Organization of chemotherapeutic preparations in advance: Do we save or waste money?

OBJECTIVE: The development of oncology day-hospital activities contributes to increase quality of life of patients and consequently have changed their perception about waiting. The extemporaneous preparation of antineoplastic has become difficult to achieve given the increasing activity, and hospital pharmacists have taken up the challenge by the implementation of the antineoplastic preparation in anticipation. Because anticipation can lead to an important number of preparations to be discarded, we also develop a recycled process for other patients to limit these waste extra costs. We aim to demonstrate the positive balance of anticipated preparation in this 4-year study report.Data sources: This prospective study was conducted in a major European oncology day-hospital from January, 2012 to December, 2015. The data were extracted from our software WinSimbad™ and updated as needed. The number and cost-associated of preparation ungiven chemotherapy doses (recycled or discarded) were compared to the global drug budget of our hospital in order to not exceed 2%.Data summary: 303,100 antineoplastic have been prepared. Approximately 35% of them were anticipated with an average of 5,431±984 that were finally ungiven. Two-third was recycled and the cost of the ungiven preparations finally discarded represents 1.7±0.15% of the global drug budget. CONCLUSIONS: This study assesses the drug wastage and its associated cost of this concept through a prospective study and discusses the cost of ungiven antineoplastic preparations. With prior consideration of the need to define the acceptable rate of discarded ungiven preparation, the hospitals with an high oncology day-hospital activity should implement this approach.

High-dose cyclophosphamide for hard-to-treat patients with relapsed or refractory B-cell non-Hodgkin's lymphoma, a phase II result.

BACKGROUND: High-dose cyclophosphamide to treat solid refractory tumors demonstrated meaningful activity, while data to treat lymphoma remain scarce. This study aims to assess high-dose cyclophosphamide to treat relapsed or refractory lymphoma. METHODS: A phase II study included adult patients with relapsed or refractory B-cell non-Hodgkin's lymphoma, previously treated by ≥2 prior lines with no other available option of therapy. High-dose cyclophosphamide was given intravenously 3 g/m2 over two consecutive days and repeated once at 28 days in responding patients. Rituximab 375 mg/m2 intravenously was added in patients not refractory to anti-CD20 antibody. RESULTS: Forty-two patients with median age 65 [56-70] years were included. Patients had previously received a median of four lines of therapies. Tumor types were diffuse large B-cell lymphoma (n = 26; 62%), indolent B-cell non-Hodgkin lymphoma (n = 10; 24%), or mantle lymphoma (n = 6; 14%). Hematologic and non-hematologic grade 3-5 toxicities occurred in 42 (100%) and 18 (43%) of patients, respectively. The overall response rate was 45%. CONCLUSION: One to two cycles of high-dose cyclophosphamide in hard-to-treat patients with relapsed or refractory B-cell non-Hodgkin lymphoma demonstrated a favorable safety and efficacy profile. This regimen could serve as a bridge to modern cellular therapy with CAR-T cell.

High-dose thiotepa-related neurotoxicity and the role of tramadol in children.

BACKGROUND: Serious neurological adverse events (NAE) have occurred during treatment with high-dose thiotepa regimens of children with high-risk solid tumours. The objective was to assess the incidence of NAE related to high-dose thiotepa and to identify potential contributing factors that could exacerbate the occurrence of this neurotoxicity. METHODS: From May 1987 to March 2011, children with solid tumours treated with high-dose thiotepa were retrospectively identified. Each NAE detected led to an independent case analysis. Potential contributing factors were pre-specified and univariate/multivariable analyses were performed. RESULTS: Three hundred seven courses of thiotepa (251 patients) were identified. The total dose per treatment ranged from 600 to 900 mg/m2. 81 NAE (26%) were identified. 46 NAE were related to high-dose thiotepa during the first course (18.3%) and 11 during the second course (19.6%). The symptoms appeared in a median time of 2 days after the introduction of thiotepa. Central and peripheral symptoms were headaches, tremors, confusion, seizures, cerebellar syndrome, and coma. High-dose thiotepa was reintroduced in 18 cases and symptoms reappeared in 5 children. For 3 patients who had seizures during the first course, premedication with clonazepam for the second course has prevented recurrence of NAE. As contributing factors, brain tumour and tramadol treatment increased the risk of thiotepa-related neurotoxicity by 2 to 6 times respectively. CONCLUSIONS: The incidence of neurotoxicity was 18.3%. Brain tumours and tramadol treatment are risk factors to consider when using high-dose thiotepa. The outcome of patients was favourable without sequelae in all cases and rechallenge with thiotepa was possible.

