Canadian monitoring program of the surface contamination with 11 antineoplastic drugs in 124 centers.

INTRODUCTION: Occupational exposure to antineoplastic drugs can lead to long-term adverse effects on workers' health. A reproducible Canadian surface monitoring program was established in 2010. The objective was to describe contamination with 11 antineoplastic drugs measured on 12 surfaces among hospitals participating in this annual monitoring program. METHODS: Each hospital sampled six standardized sites in oncology pharmacies and six in outpatient clinics. Ultra-performance liquid chromatography coupled with tandem mass spectrometry was used for cyclophosphamide, docetaxel, doxorubicin, etoposide, 5-fluorouracil, gemcitabine, irinotecan, methotrexate, paclitaxel, and vinorelbine. Platinum-based drugs were analyzed by inductively coupled plasma mass spectrometry; this excludes inorganic platinum from the environment. Hospitals filled out an online questionnaire about their practices; a Kolmogorov-Smirnov test was used for some practices. RESULTS: One hundred and twenty-four Canadian hospitals participated. Cyclophosphamide (405/1445, 28%), gemcitabine (347/1445, 24%), and platinum (71/756, 9%) were the most frequent. The 90th percentile of surface concentration was 0.01 ng/cm² for cyclophosphamide and 0.003 ng/cm² for gemcitabine. Centers that prepared 5000 or more antineoplastic per year had higher concentrations of cyclophosphamide and gemcitabine on their surfaces (p = 0.0001). Almost half maintained a hazardous drugs committee (46/119, 39%), but this did not influence the cyclophosphamide contamination (p = 0.051). Hazardous drugs training was more frequent for oncology pharmacy and nursing staff than for hygiene and sanitation staff. CONCLUSIONS: This monitoring program allowed centers to benchmark their contamination with pragmatic contamination thresholds derived from the Canadian 90th percentiles. Regular participation and local hazardous drug committee involvement provide an opportunity to review practices, identify risk areas, and refresh training.

[Evaluation of pharmaceutical practice in hospitals: An exploratory study comparing processes in France and Quebec]. / Évaluation de la pratique pharmaceutique en établissement de santé : une étude exploratoire comparant les processus en France et au Québec.

CONTEXT: To ensure compliance with the legal and normative framework, the professional orders, which supervise the practice of pharmacy have established a professional inspection process. In addition to this process, other external organizations also require an accreditation, authorization, certification or validation process for professional practices. OBJECTIVE: The main objective is to identify and compare the methods of evaluating pharmaceutical practice in hospitals in France and Quebec. RESULTS: In order to identify and compare the methods of evaluating pharmaceutical practice in hospitals in France and Quebec, our approach allowed us to identify more organizations in France (i.e., High Authority of Health, Regional Health Agencies, the National Order of Pharmacists, the Nuclear Safety Agency, the Biomedicine Agency and the National Agency for the Safety of Medicines and Health Products) than in Quebec (i.e., Accreditation Canada, Ordre des pharmaciens du Québec and Health Canada). The study highlights the legal framework and applicable standards, the surveyors, the evaluation methods and the particularities for the evaluation of the hospital, the pharmacy department and the members of the department. CONCLUSIONS: This study highlights the evaluation processes of pharmaceutical practice in hospitals. In France, as in Quebec, we recognize the importance of the drug circuit in the hospital, the development and operation of a pharmacy department and the practice of pharmacy. While there are more similarities for the assessment of the drug circuit in hospitals and pharmacy department, important differences are observed for the assessment of individuals. We believe that the publication of a comparative analysis can contribute to discussions and exchanges to benefit from the best practices of each country.

National survey of safe handling of hazardous drugs in hospital settings: Use of an innovative approach.

INTRODUCTION: Workers can reduce their risk of exposure to hazardous drugs by following safe handling guidelines. Healthcare centers need to dedicate time and resources in order to implement new safety recommendations. The objective was to present the results of a national survey about the safe handling of hazardous drugs in healthcare centers. METHODS: Quebec healthcare centers performed an auto-evaluation to the newly updated safe handling guidelines in 2021. Centers rated each criterion as compliant or non-compliant. The guidelines tailored recommendations according to three categories of hazards: G1, consisting mostly of carcinogenic drugs; G2, other hazardous drugs; and G3, those with reproductive toxicity. The questionnaire prompted participants to document their planned corrective measures for non-compliant criteria. RESULTS: Most centers participated (28/29, 97%). The overall compliance was 58% (8761/15,216 criteria). The conformity per theme was hygiene and sanitation (1290/1,878, 69%), laundry (221/367, 60%), pharmacy (2658/4,474, 59%), nursing (3436/6,017, 57%), spills and accidental exposure (353/649, 54%), and general measures (803/1,831, 44%). It was higher for recommendations regarding G1s (4226/6,115, 69%) than for G2s (1626/3557, 46%) and G3s (372/916, 41%). CONCLUSIONS: This project successfully used an innovative approach that combined a national auto-evaluation survey, an actionable report, and the involvement of a community of practice. Centers were able to benchmark their implementation of safe handling guidelines, and community of practices may help in sharing the best practices. The design of the questionnaire helped in targeting corrective measures. More work is needed for safe handling practices that relate to G2 and G3 drugs.

