A qualitative exploration of clozapine prescribing and monitoring practices in the Arabian Gulf countries

A qualitative exploration of clozapine prescribing and monitoring practices in the Arabian Gulf countries

Asian Journal of Psychiatry 39 (2019) 93–97 Contents lists available at ScienceDirect Asian Journal of Psychiatry journal homepage: www.elsevier.com...

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Asian Journal of Psychiatry 39 (2019) 93–97

Contents lists available at ScienceDirect

Asian Journal of Psychiatry journal homepage: www.elsevier.com/locate/ajp

A qualitative exploration of clozapine prescribing and monitoring practices in the Arabian Gulf countries

T



Dalia Ismaila, Karawen Tounsia, Monica Zolezzia, , Yassin Eltorkib a b

College of Pharmacy, Qatar University, PO Box 2713, Doha, Qatar Hamad Medical Corporation, Mental Health Hospital, Doha, Qatar

A R T I C LE I N FO

A B S T R A C T

Keywords: Clozapine utilization Arabian Gulf countries Treatment-resistant schizophrenia Agranulocytosis

Clozapine is considered as the first line antipsychotic for treatment resistant schizophrenia (TRS). Worldwide reports indicate an overall underutilization of clozapine in patients experiencing TRS. This study aims to understand the prescribing practices, monitoring strategies and barriers to the use of clozapine in the Arabian Gulf (AG) region. Qualitative methodology was employed to explore mental health professionals’ experience with clozapine prescribing practices. Semi-structured, individual in-depth interviews were conducted. All interviews were analyzed using a thematic approach. A total of 13 interviews were conducted with participants from six AG countries. Four major themes emerged from the analysis in relation to clozapine prescribing and monitoring practices, clozapine use guidelines, and barriers to the use of clozapine. Thematic analysis revealed a tendency to under prescribe clozapine in the AG region, which appears to be predominantly influenced by prescriber-related barriers and less likely due to the lack of a nation-wide hematological monitoring program. Future studies should explore strategies for overcoming the barriers identified.

1. Introduction About 20–30% of schizophrenic patients have been reported to experience treatment-resistant schizophrenia (TRS) (Dold and Leucht, 2014). Most guidelines consider clozapine as the first line antipsychotic for this population. Clozapine is also the only antipsychotic approved by the United States (US) Food and Drug Administration (FDA) for patients experiencing TRS (Remington et al., 2017). Unfortunately, its use has been associated with serious life threatening adverse effects, such as neutropenia, agranulocytosis, seizures, QTc-prolongation, and myocarditis (De Berardis et al., 2018). Of these, agranulocytosis has been the one of most concern as it was the reason of clozapine’s temporary withdrawal from the international market in the mid 1970s (Hippius, 1989). Neutropenia has been defined as white blood cell count (WBC) of less than 3,000/mm3 and agranulocytosis as absolute neutrophil count (ANC) of less than 500/mm3. A study in the United Kingdom (UK) and Ireland reported a prevalence of 2.9% for neutropenia and 0.8% for agranulocytosis among patients taking clozapine (Atkin et al., 1996). Because of this risk, WBC and ANC monitoring before initiating clozapine and periodically thereafter is necessary. This systematic approach for monitoring clozapine has been highly effective by virtually eliminating deaths due to agranulocytosis (Honigfeld et al., 1998). The US FDA Risk Evaluation and Mitigation ⁎

Strategies (REMS) program recently updated their clozapine guidelines, recommending that the hematological monitoring for clozapine will only be based on ANC levels, and eliminated WBC monitoring requirements (United States Food and Drug Administration (FDA), 2015; Clozapine Risk Evaluation and Mitigation Strategy (REMS), 2014). In addition, to start clozapine, the ANC level has been lowered from at least 1500/mm3 to 1000/mm3 or more (Clozapine Risk Evaluation and Mitigation Strategy (REMS), 2014). Similarly, for patients with benign ethnic neutropenia (BEN), ANC levels have also been lowered from 1000/mm3 or more to at least 500/mm3 (Clozapine Risk Evaluation and Mitigation Strategy (REMS), 2014). Numerous studies have shown that clozapine is underused in the management of TRS (Kelly et al., 2007; Fayek et al., 2003; Hermes and Rosenheck, 2012). In the review of the literature by Kelly and colleagues (Kelly et al., 2007), it was reported that clozapine prescribing for TRS is infrequent in the US, and appears to be on a steady decline. These studies have also shown that there is considerable delay in prescribing clozapine for TRS (Fayek et al., 2003; Hermes and Rosenheck, 2012). This trend is also apparent in studies undertaken in the AG countries (Alhabbad et al., 2016; Al-Za’abi et al., 2014; Al-Khaja et al., 2012). The study undertaken in the Kingdom of Saudi Arabia (KSA) reported high underutilization of clozapine among patients diagnosed with TRS, of whom only 3.1% of all inpatients and 2.4% of all

