In-use stability of ready-to-administer daratumumab subcutaneous injection solution in plastic syringes.

OBJECTIVE: In multiple myeloma patients, daratumumab is preferably injected subcutaneously. The summary of product characteristics of daratumumab subcutaneous injection solution specifies physicochemical stability for the prepared syringe for 24 hours at 2-8°C protected from light, and another 12 hours at room temperature (15-25°C) in ambient light conditions. The aim of this study was to determine the in-use stability of ready-to-administer daratumumab subcutaneous injection solution in different types of syringe and different conditions over a 28-day period. METHODS: Daratumumab subcutaneous (DARZALEX 1800 mg) injection solution was withdrawn into disposable three-piece Luer-Lock syringes (20 mL, 50 mL), capped, and stored light protected at 2-8°C or at room temperature (22±2°C) over a maximum period of 28 days. Samples were taken immediately after preparation (day 0) and after 2, 7, 14, 21, and 28 days. Physicochemical stability was determined by ion-exchange high-performance liquid chromatography (IE-HPLC) and size-exclusion high-performance liquid chromatography (SE-HPLC) with ultraviolet detection, pH measurement and visual inspection for particles or colour changes. RESULTS: In the IE-HPLC assay, peak areas and peak-to-peak area ratios remained unchanged over the whole study period, and showed no additional peaks of degraded daratumumab charge variants. In the SE-HPLC assay, neither a formation of aggregates nor of fragments was detected. Daratumumab monomer concentrations exceeded 95% of the initially measured concentrations over the entire test period. pH values remained constant. Test solutions remained clear, and no colour changes or visible particles were detected. All results were independent of storage conditions. CONCLUSION: Daratumumab subcutaneous injection solution proved to be physicochemically stable in capped three-piece plastic syringes for at least 28 days when stored light protected at 2-8°C or at room temperature (22±2°C). For microbiological reasons aseptic preparation and refrigerated storage are recommended. In-use stability of ready-to-administer daratumumab subcutaneous syringes prepared under appropriate aseptic conditions is given for 28 days.

Physicochemical stability of ready-to-administer mitomycin C solutions for intravesical instillation.

OBJECTIVE: The aim of the study was to investigate the physicochemical stability of mitomycin-containing medicinal products for bladder instillation, formulated with urea as excipient (mito-medac®, Mitomycin medac). For comparison, the stability of reconstituted Urocin® and Mitem® bladder instillation was studied. METHODS: Mitomycin-containing medicinal products were either reconstituted with the prepackaged 0.9% NaCl solution, nominal volume 20 mL (mito-medac®, Mitem®, Urocin®) or with 20 mL water for injection (Mitomycin medac, Mitem®, Urocin®) to a nominal concentration of 1 mg/mL and stored at room temperature (20-25°C). Samples were taken immediately after reconstitution and after 24 hours. Physicochemical stability was determined by reverse-phase high performance liquid chromatography with photodiode array detection, measurement of pH and osmolarity, and inspection for visible particles or colour changes. RESULTS: The initial pH values of the test solutions reconstituted with prepackaged 0.9% NaCl (5.2-5.6) were significantly lower than those reconstituted with water for injection (6.6-7.4). Solutions reconstituted with 0.9% NaCl solutions rapidly degraded and concentrations fell below the 90% limit after 24 hours of storage. When reconstituted with water for injection, degradation was less rapid. Concentrations of Mitomycin medac and Urocin remained above the 90% limit after 24 hours. CONCLUSIONS: The physicochemical stability of mitomycin 1 mg/mL bladder instillation prepared with prepackaged 0.9% NaCl in prefilled PVC bags is less than 24 hours at room temperature. Unfavourable pH values of the solvents cause rapid degradation of mitomycin. Mitomycin solutions reconstituted at the point of care should be administered immediately to avoid degradation and loss of efficacy. Urea added as excipient did not accelerate degradation.

Physicochemical stability of carmustine-containing medicinal products after reconstitution and after dilution to ready-to-administer infusion solutions stored refrigerated or at room temperature.