Canadian monitoring program of the surface contamination with 11 antineoplastic drugs in 122 centers.

INTRODUCTION: Occupational exposure to antineoplastic drugs can lead to long-term adverse effects on workers' health. Environmental monitoring is conducted once a year, as part of a Canadian monitoring program. The objective was to describe contamination with 11 antineoplastic drugs measured on surfaces. METHODS: Six standardized sites in oncology pharmacy and six in outpatient clinic were sampled in each hospital. Samples were analyzed by ultra-performance liquid chromatography coupled with tandem mass spectrometry (non-platinum drugs) and by inductively coupled plasma mass spectrometry (platinum-based drugs). The limits of detection (in ng/cm2) were: 0.0006 for cyclophosphamide; 0.001 for docetaxel; 0.04 for 5-fluorouracil; 0.0004 for gemcitabine; 0.0007 for irinotecan; 0.0009 for methotrexate; 0.004 for paclitaxel, 0.009 for vinorelbine, 0.02 for doxorubicine, 0.0037 for etoposide and 0.004 for the platinum. Sub-analyses were done with a Kolmogorov-Smirnov test. RESULTS: 122 Canadian hospitals participated. Cyclophosphamide (451/1412, 32% of positive samples, 90th percentile of concentration 0.0160 ng/cm2) and gemcitabine (320/1412, 23%, 0.0036 ng/cm2) were most frequently measured on surfaces. The surfaces most frequently contaminated with at least one drug were the front grille inside the biological safety cabinet (97/121, 80%) and the armrest of patient treatment chair (92/118, 78%).The distribution of cyclophosphamide concentration was higher for centers that prepared ≥ 5000 antineoplastic drug preparations/year (p < 0.0001). CONCLUSIONS: This monitoring program allowed centers to benchmark their contamination with pragmatic contamination thresholds derived from the Canadian 90th percentiles. Problematic areas need corrective measures such as decontamination. The program helps to increase the workers' awareness.

Surface contamination with nine antineoplastic drugs in 109 canadian centers; 10 years of a monitoring program.

INTRODUCTION: Healthcare workers exposure to antineoplastic drugs can lead to adverse health effects. Guidelines promote the safe handling of antineoplastic drugs, but no safe exposure limit was determined. Regular surface sampling contributes to ensuring workers safety. METHODS: A cross-sectional monitoring is conducted once a year with voluntary Canadian centers, since 2010. Twelve standardized sampling sites were sampled. Samples were analyzed by high performance mass coupled liquid chromatography. The limits of detection (in ng/cm2) were: 0.001 for cyclophosphamide and gemcitabine; 0.3 for docetaxel and ifosfamide; 0.04 for 5-fluorouracil and paclitaxel; 0.003 for irinotecan; 0.002 for methotrexate; 0.01 for vinorelbine. RESULTS: The surfaces from 109 centers were sampled between 01/01/2020-18/06/2020. Twenty-six centers delayed their participation because of the COVID-19 pandemic. 1217 samples were analyzed. Surfaces were frequently contaminated with cyclophosphamide (34% positive, 75th percentile 0.00165 ng/cm2) and gemcitabine (16% and <0.001 ng/cm2). The armrest of patient treatment chairs (84% to at least one drug), the front grille inside the biological safety cabinet (BSC) (73%) and the floor in front of the BSC (55%) were frequently contaminated. Centers that prepared ≥5000 antineoplastic drugs annually had higher concentration of cyclophosphamide on their surfaces (p < 0.0001). Contamination measured on the surfaces was reduced from 2010 to 2020. CONCLUSIONS: This large-scale study showed reproducible long term follow up of the contamination of standardized sites of Canadian centers and a reduction in surface contamination from 2010 to 2020. Periodic surface sampling help centers meet their continuous improvements goals to reduce exposure as much as possible. The COVID-19 pandemic had a limited impact on the program.

Occupational exposure to antineoplastic drugs: what about hospital sanitation personnel?