Corresponding author. E-mail address: [email protected] (M. Zolezzi).

https://doi.org/10.1016/j.ajp.2018.12.011 Received 23 October 2018; Received in revised form 20 December 2018; Accepted 20 December 2018 1876-2018/ © 2018 Published by Elsevier B.V.

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3. Results

outpatients were prescribed clozapine (Alhabbad et al., 2016). In the studies undertaken in Oman (Al-Za’abi et al., 2014) and Bahrain (AlKhaja et al., 2012), clozapine was reported as being the least prescribed atypical antipsychotic. Clinician perceptions regarding clozapine's adverse effects and familiarity with the management of those adverse effects are cited as key factors in the low clozapine prescribing rates observed (Kelly et al., 2007; Patel, 2012). Whether similar reasons exist for the low prescribing within the AG countries is unknown. As such, this study explored the views and experience of mental health care professionals working closely with patients experiencing TRS in the AG countries, on clozapine use and safety monitoring practices.

A total of 13 participants were recruited consisting of 8 doctors (7 psychiatrists and 1 psychiatric resident), 4 pharmacists and 1 mental health nurse from 6 AG countries (Qatar = 7, KSA = 1, Kuwait = 2, Bahrain = 1, Oman = 1, UAE = 1). No medical directors were recruited as no expressions of interest to participate were received despite several email invitations. Eight out of the 13 participants indicated having ≥ 10 years of experience in mental health practice. Nine participants were male. A total of 16 major codes categorized into 4 major themes emerged after consensus of the four researchers (DI, KT, MZ and YE). The major themes are described in detail below.

2. Methods

3.1. Clozapine prescribing practices

2.1. Participants

Several aspects in relation to the process of prescribing clozapine, such as the investigations and the patient-specific considerations necessary for initiating clozapine, dosing titration requirements and cautions when prescribing clozapine were predominantly identified as aspects in the prescribing process of clozapine. All participants were cognizant of the importance of prescribing based on hematological tests results. However, different ranges of blood test thresholds at which clozapine should be stopped were provided by participants.

This was a qualitative study using semi-structured interviews of mental health care professionals working in countries located in the AG region, namely Qatar, Bahrain, Oman, KSA, United Arab Emirates (UAE) and Kuwait. Purposive and snowballing sampling were used for recruitment of key informants. The targeted population were psychiatrists, psychiatric residents, nurses, clinical/non-clinical pharmacists and medical directors working in mental health hospitals, clinics and primary care settings. Initially, recruitment sites were located after searching in the internet for mental health hospitals in the 6 AG countries, to where invitation emails addressed to the medical directors were sent. Medical directors were thought to be the most appropriate for sending the invitation letters to, as they could forward these to potential participants. Snowballing sampling was also used to locate experts in all six countries and among attendees at a local mental health conference. All potential participants received information about the study and of the potential benefits of sharing their expert opinion in regards to clozapine utilization in the region. Interviews were arranged for all those interested. No financial incentives were provided to participants. Non-English-speaking participants and those who failed to provide an informed consent were excluded.

“What is recommended is that if [the WBC] is below 1500 you need to stop, but for me if it is less than 3000 or 2500 I stop, I am really afraid and concerned about my patient I want to be cautious” (Consultant Psychiatrist) Other aspects, such as clozapine re-challenging practices were identified as necessary in the prescribing process for clozapine. Several issues in relation to the dispensing process for clozapine in the AG countries were brought up by participants, including the infrequent availability of hematological testing results at the time of dispensing clozapine and the availability of clozapine only in pharmacies attached to a psychiatric hospital. “The first dose of initiation the patient needs to be inpatient for close observation to monitor his vital signs frequently you know” (Mental Health Nurse)

2.2. Data collection and analysis

Participants identified clozapine as indicated for TRS, and defined TRS as the failure to control symptoms of schizophrenia after trying 2 antipsychotics. However, some participants reported a delay in prescribing clozapine and acknowledged that this practice is against treatment guidelines for patients with TRS.