Computerized pediatric oncology prescriptions review by pharmacist: A descriptive analysis and associated risk factors.

BACKGROUND: Systematic prescription analyses by clinical pharmacists result in pharmacist interventions (PIs) to reduce prescription errors and improve medication safety. PIs are particularly critical in oncology, because antineoplastic drugs are highly toxic with low therapeutic indexes especially in a pediatric population. The aim of this study is to describe PIs in a pediatric oncology department and to identify potential risk factors associated with prescription errors. PROCEDURE: We conducted a 20-month observational study in a pediatric oncology department concerning electronic prescription of injectable chemotherapies was conducted. PIs were analyzed for drug-related problems (DRPs), type of intervention, population characteristics, involved drugs, and the potential risk factors. RESULTS: Clinical pharmacists made 90 PIs for 10,214 antineoplastic prescriptions for a rate of 88 PIs per 10,000 prescriptions. The majority of DRPs were dosage errors (61.8%), imputable to measurements (weight and/or height) in 47.4% or unreported dose reduction. The most common patient ages were in the range 1-10 years and the most common time for medical double checks was 2-9 pm. There were statistically more prescription errors in standardized protocols (P < 0.001). CONCLUSIONS: Not surprisingly, PIs were predominantly to correct dose errors, half of which related to height and weight measurements that were not updated. No significant risk factors for errors were identified for errors except in the standardized status of prescription, which appears to be linked in part to our software that did not automatically reflect dose reduction from one course to the next. Medical double-checking followed by a clinical pharmacist's double check were effective in order to prevent prescription errors.

The cost of molecular-guided therapy in oncology: a prospective cost study alongside the MOSCATO trial.

AIM: There is increasing use of molecular technologies to guide cancer treatments, but few cost data are available. Our objective was to assess the costs of molecular-guided therapy for patients with advanced solid tumors alongside the Molecular Screening for Cancer Treatment and Optimization (MOSCATO) trial. MATERIALS AND METHODS: The study population consisted of 529 patients. The molecular diagnosis included seven steps from tumor biopsy to the multidisciplinary molecular tumor board. The cost of a complete molecular diagnosis was assessed by micro-costing. Direct costs incurred from enrollment until progression were assessed from the French National Health Insurance perspective. RESULTS: The patients' mean age was 54 years (range: 3-82) and the mean follow-up period was 145 days (range: 1-707 days). A complete molecular diagnosis cost [euro ]2,396. There were 220 patients with an actionable target (42%), among whom 105 (20%) actually received a targeted therapy. The cost of molecular-guided therapy per patient was [euro ]31,269. The main cost drivers were anticancer drugs (54%) and hospitalizations (35%). CONCLUSION: This prospective cost analysis showed that molecular diagnosis accounts for only 6% of the cost of molecular-guided therapy per patient. The costs of drugs and hospitalizations are the main cost drivers.Genet Med advance online publication 01 December 2016.

ADAM9 expression promotes an aggressive lung adenocarcinoma phenotype.