OBJECTIVE: Occupational exposure to antineoplastic drugs (ANPs) occurs mainly through dermal contact. Our study was set up to assess the potential exposure of hospital sanitation (HS) personnel, for whom almost no data are available, through contamination of surfaces they regularly touch. METHODS: In the oncology departments of two hospitals around Montreal, surface wipe samples of 120-2000 cm2 were taken at 10 sites cleaned by the HS personnel and five other sites frequently touched by nursing and pharmacy personnel. A few hand wipe samples were collected to explore skin contamination. Wipes were analyzed by ultra-performance liquid chromatography tandem-mass spectrometry for 10 ANPs. RESULTS: Overall, 60.9% of 212 surface samples presented at least one ANP above the limits of detection (LOD). Cyclophosphamide and gemcitabine were most often detected (52% and 31% of samples respectively), followed by 5-fluorouracil and irinotecan (15% each). Highest concentrations of five ANPs were found in outpatient clinics on toilet floors (5-fluorouracil, 49 ng/cm2; irinotecan, 3.6 ng/cm2), a perfusion pump (cyclophosphamide, 19.6 ng/cm2) and on a cytotoxic waste bin cover (gemcitabine, 4.97 ng/cm2). Floors in patient rooms had highest levels of cytarabine (0.12 ng/cm2) and methotrexate (6.38 ng/cm2). Hand wipes were positive for two of 12 samples taken on HS personnel, seven of 18 samples on nurses, and two of 14 samples on pharmacy personnel. CONCLUSIONS: A notable proportion of surfaces showed measurable levels of ANPs, with highest concentrations found on surfaces cleaned by HS personnel, who would benefit from appropriate preventive training. As potential sources of worker exposure, several hospital surfaces need to be regularly monitored to evaluate environmental contamination and efficacy of cleaning.

Evaluation of decontamination efficacy of four antineoplastics (ifosfamide, 5-fluorouracil, irinotecan, and methotrexate) after deliberate contamination.

The main objective was to determine the decontamination efficacy of quaternary ammonium, 0.1% sodium hypochlorite, and water after deliberate contamination with four antineoplastics (ifosfamide, 5-fluorouracil, irinotecan, methotrexate). A stainless-steel surface was deliberately contaminated with ifosfamide (15 µg), 5-fluorouracil (10 µg), irinotecan (1 µg), and methotrexate (1 µg). First, a single decontamination step with either water, quaternary ammonium, or 0.1% sodium hypochlorite was tested. Then, the effect of up to four successive decontamination steps with either quaternary ammonium or 0.1% sodium hypochlorite was tested. Commercial wipes consisting of two layers of non-woven microfibers with an inner layer of highly absorbent viscose fibers were used. Triplicate surface samples were obtained and tested by ultra-performance liquid chromatography tandem mass spectrometry. The limits of detection were 0.004 ng/cm2 for ifosfamide, 0.040 ng/cm2 for 5-fluorouracil, 0.003 ng/cm2 for irinotecan, and 0.002 ng/cm2 for methotrexate. After a single decontamination step, the 0.1% sodium hypochlorite eliminated 100% of contamination with 5-fluorouracil, irinotecan, and methotrexate and 99.6 ± 0.5% of ifosfamide contamination. Quaternary ammonium and water also removed 100% of the 5-fluorouracil, and 99.5% to 99.9% of the other three antineoplastics. For ifosfamide, irinotecan, and methotrexate, the decontamination efficacy increased with successive decontamination steps with quaternary ammonium. 5-fluorouracil was undetectable after a single decontamination step. Methotrexate was the only drug for which decontamination efficacy was less than 100% after four decontamination steps. 100% decontamination efficacy was achieved from the decontamination step with 0.1% sodium hypochlorite for 5-fluorouracil, irinotecan, and methotrexate. For ifosfamide, 100% efficacy was achieved only after the third decontamination step. It was possible to make all traces of antineoplastic undetectable after deliberate contamination with 5-fluorouracil, irinotecan, and methotrexate with a 0.1% chlorine solution; up to three decontamination steps were needed to make ifosfamide undetectable. Water or quaternary ammonium removed more than 99.5% of deliberate contamination. In several scenarios, it was necessary to repeat the decontamination to eliminate residual traces. More work is needed to identify the optimal decontamination approach for all of the antineoplastic drugs used.

Cross-sectional evaluation of surface contamination with 9 antineoplastic drugs in 93 Canadian healthcare centers: 2019 results.

INTRODUCTION: The primary objective was to describe environmental contamination with National Institute for Occupational Safety and Health Group 1 hazardous drugs in oncology pharmacies and outpatient clinics in Canada in 2019, as part of an annual surveillance project. METHODS: In each participating center, 12 standardized sites (6 in the oncology pharmacy and 6 in outpatient clinic) were sampled. Each sample was prepared to allow quantification of six antineoplastic drugs (cyclophosphamide, ifosfamide, methotrexate, gemcitabine, 5-fluorouracil, and irinotecan) by ultra-performance liquid chromatography-tandem mass spectrometry. Samples were also tested for three additional antineoplastic drugs (docetaxel, paclitaxel, and vinorelbine) without quantification. The impact of certain characteristics of the sampling sites was evaluated with a Kolmogorov-Smirnov test for independent samples. RESULTS: Ninety-three Canadian centers participated in 2019, with a total of 1045 surfaces sampled. Cyclophosphamide was the drug most often found in the surface samples (32.4% of samples with positive result), followed by gemcitabine (20.3%). The front grille inside the biological safety cabinet (81.5% of samples positive for at least one antineoplastic drug) and the armrest of a treatment chair (75.8%) were the most frequently contaminated surfaces. Centers with more oncology inpatient and outpatient beds, those that prepared more antineoplastic drugs each year, and those that used more cyclophosphamide each year had higher concentrations of cyclophosphamide contamination on the surfaces tested (p < 0.0001). CONCLUSION: Traces of dangerous drugs were found in oncology pharmacies and oncology outpatient clinics in 93 Canadian hospitals in 2019. However, the quantities measured were very small. Every healthcare worker should consider these work areas to be contaminated and should wear appropriate protective equipment.

