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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 The comparisons of the volumes withdrawn after reconstitution were similar when using a Spike system or a needle.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 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

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 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.