of sodium thiosulfate at 16 mg/mL in 0.9 % sodium chloride polyolefin bags 1000 mL and at 72 mg/mL in 0.9 % sodium chloride polyolefin bags 250 mL, at 25 °C, protected or unprotected from light. Methods Chemical stability was analysed by high performance liquid chromatography (HPLC) coupled to a photodiode array detector after preparation and after 6-hour or 24-hour storage. The method was validated according to the International Conference on Harmonisation (ICH). Physical stability was evaluated by visual and subvisual inspection (turbidimetry by UV spectrophotometry at 550 nm). Three bags for each condition were prepared. On each time of the analysis, three samples were prepared for each bag and analysed by HPLC. pH values were evaluated on each moment of the analysis. Results Sodium thiosulfate solutions diluted in 0.9 % sodium chloride at 16 and 72 mg/mL retained more than 95 % of the initial concentration during 24 hours. Concerning pH measurements, the maximum variation was 0.24 pH unit. No visual modification such as colour change, precipitation or gas formation was observed. The absorbance at 550 nm obtained for each sample was less than 0.010 AU. Conclusions Sodium thiosulfate solutions at 16 mg/mL in 1000 mL 0.9 % sodium chloride and at 72 mg/mL in 250 mL 0.9 % sodium chloride are stable physically and chemically over a period of 24 hours at 25 °C, with or without protection from light. This stability study allows the use of sodium thiosulfate in renal protection protocols during cisplatin hyperthermic intraperitoneal chemotherapy.

Background: In severe infections, high-concentration vancomycin may be administered by continuous infusion. The dosage of vancomycin may reach 60 mg/kg per day. Objectives: To study the feasibility of preparing high-concentration vancomycin solutions (40 to 83.3 mg/mL), to study the effect of an electric syringe pump on the physical stability of high-concentration vancomycin, and to study the stability of vancomycin 62.5 and 83.3 mg/mL in 0.9% sodium chloride (0.9% NaCl) or 5% dextrose in water (D5W) with storage up to 48 h at room temperature. Methods: The following sets of syringes were prepared: (1) 4 syringes of vancomycin in 0.9% NaCl for each of 5 concentrations between 40 and 83.3 mg/mL (total 20 syringes); (2) 6 syringes at 83.3 mg/mL in 0.9%NaCl and 6 syringes at 83.3 mg/mL in D5W; and (3) 30 syringes at 83.3 mg/mL in D5W. Visual inspection was performed for all 3 syringe sets, and subvisual inspection for sets 1 and 2 (for periods of 24 h for set 1 and 48 h for sets 2 and 3). One syringe of vancomycin 83.3 mg/mL with each solvent was inserted into an electric syringe pump, and samples from the infusion line and collected after transit through the pump were inspected visually. Chemical stability was evaluated by high-performance liquid chromatography, and physical stability, pH, and osmolality were investigated. Results: For all sets of syringes, no physical modification was observed over time, nor were any changes observed after transit through the electric syringe pump. In 0.9% NaCl, vancomycin 62.5 and 83.3 mg/mL retained more than 90% of the initial concentration after 48 and 24 h, respectively; however, for the 83.3 mg/mL solution, precipitate was visible after 48 h. In D5W, vancomycin at 62.5 and 83.3 mg/mL retained more than 90%of the initial concentration after 48 h. Conclusion: It was feasible to prepare high-concentration solutions of vancomycin. The electric syringe pump did not cause any precipitation. Vancomycin in D5W at 62.5 and 83.3 mg/mL was stable over 48 h at room temperature. Precipitation occurred in 0.9% NaCl. D5W is therefore recommended as the solvent for this drug.RÉSUMÉContexte : En cas d’infection grave, de la vancomycine à forte concentration peut être administrée par perfusion continue à une dose pouvant atteindre 60 mg/kg par jour. Objectifs : Mener une étude de faisabilité portant sur la préparation de solutions de vancomycine à forte concentration (de 40 à 83,3 mg/mL); étudier l’effet d’un pousse-seringue électrique sur la stabilité physique de la vancomycine à forte concentration; et étudier la stabilité de la vancomycine (62,5 et 83,3 mg/mL) dans une solution de chlorure de sodium à 0,9 % (NaCl à 0,9 %) ou dans une solution aqueuse de dextrose à 5 % (D5W) après 48 h à la température ambiante.Méthodes : Trois ensembles de seringues ont été préparés : (1) quatre seringues de vancomycine dans une solution de NaCl à 0,9 %, à chacune des cinq concentrations comprises entre 40 et 83,3 mg/mL (20 seringues au total); (2) six seringues à 83,3 mg/mL dans une solution de NaCl à 0,9 % et six seringues à 83,3 mg/mL dans une solution de D5W; et (3) 30 seringues à 83,3 mg/mL dans une solution de D5W. Une inspection visuelle des trois ensembles de seringues et une inspection « sous-visuelle » des ensembles 1 et 2 ont eu lieu (période de 24 h pour l’ensemble 1 et de 48 h pour les ensembles 2 et 3). Une seringue contenant de la vancomycine à 83,3 mg/mL mélangée à chaque solvant a été insérée dans un pousse-seringue électrique, et les échantillons prélevés dans le tube de perfusion et ceux recueillis après leur passage dans la pompe ont été inspectés visuellement. La stabilité chimique a été évaluée par chromatographie liquide à haute performance et la stabilité physique, le pH ainsi que l’osmolalité ont eux aussi été étudiés. Résultats : Les trois ensembles de seringues n’ont présenté aucune modification physique avec le temps. Aucun changement n’a non plus été observé après le passage dans le pousse-seringue électrique. Dans la solution de NaCl à 0,9 %, la vancomycine à 62,5 et à 83,3 mg/mL a conservé plus de 90 % de sa concentration initiale respectivement après 48 et 24 h. Cependant, le précipité de la solution à 83,3 mg/mL était visible après 48 h. Dans la solution de D5W, la vancomycine à 62,5 et à 83,3 mg/mL a conservé plus de 90 % de sa concentration initiale après 48 h. Conclusion : La préparation de solutions de vancomycine à forte concentration est faisable. Le pousse-seringue électrique n’a pas causé de précipitation. La vancomycine dans la solution de D5W à 62,5 et à 83,3 mg/mL est restée stable pendant plus de 48 h à la température ambiante. Les précipitations se sont produites dans les solutions de NaCl à 0,9 %. On recommande donc la solution de D5W comme solvant pour ce médicament.