Evaluation of decontamination strategies for cyclophosphamide.

PURPOSE: The main objective was to determine the efficacy of various types of cleaning equipment and products after deliberate contamination with cyclophosphamide. The secondary objective was to test various cleaning scenarios using these equipment and products. METHODS: The study had two phases: testing of cleaning equipment (wipe : woven microfibers - Hygen®, two layers of non-woven microfibres and an inner layer of highly absorbent viscose fibres - MicronSolo®, two layers of non-woven microfibres and an inner layer of highly absorbent viscose fibres - MicroMix®, simili-tissu (low filament production) - Tork® and, mop : woven microfibers - Hygen®, microfibre and viscose - MicroOne®) and products (disinfectant : quaternary ammonium - DR100®, chlorine 0.1% - Zochlor® - Brutab® - PCS® NPH, sodium hypochlorite 2%, cleaner : detergent - Nu- Action 3®, cleaner and disinfectant: sodium hypochlorite 0.6% + detergent - Aliflex® and water) in phase 1 and testing of various cleaning procedures in phase 2. Specific areas of a room with a laminar flow hood (class II/type B2) were contaminated with 10 mcg of cyclophosphamide. Different types of surfaces were cleaned with various scenarios and the remaining cyclophosphamide was measured by the Institut national de santé publique du Québec. All tests were performed in triplicate. RESULTS: A total of 189 samples were obtained: 42 negative controls and positive controls, 54 during phase 1 and 93 during phase 2. All products were more than 96.5% effective. The 0.1% chlorines were the most effective products. Cleaning procedures with two or three products had average cleaning efficacies of 99.94-99.99%. Efficacy increased with the number of successive cleanings. When two products were used, the average cleaning efficacy varied between 99.78% and 99.98%, depending on the surface. CONCLUSION: All cleaning products tested reduced cyclophosphamide contamination by more than 96.58%. Cleaning efficacy increased with successive cleaning. No scenario was effective in removing 100% of traces. Additional studies with larger samples should be conducted to confirm these results.

Quantification of healthcare workers' exposure to cyclophosphamide, ifosfamide, methotrexate, and 5-fluorouracil by 24-h urine assay: A descriptive pilot study.

PURPOSE: The objective of this pilot study was to determine the frequency of urination and the concentration of four hazardous drugs (cyclophosphamide, ifosfamide, methotrexate, and fluorouracil) in workers' 24-h urine samples in relation to exposure to traces with hazardous drugs. METHODS: The study was conducted in three healthcare centers in the region of Montréal, Quebec, Canada. We recruited healthcare workers (nurses and pharmacy technicians) assigned to the hematology-oncology department. Each participant was asked to collect all urine voided during a 24-h period, to fill out an activity journal documenting tasks performed and to document the use of personal protective equipment. Samples were analyzed for cyclophosphamide, ifosfamide, methotrexate, and alpha-fluoro-beta-alanine (FBAL, the main urinary metabolite of 5-fluorouracil). Drugs were quantified by ultra-performance liquid chromatography-tandem mass spectrometry (positive electrospray MRM mode). RESULTS: Eighteen healthcare workers (10 nurses and 8 technicians) were recruited and provided consent to participate. Urine samples were obtained between 1 September and 30 September 2019. The number of urinations over the 24-h collection period ranged from 3 to 11 per participant. A total of 128 urine samples were analyzed for the 18 workers. All urine samples were negative for the four antineoplastics tested. CONCLUSION: No traces of cyclophosphamide, ifosfamide, methotrexate, or FBAL were found in the 24-h urine samples of 18 healthcare workers practicing in three healthcare facilities in Quebec. Although it was feasible to collect 24-h urine samples in this research project, it appears unrealistic to do so recurrently as part of a large-scale surveillance program.

Determination of good pharmacovigilance reporting practices in Quebec hospital pharmacies using a modified Delphi method.

