Impact statements

  • Healthcare providers need to be aware of the potential risks associated with clozapine use, especially errors related to prescription information, dosing, and medication names.

  • Future efforts should focus on developing prescribing safety indicators specifically tailored to clozapine use to ensure safe prescribing practices.

  • Regulatory agencies should reassess existing clozapine prescribing policy and evaluate its implementation in practice.

  • Qualitative analysis using a theoretical framework is a priority for future research to ensure a thorough understanding of the underlying causes of clozapine-related errors, facilitating the development of effective remedial interventions.

Introduction

Medication errors (MEs) are a major patient safety concern worldwide and are considered a significant cause of morbidity and mortality [1, 2]. They are not only associated with patient-related harm but also associated with financial costs [1]. A medication error is defined as “any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the healthcare professional, patient, or consumer. Such events may be related to professional practice, healthcare products, procedures, and systems, including prescribing; order communication; product labelling, packaging, and nomenclature; compounding; dispensing; distribution; administration; education; monitoring; and use”[3]. According to the World Health Organization (WHO), MEs are estimated to cost $42 billion annually in the United States (US) [2]. In the United Kingdom (UK), preventable medication-related harm is estimated to cost the National Health Service (NHS) approximately £98 million annually [4]. Therefore, reducing preventable MEs is a priority area for the WHO’s Global Patient Safety Challenge [2]. Consequently substantial investments have been made internationally to establish medication incident reporting programmes to better understand the scale and causes of MEs occurring in health care systems such as the National Reporting and Learning System (NRLS) in England and Wales [5], the Institute for Safe Medication Practices (ISMP) in the US [6], and the British Columbia Patient Safety and Learning System in Canada [7]. These reporting programmes analyse reports of MEs systematically to generate learning and thereby improve future practices.

In Saudi Arabia, the General Administration of Pharmaceutical Care at the Ministry of Health (MOH) is responsible for collecting data on MEs from government hospitals and primary healthcare settings [8]. The MOH supports the mandatory reporting of all MEs to maximize the potential for generating learning that can be used to guide the design of interventions aimed at reducing potential MEs in hospitals across Saudi Arabia. The MOH supports reporting by regularly providing an online medication safety learning module that covers human and systematic factors underpinning MEs and ways to reduce the risk of harm resulting from medication use [9].

In a recent study, a total of 71,332 MEs were reported from the MOH database between March 2018 and June 2019; approximately 6% of those errors affected patients, with antipsychotic medications being one of the frequently reported medication classes involved with MEs [8].

Clozapine, an atypical antipsychotic, is one of the most effective medications for treating schizophrenia and is listed on the WHO Model list of essential medicines [10]. It exhibits superior effect in managing positive, negative, and overall symptoms, as well as relapse rates among individuals with schizophrenia [11, 12]. In line with international schizophrenia treatment guidelines, clozapine use in Saudi Arabia is restricted to individuals with treatment-resistant refractory schizophrenia, and can be prescribed only by the consultant psychiatrists in government and nongovernment hospitals [13]. In Saudi Arabia, there is evidence indicating that clozapine is underutilised among patients diagnosed with this condition. A cross-sectional observational study conducted in psychiatric wards in five regions of Saudi Arabia between July 2012 and June 2014, reported that the use of clozapine was low, with only 3.1% of total inpatients and 2.4% of total outpatients receiving the medication [14].

Despite its efficacy in treating refractory schizophrenia, clozapine is associated with a wide range of safety challenges that may increase the risk of MEs [15, 16]. Clozapine is a high-risk medication with a narrow therapeutic index, which adds further urgency to careful dosing and drug-level monitoring [17, 18]. The risk factors include those resulting from drug‒drug interactions [19], the risk of adverse effects (i.e., weight gain, hypersalivation, sedation) and some life-threatening complications such as agranulocytosis, myocarditis, gastrointestinal hypomotility, and seizures [17]. In addition, clozapine cannot be prescribed without the patient having been registered with the drug company or without the appropriate monitoring services performed [20]. In a mixed analysis based on reports of clozapine-related MEs reported to the NRLS over one year, a total of 1,548 reports were found. Among those, the majority of clozapine-related MEs occurred in the administration stage and were associated with errors related to wrong doses, dose omissions, and wrong quantity. The most frequent underlying factors of reported errors concern challenges related to availability, stock, and supply [21]. In Saudi Arabia, no study has examined the characteristics and contributory factors of clozapine-related MEs at the national level.