Background Stabilis® is an international database on stability and compatibility of drugs. The stability data comes mainly from publications of pharmaceutical journals. As the quality of the published stability studies is not equivalent, the objective of this work was to propose a level of evidence for the physico-chemical stability studies selected for the database. Methods At first, we evaluated the main pharmacological class consulted by the users. This work was then divided into 5 steps: (1) updating of the criteria to validate a stability study, (2) creating a grid rating articles, (3) rating of the articles of stability studies for anticancer, antifungal and antiviral drugs by 2 evaluators, (4) creation of new screens in the database to enter rating, to visualize the pictograms and commentaries by the users, (5) creation of a guideline to explain the different levels of evidence. Results The main pharmacological class consulted by Stabilis® users is the anticancer drugs and then antiinfectives. We have selected anticancer, antifungal and antiviral drugs for our study. Two hundred and forty publications were evaluated. The highest level attributed was A for anticancer and antifungal drugs and C for antiviral drugs. This difference can be explained by the fact that the majority of publications about antiviral drugs were older. The most frequent anomalies in the rating of articles were an incomplete or imperfect validation of the analytical method (high value of the coefficient of variation) and a defect in the evaluation of the stability indicating capacity. It must be noted that the level of evidence is not the quality level of the analytical method but the mixture of the quality of the method validation and of the results. This aspect was a choice of the Stabilis® team and seems important because the security of the patient is impacted by both aspects. Conclusions This new function contributes to help the Stabilis® users to evaluate the stability data published and to take a decision for their use in daily practice. This function will be progressively extended to other pharmacological classes of injectable drugs and then for non-injectable preparations.

International audience; AbstractIntroduction : Nefopam has been reported to be effective in postoperative pain control with an opioid-sparing effect, but the use of nefopam can lead to nausea and vomiting. To prevent these side effects, droperidol can be mixed with nefopam. In intensive care units, high concentrations of nefopam and droperidol in syringes can be used with a continuous flow.Objectives : The first objective of this work was to study the physicochemical stability of a nefopam solution 2.5 mg/mL diluted in NaCl 0.9% in polypropylene syringes immediately after preparation and after 6, 24 and 48 hours at room temperature. The second objective was to study the physicochemical stability of mixtures of nefopam 2.5 mg/mL and droperidol 52 µg/mL diluted in NaCl 0.9% in polypropylene syringes at room temperature over 48 hours.Materials and methods : Three syringes for each condition were prepared. For each time of analysis, three samples for each syringe were prepared and analysed by high performance liquid chromatography coupled to photodiode array detection. The method was validated according to the International Conference on Harmonisation Q2(R1). Physical stability was evaluated by visual and subvisual inspection (turbidimetry by UV spectrophotometry). pH values were measured at each time of analysis.Results : Solutions of nefopam at 2.5 mg/mL and the mixture of nefopam 2.5 mg/mL with droperidol 52 µg/mL, diluted in NaCl 0.9%, without protection from light, retained more than 90% of the initial concentration after 48 hours storage at 20–25°C. No modification in visual or subvisual evaluation and pH values were observed.Conclusion : Nefopam solutions at 2.5 mg/mL and the mixture of nefopam 2.5 mg/mL with droperidol 52 µg/mL diluted in NaCl 0.9% were stable over a period of 48 hours at room temperature. These stability data provide additional knowledge to assist intensive care services in daily practice.