PURPOSE: Many published guidelines are available for health care providers describing the best way to manage patient's adverse drug reactions (ADRs). However, there is a lack of guidance on the best way to promote and manage ADR reporting within hospitals. The goal of this study was to develop good pharmacovigilance reporting practices (GPRPs). METHODS: This descriptive study used a modified Delphi method. The research team developed 41 statements, according to a modified Specific Measurable Attainable Realistic Timely (SMART) method and grouped them in six categories: organization (n = 12 statements), pharmacovigilance committee (n = 4), database (n = 5), training (n = 5), tools (n = 3), and quality (n = 12). The Delphi consultation (two online rounds, conducted in 2018) involved directors of pharmacy in Quebec hospitals. RESULTS: Of 30 directors of pharmacy invited to participate in the first round, 27 (90%) did so. Following this round, the wording of five statements was modified according to pre-established rules. Twenty-five (93%) of the original 27 participants responded during the second round. Of the initial 41 statements, 37 were selected (average score ≥ 7); the other four were eliminated. Of the 37 statements selected, 22 had a "must do" formulation, 12 had a "should do" formulation, and three had a "may do" formulation. CONCLUSION: Using a modified Delphi method, we established a set of GPRPs for hospital pharmacy based on 37 statements. To our knowledge, these are the first GPRPs published in the hospital pharmacy literature.

Investigational drug labeling variability.

BACKGROUND/AIMS: In comparison with commercial drugs, there are few regulations concerning the labeling of investigational drugs. This leads to variability in their content and layout. This increases the risk of errors during storage, validation, compounding, dispensing and administration. The aim of this study was to evaluate the conformity and variability of investigational drug labels. Additional exploratory aims were to evaluate the use of an automated script to describe the labels and to identify the factors associated with the ease of finding a kit number. METHODS: An 87-criterion list was developed to evaluate content, format and readability. It included eight criteria to evaluate the conformity to the Canadian Food and Drugs Regulation. A systematic cross-sectional evaluation of all investigational drug labels in our 500-bed mother-child center was performed. All active protocols during the period of 14-22 February 2018 were included. Labels from drugs that were sourced locally were excluded. Labels affixed to the outside (external) and inside (internal) containers, as well as labels from American and European sponsors, were compared with the chi-square and Student's t tests. A script was developed in Python to automatically determine key information (number of words, main colors and their proportion). A short survey was conducted with a convenience sample of pharmacists to rate the ease of finding the kit number on labels. Correlation was evaluated with different factors. RESULTS: A total of 27 protocols were included (24 internal and 34 external labels). The majority (33/34) of external labels were compliant with the Regulation. Some internal labels did not state the expiry date (9/13), the sponsor address (2/13) or storing conditions (1/13). A total of 10 criteria were different between internal and external labels, for instance, the number of languages was higher on external labels (median 3 (2-14) vs 10 (2-50); p = 0.013). Five criteria were different depending on the sponsors' location, for instance, European sponsors were more prone to use bold characters (25% vs 61%, p = 0.034). There was a mean of 146 ± 111 words and 78.3% ± 7.3% empty space per label. These were positively correlated (p < 0.001). The proportion of free space on a label was also correlated with the ease of finding the kit number (p = 0.002). CONCLUSION: We measured a high variability in the labeling of investigational drugs. Key information was missing from labels affixed to internal containers, despite the use of a high number of pages. The automation worked well and further work is needed to identify criteria that may improve readability and reduce error risk. Detailed and harmonized international guidelines are needed.

Pediatric SJS/TEN Subdued by a Combination of Dexamethasone, Cyclosporine, and Etanercept.

We report a case of an 17-year-old male with a drug reaction in the spectrum of Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), triggered by carbamazepine, who was succesfully treated with the combination of dexamethasone, cyclosporine, and etanercept. This triple therapy halted and prevented skin epidermolysis without immediate or late onset complications.

Visual disorders with psychostimulants: A paediatric case report.

Methylphenidate- and amphetamine-based psychostimulants are the most common medications used to treat the symptoms of attention-deficit/hyperactivity disorder in children. Ocular side effects including dry eyes, mydriasis, accommodation disturbance, and blurry vision are listed in the product monograph but interestingly, are rarely reported in the paediatric literature. Our patient, a 9-year-old boy, presented a significant decrease in visual acuity secondary to accommodation disorder after being treated with methylphenidate hydrochloride controlled release (Biphentin) and lisdexamfetamine (Vyvanse). The unusual acute adverse effect, altered accommodation leading to a decline in visual acuity, emphasizes the importance of considering any change in vision following the introduction of psychostimulant medication as a potential adverse effect. This case highlights the importance of pharmacovigilance especially in paediatrics where data are lacking.

Patient access to compounded drugs in paediatrics after discharge from a tertiary centre.

OBJECTIVE: To describe the problems faced by young patients and their parents when obtaining and using compounded drugs. METHODS: This prospective observational descriptive study included patients 0 to 21 years of age who were discharged from a mother-child tertiary hospital with a prescription containing at least one compounded drug between February 2016 and July 2016. Families were called 7 to 10 business days after discharge to complete a telephone follow-up questionnaire. Retail pharmacies were contacted to obtain additional information in order to compare the dispensed compounded drug with the prescription and published master formulas. RESULTS: The parents of 71 patients with a median age of 6.9 months were surveyed regarding 99 compounded drugs corresponding to 34 different oral formulations. Out of 314 issues identified, 252 were considered as problems: 9 involved major and 243 minor problems with real or potential consequences. CONCLUSION: This study identified a significant number of compounding-related problems. It suggests that current practice standards are insufficient and action should be taken to improve the use and the dispensation of compounded drugs to ensure patients' safety.