Face-to-face semi-structured interviews lasting between 40–60 minutes were conducted between February and December of 2017 by two researchers (DI and KT) with participants who were available in person within Qatar, and Skype voice calls with those who were located outside of Qatar. A topic guide for conducting the interviews was used, covering key areas of interest regarding clozapine utilization and monitoring practices. The guide was developed through identifying key areas of enquiry based on a thorough literature review, piloted and amended following feedback from a clinical pharmacist from the Mayo Clinic Hospital in the US, who had experience with the US FDA REMS program for clozapine. Grounded theory was the method employed for data analysis through the process of constant comparison and reflexivity to explore the personal experiences with clozapine prescribing as perceived by the participants (Austin, 2014; Smith et al., 2009). Verbatim transcripts of taped interviews were produced by DI and KT, and initial codes were generated by each researcher individually immediately after conducting the interviews. Then, each researcher checked each other’s codes for differences and similarities. All codes were then discussed with MZ and YE to establish emerging themes by consensus. Subthemes reflecting groupings of codes began to emerge through this process. All codes were entered into an Excel database to assist in the analysis process. Ethical approval was obtained from the Institutional Review Board at Qatar University on October 9, 2016, with approval number: QU-IRB 659-E/16.

“Clozapine [is indicated] when patients [have been] on two antipsychotics and with no effect, so we start clozapine” (Pharmacist) All participants stated that when prescribing clozapine dose titration is followed, with initial dose ranges from 12.5 to 25 mg/day and the maximum dose not exceeding 900 mg/day. Participants predominantly viewed clozapine prescribing as being infrequent. With the exception of one of the AG countries, participants indicated that prescribing clozapine for patients with BEN was rare. 3.2. Clozapine monitoring practices Participants were aware of the monitoring requirements when prescribing clozapine and described the hematological monitoring services available within their health-system, management of clozapine adverse effects, and experience with a clozapine clinic. Participants predominantly indicated a lack of a national-wide program in their countries, although laboratory services for hematological monitoring were readily available. Some participants reported unique clozapine monitoring practices such as the provision of clozapine home services. Management strategies to improve the safety profile of clozapine were described, including awareness of the association between side 94

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services, such as transportation and crowdedness, may affect the ability to effectively monitor patients on clozapine. Ensuring access to clozapine and support to prescribers regarding safety monitoring under the vigilance of a multidisciplinary team, as the one available in clozapine clinics, were mentioned as necessary to overcome the barriers. Patient and family education was also highlighted as a way to improve clozapine utilization.

effects and dose, and interventions if agranulocytosis occurs. Some participants commented on the availability and use of clozapine-specific assessment scales to assist in the identification of clozapine’s most severe adverse drug reactions (ADRs) and on the role of other health care professionals in monitoring and managing clozapine side effects. Some participants described clozapine clinics including hours of operation, staffing, patient numbers, equipment and details on the roles of the different health care professionals within the clinic. All participants perceived clozapine clinics facilitate the monitoring process, allow a more regular follow up with patients to assess their compliance and are a venue for providing patient and family education on how to optimize the use of clozapine.

“We need tighter follow up for the patients, having a clear system to overcome these barriers. As well as, more education for patients and their families, we can clearly adopt one of the main guidelines internationally like FDA, if we can adopt them as our guidelines or create our own guideline, get everyone on board, this will make things easier and more comfortable”(Medical Psychiatry Resident)

“Clozapine clinic is one of the tools that will facilitate and increase the percentage of clozapine prescribing for the patients because it will share responsibilities with the prescriber, facilitate monitoring and follow up with patients” (Clinical Pharmacist)