A disintegrin and metalloproteinase 9 (ADAM9) possesses potent metastasis-inducing capacities and is highly expressed in several cancer cells. Previous work has shown that ADAM9 participates in the adhesive-invasive phenotype in lung cancer cells in vitro. In this study, we evaluated whether ADAM9 expression plays a critical role in metastatic processes in vivo and in angiogenesis. We first found that high ADAM9 expression was correlated with poor lung adenocarcinoma patient prognosis on Prognoscan data base. In vivo model based on intravenous injection in nude mice showed that a stable downregulation of ADAM9 in A549 (TrA549 A9-) cells was associated with a lower number of nodules in the lung, suggesting lower potentials for extravasation and metastasis. On a subcutaneous xenograft we showed that TrA549 A9- produced significantly smaller tumours and exhibited fewer neovessels. In addition, in vitro human umbilical vein endothelial cells exposed to supernatant from TrA549 A9- could reduce the formation of more vessel-like structures. To further understand the mechanism, a human antibody array analysis confirmed that five cytokines were downregulated in TrA549 A9- cells. Interleukin 8 was the most significantly downregulated, and its interaction with CXCR2 was implicated in angiogenesis on an in vitro model. These results emphasize the critical influence of ADAM9 on lung cancer progression and aggressiveness. ADAM9 should at least be a marker of cancer aggressiveness and a potential therapeutic target for cancer treatment.

Impacts of a navigation program based on health information technology for patients receiving oral anticancer therapy: the CAPRI randomized controlled trial.

BACKGROUND: The emergence of oral delivery in cancer therapeutics is expected to result in an increased need for better coordination between all treatment stakeholders, mainly to ensure adequate treatment delivery to the patient. There is significant interest in the nurse navigation program's potential to improve transitions of care by improving communication between treatment stakeholders and by providing personalized organizational assistance to patients. The use of health information technology is another strategy aimed at improving cancer care coordination that can be combined with the NN program to improve remote patient follow-up. However, the potential of these two strategies combined to improve oral treatment delivery is limited by a lack of rigorous evidence of actual impact. METHODS/DESIGN: We are conducting a large scale randomized controlled trial designed to assess the impact of a navigation program denoted CAPRI that is based on two Nurse Navigators and a web portal ensuring coordination between community and hospital as well as between patients and navigators, versus routine delivery of oral anticancer therapy. The primary research aim is to assess the impact of the program on treatment delivery for patients with metastatic cancer, as measured by Relative Dose Intensity. The trial involves a number of other outcomes, including tumor response, survival, toxic side effects, patient quality of life and patient experience An economic evaluation adopting a societal perspective will be conducted, in order to estimate those health. care resources' used. A parallel process evaluation will be conducted to describe implementation of the intervention. DISCUSSION: If the CAPRI program does improve treatment delivery, the evidence on its economic impact will offer important knowledge for health decision-makers, helping develop new follow-up services for patients receiving oral chemotherapy and/or targeted therapy. The process evaluation will determine the best conditions in which such a program might be implemented. TRIAL REGISTRATION: NCT 02828462 . Registered 29 June 2016.

Arsenic trioxide exerts antitumor activity through regulatory T cell depletion mediated by oxidative stress in a murine model of colon cancer.

Immunotherapy is a promising antitumor strategy that can successfully be combined with current anticancer treatment. In this study, arsenic trioxide (As(2)O(3)) was shown to increase the antitumor immune response in CT26 colon tumor-bearing mice through the modulation of regulatory T cell (T(reg)) numbers. As(2)O(3) induced T(reg)-selective depletion in vitro. In vivo, tumor-bearing mice injected with 1 mg/kg As(2)O(3) showed a significant decrease in the T(reg)/CD4 cell ratio and in absolute T(reg) count versus controls. As(2)O(3) exerted antitumor effects only in immunocompetent mice and enhanced adoptive immunotherapy effects. Inhibition of As(2)O(3)-induced T(reg) depletion by the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester and the superoxide dismutase mimic manganese [III] tetrakis-(5, 10, 15, 20)-benzoic acid porphyrin suggested that it was mediated by oxidative and nitrosative stress. The differential effect of As(2)O(3) on T(reg) versus other CD4 cells may be related to differences in the cells' redox status, as indicated by significant differences in 2'7'dichlorodihydrofluorescein diacetate and 4,5-diaminofluorescein diacetate fluorescence levels. In conclusion, these results show for the first time, to our knowledge, that low doses As(2)O(3) can delay solid tumor growth by depleting T(regs) through oxidative and nitrosative bursts, and suggest that As(2)O(3) could be used to enhance the antitumor activity of adoptive immunotherapy strategies in human cancer.