Closed-system drug-transfer devices plus safe handling of hazardous drugs versus safe handling alone for reducing exposure to infusional hazardous drugs in healthcare staff.

BACKGROUND: Occupational exposure to hazardous drugs can decrease fertility and result in miscarriages, stillbirths, and cancers in healthcare staff. Several recommended practices aim to reduce this exposure, including protective clothing, gloves, and biological safety cabinets ('safe handling'). There is significant uncertainty as to whether using closed-system drug-transfer devices (CSTD) in addition to safe handling decreases the contamination and risk of staff exposure to infusional hazardous drugs compared to safe handling alone. OBJECTIVES: To assess the effects of closed-system drug-transfer of infusional hazardous drugs plus safe handling versus safe handling alone for reducing staff exposure to infusional hazardous drugs and risk of staff contamination. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, OSH-UPDATE, CINAHL, Science Citation Index Expanded, economic evaluation databases, the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov to October 2017. SELECTION CRITERIA: We included comparative studies of any study design (irrespective of language, blinding, or publication status) that compared CSTD plus safe handling versus safe handling alone for infusional hazardous drugs. DATA COLLECTION AND ANALYSIS: Two review authors independently identified trials and extracted data. We calculated the risk ratio (RR) and mean difference (MD) with 95% confidence intervals (CI) using both fixed-effect and random-effects models. We assessed risk of bias according to the risk of bias in non-randomised studies of interventions (ROBINS-I) tool, used an intracluster correlation coefficient of 0.10, and we assessed the quality of the evidence using GRADE. MAIN RESULTS: We included 23 observational cluster studies (358 hospitals) in this review. We did not find any randomised controlled trials or formal economic evaluations. In 21 studies, the people who used the intervention (CSTD plus safe handling) and control (safe handling alone) were pharmacists or pharmacy technicians; in the other two studies, the people who used the intervention and control were nurses, pharmacists, or pharmacy technicians. The CSTD used in the studies were PhaSeal (13 studies), Tevadaptor (1 study), SpikeSwan (1 study), PhaSeal and Tevadaptor (1 study), varied (5 studies), and not stated (2 studies). The studies' descriptions of the control groups were varied. Twenty-one studies provide data on one or more outcomes for this systematic review. All the studies are at serious risk of bias. The quality of evidence is very low for all the outcomes.There is no evidence of differences in the proportion of people with positive urine tests for exposure between the CSTD and control groups for cyclophosphamide alone (RR 0.83, 95% CI 0.46 to 1.52; I² = 12%; 2 studies; 2 hospitals; 20 participants; CSTD: 76.1% versus control: 91.7%); cyclophosphamide or ifosfamide (RR 0.09, 95% CI 0.00 to 2.79; 1 study; 1 hospital; 14 participants; CSTD: 6.4% versus control: 71.4%); and cyclophosphamide, ifosfamide, or gemcitabine (RR not estimable; 1 study; 1 hospital; 36 participants; 0% in both groups).There is no evidence of a difference in the proportion of surface samples contaminated in the pharmacy areas or patient-care areas for any of the drugs except 5-fluorouracil, which was lower in the CSTD group than in the control (RR 0.65, 95% CI 0.43 to 0.97; 3 studies, 106 hospitals, 1008 samples; CSTD: 9% versus control: 13.9%).The amount of cyclophosphamide was lower in pharmacy areas in the CSTD group than in the control group (MD -49.34 pg/cm², 95% CI -84.11 to -14.56, I² = 0%, 7 studies; 282 hospitals, 1793 surface samples). Additionally, one interrupted time-series study (3 hospitals; 342 samples) demonstrated a change in the slope between pre-CSTD and CSTD (3.9439 pg/cm², 95% CI 1.2303 to 6.6576; P = 0.010), but not between CSTD and post-CSTD withdrawal (-1.9331 pg/cm², 95% CI -5.1260 to 1.2598; P = 0.20). There is no evidence of difference in the amount of the other drugs between CSTD and control groups in the pharmacy areas or patient-care areas.None of the studies report on atmospheric contamination, blood tests, or other measures of exposure to infusional hazardous drugs such as urine mutagenicity, chromosomal aberrations, sister chromatid exchanges, or micronuclei induction.None of the studies report short-term health benefits such as reduction in skin rashes, medium-term reproductive health benefits such as fertility and parity, or long-term health benefits related to the development of any type of cancer or adverse events.Five studies (six hospitals) report the potential cost savings through the use of CSTD. The studies used different methods of calculating the costs, and the results were not reported in a format that could be pooled via meta-analysis. There is significant variability between the studies in terms of whether CSTD resulted in cost savings (the point estimates of the average potential cost savings ranged from (2017) USD -642,656 to (2017) USD 221,818). AUTHORS' CONCLUSIONS: There is currently no evidence to support or refute the routine use of closed-system drug transfer devices in addition to safe handling of infusional hazardous drugs, as there is no evidence of differences in exposure or financial benefits between CSTD plus safe handling versus safe handling alone (very low-quality evidence). None of the studies report health benefits.Well-designed multicentre randomised controlled trials may be feasible depending upon the proportion of people with exposure. The next best study design is interrupted time-series. This design is likely to provide a better estimate than uncontrolled before-after studies or cross-sectional studies. Future studies may involve other alternate ways of reducing exposure in addition to safe handling as one intervention group in a multi-arm parallel design or factorial design trial. Future studies should have designs that decrease the risk of bias and enable measurement of direct health benefits in addition to exposure. Studies using exposure should be tested for a relevant selection of hazardous drugs used in the hospital to provide an estimate of the exposure and health benefits of using CSTD. Steps should be undertaken to ensure that there are no other differences between CSTD and control groups, so that one can obtain a reasonable estimate of the health benefits of using CSTD.