Aim

The aim of this study was to characterize the nature and contributory factors of clozapine-related MEs reported to the national MOH database from government hospitals and primary care centres in order to highlight potential areas for improvement.

Ethics approval

This study was granted ethical approval by the Central Institutional Review Board of the Ministry of Health (Reference number: 22-55 E, Date: 16-11-2022).

Method

Study design

This cross-sectional study examined clozapine-related ME reports extracted from the MOH database between January 2018 and September 2022. This study is reported in accordance with the Reporting of Studies Conducted via the Observational Routinely Collected Dealth Data (RECORD) Statement [22].

Data source and variables

The MOH database is a national reporting system that is expected to receive an average of 400,000 reports annually. The database collects errors related to all medications used in government hospitals and primary care centres in Saudi Arabia, where reporters are expected to fill out the ME report and submit it to the MOH electronically in large batches for analysis [8]. All data containing ‘Clozapine’ under the MOH’s preexisting field ‘medication name category’ were extracted and included in this study. Each ME report contains categorical information about the date of occurrence, the patient involved in the error (i.e., age and gender), the region where the reported hospital/primary care centre is located, the profession of the reporter, the type of error (e.g. incorrect dose, dose omission), the stage at which the error occurred (i.e., prescribing, dispensing, administration, and monitoring stage, (Table 1)), the contributory factors believed by the reporter to increase the risk of error occurrence, and the reporter’s perception of harm level [8]. The harm-related outcomes were categorized by the reporter using the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) index for categorizing MEs. The NCC MERP proposed categorizing errors into nine categories (categories A to I) on the basis of the level of harm they caused [3]. In this study, we used the categorical information as entered by reporters without modification or reclassification by the research team.

Table 1 Definition of MEs in relation to the stage of the treatment process
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Data analysis

A descriptive analysis was carried out to summarize the data. Frequency tables were used to characterize the ME reports related to clozapine according to their main characteristics including the number of medication errors over time, patient age, profession of the reporter(s), type/stage of ME, level of harm, and contributory factors. The data were further analysed via cross-tabulations to explore the relationships between variables, including error outcomes and error categories.

Results

Among the 35,077 antipsychotic ME reports, 1,165 (3.3%) were found to be clozapine-related and were thus included in the analysis. All the clozapine-related MEs had been reported from government hospitals. The year with the lowest number of reports was 2018 with 14 reports, whereas the highest number of reports was in 2020, with 376 reports. The majority of reported errors involved patients aged > 18 years (99.1%; 1,154), with the majority of those being male patients (72.2%; 841). The majority of ME reports were reported from the central region of Saudi Arabia (32.3%; 376), followed by the western (23.2%; 270), northern (20.2%; 235), and eastern regions (17.9%; 208). Pharmacy staff were found to be the profession that most frequently reported MEs (82.6%; 963), followed by nurses (11.9%; 139), physicians (4.1%; 48), patients/caregivers (0.9%; 11), and other (0.3%; 3). Table 2 summarizes the characteristics of clozapine-related MEs.

Table 2 Characteristics of clozapine-related medication errors (n = 1,165)
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The majority of reported clozapine-related errors originated at the prescribing stage (77.8%; 906), with fewer during the dispensing stage (9.9%, n = 115), (Fig. 1). Missing prescription information (30.1%; 351), incorrect/unclear/missing doses (18.4%; 214), and incorrect/unclear/missing medication names (11.9%; 139) were the most frequently reported types of MEs, as presented in Table 3. On the basis of the NCC MERP index for categorizing MEs according to their outcomes, the highest percentage (92.3%; 1,075) of clozapine-related errors were Category A (33.6%; 391), an event with the capacity to cause error. This was followed by Category B (58.7%; 684), an error occurred but did not reach the patient. Among those errors that reached the patients, a minority were Category C (2.8%; 33), the errors resulted in no harm to the patients, with slightly more Category D (4.5%; 53), the errors reached the patients and might need careful monitoring to confirm whether they resulted in harm and/or necessitated actions to preclude harm. A few errors resulted in harm, Category E (0.1%, n = 1) and Category F (0.2%, n = 2) missing prescription information and drug‒drug interactions, respectively. Details of the reported harmful outcomes related to clozapine and their associated types of errors are summarized in Tables 4 and 5, respectively.