Development of a Hospital Compounded, Taste-Masked, Temozolomide Oral Suspension and 5-Year Real-Life Experience in Treating Paediatric Patients.

The development of oral pediatric forms by pharmaceutical companies is still insufficient. In fact, many drugs used in paediatric oncology, such as temozolomide, are not labeled and adapted for paediatric use. Temozolomide (TMZ) is an alkylating agent used as the standard of care for many adult and pediatric brain tumours, such as neuroblastoma, glioblastoma and medulloblastoma. The present study was carried out to propose a suitable and palatable formulation of the oral liquid preparation of TMZ. The suspension is composed of TMZ suspended in SyrSpend SF pH 4, as well as TMZ crystallization stabilizing agents and sweetening agents. To reach this formulation, several taste-masking agents were evaluated. Here, we describe the method of preparation of the formation as well as the monocentric population treated with the formulation over a 5-year period. A 20 mg/mL TMZ suspension was developed. TMZ suspension is stable for 6 weeks, stored between 2 and 8 degrees, protected from light, and compatible with nasogastric tubes. Thirty-eight patients participated in the palatability study and choose cola flavour, and 104 patients were treated in Gustave Roussy with the developed suspension; no unexpected event was reported. To conclude, we propose here a new TMZ liquid formulation which is stable for at least 6 weeks and well-tolerated with extensive feedback.

Digital remote monitoring plus usual care versus usual care in patients treated with oral anticancer agents: the randomized phase 3 CAPRI trial.

Strategies that individualize the care of cancer patients receiving oral anticancer agents offer opportunities to improve treatment adherence and patient care. However, the impact of digital remote monitoring systems in this setting has not been evaluated. Here, we report the results of a phase 3 trial (CAPRI, NCT02828462) to assess the impact of a nurse navigator-led program on treatment delivery for patients with metastatic cancer. Patients receiving approved oral anticancer agents were randomized (1:1) to an intervention combining a nurse navigator-led follow-up system and a web portal-smartphone application on top of usual care, or to usual symptom monitoring at the discretion of the treating oncologist, for a duration of 6 months. The primary objective included optimization of the treatment dose. Secondary objectives were grade ≥3 toxicities, patient experience, rates and duration of hospitalization, response and survival, and quality of life. In 559 evaluable patients the relative dose intensity was higher in the experimental arm (93.4% versus 89.4%, P = 0.04). The intervention improved the patient experience (Patient Assessment of Chronic Illness Care score, 2.94 versus 2.67, P = 0.01), reduced the days of hospitalization (2.82 versus 4.44 days, P = 0.02), and decreased treatment-related grade ≥3 toxicities (27.6% versus 36.9%, P = 0.02). These findings show that patient-centered care through remote monitoring of symptoms and treatment may improve patient outcomes and experience.

Bystander effect of vinorelbine alters antitumor immune response.

The bystander effect (BE) is the ability of malignant cells affected by an anticancer agent to induce damage in neighboring cancer cells. In this study, we showed that it could also affect immune cells surrounding the tumor and interfere with the antitumor immune response. We observed that the exposure of human lung cancer cells A549 to vinorelbine induced a BE on neighboring human peripheral blood mononuclear cells (PBMCs) in vitro and on mice splenocytes in vivo. In vitro, the number of PBMCs killed because of their coculture with vinorelbine-pretreated A549 cells was 33% higher than those killed by A549 control cells (p = 0.003). In addition, we showed that when vinorelbine-pretreated A549 cells were injected into immunocompetent mice, splenocyte proliferation ex vivo toward tumor cells decreased by 27% compared with that seen in mice injected with untreated A549 cells (p = 0.03). Finally, in vivo experiment in A549 tumor bearing nude mice showed that adoptive transfer of A549 immune splenocytes was not able to delay tumor growth when vinorelbine-pretreated A549 cells were used for immunization. Inhibition of the BE by the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester, and the superoxide dismutase mimic, mangafodipir, suggested that it was mediated by oxidative and nitrosative stress. In conclusion, exposure of cancer cells to vinorelbine alters the antitumor immune response through a BE mediated by cellular oxidative and nitrosative stress. Our results offer new prospects for using oxidative stress modulators to restore the antitumor immune response in patients treated with anticancer agents.