Background In intensive care units (ICUs), intravenous (I.V) accesses are usually limited, leading to concomitant administration of different drugs in the same infusion line. Purpose The objectives were: to perform an observation of the administration of anti-infective drugs (antibiotics, antiviral and antifungal drugs) in the ICUs; to compare with compatibility data available in the literature; and in the absence of compatibility data, to test the physical compatibility in our laboratory. Material and methods Between April and June 2018, an observational prospective study was realised over 2 weeks in each of the three ICUs selected. Patients receiving more than one I.V drug including an anti-infective drug in the same line simultaneously (Y-site injection or mixed in the same container) were included. All I.V. drugs were recorded as concentration, solvent, type of container and flow rate. Compatibilities were assessed pairwise by using three databases: The Handbook on Injectable Drugs 19th edition, King Guide to Parenteral Admixtures and Stabilis. For missing data, three tests were realised for some pairwise: (drug A/drug B): 1 mL/9 mL; 9 mL/1 mL; and 5 mL/5 mL. Drugs were considered compatible if no precipitate, colour change or gas formation were observed after preparation and after a 1 hour and 4 hour storage at room temperature. For subvisual evaluation, turbidimetry by UV spectrophotometry was performed at 350, 410 and 550 nm as recommended by the European Consensus Conference. Results A total of 123 associations between an anti-infective drug and another medication were observed. According to the literature, 33.3% (n=41/123) associations were compatible, 9.8% (n=12/123) were incompatible, 6.5% (n=8/123) had divergent data according to the databases and 50.4% (n=62/123) had no data available. Thirty-eight pairwise mixtures were studied. After laboratory tests, 71.0% (n=27/38) were evaluated as physically compatible, 7.9% (n=3/38) were found to be incompatible after visual evaluation and 21.1% (n=8/38) after only subvisual evaluation. Conclusion This study demonstrated that some incompatible drugs were mixed before administration to the patient. After laboratory tests, new incompatibilities were found which gives additional information to the literature. However, many other mixtures should be still studied due to missing data. References and/or acknowledgements No conflict of interest.

Background Norepinephrine is usually used in emergency situations as in intensive care units (ICUs) for the restoration of blood pressure. High doses at 3–5 µg/kg/min can be used in the treatment of septic or hemorrhagic shock. Purpose The objective was to study the stability of high concentrated solutions of norepinephrine at 0.50 mg/mL and 1.16 mg/mL, diluted in glucose 5% (G5%) in polypropylene syringes, protected or not from light, after the preparation and after a 6 hour, 24 hour and 48 hour storage at room temperature. Material and methods Chemical stability was analysed by high-performance liquid chromatography coupled to a photodiode array detector at each time of analysis. The method was validated according to the International Conference on Harmonisation Q2 (R1). Physical stability was evaluated by visual and subvisual inspection (turbidimetry by UV spectrophotometry at 350, 410 and 550 nm as recommended by the European Consensus Conference). Three syringes for each condition were prepared. At each time of analysis, three samples were prepared and analysed for each syringe. pH values were evaluated at each moment of the analysis. Results Solutions of norepinephrine at 0.50 and 1.16 mg/mL, diluted in G5%, with or without protection from light, retained more than 95% of the initial concentration after 48 hours of storage at 20°C–25°C. Solutions remained clear, without change of colour or precipitation during the study. Concerning turbidity assays, values of absorbance remained inferior to 0.010 AU. No degradation product appeared during stressed degradation was observed during the study, but an additional peak with a retention time at 3.8 min was observed and constant. This peak was equally observed on chromatograms of the G5% solution. A solution of 5-hydroxymethylfurfural (5-HMF), a degradation product of glucose, was prepared and analysed by HPLC. The retention time was also 3.8 min and the spectrum was identical. This additional peak was identified as 5-HMF. Conclusion Norepinephrine diluted in G5% at 0.50 mg/mL and 1.16 mg/mL were physically and chemically stable over a period of 48 hours at room temperature. These stability data of highly concentrated solutions provide additional knowledge to assist ICUs in daily practice. References and/or acknowledgements No conflict of interest.