Fig. 1
figure 1

Clozapine-related errors at different stages of the treatment process

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Table 3 Number of medication errors by category (n = 1,165)
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Table 4 Clinical outcomes associated with clozapine-related errors (n = 1,165)
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Table 5 Category of error with harmful and/or non-harmful outcome (n = 1165)
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In terms of potential factors reported to contribute to clozapine-related errors, lack of policy related to prescribing and monitoring aspects of clozapine (29.4%; n = 343), factors related to staffing or workflow (18.1%; n = 211), and environmental factors (15.2%, n = 177) were the most frequently reported. However, approximately 8% (n = 96) of the reports lacked information about potential factors contributing to these errors. Tables 6 (Electronic Supplementary Material) summarizes the reported contributory factors relating to clozapine-related MEs.

Discussion

Statement of key findings

To our knowledge, this is the first study to retrospectively identify the number and characteristics of medication errors related to clozapine that were reported to the national database at the MOH over a period of five years. This study highlighted the risks associated with clozapine use in relation to patient safety. Clozapine-related errors were found to involve mostly adult male patients, who were most frequently reported from the central region of Saudi Arabia by the pharmacy staff. Clozapine-related errors were associated mainly with the prescribing and dispensing stages and were related mostly to prescription information, dosing, and medication names. The predominant factors contributory to clozapine-related errors were mostly related to a lack of policy related to prescribing and monitoring aspects of clozapine and issues related to staffing, workflow, and the work environment.

Strengths and weaknesses

This is the first study to summarize evidence regarding the nature of and contributing factors for clozapine-related MEs in Saudi Arabia over a period of 5 years. Our findings may be used to inform the national effort to reduce MEs and related patient harm from clozapine use. However, this study also has several limitations. While the majority of ME reports were complete, the level of detail concerning the description of errors as well as their contributory factors was minimal, which might limit the understanding of the context of each ME occurrence [8, 23, 24]. The level of causality between the MEs and outcomes was not established due to the inherent nature of secondary datasets. The fact that the majority of MEs were reported by pharmacists introduces potential bias in which pharmacists might be more inclined to identify prescribing errors over dispensing errors potentially attributing more errors to physicians. This should be considered when interpreting the study findings. In this study, we used the MOH’s existing classification of errors, which was mainly based on the personal judgement of reporters, which might not have reflected the actual characteristics of those errors [8].

Interpretation

Our findings suggest that a considerable number of MEs were associated with clozapine. The number of reported MEs peaked in 2020, followed by a slight decline in reporting in the years that followed. The increase in the number of MEs can potentially be related to the COVID-19 pandemic, in which some studies reported high rates of MEs during this period. A pre-post single-centre retrospective study in Saudi Arabia reported 1.5 MEs per 100 orders in the pre-COVID-19 period and 19 MEs per 100 medication orders after the onset of the pandemic [25]. Our study also revealed that the majority of patients receiving clozapine were adults, which was expected, as clozapine is used by mainly young to middle-aged patients [26]. In addition, the safety and effectiveness of clozapine among paediatric patients have not been established according to the European medicines agency (EMA) and the US Food and Drug Administration (FDA), which explains the lack of ME reports among paediatric patients [27, 28].The preponderance of males in this study can be explained by the nature of schizophrenia, as the risk of the disease is greater in male patients than in female patients [29, 30]. In terms of the profession of reporters, the pharmacist was the healthcare provider who detected MEs the most. This is consistent with previous studies that reported pharmacists reported more MEs during the preparation and dispensing stages [31]. Pharmacist interventions play an essential role in significantly minimizing MEs by conducting educational training for healthcare providers, as well as reviewing and validating medication prescriptions before dispensing medications [32, 33].