4. Discussion 4.1. Summary of findings

3.3. Clozapine guidelines Despite the established superior efficacy of clozapine in the management of TRS, there is evidence from countries such as the US, UK and New Zealand (NZ) that it is underutilized in patients with TRS (Kelly et al., 2007; Warnez and Alessi-Severini, 2014; Stroup et al., 2014; Wheeler, 2008). Our review of the literature identified only three studies undertaken in the AG region (KSA, Oman and Bahrain) that provide data on antipsychotic prescribing practices (Alhabbad et al., 2016; Al-Za’abi et al., 2014; Al-Khaja et al., 2012) and which suggest an under-utilization of clozapine. The results of our study are indicative that although mental health professionals in the AG region are aware of the effectiveness of clozapine and its efficacy for TRS, there is a tendency in avoiding its use, even when indicated, until all other treatment options have been explored, including the use of antipsychotic polypharmacy, causing an overall delay in initiating clozapine in patients who would have benefitted from this medication earlier. This finding confirms those of research conducted in other countries, for example in the US, the rate of clozapine prescribing is considerably lower than the estimated prevalence of TRS (Kelly et al., 2007; Taylor et al., 2003). A study conducted in the UK estimated that over two-thirds of schizophrenia patients wait years prior to clozapine initiation (Howes et al., 2012). In the CATIE trial (Stroup et al., 2009), which examined the clinical effectiveness of antipsychotic medication for chronic schizophrenia, only 11% of patients used clozapine during phase 3 of the trial, although 51% had previously discontinued other medications because of inadequate therapeutic effectiveness. When discussing the barriers for clozapine prescribing, participants in our study appeared to be preoccupied about patients’ fears from the side effects of clozapine and were concerned about the frequent blood tests required. Interestingly however, studies have shown that patients tend to be less concerned about these disadvantages and have more favorable attitudes toward clozapine treatment than what is expected from their prescribers (Hodge and Jespersen, 2008). Participants in our study also indicated that a formal and healthsystem-wide hematological monitoring program for clozapine is not available in any of the AG countries. However, they did not perceive this unavailability as negatively influencing the prescribing rate of clozapine. Alternative monitoring services appear to be in place and participants seemed to be comfortable with the available local protocols to ensure the safe use of clozapine. Furthermore, with a few exceptions, participants were not even fully informed about internationally known monitoring programs such as the US FDA REMS for clozapine, or its updates. This was evidenced as participants in our study indicated to be monitoring both, ANC and WBC despite the recent updated version of the US FDA REMS which only recommends monitoring the ANC (Clozapine Risk Evaluation and Mitigation Strategy (REMS), 2014). Participants in our study also indicated that clozapine was inappropriate for patients with BEN, although most recent guidelines

Various different local protocols to assure some uniformity in the utilization of clozapine within their institution were described by participants, such as a clozapine dosing protocol, side effect management protocol, clozapine dispensing protocol, or protocols when a clozapine re-challenge is being considered. Participants were also familiar with at least one internationally known, evidence-based treatment guideline for schizophrenia, and understood where in the treatment pathway clozapine is recommended for patients experiencing TRS. Participants also indicated that most guidelines do not recommend antipsychotic polypharmacy preceding clozapine utilization in TRS. A variety of international guidelines were mentioned as being followed by participants, including those derived from the National Institute for Health and Clinical Excellence (NICE), the American Psychiatric Association (APA) and the Maudsley Prescribing Guidelines. Participants indicated to favor the use of guidelines which they were most familiar with based on where they were initially trained or on those that are being adopted at their current practice setting. “Generally, in the hospital we have people who are UK trained and we have people who are US trained so [the guidelines being followed] depends on their preferences” (Medical Psychiatry Resident) Overall, participants were not familiar with the US FDA REMS, the recent changes to ANC and WBC monitoring requirements, or its role in improving the safety profile of clozapine. When participants were explained of these changes during the interview, one participant indicated disagreement with these guidelines. “For me I will not follow this [REMS]” (Consultant Psychiatrist) 3.4. Barriers to the use of clozapine Prescribers’ fears from having to deal with their patients’ emergent side effects and the strict and regular need for hematological monitoring, were the predominant barriers identified. Other patient-related barriers identified by participants included lack of education and poor adherence to the clozapine regimen. Some participants also identified that not having a pharmacist properly trained at the time of clozapine dispensing is a barrier for ensuring the patient’s compliance with the hematological monitoring required. Health-system barriers were also identified, including the lack of a nation-wide monitoring program, the diversity of prescribing practices among practitioners, and the lack of proper communication channels among the various patient care settings and services. In Qatar, participants explained that clozapine can only be initiated in hospitals. Thus, shortage of beds was said to contribute to the underutilization of clozapine. Some participants reported that deficits in the access to 95

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comparing the results to those from other studies. However, we did not use more than one method for data collection to reduce biases introduced by researchers. Future quantitative studies, such as a mail or online survey, can be used to address the limitations in our study. Further exploration not only from the perspective of clozapine prescribers but also from patients who have tried or are currently taking clozapine, can also be useful in clarifying some of the issues in relation to clozapine use that emerged from this qualitative study.