Multicenter study of environmental contamination with cyclophosphamide, ifosfamide, and methotrexate in 48 Canadian hospitals.

Context Oncology workers are occupationally exposed to antineoplastic drugs. This exposure can induce adverse health effects. In order to reduce their exposure, contamination on surfaces should be kept as low as possible. Objectives To monitor environmental contamination with cyclophosphamide, ifosfamide, and methotrexate in oncology pharmacy and patient care areas in Canadian hospitals. To describe the impact of some factors that may limit contamination. Methods This is a descriptive study. Twelve standardized sites were sampled in each participating center (six in the pharmacy and six in patient care areas). Samples were analyzed for the presence of cyclophosphamide, ifosfamide, and methotrexate by ultra-performance liquid chromatography tandem mass spectrometry technology. Descriptive statistical analyses were done and results were compared with a Kolmogorov-Smirnov test for independent samples. Results In 2015, 48 hospitals participated in this study (48/202, 24%). Overall, 34% (181/525) of the samples were positive for cyclophosphamide, 8% (41/525) for ifosfamide, and 6% (31/525) for methotrexate. The 75th percentile value of cyclophosphamide surface concentration was 6.9 pg/cm2. For ifosfamide and methotrexate, they were lower than the limit of detection. Centers who prepared more antineoplastic drugs per year and centers who used more cyclophosphamide per year showed significantly higher surface contamination ( p < 0.0001). Over the years, we observed a reduction in surface contamination. Conclusion In comparison with other multicenter studies that were conducted in Canada, the concentration of antineoplastic drugs measured on surfaces is decreasing. Regular environmental monitoring is a good practice in order to maintain contamination as low as reasonably achievable.

Pilot study of biological monitoring of four antineoplastic drugs among Canadian healthcare workers.

Purpose There are health risks to workers occupationally exposed to antineoplastic drugs. We hypothesized that implementing a biological monitoring program would be feasible. The goal was to present the results of our pilot cross-sectional study of biological monitoring of four antineoplastic drugs. Methods We recruited workers from the hematology-oncology department and control workers in a mother-child university health center. This study was preceded by an information period during which we aimed at enhancing the workers' awareness and knowledge of the risks of occupational exposure. Participants filled out a journal containing activities performed and personal protective equipment worn. One urine sample was collected at the end of their shift. Samples were analyzed by UPLC/MS-MS for the presence of cyclophosphamide, ifosfamide, methotrexate, and alpha-fluoro-beta-alanine (5-fluorouracile's main urinary metabolite). Results The participation rate was 85.7% (102/119). No urine sample had detectable concentrations of any of the four drugs evaluated (0/101; 0/74 nurses, 0/11 pharmacists, 0/9 pharmacy technicians, and 0/7 doctors). In the 5 days before sampling, 67/92 (72.8%) hematology-oncology participants performed at least one activity with antineoplastic drugs. Nurses wore all of the recommended protection for technical activities (86.2%), but rarely for non-technical activities (14.9%). Pharmacists and pharmacy technicians wore all of the recommended protection for all activities (100.0%). Conclusions This pilot study had a good participation rate. The absence of positive samples was a good indication that the measures in place ensured workers' safety, even though we found areas where the worker protection can be enhanced.

The Québec NTBC Study.