Our study reported that a majority of clozapine-related MEs originated from the prescribing stage and involved errors related to prescription information. However, a UK-based study reported errors that occurred in the administration stage of the medication treatment process, with omitted medicine being error most frequently implicated error [21]. Furthermore, similar findings were observed in which dispensing errors and errors involved in clozapine dosing were among the most frequently reported, with the majority of errors reported in both studies resulting in low or no harm to patients. Therefore, it is necessary to create prescribing safety indicators tailored specifically to cover prescribing practices related to clozapine use. These indicators to be further validated through a consensus-based process involving experts in psychiatry and medication management and can be integrated into informatics tools to identify risks associated with clozapine use [34]. Similar approaches, such as the Salford medication safety (SMASH) dashboard and the PINCER tool, have been successfully implemented across health care settings in the UK [35, 36]. This approach could also be considered for application in the context of clozapine use in Saudi Arabia. Additionally, previous research has prominently addressed factors related to staffing and the work environment in understanding error causation in psychiatric settings [37,38,39,40]. Nevertheless, there is a continued need for contextual details unique to psychiatric settings in Saudi Arabia. Such details are vital for developing effective remedial interventions.

Our findings also highlight the main risk factors reported to contribute to clozapine-related MEs, including risks related to lack of policy related to prescribing and monitoring of clozapine, staffing/workflow, and environmental factors. While the working environment and low staffing-related factors were similar to those reported in previous studies in psychiatric hospitals [40], our study identified the lack of policy on clozapine use as the most frequently reported contributory factor as observed in a nationwide study of MEs reported by 265 government hospitals and primary care centres [8]. The variability observed in contributory factors across countries could be explained in part by differences in clinical practices, ME reporting practice, and study design [41]. Importantly, the MOH established a policy to ensure the safe use of clozapine [42]. However, there is limited evidence of its implementation in hospitals in Saudi Arabia. Therefore, future research on this issue is essential for understanding and mitigating this influential contributory factor.

To ensure the safe use of clozapine, several regulations exist worldwide to standardize its use in terms of prescribing and monitoring it. There are some restrictions in place regarding prescribing clozapine, in that only psychiatrists are allowed to prescribe clozapine in countries such as Denmark, Romania, and Japan [43]. In terms of monitoring, haematological monitoring is mandatory in all countries, although they differ substantially with regard to the frequency of monitoring [43]. In Denmark, weekly monitoring is required for 18 weeks, and then monthly monitoring is required thereafter; in Japan, weekly monitoring is mandatory for 26 weeks, followed by monitoring every two weeks [43]. In addition, in most countries, the manufacturer keeps a haematological monitoring database in which clozapine cannot be dispensed without acceptable white blood and absolute neutrophil level results [43]. In other countries such as New Zealand, the local guidelines recommend echocardiography and a routine troponin level during the initial treatment with clozapine [43]. In Saudi Arabia, clozapine prescribing and monitoring are managed under the Risk Evaluation and Mitigation Strategy (REMS) programme as per the US FDA requirements [44]. Additionally, the Saudi Food and Drug Authority (SFDA) has created risk minimization measures for both patients and healthcare providers to ensure the safe use of clozapine [45]. However, data regarding the level of implementation across Saudi Arabia as well as compliance remain an area for future research.

Despite the valuable data identified in this study, the level of detail provided by reporters was minimal. Several studies have investigated the barriers that influence ME reporting among healthcare providers in hospitals [46, 47]. In Saudi Arabia, the fear of legal implications, lack of time, and loss of reputation are the most reported barriers to ME reporting and learning [48]. However, poor physical and mental well-being due to patient violence, excessive workload, and lack of resources has resulted in an increased risk of staff burnout and emotional exhaustion has been reported as a barrier in psychiatry settings [49, 50]. Therefore, investigating the attitudes of Saudi healthcare providers and the challenges they face in reporting clozapine-related MEs is a priority area for future research.

Further research

Further research is needed to enhance the safety of clozapine use through an in-depth qualitative study that investigates the underlying causes of clozapine-related MEs via theoretical frameworks such as Reason’s Model of Accident Causation to determine the contextual and systemic factors associated with their occurrence [40, 51,52,53]. In addition, future research would be necessary to assess the quality of ME data more thoroughly to suggest potential solutions for improving the accuracy of the reported data and thereby to reduce the risk of subjectivity and data inconsistencies.

Conclusion

This is the first nationwide study of the nature of and contributory factors for clozapine-related MEs reported to the General Administration of Pharmaceutical Care at the MOH in Saudi Arabia. We found that such errors were commonly associated with the prescribing stage and were mostly related to missing prescription information and errors associated with the clozapine dose. We identified the origin of these errors at the staff and organizational levels, which could provide effective guidance to relevant health care authorities and policy-makers in their endeavours to develop preventive measures to reduce clozapine-related MEs.