[What are the expectations of coordination and accompaniment of French patients with cancer towards their community pharmacist?] / Quelles sont les attentes de coordination et d'accompagnement des patients français atteints de cancer vis-à-vis de leur pharmacien de ville ?

PURPOSES: Analyze the relationship and expectations of cancer patients towards the community pharmacist in a pharmaceutical care coordination project. METHODS: In November 2014, a questionnaire was distributed to ambulatory patients of a university hospital specialized in oncology. Thirteen questions explored the consumption habits and the usage of the pharmacy (typology of consumers, use of goods and benefits consumed), and collected their expectations for pharmaceutical benefits in the context of the management of their cancer. RESULTS: One thousand two hundred and seventy two patients were included for a final response rate of 78%. Characteristics of the respondents: 64% were women, 63% lived in Île-de-France and 49% took cancer-related treatments (anticancer drugs, supportive care medications). More than 84% of respondents went to pharmacies at least once a month and 95% reported resorting to a single pharmacy. 36% to be ready to share their hospital discharge report with their pharmacist and 61% to have their hospitalization order sent to their "referral" pharmacy to anticipate treatments. Discussion Community pharmacists were perceived positively by the respondents. Patients were willing to share information and be accompanied by this health professional in their cancer care. Their expectations were first and foremost the management of drug-related iatrogenic effects with a report of adverse effects to the hospital, and validated solutions for their management.

Development of a 'ready-to-use' tool that includes preventability, for the assessment of adverse drug events in oncology.

Background Adverse drug events (ADEs) occur frequently in oncology and justify continuous assessment and monitoring. There are several methods for detecting them, but the trigger tool method seems the most appropriate. Although a generic tool exists, its use for ADEs in oncology has not been convincing. The development of a focused version is therefore necessary. Objective To provide an oncology-focused trigger tool that evaluates the prevalence, harm, and preventability in a standardised method for pragmatic use in ADE surveillance. Setting Hospitals with cancer care in France. Method The tool has been constructed in two steps: (1) constitution of an oncology-centred list of ADEs; 30 pharmacists/practitioners in cancer care from nine hospitals selected a list of ADEs using a method of agreement adapted from the RAND/UCLA Appropriateness Method; and (2) construction of three standardised dimensions for the characterisation of each ADE (including causality, severity, and preventability). Main outcome measure The main outcome measure was validation of the tool, including preventability criteria. Results The tool is composed of a final list of 15 ADEs. For each ADE, a 'reviewer form' has been designed and validated by the panel. It comprises (1) the trigger(s), (2) flowcharts to guide the reviewer, (3) criteria for grading harm, and (4) a standardised assessment of preventability with 6-14 closed sentences for each ADE in terms of therapeutic management and/or prevention of side-effects. Conclusion A complete 'ready-to-use' tool for ADE monitoring in oncology has been developed that allows the assessment of three standardised dimensions.

Olanzapine as antiemetic drug in oncology: a retrospective study in non-responders to standard antiemetic therapy.