Background In severe infections such as in intensive care units (ICUs), the recommended dose of vancomycin may be 60 mg/kg/day. Studies demonstrated that continuous infusion of vancomycin allowed rapid target concentration. In ICUs, a minimum volume is used to avoid fluid overload for patients requiring fluid restriction, leading to high concentrations of vancomycin. Purpose The first objective of this work was to study the impact of an electric syringe pump on physical stability. The second objective was to study the stability of vancomycin solutions at 62.5 mg/mL and 83.3 mg/mL, diluted in two solvents: 0.9% sodium chloride or 5% glucose, in polypropylene syringes after the preparation and after a 6 hour, 24 hour and 48 hour storage at room temperature. Material and methods Chemical stability was analysed by high-performance liquid chromatography coupled to a photodiode array detector at each time of analysis. The method was validated according to the International Conference on Harmonisation Q2 (R1). Physical stability was evaluated by visual and subvisual inspection (turbidimetry by UV spectrophotometry at 350, 410 and 550 nm as recommended by the European Consensus Conference). Three syringes for each condition were prepared. At each time of analysis, three samples were analysed for each syringe. pH and osmolality values were evaluated at each moment of the analysis. Chemical stability was defined as not less than 90% of the initial concentration. Results The action of an electric syringe pump did not cause visual modification. Vancomycin diluted in 0.9% sodium chloride at 62.5 mg/mL and at 83.3 mg/mL retained more than 90% of the initial concentration after 48 hours and 24 hours respectively. Diluted in 5% glucose and stored at 20°C–25°C, vancomycin solutions at 62.5 mg/mL and 83.3 mg/mL retained more than 90% of the initial concentration after 48 hours. Some precipitates were visible after 48 hour storage for the vancomycin syringe at 83.3 mg/mL in 0.9% sodium chloride. In other conditions, no visual modification was observed. Conclusion Vancomycin hydrochloride diluted in 5% glucose at 62.5 mg/mL and 83.3 mg/mL were physically and chemically stable over a period of 48 hours at room temperature. For high concentrations of vancomycin, 5% glucose as solvent is recommended. References and/or acknowledgements No conflict of interest.

Background Cefotaxime is an antibiotic used to treat severe infections such as in intensive care units (ICUs). The dose of cefotaxime can vary from 3 g to 24 g per day and the literature has demonstrated that continuous administration is the preferred mode of administration. In ICUs, a minimum volume is used for patients requiring fluid restriction, leading to high concentrations of cefotaxime. Purpose The objective was to study the stability of cefotaxime solutions at 83.3 mg/mL and 125 mg/mL, diluted in 0.9% sodium chloride (0.9% NaCl) or 5% glucose (G5%), in polypropylene syringes after preparation and after a 6 hour and 12 hour storage at 20°C–25°C. Material and methods Three syringes for each condition were prepared. At each time of analysis, three samples for each syringe were prepared and analysis by high-performance liquid chromatography (HPLC) coupled to a photodiode array detector. The method was validated according to the International Conference on Harmonisation Q2 (R1). Physical stability was evaluated by visual and subvisual inspection (turbidimetry by UV spectrophotometry at 350, 410 and 550 nm as recommended by the European Consensus Conference). pH and osmolality values were measured. Results For each solvent, cefotaxime solutions at 83.3 mg/mL and 125 mg/mL retained more than 90% of the initial concentration after 12 hours. During the study, pH values decreased slightly, the intensity of the yellow colour increased and absorbance values increased progressively for each wavelength and each condition. An additional peak with a relative retention at 3.01 was also observed after the forced degradation gradually increased up to 4.01% in 0.9% NaCl and 3.17% in G5% of the total surface area of the peaks present on the chromatogram after 12 hours. Conclusion In view of the results and despite the fact that the solutions retained more than 90% of the initial concentration after HPLC analysis, we propose to limit the stability of cefotaxime in 0.9% NaCl and G5% at 83.3 and 125 mg/mL at 6 hours. These stability data of highly concentrated solutions provide additional knowledge to assist ICUs in daily practice. Highly concentrated cefotaxime solutions are unstable after a 6 hour storage and cannot be administered as a daily infusion. References and/or acknowledgements No conflict of interest.

The chemical stability of pemetrexed solutions diluted in 0.9% sodium chloride (0.9% NaCl) and 5% dextrose (D5%) in PVC infusion bags at 2–8°C was determined by High Performance Liquid Chromatography (HPLC) for 1 month by Zhang and Trissel1 and Rondelot et al .2 However, subvisual examination shows an increase in turbidimetry and in the number of microparticulates after storage at 2–8°C. The hypothesis of an interaction with PVC was advanced and the use of an inline filter was advised.1 The discrepancy between the nephelometric evaluation and HPLC analysis could be due to the requirement to dilute the samples with the HPLC method. Dilution before analysis increases the solubility, a microprecipitate can be dissolved, …