recommend clozapine can be used in these patients when the ANC level is 500/mm3 or above (Clozapine Risk Evaluation and Mitigation Strategy (REMS), 2014). Prescriber education may help address these misconceptions. A study in the US found that low utilization rates of clozapine was associated with a lack of support systems to deal with complex and time-consuming clozapine processes in relation with the FDA REMS (Gören et al., 2016). Similar health-system related barriers were identified by participants in our study. Limited communication between various levels of care settings, hospital-based initiation of clozapine, and limited access to services suggest that implementation of such nation-wide monitoring systems in the AG countries may add to the complexity of prescribing clozapine when compared to prescribing other antipsychotics, and consequently may actually contribute to its underutilization. Something similar was suggested in a study undertaken in Bahrain, where authors suggested that the mandatory hematological monitoring was leading to clozapine underutilization (AlKhaja et al., 2012). Despite these barriers, participants in our study also viewed that having a system-wide monitoring program would provide a safer access to clozapine and would ensure the availability of other health care providers, such as pharmacists, for optimizing the dispensing and monitoring processes of clozapine. Studies have reported improving the clozapine utilization rates in facilities where clozapine clinics have been implemented (Gören et al., 2016; Williams and Purvis, 2012). In these settings, clozapine clinics are usually run by multidisciplinary teams and able to accommodate increased visit frequency of patients. The Veterans Administration report describes a pharmacist-run clozapine clinic that led to cost savings, high clozapine continuation rates, patient and family satisfaction, and early intervention in cases of decompensation and suicidal ideation (Williams and Purvis, 2012). Participants in our study who had previous working experience with clozapine clinics also spoke highly of these types of services in support of clozapine prescribing. The barriers as perceived from participants in our study have also been reported by other investigators in a similar UK qualitative study about clozapine underutilization (Tungaraza and Farooq, 2015). To overcome these barriers, participants have suggested providing more education for prescribers and for patients and their families. Similar recommendations have been provided in other studies which found most of clozapine’s underutilization was due to lack of awareness about side effects management (Nielsen et al., 2010). Knowledge of and following evidence-based guidelines for the management of patients with TRS may also contribute to improving clozapine’s underutilization. For example, a recent NZ study reported a 13.6% increase in clozapine use when audit and feedback were used as an intervention to promote adherence to best practice guidelines for the treatment of schizophrenia (Wheeler et al., 2009).

5. Conclusion The current study explored experiences with clozapine prescribing practices in six countries in the AG region. Findings suggest that the underuse of clozapine in this region may be predominantly influenced by prescriber-related barriers and less likely due to the lack of a nationwide hematological monitoring program. Implementing clozapine clinics may be a viable strategy to address many of the barriers identified surrounding clozapine’s optimal utilization and monitoring requirements in the AG countries. While other strategies could also be considered, policy changes in the delivery of health care may be required that could prove challenging to pursue in the region. Future studies should attempt to clarify these findings and further explore strategies for overcoming some of the other barriers to the wider utilization of clozapine in TRS in the AG region. Acknowledgements This research was funded by a Qatar University Undergraduate Student grant (reference: QUST-2-CPH-2017-9). We would like to thank all participants in the six AG countries and those who assisted us with the recruitment process. We would like to extend particular thanks to Dr. Jonathan G. Leung, psychiatric clinical pharmacist at Mayo Clinic Hospital in the United States who helped us piloting the interview guide questions in addition to his guidance in regards to the US FDA REMS program for clozapine. References Alhabbad, A., Alosaimi, F., Abalhassan, M., Fallata, E., Alzain, N., Alassiry, M.Z., et al., 2016. Patterns of psychotropic medication use in inpatient and outpatient psychiatric settings in Saudi Arabia. Neuropsychiatr. Dis. Treat. 12, 897–907. Al-Khaja, K.A.J., Sequeira, R.P., Al-Haddad, M.K., Al-Offi, A.R., 2012. Psychotropic drug prescribing trends in Bahrain: implications for sexual functions. Int. J. Clin. Med. 3 (04), 276–282. Al-Za’abi, M., Al-Hinai, A.S., Al-Busaidi, S.A., 2014. Utilization pattern of antipsychotics at a tertiary care hospital in Oman. Afr. J. Psychiatry (Johannesbg) 17 (6), 1000171. Atkin, K., Kendall, F., Gould, D., Freeman, H., Liberman, J., O’Sullivan, D., 1996. Neutropenia and agranulocytosis in patients receiving clozapine in the UK and Ireland. Br. J. Psychiatry 169 (4), 483–488. Austin, Z., 2014. Qualitative research: getting started. Can. J. Hosp. Pharm. 67 (6), 436–440. Clozapine Risk Evaluation and Mitigation Strategy (REMS), 2014. Clozapine and the Risk of Neutropenia: an Overview for the Healthcare Provider. Retrieved from URL. (Accessed 06 September 2018). https://www.clozapinerems.com/ CpmgClozapineUI/rems/pdf/resources/ANC_Table.pdf. De Berardis, D., Rapini, G., Olivieri, L., Di Nicola, D., Tomasetti, C., Valchera, A., et al., 2018. Safety of antipsychotics for the treatment of schizophrenia: a focus on the adverse effects of clozapine. Ther. Adv. Drug Saf. 9 (5), 237–256. Dold, M., Leucht, S., 2014. Pharmacotherapy of treatment-resistant schizophrenia: a clinical perspective. Evid Based Mental Health 17 (2), 33–37. Fayek, M., Flowers, C., Signorelli, D., Simpson, G., 2003. Psychopharmacology: underuse of evidence-based treatments in psychiatry. Psychiatr. Serv. 54 (11) 1453-4, 1456. Gören, J.L., Rose, A.J., Engle, R.L., Smith, E.G., Christopher, M.L., Rickles, N.M., et al., 2016. Organizational characteristics of Veterans Affairs clinics with high and low utilization of clozapine. Psychiatr. Serv. 67 (11), 1189–1196. Hermes, E., Rosenheck, R., 2012. Choice of randomization to clozapine versus other second generation antipsychotics in the CATIE schizophrenia trial. J. Psychopharmacol. (Oxford) 26 (9), 1194–1200. Hippius, H., 1989. The history of clozapine. Psychopharmacology 99, S3–S5. Hodge, K., Jespersen, S., 2008. Side effects and treatment with clozapine: a comparison between the views of consumers and their clinicians. Int. J. Ment. Health Nurs. 17 (1), 2–8. Honigfeld, G., Arellano, F., Sethi, J., Bianchini, A., Schein, J., 1998. Reducing clozapine-