Background The role of olanzapine in the treatment of chemotherapy-induced nausea and vomiting (CINV) in addition to the antiemetic therapeutic combination with aprepitant, setrons, and corticosteroids has not been well defined. Objective To investigate the effectiveness of the addition of olanzapine to a standard triplet therapy for the prevention of CINV in patients who experienced CINV during their first chemotherapy course, despite receiving a well-managed prevention protocol. Setting One comprehensive cancer centre in France. Method In a retrospective study with comparator, patients with a high risk of emesis were assigned to two groups during two different 6-month periods, before and after the introduction of olanzapine in clinical practice, respectively. In the olanzapine group, the antiemetic protocol for the second course of chemotherapy was reinforced by the addition of olanzapine at 5 mg/day from day 1 to 5 in contrast with the control group. Main outcome measure The proportion of patients who experienced neither nausea nor emesis during the delayed phase (24-120 h). Results The 25 patients in each group exhibited comparable characteristics and emetic chemotherapy level. During the first course, no significant difference was observed. During the second course, nausea and vomiting were ameliorated in 12 patients in the olanzapine group and 4 patients in the control group (p < 0.05). Nausea (12 vs. 4, p < 0.05) and vomiting (18 vs. 11, p < 0.05) also significantly improved. In the OLZ group, no adverse event was linked to olanzapine use. Conclusion The addition of olanzapine was observed to effectively restore CINV prevention in patients who did not respond to standard antiemetic therapy.

Permeability of expander breast implants: In vitro and in vivo analyses.

INTRODUCTION: The biocompatibility of the polysiloxane breast implant has been studied moderately. The aging of these implants due to lipid penetration and the release of polymerization impurities, such as Platine or octamethylcyclotetrasiloxane (named D4), has already been documented. Since these studies, manufacturing procedures have been improved; thus, the security of breast implants has also improved. Although polymerization and the choice of monomer influence the shell properties, few studies have compared these together in breast implants. Our study compares the permeability and mechanical resistance of 3 breast expander shells after in vivo and in vitro aging. RESULTS: In vitro, all tested shells quickly sorbed linear molecules, such as fatty acids, and released siloxane impurities. The penetration of a molecule with steric hindrance, such as cholesterol, is slower. Allergan shells have the highest rates of molecule sorption and siloxane release. In vivo, after implantation, Allergan shells lost their initial mechanical properties over time. This observation was not found for mentor shells. For all brands, many biological molecules penetrate the shells, among which cholesterol and fatty acids are always present. DISCUSSION: The aging of polysiloxane shells depends on the sorption of many biological molecules and the release of siloxane impurities. The siloxanes are impurities and / or degradation products that are due to aging. Moreover, according to our results, the shells act as matrices that separate molecules according to their chemical and physical properties. CONCLUSION: Not all polysiloxane expander shells have the same properties during aging. The manufacturing procedures and the choice of siloxane monomers are the two most probative factors that explain the observed differences.

High incidence of cetuximab-related infusion reactions in head and neck patients.

BACKGROUND: Cetuximab is crucial in the management of squamous cell carcinoma of the head and neck of patients. Grade 3-4 cetuximab-induced infusion reactions (CI-IRs) occur in 2% of patients with colorectal cancer. Despite the 2.7% CI-IR rate in the EXTREME trial, higher rates were reported in small series of patients with head and neck squamous cell carcinoma (HNSCC) (6%-18%). There is an urgent need to better appraise the natural history and the predictive factors for CI-IRs in patients with HNSCC exposed to cetuximab. METHODS: The medical records from patients with HNSCC (n=428) treated by cetuximab at Gustave Roussy from January 2013 to December 2015 were reviewed. The impact of potential risk factors was analysed. RESULTS: Out of 428 patients, 24 patients (5.4%) presented CI-IR, including grade 3-4 (95.7%); about 21% (5/24) requiring intensive care unit referral and quasi all occurred within the first cycle (21/24). In a multivariate analysis, the occurrence of grade 3-4 CI-IR was associated with tobacco and alcohol history (p=8.5e-3) and with prior allergy history (p=2.9e-3). CI-IRs tended to be associated with poor overall survival in patients with recurrent and metastatic HNSCC and with a higher number of further lines of chemotherapy. CONCLUSION: In real life, CI-IRs appear far more common in patients with HNSCC (5.4%) than reported in prospective trials. This is the largest series of patients ever focusing on the risk of CI-IR in patients with HNSCC. Prior allergy history and tobacco history are associated with CI-IR and could be used to better allocate treatment. Further prospective data are required to confirm these findings.