INTRODUCTION: The aim of this study was to determine and compare the physicochemical stability of two carmustine-containing medicinal products licensed and marketed in Europe as Carmustin Obvius (Medac GmbH) and Carmubris (Tillomed Pharma GmbH). Reconstituted stock solutions and diluted ready-to-administer infusion solutions of the two products were investigated. METHODS: Reconstituted carmustine stock solutions (3.3 mg/mL) and ready-to-administer infusion solutions (0.2 mg/mL, 1.0 mg/mL) prepared in prefilled 5% glucose injection solution PP/PE bags were stored at 22°C or 2-8°C over a maximum period of 66 hours protected from light. Samples were taken immediately after reconstitution or dilution and after 3.5, 6, 8.5 and 11 hours when stored at 22°C or after (12), 24, 48 and 60 hours when stored at 2-8°C, followed by 3- and 6-hour storage at 22°C (60+3 hours, 60+6 hours). Physicochemical stability was determined by reversed-phase high-performance liquid chromatography with UV detection, measurement of pH, osmolarity and inspection for visible particles or colour changes. RESULTS: Carmustin Obvius and Carmubris reconstituted stock solutions were physicochemically stable for at least 48 hours when stored at 2-8°C. Carmustin Obvius and Carmubris infusion solutions 0.2 mg/mL were physicochemically stable for at least 8.5 hours and 60 hours when stored at 22°C and 2-8°C, respectively. After subsequent storage of the 60-hour refrigerated test solutions for 3 hours at 22°C, the carmustine concentrations averaged the 90% limit and fell below the 90% limit after 6 hours. Carmustin Obvius infusion solutions 1.0 mg/mL were physicochemically stable for at least 8.5 hours when stored at 22°C and for 60 hours when stored at 2-8°C. CONCLUSION: According to the physicochemical stability data, the shelf life (95% limit) of the refrigerated stock solutions is 48 hours and the shelf life (90% limit) of ready-to-administer infusion solutions (0.2 mg/mL, 1.0 mg/mL) is 60 hours at 2-8°C or 8.5 hours at 22°C under light protection. These results facilitate the use of both medicinal products in a pharmacy-based centralised cytotoxic preparation unit.

Cleveland Clinic International IV Robotics Summit.

PURPOSE: The proceedings of an international summit on the current and desired future state of use of robotic systems to compound intravenous (IV) solutions are summarized. SUMMARY: The International IV Robotics Summit was held at the Cleveland Clinic main campus in Cleveland, OH, on April 29 and 30, 2019. The purpose of the summit was 2-fold: (1) to define the current state of robotic IV compounding and (2) to develop a guide for automation companies, pharmacy departments, and drug manufacturers to improve the technology and expand the use of IV robotics in health systems in the future. The first day of the summit included 45-minute presentations by each of the speakers. Each lecturer recounted a different hospital's experience implementing and using IV robotics. On day 2 of the summit, an expert panel dedicated to mapping the future of IV robotics was convened to determine barriers to widespread adoption of IV robotics in health systems and offer potential solutions to remove these barriers. The expert panel targeted 3 specific audiences: robot manufacturers, drug manufacturers, and fellow pharmacy leaders. CONCLUSION: It is the hope of the international faculty that the information that emerged from the summit can be used by others to successfully implement IV compounding robotics in their sterile products areas to maximize patient safety. The summit also served as a call to action for pharmacy leaders, drug manufacturers, and robotic companies to develop a safer, more efficient future for patients by working together to optimize the development and operation of IV robotics.

Early steroid-free immunosuppression with FK506 after liver transplantation: long-term results of a prospectively randomized double-blinded trial.

BACKGROUND: The aim of this prospective, randomized, double-blinded, placebo-controlled single center study was to evaluate an early steroid-free immunosuppression in liver transplant patients. METHODS: From March 2000 to October 2004, 110 patients were included. All patients received tacrolimus and steroids during the first 2 weeks after orthotopic liver transplantation (OLT). Thereafter, patients in the steroid group (n=54) received steroids and the remaining 56 a placebo. After 6 months, the immunosuppression for all was steroid free. Thirty patients were hepatitis C positive. Five years after inclusion, patient survival, organ survival, steroid side effects, and recirrhosis in hepatitis C virus (HCV) patients were reevaluated. RESULTS: After 5 years, the following parameters were comparable in both groups: patient survival (P=0.236), organ survival (P=0.509), and acute rejections (P=0.409). Steroid-free immunosuppression lead to a higher rate of chronic rejections (P=0.023). Six months after OLT, there was a difference in rates of posttransplant diabetes mellitus (PTDM) (P=0.024) and hypercholesterolemia (P=0.002). However, 5 years after OLT, there was no difference in hypertension (P=0.647), PTDM (P=0.453), hypercholesterolemia (P=0.412), and osteoporosis (P=0.624). In HCV patients, we could not find any differences in patient survival (P=0.096), organ survival (P=0.424), time free from recirrhosis (P=0.647). The rate of recirrhosis was influenced by steroid bolus therapy (P=0.01) but not by avoiding continuous steroid therapy. CONCLUSIONS: Early tapering down of steroids to a tacrolimus monotherapy is possible with comparable acute rejection rates. During steroid therapy, PTDM and hypercholesterolemia are cumulative. These side effects are reversible. The recirrhosis in HCV patients is not influenced by continuous steroid therapy but more frequent in HCV patients receiving a steroid bolus therapy.