4.2. Strengths and limitations This study is the first qualitative exploration of mental health care providers’ perceptions on their experiences with clozapine use in the AG region. The study faced some limitations, primarily in recruiting participants from countries outside Qatar, thus not being able to assess similarities or contrasting views for countries for which only one participant was recruited. Initial emails sent to medical directors of psychiatric hospitals in the AG region was not successful in recruiting participants to the study. It is possible that the invitation emails were deleted before being read or that simply there was no interest in participation. Snowballing rendered better recruitment outcomes and thus it may be the best approach when seeking expert opinion or when recruiting key informants. Attempts were also made to check back with participants to confirm findings via electronic mail, although no responses or feedback was obtained. Mitigation of this limitation was attempted by testing the accuracy and representation of the results by 96

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variation in clozapine use in the United States. Psychiatr. Serv. 65 (2), 186–192. Taylor, D.M., Young, C., Paton, C., 2003. Prior antipsychotic prescribing in patients currently receiving clozapine: a case note review. J. Clin. Psychiatry 64 (1), 30–34. Tungaraza, T.E., Farooq, S., 2015. Clozapine prescribing in the UK: views and experience of consultant psychiatrists. Ther. Adv. Psychopharmacol. 5 (2), 88–96. United States Food and Drug Administration (FDA), 2015. Drug Safety Communication. FDA Modifies Monitoring for Neutropenia Associated With Schizophrenia Medicine Clozapine; Approves New Shared REMS Program for All Clozapine Medicines. Retrieved from URL. (Accessed 06 September 2018). https://www.fda.gov/ downloads/Drugs/DrugSafety/UCM462193.pdf. Warnez, S., Alessi-Severini, S., 2014. Clozapine: a review of clinical practice guidelines and prescribing trends. BMC Psychiatry 14 (1), 102. Wheeler, A.J., 2008. Treatment pathway and patterns of clozapine prescribing for schizophrenia in New Zealand. Ann. Pharmacother. 42 (6), 852–860. Wheeler, A., Humberstone, V., Robinson, E., Sheridan, J., Joyce, P., 2009. Impact of audit and feedback on antipsychotic prescribing in schizophrenia. J. Eval. Clin. Pract. 15, 441–450. Williams, T., Purvis, T.L., 2012. Development of an outpatient pharmacist-managed clozapine clinic. Am. J. Health. Syst. Pharm. 69 (14), 1192–1195.

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