In this chapter we describe the current Quebec NTBC Study protocol. Quebec's unique characteristics have influenced the development of the protocol, including a high prevalence of hepatorenal tyrosinemia (HT1), universal newborn screening for HT1, availability of treatment with nitisinone (NTBC) and special diet, a large territory, where HT1 treatment is coordinated by a small number of centers. Screened newborns are seen within 3 weeks of birth. Patients with liver dysfunction (prolonged prothrombin time and/or international normalized ratio (INR) provide sensitive, rapidly available indicators) are treated by NTBC and special diet. The specific diagnosis is confirmed by diagnostic testing for succinylacetone (SA) in plasma and urine samples obtained before treatment. After an initial period of frequent surveillance, stable patients are followed every 3 months by assay of plasma amino acids and NTBC and plasma and urine SA. Abdominal ultrasound is done every 6 months. Patients have an annual visit to the coordinating center that includes multidisciplinary evaluations in metabolic genetics, hepatology, imaging (for abdominal ultrasound and magnetic resonance imaging) and other specialties as necessary. If hepatocellular carcinoma is suspected by imaging and/or because of progressive elevation of alphafetoprotein, liver transplantation is discussed. To date, no patient in whom treatment was started before 1 month of age has developed hepatocellular carcinoma, after surveillance for up to 20 years in some. This patient group is the largest in the world that has been treated rapidly following newborn screening. The protocol continues to evolve to adapt to the challenges of long term surveillance.

Unlicensed and off-label drug use in paediatrics in a mother-child tertiary care hospital.

OBJECTIVE: To assess unlicensed and off-label drug use in a tertiary care paediatric hospital in Canada on a single day. METHODS: A cross-sectional study in a tertiary care paediatric hospital was conducted on one randomly selected day. Active prescriptions for children <18 years of age were analyzed. Unlicensed drug use was defined as the use of nonmarketed drugs in Canada or marketed drugs with pharmacy compounding. Off-label drug use was defined as the use of marketed drugs in Canada for an unapproved age group, indication, dosing, frequency and/or route of administration. Off-label drug uses associated with strong scientific support were analyzed using the Pediatric Dosage Handbook, 14th edition and Micromedex(®) Solutions. Number and proportion of unlicensed and off-label drug uses, and off-label drug uses associated with strong scientific support were measured. RESULTS: A total of 2145 drug prescriptions were extracted on March 5, 2014, for inclusion in the present study. The unlicensed drug use rate was 8.3% (57 unlicensed drug products; 75 nonmarketed drug prescriptions and 103 pharmacy compounding prescriptions) and the off-label drug use rate was 38.2% (161 substances; 819 prescriptions). Reasons for off-label drug use included unapproved age group (n=436 [53.2%]), dosing (n=226 [27.6%]), frequency (n=206 [25.2%]), indication (n=45 [5.5%]) and administration route (n=46 [5.6%]). Of the off-label drug prescriptions, 39.3% (n=322) were associated with strong scientific support. CONCLUSIONS: On a randomly selected day, 8.3% of prescriptions were unlicensed and 38.2% were off-label for children hospitalized at the authors' institution. Of off-label prescriptions, only 39.3% were associated with strong scientific support.

OBJECTIF: Évaluer l'emploi des médicaments non brevetés et utilisés dans une indication non autorisée en une seule journée dans un hôpital pédiatrique de soins tertiaires du Canada. MÉTHODOLOGIE: Des chercheurs ont réalisé une étude transversale dans un hôpital pédiatrique de soins tertiaires au cours d'une journée sélectionnée au hasard. Ils ont analysé les prescriptions actives des enfants de moins de 18 ans. Les médicaments non brevetés désignaient les médicaments non commercialisés au Canada ou commercialisés, mais préparés en pharmacie. Les médicaments utilisés dans une indication non autorisée (MUINA) désignaient les médicaments commercialisés au Canada utilisés dans un groupe d'âge, une indication, une dose, une fréquence ou une voie d'administration non approuvé. Les chercheurs ont analysé les MUINA associés à un solide appui scientifique au moyen du Pediatric Dosage Handbook, 14th edition et de Micromedex® Solutions. Ils ont calculé le nombre et la proportion de médicaments non brevetés et de MUINA prescrits, ainsi que celui des MUINA liés à un solide appui scientifique. RÉSULTATS: Le 5 mars 2014, les chercheurs ont extrait 2 145 prescriptions de médicaments qu'ils ont incluses dans la présente étude. Le taux d'utilisation de médicaments non brevetés s'élevait à 8,3 % (57 produits non brevetés, 75 médicaments non commercialisés et 103 préparations pharmaceutiques) et celui de MUINA, à 38,2 % (161 substances; 819 prescriptions). Les raisons pour lesquelles les prescriptions étaient considérées comme des MUINA étaient un groupe d'âge (n=436 [53,2 %]), une dose (n=226 [27,6 %]), une fréquence (n=206 [25,2 %]), une indication (n=45 [5,5 %]) ou une voie d'administration (n=46 [5,6 %]) non approuvé. Parmi les MUINA, 39,3 % (n=322) étaient liés à un solide appui scientifique. CONCLUSIONS: Au cours d'une journée sélectionnée au hasard, 8,3 % des prescriptions n'étaient pas brevetées et 38,2 % étaient utilisées dans une indication non autorisée chez les enfants hospitalisés dans l'établissement des auteurs. Parmi les MUINA, seulement 39,3 % étaient liés à un solide appui scientifique.