Evaluating iatrogenic prescribing: development of an oncology-focused trigger tool.

BACKGROUND: Drug-related iatrogenic effects are common in oncology because chemotherapy is toxic. The evaluation of the application of the guidelines may be a way to understand the occurrence of adverse drug-related event (ADE). There is no specific method for identifying ADEs and measuring harm to patients in oncology. OBJECTIVE: Our objective was to develop and test an Oncology Trigger Tool (OTT) for ADEs and to describe ADE characteristics and incidence. METHODS: A clinical advisory panel identified situations at high risk of ADE occurrence and built 22 triggers with, in each case, an analysis flowchart to confirm or refute occurrence. The OTT was used to review 288 random admissions (Oct. 2010-Sept. 2011) and measure ADE incidence and severity (CTCAE 4.03 - Common Terminology Criteria for Adverse Events). Tool feasibility (time required), inter-rater (IR) reproducibility and positive predictive value (PPV) were measured. RESULTS: Overall, 884 triggers were detected and 122 ADEs, with 42.4 ADEs/100 admissions or 46.0 ADEs/1000 patient-days, and a 31.1% rate of severe ADEs. The most common ADEs were hyperglycaemia (14.5%), unplanned drug-related admission within 30 days (13.7%) and opiate-induced constipation (12.1%). Unplanned drug-related admission was the most serious (82.4% incidence of severe harm). Mean time for OTT implementation was 21.8 min; IR reproducibility was high (κ=0.965 (trigger); κ=0.935 (ADE); κ=0.853 (harm)); PPV 22-trigger version was 20.7%. CONCLUSIONS: ADE analysis flowcharts coupled with standardised grading of harm considerably reduced IR variability, thus providing a robust oncology-focused trigger tool for use in ADE audits and hospital comparisons. The involvement of a clinical advisory panel in tool development should help drive changes for improving practice. Further research on the OTT is warranted.

Physico-chemical stability of busulfan in injectable solutions in various administration packages.

BACKGROUND AND OBJECTIVES: Busulfan is used as part of a conditioning regimen prior to hematopoietic stem cell transplantation for the treatment of certain cancers and immune deficiency syndromes. Due to its instability in aqueous preparations, busulfan for infusion is prepared from a concentrate and has a relatively short shelf life once prepared. The purpose of this study was to identify the most suitable storage container and temperature to maximize the shelf life of busulfan therapeutic infusions prepared from Busilvex(®). METHODS: Busilvex(®) 6 mg/mL was diluted to 0.55 mg/mL with 0.9 % NaCl and aliquots dispensed into polypropylene syringes, polyvinyl chloride bags, and glass bottles. Three storage temperatures were evaluated: 2-8 °C, 13-15 °C (thermostatically controlled chamber), and room temperature (20 ± 5 °C). At set time points, samples were analysed for busulfan content, using a high-performance liquid chromatography (HPLC) system with ultraviolet detection. The change in pH and osmolarity on storage was also determined, and solutions were inspected visually for formation of a precipitate or colour change. To determine the contribution of precipitation to loss of busulfan content on storage, samples from one time series were treated with the solvent dimethylacetamide prior to HPLC separation and quantitation of busulfan. RESULTS: The results of the active substance content monitoring study over a 48-h period demonstrate that busulfan solution is stable at a 5 % threshold, at 2-8 °C for 16 h in syringes, 14 h in glass bottles, and 6 h in bags. In addition, the period of stability decreases as the temperature increases (4 h at 20 ± 5 °C). The solution is considered to be stable, subject to precipitation liable to be observed regardless of the temperature. CONCLUSION: The best stability was observed for busulfan solutions placed at 2-8 °C in syringes. This study demonstrated that precipitation, in addition to hydrolysis, has a significant influence on the busulfan content.